TOXICOLOGICAL PROFILE FOR
 

CRESOLS
 


 


 


 


 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
 

Public Health Service
 

Agency for Toxic Substances and Disease Registry
 

September 2008 
 

CRESOLS ii 

DISCLAIMER 

The use of company or product name(s) is for identification only and does not imply endorsement by the 

Agency for Toxic Substances and Disease Registry. 
 

CRESOLS iii 

UPDATE STATEMENT
 

A Toxicological Profile for Cresols, 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 previously released profiles, contact ATSDR at: 

Agency for Toxic Substances and Disease Registry
 

Division of Toxicology and Environmental Medicine/Applied Toxicology Branch
 

1600 Clifton Road NE
 

Mailstop F-32
 

Atlanta, Georgia 30333
 
 

CRESOLS iv 

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CRESOLS v 

FOREWORD
 

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

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

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

and republished as necessary. 

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

information for 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 intended 

to be an exhaustive document; however, more comprehensive sources of specialty information are 

referenced. 

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

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

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

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

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

significance to protection of public health are identified by ATSDR 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 chronic health effects; and 

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

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

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

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

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

peer-reviewed. 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 panel 
 

 

CRESOLS vi 

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 Louise 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 December 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. 
 

 

 

 

 

 

 

CRESOLS vii 

QUICK REFERENCE FOR HEALTH CARE PROVIDERS 

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

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

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

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

answers to often-asked questions. 

Primary Chapters/Sections of Interest 

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

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

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

the general health effects observed following exposure. 

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

and assesses the significance of toxicity data to human health. 

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

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

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

reported in this section. 

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

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

following exposure. 

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

issues: 

Section 1.6 How Can (Chemical X) Affect Children?
 

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

Section 3.7 Children’s Susceptibility
 

Section 6.6 Exposures of Children
 

Other Sections of Interest: 

Section 3.8 Biomarkers of Exposure and Effect 

Section 3.11 Methods for Reducing Toxic Effects 

ATSDR Information Center 

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

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

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

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

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

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

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

Toxicity; and numerous chemical-specific case studies. 
 

 

 

 

 

 

 

CRESOLS viii 

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

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

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

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

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

professionals treating patients exposed to hazardous materials. 

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

Other Agencies and Organizations 

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

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

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

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

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

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

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

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

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

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

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

• Phone: 800-35-NIOSH. 

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

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

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

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

Referrals 

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

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

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

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

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

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

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

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

CONTRIBUTORS 

CHEMICAL MANAGER(S)/AUTHOR(S): 

Malcolm Williams, Ph.D.
 

John Risher, Ph.D.
 

Mike Fay, Ph.D.
 

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

Fernando Llados, Ph.D.
 

Sari Paikoff, Ph.D.
 

Jennifer Rhoades, B.S.
 

Syracuse Research Corporation, North Syracuse, New York
 

THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS: 

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

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

end points. 

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

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

profile, and makes recommendations for derivation of MRLs. 

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

consistency across profiles and adherence to instructions in the Guidance. 

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

CRESOLS x 

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CRESOLS xi 

PEER REVIEW 

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

1.	 David Kalman, Ph.D., Chair and Professor, Department of Environmental and Occupational 

Health Sciences, University of Washington, Health Sciences Building, F-463, Seattle, 

Washington; 

2.	 John R. Balmes, M.D., Professor, Pulmonary and Critical Care Division, University of California 

San Francisco, San Francisco General Hospital, San Francisco, California; and 

3.	 Rolf Hartung, Ph.D., DABT, Consultant in Environmental Toxicology, Professor of 

Environmental Toxicology (Retired), University of Michigan, 3125 Fernwood Avenue, Ann 

Arbor, Michigan. 

These experts collectively have knowledge of cresol's physical and chemical properties, toxicokinetics, 

key health end points, mechanisms of action, human and animal exposure, and quantification of risk to 

humans. All reviewers were selected in conformity with the conditions for peer review specified in 

Section 104(I)(13) of the Comprehensive Environmental Response, Compensation, and Liability Act, as 

amended. 

Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have reviewed the peer 

reviewers' comments and determined which comments will be included in the profile. A listing of the 

peer reviewers' comments not incorporated in the profile, with a brief explanation of the rationale for their 

exclusion, exists as part of the administrative record for this compound. 

The citation of the peer review panel should not be understood to imply its approval of the profile's final 

content. The responsibility for the content of this profile lies with the ATSDR. 
CRESOLS xii 

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CRESOLS xiii 

CONTENTS
 

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

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

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

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

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

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

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

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

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

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

1.1 WHAT ARE CRESOLS?...............................................................................................................2
 

1.2 WHAT HAPPENS TO CRESOLS WHEN THEY ENTER THE ENVIRONMENT? .................2
 

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

1.4 HOW CAN CRESOLS ENTER AND LEAVE MY BODY?........................................................4
 

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

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

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

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

TO CRESOLS? ..............................................................................................................................6
 

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 

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

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

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

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO CRESOLS IN THE UNITED 

STATES .........................................................................................................................................9
 

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

2.3 MINIMAL RISK LEVELS (MRLs) ............................................................................................12
 

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

3.2.1.4 Neurological Effects ......................................................................................................24
 

3.2.1.5 Reproductive Effects......................................................................................................25
 

3.2.1.6 Developmental Effects...................................................................................................25
 

3.2.1.7 Cancer............................................................................................................................25
 

3.2.2 Oral Exposure........................................................................................................................25
 

3.2.2.1 Death.............................................................................................................................. 25
 

3.2.2.2 Systemic Effects.............................................................................................................27
 

3.2.2.3 Immunological and Lymphoreticular Effects................................................................85
 

3.2.2.4 Neurological Effects ......................................................................................................86
 

3.2.2.5 Reproductive Effects......................................................................................................88
 

3.2.2.6 Developmental Effects...................................................................................................89
 

3.2.2.7 Cancer............................................................................................................................90
 

3.2.3 Dermal Exposure...................................................................................................................92
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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3.2.3.1 Death..............................................................................................................................92
 

3.2.3.2 Systemic Effects.............................................................................................................92
 

3.2.3.3 Immunological and Lymphoreticular Effects................................................................95
 

3.2.3.4 Neurological Effects ......................................................................................................95
 

3.2.3.5 Reproductive Effects......................................................................................................96
 

3.2.3.6 Developmental Effects...................................................................................................96
 

3.2.3.7 Cancer............................................................................................................................96
 

3.3 GENOTOXICITY........................................................................................................................96
 

3.4 TOXICOKINETICS...................................................................................................................101
 

3.4.1 Absorption...........................................................................................................................101
 

3.4.1.1 Inhalation Exposure .....................................................................................................101
 

3.4.1.2 Oral Exposure ..............................................................................................................102
 

3.4.1.3 Dermal Exposure .........................................................................................................102
 

3.4.2 Distribution .........................................................................................................................103
 

3.4.2.1 Inhalation Exposure .....................................................................................................103
 

3.4.2.2 Oral Exposure ..............................................................................................................103
 

3.4.2.3 Dermal Exposure .........................................................................................................103
 

3.4.2.4 Other Routes of Exposure............................................................................................104
 

3.4.3 Metabolism..........................................................................................................................104
 

3.4.4 Elimination and Excretion...................................................................................................105
 

3.4.4.1 Inhalation Exposure .....................................................................................................105
 

3.4.4.2 Oral Exposure ..............................................................................................................105
 

3.4.4.3 Dermal Exposure .........................................................................................................105
 

3.4.4.4 Other Routes of Exposure............................................................................................107
 

3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models...........107
 

3.5 MECHANISMS OF ACTION ...................................................................................................110
 

3.5.1 Pharmacokinetic Mechanisms.............................................................................................110
 

3.5.2 Mechanisms of Toxicity......................................................................................................111
 

3.5.3 Animal-to-Human Extrapolations.......................................................................................112
 

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS...........................112
 

3.7 CHILDREN’S SUSCEPTIBILITY............................................................................................114
 

3.8 BIOMARKERS OF EXPOSURE AND EFFECT .....................................................................117
 

3.8.1 Biomarkers Used to Identify or Quantify Exposure to Cresols...........................................118
 

3.8.2 Biomarkers Used to Characterize Effects Caused by Cresols.............................................119
 

3.9 INTERACTIONS WITH OTHER CHEMICALS .....................................................................119
 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE ............................................119
 

3.11 METHODS FOR REDUCING TOXIC EFFECTS................................................................120
 

3.11.1 Reducing Peak Absorption Following Exposure.............................................................120
 

3.11.2 Reducing Body Burden ...................................................................................................121
 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects..........................................121
 

3.12 ADEQUACY OF THE DATABASE.....................................................................................121
 

3.12.1 Existing Information on Health Effects of Cresols..........................................................122
 

3.12.2 Identification of Data Needs............................................................................................124
 

3.12.3 Ongoing Studies ..............................................................................................................131
 

4. CHEMICAL AND PHYSICAL INFORMATION..............................................................................133
 

4.1 CHEMICAL IDENTITY............................................................................................................133
 

4.2 PHYSICAL AND CHEMICAL PROPERTIES.........................................................................133
 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL..........................................................137
 

5.1 PRODUCTION ..........................................................................................................................137
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CRESOLS xv 

5.2 IMPORT/EXPORT ....................................................................................................................144
 

5.3 USE ............................................................................................................................................144
 

5.4 DISPOSAL.................................................................................................................................146
 

6. POTENTIAL FOR HUMAN EXPOSURE .........................................................................................147
 

6.1 OVERVIEW...............................................................................................................................147
 

6.2 RELEASES TO THE ENVIRONMENT...................................................................................147
 

6.2.1 Air .......................................................................................................................................152
 

6.2.2 Water...................................................................................................................................158
 

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

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

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

6.3.2 Transformation and Degradation ........................................................................................166
 

6.3.2.1 Air................................................................................................................................166
 

6.3.2.2 Water............................................................................................................................167
 

6.3.2.3 Sediment and Soil ........................................................................................................170
 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT..................................171
 

6.4.1 Air .......................................................................................................................................171
 

6.4.2 Water...................................................................................................................................172
 

6.4.3 Sediment and Soil ...............................................................................................................174
 

6.4.4 Other Environmental Media................................................................................................175
 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE........................................176
 

6.6 EXPOSURES OF CHILDREN..................................................................................................178
 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES ..............................................178
 

6.8 ADEQUACY OF THE DATABASE ........................................................................................179
 

6.8.1 Identification of Data Needs ...............................................................................................180
 

6.8.2 Ongoing Studies..................................................................................................................183
 

7. ANALYTICAL METHODS................................................................................................................185
 

7.1 BIOLOGICAL MATERIALS....................................................................................................185
 

7.2 ENVIRONMENTAL SAMPLES ..............................................................................................187
 

7.3 ADEQUACY OF THE DATABASE ........................................................................................191
 

7.3.1 Identification of Data Needs ...............................................................................................192
 

7.3.2 Ongoing Studies..................................................................................................................193
 

8. REGULATIONS AND ADVISORIES ...............................................................................................195
 

9. REFERENCES ....................................................................................................................................199
 

10. GLOSSARY ......................................................................................................................................227
 

APPENDICES 

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

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

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

D. INDEX ................................................................................................................................................D-1
 
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CRESOLS xvii 

LIST OF FIGURES
 

3-1. Levels of Significant Exposure to Cresols – Oral............................................................................... 66
 

3-2. Bioactivation Pathways of p-Cresol in Human Liver Microsomes..................................................106
 

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

Hypothetical Chemical Substance....................................................................................................109
 

3-4. Existing Information on Health Effects of Cresols...........................................................................123
 

6-1. Frequency of NPL Sites with o-Cresol Contamination ....................................................................148
 

6-2. Frequency of NPL Sites with m-Cresol Contamination ...................................................................149
 

6-3. Frequency of NPL Sites with p-Cresol Contamination ....................................................................150
 

6-4. Frequency of NPL Sites with Cresols (Mixed Isomers) Contamination ..........................................151
 
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CRESOLS xix 

LIST OF TABLES
 

3-1. Levels of Significant Exposure to Cresols – Oral............................................................................... 28
 

3-2. Levels of Significant Exposure to Cresols – Dermal.......................................................................... 93
 

3-3. Genotoxicity of Cresols In Vitro.........................................................................................................97
 

3-4. Genotoxicity of Cresols In Vivo .......................................................................................................100
 

4-1. Chemical Identity of Cresols............................................................................................................134
 

4-2. Physical and Chemical Properties of Cresols...................................................................................135
 

5-1. Facilities that Produce, Process, or Use o-Cresol .............................................................................138
 

5-2. Facilities that Produce, Process, or Use m-Cresol ............................................................................139
 

5-3. Facilities that Produce, Process, or Use p-Cresol .............................................................................140
 

5-4. Facilities that Produce, Process, or Use Cresol (Mixed Isomers).....................................................141
 

5-5. Current U.S. Producers of Cresol .....................................................................................................143
 

6-1. Releases to the Environment from Facilities that Produce, Process, or Use o-Cresol......................153
 

6-2. Releases to the Environment from Facilities that Produce, Process, or Use m-Cresol.....................154
 

6-3. Releases to the Environment from Facilities that Produce, Process, or Use p-Cresol......................155
 

6-4. Releases to the Environment from Facilities that Produce, Process, or Use Cresol
 

(Mixed Isomers)...............................................................................................................................156
 

6-5. Detection of o-Cresol in the Groundwater of Hazardous Waste Sites and Landfills .......................160
 

6-6. Detection of m-Cresol in the Groundwater of Hazardous Waste Sites and Landfills.......................161
 

6-7. Detection of p-Cresol in the Groundwater of Hazardous Waste Sites and Landfills .......................162
 

6-8. Detection of p- and m-Cresol in the Groundwater of Hazardous Waste Sites and Landfills ...........163
 

7-1. Analytical Methods for Determining Cresols in Biological Materials.............................................186
 

7-2. Analytical Methods for Determining Cresols in Environmental Materials......................................188
 

8-1. Regulations and Guidelines Applicable to Cresols...........................................................................196
 
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CRESOLS 1 

1. PUBLIC HEALTH STATEMENT 

This public health statement tells you about cresols and the effects of exposure to these substances. 

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

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

federal clean-up activities. o-Cresol, m-cresol, p-cresol, and mixed cresols have been identified in at least 

210, 22, 310, and 70 of the 1,678 current or former NPL sites, respectively. Although the total number of 

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

which cresols are found may increase in the future as more sites are evaluated. This information is 

important because these sites may be sources of exposure, and exposure to these substances may be 

harmful. 

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

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

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

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

If you are exposed to cresols, many factors will determine whether you will be harmed. These factors 

include the dose (how much), the duration (how long), and how you come in contact with it. You must 

also consider any other chemicals you are exposed to and your age, sex, diet, family traits, lifestyle, and 

state of health. 
CRESOLS 2 

1. PUBLIC HEALTH STATEMENT 

1.1 WHAT ARE CRESOLS? 

Description Three types (or isomers) of cresols exist: ortho-cresol, meta -cresol, and 

para-cresol; abbreviated as o-cresol, m-cresol, and p-cresol. 

Pure cresols are solid, while mixtures tend to be liquid. 

Cresols have a medicinal smell. 

Uses 

 • Manufacturing 

 • Consumer 

products 

Cresols are both manufactured chemicals and natural components in many 

foods. Large amounts of cresols are produced in the United States. 

Cresols are used to manufacture other chemicals and as solvents. 

Cresols kill microorganisms and are added to soaps as disinfectants. 

For more information on the physical and chemical properties of cresols, and their production, disposal 

and use, see Chapters 4 and 5. 

1.2 WHAT HAPPENS TO CRESOLS WHEN THEY ENTER THE ENVIRONMENT? 

Sources Cresols are released to the environment during the burning of wood, coal, 

and fossil fuels, as well as from their manufacture and the use of products 

containing cresols. 

Break down 

 • Air 

 • Water 

 • Soil

Cresols are quickly broken down in the air, usually within 1–2 days. They can 

also be removed from the air by rain. 

Cresols in water are degraded within days by microorganisms. 

Cresols are degraded rapidly in soil by microorganisms, but a portion may 

move into groundwater. 

For more information on cresols in the environment, see Chapter 6. 
CRESOLS 3 

1. PUBLIC HEALTH STATEMENT 

1.3 HOW MIGHT I BE EXPOSED TO CRESOLS? 

Air—primary 

source of 

exposure 

The primary way you can be exposed to cresols is by breathing air 

containing them. Releases of cresols into the air occur from: 

 • industries using or manufacturing cresols 

 • automobile exhaust 

 • cigarette smoke 

 • wood and trash burning 

A national emissions study conducted from 1990 to 1998 reported an 

average county-level concentration of 31.7 nanograms per cubic meter 

(ng/m3

) for all cresol isomers combined. 

Water Cresols have been detected in surface waters and groundwater, but 

generally at low levels (approximately 1 microgram per liter [μg/L] or less). 

Higher levels have been detected: 

 • where petroleum spills have occurred 

 • near hazardous waste sites 

 • in industrial effluents 

Workplace A large number of workers are potentially exposed to cresols. Potential 

exposures occur in: 

 • manufacture of cresols 

 • chemical laboratories 

 • coal gasification facilities 

 • paint and varnish application 

 • application of insulation lacquers to copper wires 

 • wood-preserving facilities 

Exposure may occur through breathing and dermal contact with 

contaminated air and/or liquid cresols or products containing cresols. 

Food Low levels of cresols have been found in some foods such as tomatoes, 

tomato ketchup, asparagus, cheeses, butter, bacon, and smoked foods. 

Some drinks also contain cresols (coffee, black tea, wine, Scotch whisky, 

brandy, and rum). 

Consumer 

products 

Exposure may occur through accidental or intentional ingestion or contact of 

the skin with cleaners or disinfectants containing cresols. 

For more information on human exposure to cresols, see Chapter 6. 
CRESOLS 4 

1. PUBLIC HEALTH STATEMENT 

1.4 HOW CAN CRESOLS ENTER AND LEAVE MY BODY? 

Enter your body 

 • Inhalation 

 • Ingestion 

 • Dermal contact 

There is no information to determine whether cresols can enter the 

bloodstream through your lungs if you breathe air contaminated with these 

substances. 

Cresols in food or water may rapidly enter your body through the digestive 

tract. 

Cresols may enter through your skin when you come into contact with 

liquids containing cresols. 

Leave your body Once in your body, cresols are transformed into other chemicals called 

metabolites. Most of these metabolites leave your body in the urine within 

1 day. 

For more information on how cresols enter and leave the body, see Chapter 3. 

1.5 HOW CAN CRESOLS AFFECT MY HEALTH? 

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

Humans 

 • Inhalation 

 • Oral 

 • Dermal 

Brief exposures to 6 mg/m3 o-cresol in the air caused nose and throat irritation. 

Ingestion of liquid products containing cresols can cause serious 

gastrointestinal damage and even death. 

Application of concentrated cresols to the skin can cause severe skin damage 

and even death. 

Laboratory 

animals 

 • Inhalation 

 • Oral 

 • Dermal 

Short-term exposure to cresols in air has caused irritation of the respiratory 

tract and muscle twitching. 

Placing cresols in the stomach of animals by means of a feeding tube has 

caused muscle twitching and loss of coordination. 

Eating food contaminated mostly with p-cresol or with a mixture of m- and 

p-cresol for 28 days or longer has caused lesions inside the nose of rats and 

mice; mice also developed lesions in the lungs and in the thyroid gland. 

Short-term application of cresols to the skin of animals has produced skin 

irritation. 
CRESOLS 5 

1. PUBLIC HEALTH STATEMENT 

Cancer The EPA has determined that cresols are possible human carcinogens. The 

International Agency for Research on Cancer (IARC) has not classified cresols 

as to their carcinogenicity. 

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

Chapters 2 and 3. 

1.6 HOW CAN CRESOLS 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 There are no studies of children exposed to cresols, but it is expected that 

children exposed to cresols will suffer the same effects observed in exposed 

adults. 

There is a report of a baby who suffered serious damage to the skin, liver, 

and kidneys, went into a coma, and eventually died 4 hours after liquid 

cresol was accidentally spilled on his head. 

Birth defects Fetal toxicity and birth defects have been reported in animals given cresols. 

This generally occurred with doses that were also toxic to the mothers. 

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

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

Tobacco smoke Cresols are components of tobacco smoke. 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 cleaners and disinfectants containing cresols should be stored 

out of the reach of young children to prevent accidental poisonings and skin 

burns and follow manufacturer’s directions on the label. 
CRESOLS 6 

1. PUBLIC HEALTH STATEMENT 

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

CRESOLS? 

Detecting 

exposure 

Cresols can be measured in blood and urine. Cresols are normal 

constituents of human urine. 

Measuring 

exposure 

A higher-than-normal concentration of cresols in the urine may suggest 

recent exposure to these substances or to substances that are converted to 

cresols in the body. 

The detection of cresol and/or its metabolites in your urine cannot be used 

to predict the kind of health effects that might develop from that exposure. 

Information about tests for detecting cresols 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 regulations and recommendations to protect public health. Regulations 

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

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

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

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

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

recommendations for toxic substances. 

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

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

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

these not-to-exceed levels differ among federal organizations because they used different exposure times 

(an 8-hour workday or a 24-hour day), different animal studies, or other factors. 

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

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

1. PUBLIC HEALTH STATEMENT 

Some regulations and recommendations for cresols include the following: 

Drinking water EPA has not established drinking water standards and health advisories for 

cresols. 

Workplace air OSHA set a legal limit of 5 parts per million (ppm) cresols (all isomers) 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 ATSDR at the address and phone number below. 

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

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

substances. 

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

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

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

to: 

 Agency for Toxic Substances and Disease Registry 

 Division of Toxicology and Environmental Medicine 

 1600 Clifton Road NE 

 Mailstop F-32 

 Atlanta, GA 30333 

 Fax: 1-770-488-4178 

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

 National Technical Information Service (NTIS) 

 5285 Port Royal Road 

 Springfield, VA 22161 

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

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

CRESOLS 8 

1. PUBLIC HEALTH STATEMENT 

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CRESOLS 9 

2. RELEVANCE TO PUBLIC HEALTH
 

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO CRESOLS IN THE UNITED 

STATES 

Cresols are widely distributed in the environment and the general population may be exposed to low 

levels of cresols mainly through the inhalation of contaminated air. Cresols are readily degraded in the 

atmosphere; atmospheric concentrations outside of source-dominated areas are typically low. Since 

cresols are released via automobile exhaust, areas of high traffic and gas stations are likely to have 

increased atmospheric levels of cresols. Cresols are also the 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 cresols. There are limited air 

monitoring data for cresols; a median concentration of 1.5 μg/m3 

o-cresol was detected in air samples 

from 3 locations, the range of p-cresol at 11 locations was 0.5–20 μg/m3

, and m-cresol was not detected in 

air samples from 2 locations. A national emissions study conducted from 1990 to 1998 reported a 

county-level estimated ambient average concentration of 31.7 ng/m3 for all cresol isomers combined. 

Cresol levels in soil and water are usually low. When detected in surface water, cresol levels are typically 

around 1 μg/L or less. Higher levels are occasionally observed in groundwater or surface water where 

petroleum spills have occurred or near hazardous waste sites. In a study of public groundwater at 

superfund sites, o-cresol and p-cresol were detected at maximum concentrations of 390 and 150 μg/L, 

respectively; however, neither was detected in well fields or finished water from treatment plants (no data 

were provided for m-cresol). Due to their relatively rapid rate of biodegradation, cresols are only 

occasionally detected in soils, primarily in areas where petroleum products were spilled or produced. 

o-Cresol was detected at maximum concentrations of 12,000–34,000 μg/kg in soil samples obtained from 

an abandoned pine tar manufacturing plant in Gainesville, Florida. 

Employees in occupations that routinely involve the combustion of coal or wood may be exposed to 

higher levels of cresols than the general population. Environmental tobacco smoke is also a source of 

cresol exposure. Depending on the brand and type of cigarette, the average cresol concentration in a 

45 cubic meter chamber after six cigarettes had been smoked ranged from 0.17 to 3.9 μg/m3

. 

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

major sources of exposure for most people. Cresols have been reported in tea leaves, tomatoes, and 

ketchup as well as butter, oil, and various cheeses, but levels are not available. People with contaminated 
 

 

 

 

 

 

 

CRESOLS 10 

2. RELEVANCE TO PUBLIC HEALTH 

tap water can be exposed from drinking the water or eating foods prepared with it. In addition, inhalation 

can occur from volatilized cresol during showering, bathing, and cooking activities with contaminated 

water. Dermal exposure to cresols may also occur due to bathing or showering with contaminated water. 

Exposure to children occurs by the same routes that affect adults. There are no known specific sources of 

exposure to children. Cresol has not been reported in breast milk or baby foods. Children are likely to be 

exposed to cresols through inhalation of contaminated air from automobile exhaust, waste incineration, 

and second-hand smoke. 

2.2 SUMMARY OF HEALTH EFFECTS 

Information about the effects of cresols in humans is derived mainly from case reports of accidental or 

intentional ingestion of cresol solutions or from accidental contact of cresol with the skin. Cresols 

produce corrosive damage at sites of contact; therefore, the skin and mucosal membranes are targets for 

cresols toxicity. In a single study of controlled exposures in volunteers, brief exposures to 6 mg/m3 

o-cresol caused 8 out of 10 subjects to complain of respiratory irritation. Fatalities due to ingestion and 

dermal exposure to cresols have been described. Other effects reported in these acute high oral and/or 

dermal exposure scenarios include respiratory failure, tachycardia and ventricular fibrillation, abdominal 

pain, vomiting, and corrosive lesions of the gastrointestinal tract, methemoglobinemia, leukocytosis and 

hemolysis, hepatocellular injury, renal alterations, skin damage, metabolic acidosis, and unconsciousness. 

Many of these effects may not have been caused directly by cresols, but may be a result of secondary 

reactions to shock caused by external and internal burns. 

Inhalation or dermal exposure of animals to cresols has produced irritation and corrosion at the site of 

contact. Animals exposed acutely to cresol vapors and aerosols showed signs of respiratory irritation, 

although the levels associated with irritation have not been reliably documented. Inflammation and 

irritation of the upper respiratory tract, pulmonary edema, and hemorrhage and perivascular sclerosis in 

the lungs were seen in a variety of animal species exposed intermittently to 9–50 mg/m3 of o-cresol for 

≥1 month; other isomers were not tested. White mice exposed acutely to commercial mixtures of cresol 

isomers exhibited irritation and inflammation of the eyes and nose. Also noticed in these inhalation 

studies were effects on the nervous system (excitation, fatigue, convulsions). Animals that died had fatty 

degeneration and necrosis of the liver, degeneration of the tubular epithelium in the kidneys, bronchitis, 

pulmonary hemorrhage, and dystrophic changes in the heart and in nerve cells and glia in the brain. All 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CRESOLS 11 

2. RELEVANCE TO PUBLIC HEALTH 

three cresol isomers, either alone or in combination, severely irritated the skin of rabbits, producing 

visible and irreversible tissue destruction. 

From a limited number of intermediate oral studies, nasal epithelial lesions appear to be a particularly 

sensitive target for cresols’ toxicity. Dietary exposure of rats and mice to p-cresol or to a mixture of 

m/p-cresol (58.5% m-cresol, 40.9% p-cresol) for 28 days or 13 weeks induced dose-related alterations in 

the nasal respiratory epithelium at doses of 95 mg/kg/day and higher. The severity of the lesions also was 

dose-related. The lesions were located at the most anterior portions of the nasal septum, dorsal arch, and 

medial aspect of the nasal turbinates. No such lesions were seen with o- or m-cresol in the 28-day study 

or with o-cresol in the 13-week study (neither m-cresol nor p-cresol alone were tested in the 13-week 

study). Nasal lesions were also observed in male rats and female mice exposed to a mixture of m/p-cresol 

in the feed for 2 years; the results suggested that the lesions already had developed by week 13 and did 

not increase in severity during the remainder of the dosing period. Intermediate-duration oral gavage 

studies and two multi-generation reproductive dietary studies in mice did not examine the nasal 

respiratory epithelium of the animals. It is also relevant to note that in the inhalation studies discussed 

above, there is no specific mention of evaluation of the nasal cavity. Additional studies may be necessary 

to rule out the possibility that the nasal lesions are due to direct contact of cresol with the nasal epithelium 

(see Section 2.3 for a more detailed discussion on this particular issue). 

The nervous system also appears to be a sensitive target of cresols toxicity in oral studies, although this 

seems to be limited to oral gavage studies. Rodents administered cresols by oral gavage for acute or 

intermediate durations showed neurological signs such as hypoactivity, excessive salivation, labored 

respiration, and tremors, in addition to decreased body weight gain. Some neurological signs were 

observed in rats dosed by gavage with as low as 50 mg/kg/day of cresol isomers. None of these effects 

have been seen in dietary studies, or if seen, they have occurred at much higher dose levels than in oral 

gavage studies. The reason for this difference is unknown, but it probably is related to toxicokinetic 

differences between the two modes of oral dosing. 

Dietary exposure to higher doses of cresols, generally >240 mg/kg/day, caused increases in liver weight; 

thresholds for these changes in liver weight were comparable among cresol isomers. Kidney weight was 

only increased in rats dosed with ≥861 mg/kg/day o-cresol for 28 days. Clinical chemistry tests gave no 

indication of altered function in these organs and no gross and microscopic alterations were seen, even at 

the highest doses administered (>1,000 mg/kg/day). Other systemic effects observed in rats and mice 

treated with relatively high doses of cresols (>1,000 mg/kg/day) in the diet for 13 weeks included 
 

 

 

 

 

 

 

 

 

 

CRESOLS 12 

2. RELEVANCE TO PUBLIC HEALTH 

decreased weight gain (all isomers). A 2-year study also provided evidence of kidney toxicity in rats 

(720 mg/kg/day m/p-cresol) and thyroid gland toxicity in mice (≥100 mg/kg/day m/p-cresol). 

Reproductive effects of cresols isomers administered to rats and mice in the diet were limited to mild to 

moderate uterine atrophy and lengthening of the estrous cycle, generally at the highest dose levels tested 

(>2,000 mg/kg/day). Dietary multi-generation studies in mice with o-cresol and m/p-cresol found no 

significant effects with o-cresol; m/p-cresol at the highest level tested (1,682 mg/kg/day) caused minor 

maternal toxicity (reduced body weight gain), decreased number of pups/litter, and increased cumulative 

days to litter (delay in producing additional F1 offspring). Developmental studies that treated rats and 

rabbits by oral gavage during gestation observed fetal effects (skeletal variations and delayed ossification) 

at dose levels that also caused maternal toxicity. 

A 2-year bioassay found equivocal evidence of carcinogenetic activity of m/p-cresol (60%/40%) in male 

Fischer-344 rats based on a nonsignificant increase in the incidence of renal tubule adenoma. The same 

study found some evidence of carcinogenetic activity in female B6C3F1 mice based on an increased 

incidence of forestomach squamous cell papilloma. Cresols gave indications of promotion potential in a 

dermal skin promotion assay; p-cresol was the least potent isomer, o-cresol was approximately 3 times 

more potent than p-cresol, and m-cresol was in between. The EPA has determined that cresols are 

possible human carcinogens (Group C) based on inadequate data in humans and limited data in animals 

(the assessment is dated 10/89). According to EPA’s updated criteria for classifying chemicals, cresols 

fall in the category of chemicals for which there is “inadequate information to assess carcinogenic 

potential.” 

The database in animals is insufficient to propose a toxicity ranking for cresol isomers, even though 

p-cresol seemed to be the most potent for induction of the critical effect, nasal respiratory lesions, in rats 

and mice in the National Toxicology Program (NTP) study. The human database is inadequate to propose 

a toxicity ranking for cresol isomers. 

2.3 MINIMAL RISK LEVELS (MRLs) 

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

 

 

 

 

 

 

 

 

CRESOLS 13 

2. RELEVANCE TO PUBLIC HEALTH 

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

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

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

methodology does not exist to develop MRLs for dermal exposure. 

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

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

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

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

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

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

significant human exposure improve, these MRLs will be revised. 

Inhalation MRLs 

The available health effects data for humans or animals exposed to cresols by inhalation are inadequate to 

establish concentration-response relationships, which are needed to identify adverse effects levels. 

Therefore, inhalation MRLs were not derived for cresols. In an experiment in humans, brief exposures to 

6 mg/m3 

o-cresol caused 8 out of 10 subjects to complain of respiratory irritation (Uzhdavini et al. 1972). 

No information was provided on how the cresol vapor was generated or sampled. Two animal studies 

were available in which exposure involved mixtures of vapors and aerosols that provided insufficient 

information to reliable estimate exposure levels (Campbell 1941; Uzhdavini et al. 1972). o-Cresol (9– 

50 mg/m3

) was tested in the studies of Uzhdavini et al. (1972) in a variety of species, whereas Campbell 

(1941) tested commercial mixtures of cresol isomers in white mice. These studies provided data on 

lethality, as well as information on effects on the respiratory system (irritation, inflammation, edema, 

hemorrhage), and nervous system (excitation, fatigue, convulsions). Animals that died had fatty 

degeneration and necrosis of the liver, degeneration of the tubular epithelium in the kidneys, bronchitis, 

pulmonary hemorrhage, and dystrophic changes in the heart and in nerve cells and glia in the brain. 

Because of limitations in study design (mainly in the methodology for generating and monitoring the 

vapor concentrations) and reporting, these studies are not useful for risk assessment. 
 

 

 

 

 

 

 

 

CRESOLS 14 

2. RELEVANCE TO PUBLIC HEALTH 

Oral MRLs 

As mentioned in Section 2.2, effects of cresol administered by oral gavage are markedly different than 

those observed in dietary studies. Administration of cresols by oral gavage to animals results in lowestobserved-adverse-effect levels (LOAELs) much lower than LOAELs defined in dietary studies. For 

example, LD50 values for undiluted cresols in rats ranged from 121 to 242 mg/kg/day (EI du Pont 1969), 

whereas dietary doses in the range of 1,000–2,000 mg/kg/day for intermediate durations caused little or 

no toxicity in rats and mice (NTP 1992b). Serious neurological effects (i.e., lethargy, tremors, 

convulsions) were seen in rats dosed by oral gavage with doses ranging from 450 to 600 mg/kg/day for 

90 days (EPA 1988b, 1988c, 1988d; TRL 1986; Tyl 1988a, 1988b), but no such effects were observed in 

the dietary studies at much higher dose levels (NTP 1992a, 1992b, 1992c, 2008). The reason for this 

difference is not known, but it is most likely related to differences in toxicokinetics between the two 

methods of cresol administration. There are no studies that compared the toxicokinetics of cresols 

following dietary and gavage administration, but there is information for a related chemical, phenol. 

Phenol toxicity following oral gavage dosing is different than following administration in the drinking 

water. In the case of phenol, there are data that suggest that toxicity is correlated with peak blood 

concentration rather than with total dose, such as the area under the blood concentration curve (AUC) 

following a single gavage dose or repeated daily doses. This is consistent with data from Bray et al. 

(1950), who observed that p-cresol was more toxic when given by stomach tube to fasting rabbits than 

when the rabbits were given their daily food 1–2 hours before dosing with p-cresol; the assumption is that 

p-cresol became mixed with the food, which delayed its absorption. Also relevant is a recent study by 

Morinaga et al. (2004), which found concentrations of free cresols in liver and spleen from rats given a 

single oral gavage dose much higher than in blood at all times after dosing (up to 8 hours). Based on 

these observations and the fact that an oral gavage exposure protocol does not resemble human 

environmental exposure scenarios to cresols, only dietary studies are considered for MRL derivation, 

even though some LOAELs by gavage are lower than dietary LOAELs. 

No acute-duration oral MRL was derived for cresols due to lack of acute dietary exposure studies. 

•	 An MRL of 0.1 mg/kg/day has been derived for intermediate-duration oral exposure (15–
 

364 days) to cresols.
 

Almost all of the information available on health effects from intermediate-duration oral exposure is 

derived from a comprehensive study in rats and mice administered o-, m-, or p-cresol or a cresol mixture 

of m- and p-cresol for 28 days or 13 weeks (NTP 1992b). There are also two multigeneration 
 

 

 

 

 

 

 

 

 

 

 

 

CRESOLS 15 

2. RELEVANCE TO PUBLIC HEALTH 

reproductive toxicity studies in mice dosed with o-cresol (NTP 1992a) and a mixture of m- and p-cresol 

(NTP 1992c). In the NTP (1992b) study, rats and mice dosed with p-cresol or an m/p-cresol mixture 

showed lesions in the nasal respiratory epithelium. The nasal lesions occurred in rats dosed with p-cresol 

for 28 days (≥770 mg/kg/day), in rats exposed to m/p-cresol for 28 days (≥95 mg/kg/day), in mice 

exposed to p-cresol for 28 days (≥163 mg/kg/day), in mice exposed to m/p-cresol for 28 days 

(≥604 mg/kg/day), in rats exposed to m/p-cresol for 13 weeks (≥123 mg/kg/day), and in mice exposed to 

m/p-cresol for 13 weeks (≥472 mg/kg/day). The lesions were located at the most anterior portions of the 

nasal septum, dorsal arch, and medial aspect of the nasal turbinates. The hyperplasia was characterized 

by increased number of goblet cells and pseudogland formation due to the infolding of the hyperplastic 

cells. The hyperplastic areas were associated with single cell necrosis. The intermediate-duration oral 

gavage studies (EPA 1988b, 1988d) and two multi-generation reproductive dietary studies in mice (NTP 

1992a, 1992c) did not examine the nasal respiratory epithelium of the animals. Small increases in liver 

weight were observed in rats and mice at higher doses (≥242 mg/kg/day) in both the 28-day and 13-week 

studies; kidney weight was only increased in rats dosed with ≥861 mg/kg/dayo-cresol for 28 days. 

However, the changes in organ weight were not associated with alterations in clinical tests of liver and 

kidney function or gross and microscopic alterations (NTP 1992b). Decreased weight gain was also 

observed in rats and mice at relatively high doses (>1,000 mg/kg/day). 

In addition to the systemic effects observed in the 28-day and 13-week studies (NTP 1992b), exposure to 

high doses of cresols has resulted in reproductive and developmental effects. Mild to moderate uterine 

atrophy and lengthening of the estrous cycle were generally observed at the highest dose levels tested 

(>2,000 mg/kg/day) for all three isomers. Exposure of mice to 1,682 mg/kg/day m/p-cresol caused minor 

maternal toxicity (reduced body weight gain), decreased number of pups/litter, and increased cumulative 

days to litter (delay in producing additional F1 offspring). These effects were not observed in mice 

exposed to 660 mg/kg/day o-cresol (NTP 1992a). 

Evaluation of the results of the available intermediate-duration dietary studies indicates that the most 

sensitive end point was the nasal respiratory epithelium of rats and mice dosed with p-cresol or a mixture 

of m- and p-cresol (NTP 1992b). The effects occurred in male and female rats and mice dosed for 

28 days or 13 weeks. The data sets considered for MRL derivation were the 28-day experiment in female 

rats and the 13-week experiment in male rats based on the lowest effect levels identified in both sets, 

95 mg/kg/day in the 28-day experiment and 123 mg/kg/day in the 13-week experiment. In the 28-day 

study, the incidences of hyperplasia of the nasal respiratory epithelium in female rats dosed with 0, 27, 

95, 268, 886, and 2,570 mg/kg/day of m/p-cresol were 0/5, 0/5, 3/4, 5/5, 5/5, and 5/5, respectively. In the 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CRESOLS 16 

2. RELEVANCE TO PUBLIC HEALTH 

13-week study, the incidences in male rats dosed with 0, 123, 241, 486, 991, and 2,014 mg/kg/day 

m/p-cresol were 0/10, 3/10, 8/10, 10/10, 8/10, and 10/10, respectively. The latter series is preferred 

because of the longer duration of exposure and because of the increased reliability of a dose-response 

curve based on 10 rats per group rather than on only 5 rats per group in the 28-day study. 

An issue that has to be considered is the possibility that the nasal lesions were caused by evaporation of 

the cresol from the food (even though cresols have relatively low vapor pressure, particularly p-cresol) 

and thus due to direct contact of the airborne chemical with the nasal respiratory epithelium. The 

inhalation database consists of a study by Uzhdavini et al. (1972) who exposed various animal species to 

o-cresol (o-cresol did not induce nasal lesions in the NTP study) for various periods of time. Acute 

exposures of mice produced irritation of mucous membranes and higher concentrations induced 

pulmonary edema and histopathological changes in the lungs. Repeated exposures of mice also induced 

symptoms of irritation of the respiratory tract, but there is no specific mention of the nasal cavity. 

Exposures of rats and guinea pigs for 4 months produced symptoms of irritation and inflammation in the 

upper respiratory tract, local edema, and perivascular sclerosis in the lungs. Because of limitations in 

study design and reporting, few conclusions can be drawn from the experiments of Uzhdavini et al. 

(1972) other than that o-cresol is a respiratory irritant at the concentrations tested. NTP (1992b) 

conducted preliminary studies to assess the stability of the various cresol isomer-feed mixtures and 

detected losses due to evaporation from 10 to 12% after storage for 7 days under simulated cage 

conditions. Therefore, fresh chemical-diet mixtures were supplied twice weekly during the studies. 

Estimating the concentration of cresol in the air from such losses from food is virtually impossible due to 

numerous uncertainties. The threshold for nasal lesions in rats was about 2,000 mg/kg of m/p-cresol in 

the food. A loss of 10% per week represents 200 mg of cresol/kg of food per week or about 1.2 mg/kg 

feed per hour. However, a concentration of cresol in air cannot be estimated because of many unknown 

factors such as volume of distribution, air flow speed, etc. A somewhat related possibility is that cresol 

evaporates inside the mouth of the animal aided by the higher temperature (about 38 °C) and reaches the 

nasal cavity from inside the mouth. There is also the possibility of nasal exposures due to exhalation of 

the cresols previously ingested, although there is no indication from toxicokinetics studies that this may 

occur. Until it can be demonstrated with some certainty that the nasal lesions are not caused by a 

systemic effect of cresol and in the interest of protecting humans potentially exposed under similar 

conditions, the MRL was based on the increased incidence of the nasal lesions in rats. 

In the principal study for the MRL, groups of Fischer 344 rats (20/sex/group) were administered 

m/p-cresol (58.5% m-cresol, 40.9% p-cresol) in the diet at levels of 0, 1,880, 3,750, 7,500, 15,000, or 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CRESOLS 17 

2. RELEVANCE TO PUBLIC HEALTH 

30,000 ppm for 13 weeks (NTP 1992b). The corresponding doses of test compound estimated by the 

investigators were 0, 123, 241, 486, 991, and 2,014 mg/kg/day for males and 0, 131, 254, 509, 1,024, and 

2,050 mg/kg/day for females. End points evaluated included clinical signs, food consumption, organ 

weights, clinical chemistry and hematology, and gross and microscopic appearance of organs and tissues. 

Although the dose groups consisted of 20 rats of each sex, 10 males and 10 females were used for clinical 

chemistry, hematology, and urinalysis studies and the remaining 10 rats/sex/group were used in gross 

pathology, organ weight, and histopathological studies. There were no deaths during the study. Final 

body weight in the 2,014/2,050 mg/kg/day males and females was reduced 17 and 12%, respectively, 

relative to controls. Food consumption was also reduced (about 10%) in this group during the first week 

of the study. Additionally, males and females in this group exhibited rough hair coat; females also had a 

thin appearance. Absolute and relative liver weights were significantly increased (11–12%) in males at 

486 mg/kg/day and in females at 1,024 mg/kg/day. Absolute and relative kidney weight was increased in 

males at 991 mg/kg/day. In general, hematology findings were unremarkable, although there was a 

tendency to hemoconcentration at 2,014/2,050 mg/kg/day early in the study. Clinical chemistry tests 

showed an increase in serum alanine aminotransferase (ALT) in males and females exposed to 

2,014/2,050 mg/kg/day and in sorbitol dehydrogenase (SDH) in males at 2,014 mg/kg/day only on day 5. 

Bile acids in serum were increased in females at 2,050 mg/kg/day on day 90 and at 241 and 

991 mg/kg/day in males also on day 90. There was no indication of renal injury as judged by the results 

of urinalyses. Significant histopathological changes included minimal bone marrow hypocellularity in 

males and females (likely secondary to decreased weight gain) at 2,014/2,050 mg/kg/day, and increased 

colloid (minimal) in thyroid follicular cells in females at 509 mg/kg/day and in males at 15,000 ppm 

(991 mg/kg/day). An increased dose-related incidence and severity of hyperplasia and glandular 

hyperplasia of the nasal respiratory epithelium was observed in male and female rats. Severity was 

minimal at 123/131 mg/kg/day, mild at 486/509 mg/kg/day, and moderate at 2,014/2,050 mg/kg/day. The 

lesions were located at the most anterior portions of the nasal septum, dorsal arch, and medial aspect of 

the nasal turbinates. The hyperplasia was characterized by increased number of goblet cells and 

pseudogland formation due to the infolding of the hyperplastic cells. The hyperplastic areas were 

associated with single cell necrosis. The incidences in males dosed with 0, 123, 241, 486, 991, and 

2,014 mg/kg/day were 0/10, 3/10, 8/10, 10/10, 8/10, and 10/10, respectively. A similar trend was seen in 

female rats, but 3/10 control females also exhibited hyperplasia (3/10, 1/10, 5/10, 9/10, 8/10, and 10/10 at 

0, 131, 254, 509, 1,024, and 2,050 mg/kg/day, respectively). 

Data from the NTP (1992b) were considered adequate for analysis using the benchmark dose approach 

for MRL derivation. Benchmark dose models in the EPA Benchmark Dose Software (BMDS) 
 

 

 

 

 

 

 

 

 

 

 

 

 

CRESOLS 18 

2. RELEVANCE TO PUBLIC HEALTH 

(version 2.0) were fit to the incidence data for nasal lesions in male and female rats exposed to m/p-cresol 

in the diet for 13 weeks in order to determine potential points of departure for the MRL (details of the 

modeling are presented in Appendix A). Comparing fits across nine different models, the log-logistic 

model was determined to be the best-fitting model for the male rat data set, whereas the quantal linear 

model was the best-fitting model for the female rat data set. Following EPA’s Benchmark Dose 

Guidance (EPA 2000a) to select a point of departure, a benchmark response (BMR) of 10% was selected 

for the benchmark analysis of nasal lesion incidence data in the 13-week NTP (1992b) study. The 

benchmark dose (BMD) corresponding to a BMR of 10% extra risk is 55.89 mg/kg/day. BMDL10s (i.e., 

95% lower confidence limits on the model-estimated dose associated with a 10% extra risk for nasal 

lesions) calculated with the best-fitting models for each data set were 13.9 mg/kg/day for males and 

30.8 mg/kg/day for females. While this difference in benchmark dose may indicate that male rats are 

more sensitive than females, it also can be just a statistical artifact in a rather small sample size, only 

10 rats per group. The male rat data set was selected for determining the point of departure for MRL 

derivation in order to be public health protective. Applying an uncertainty factor of 100 (10 for 

extrapolation from animals to humans and 10 for human variability) to the BMDL10 of 13.9 mg/kg/day 

yields an intermediate-duration oral MRL of 0.1 mg/kg/day for m/p-cresol. 

•	 An MRL of 0.1 mg/kg/day has been derived for chronic-duration oral exposure (365 days or 

more) to cresols. 

The only chronic-duration dietary study with cresols is the NTP (2008) toxicology and carcinogenesis 

studies in male Fischer-344/N rats and female B6C3F1 mice. Although the report has not yet been 

finalized by the NTP, a draft technical report has been reviewed by the NTP Board of Scientific 

Counselors Technical Reports Review Subcommittee, and a draft abstract, pathology tables, and survival 

and growth curves are available on the NTP web site. In the study, the male Fischer-344/N rats were fed 

diets that provided mean time-weighted average (TWA) doses of m/p-cresol of approximately 0, 70, 

230, or 720 mg/kg/day for 2 years. Survival rates were not affected by treatment with m/p-cresol. 

Inspection of the data shows that the most sensitive end point in rats was the nasal respiratory epithelium, 

as in the shorter-term studies (NTP 1992b). Other less sensitive effects observed in rats included 

hyperplasia of the transitional epithelium of the renal pelvis, squamous metaplasia in the nasal respiratory 

epithelium, inflammation of the nose, and eosinophilic foci in the liver. Incidences of respiratory 

epithelium hyperplasia of minimal to mild severity were 3/50, 17/50, 31/50, and 47/50 in the control, 

low-, mid-, and high-dose groups, respectively. During the first 13 weeks of the 2-year study, the mean 

dose in the low-dose group was 123 mg/kg/day (calculated from weekly averages provided in the report), 

the same as in the earlier 13-week study (NTP 1992b), and the incidence of respiratory hyperplasia in this 
 

 

 

 

 

 

 

 

 

 

 

CRESOLS 19 

2. RELEVANCE TO PUBLIC HEALTH 

group at termination was 17/50 (34%), almost the same as in the earlier 13-week study, 3/10 (30%). This 

suggests that, over the range of doses used in these studies, exposure beyond 13 weeks (i.e., duration of 

exposure) had little or no effect on the incidence or severity of the lesions, indicating that the 

intermediate-duration MRL is protective of nasal lesions for a 2-year exposure period. This is supported 

by the fact that fitting the incidence data for nasal respiratory epithelium hyperplasia from the 2-year 

study to the same BMDS model (Log-Logistic) that provided the BMDL10 used to derive the 

intermediate-duration oral MRL yields a BMDL10 for chronic exposure to m/p-cresol of 

13.9017 mg/kg/day, essentially the same as the BMDL10 of 13.9381 mg/kg/day used to derive the 

intermediate-duration oral MRL for m/p-cresol. Thus, the intermediate-duration oral MRL should be 

protective of nasal respiratory lesions in rats induced by chronic-duration exposure. 

The female B6C3F1 mice were fed diets that provided TWA doses of approximately 0, 100, 300, or 

1,040 mg m/p-cresol/kg/day for 2 years. Survival rates were comparable among dose groups. Significant 

treatment-related, non-neoplastic effects occurred in the lung (bronchiole hyperplasia), nose (respiratory 

epithelium hyperplasia), thyroid gland (follicular degeneration), and liver (eosinophilic foci). In the lung, 

the incidences of minimal to moderate bronchiole hyperplasia were 0/50, 42/50, 44/49, and 47/50 in the 

control, low-, mid-, and high-dose groups, respectively. In the nose, the corresponding incidences of 

minimal to mild respiratory epithelium hyperplasia were 0/50, 0/50, 28/49, and 45/49. In the thyroid, the 

corresponding incidences of mild follicular degeneration were 7/48, 24/48, 24/49, and 21/50. The 

corresponding incidences of eosinophilic foci in the liver were 1/50, 0/50, 2/49, and 12/50. Clearly, the 

thresholds for thyroid follicular degeneration and bronchiole hyperplasia were lower than those for nasal 

epithelial hyperplasia and liver foci; therefore, the incidence data for the former two lesions were 

considered for derivation of a chronic-duration oral MRL for m/p-cresol. After inspection of the dose 

response data, the use of a LOAEL/NOAEL approach for MRL derivation was considered to be more 

appropriate than the use of benchmark dose analysis because of the steep increase in the response rates 

between the control groups and the first exposure levels. It should be noted that neither bronchiole 

hyperplasia nor thyroid follicular degeneration were present in female mice in the 13-week study with 

m/p-cresol (NTP 1992b), suggesting that longer periods of exposure were necessary for these lesions to 

develop. Applying an uncertainty factor of 1,000 (10 for use of a LOAEL, 10 for extrapolation from 

animals to humans, and 10 for human variability) to the LOAEL of 100 mg/kg/day for bronchiole 

hyperplasia of the lung and follicular degeneration of the thyroid gland in female mice, yields an chronicduration oral MRL of 0.1 mg/kg/day for m/p-cresol. 
 

 

 

 

 

CRESOLS 20 

2. RELEVANCE TO PUBLIC HEALTH 

The most comprehensive study of cresols by dietary exposure is the NTP (1992b) study. In that study, 

each individual isomer and an m/p-cresol mixture were tested in rats and mice for 28 days; in addition, 

o-cresol and m/p-cresol were tested in rats and mice for 13 weeks. Assessing the comparative toxicity of 

the cresol isomers, NTP (1992b) noted that: “In general, there were no significant indications of distinct 

toxicities between the three isomers.” However, nasal lesions only occurred in rats and mice dosed with 

p-cresol and m/p-cresol in the 28-day studies and in rats and mice dosed with m/p-cresol in the 13-week 

studies. Since m-cresol alone was not tested in the 13-week studies, it is unknown whether longer dietary 

exposure to this isomer would produce similar lesions. Thus, it would appear that p-cresol is the most 

toxic of the isomers with regard to inducing nasal lesions and, since no other significant toxicities were 

observed in these dietary studies, the MRL for m/p-cresol should also be protective for exposures to the 

individual cresol isomers. Therefore, the intermediate- and chronic-duration oral MRLs for m/p-cresol 

also can be adopted for o-, m-, and p-cresol. 
 

 

 

 

 

 

 

CRESOLS 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 groups with an overall perspective on the toxicology of cresols. It 

contains descriptions and evaluations of toxicological studies and epidemiological investigations and 

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

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

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

 

 

 

 

 

 

CRESOLS 22 

3. HEALTH EFFECTS 

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

effects to human health. 

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

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

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

associated with more subtle effects in humans or animals (LOAELs) or exposure levels below which no 

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

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

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

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

3.2.1 Inhalation Exposure 

Studies of the inhalation toxicity of cresols have not been adequately detailed. The exposures involved 

mixtures of vapors and aerosols that were not characterized sufficiently to estimate exposure levels 

reliably. Furthermore, methods for evaluating the toxicological end points were not adequately described. 

In addition, it is very likely that dermal exposure, and thus dermal absorption, also occurred. Therefore, 

no LSE table or figure containing levels of significant exposure was constructed for this route. 

Nevertheless, certain general conclusions can be drawn from the reports regarding the toxic potential of 

inhaled cresols. These are discussed below. 

3.2.1.1 Death 

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

Cresols may be lethal to animals when inhaled (Campbell 1941; Uzhdavini et al. 1972). The inhalation 

exposure levels and durations that kill animals have not been reliably documented. Lethality has been 

reported in mice exposed to approximately 178 mg/m3 of o-cresol aerosol for an unspecified acute 

duration, suggesting that the minimal lethal exposure level for cresol aerosols may be <178 mg/m3 

(Uzhdavini et al. 1972). For longer-term exposure, the minimal lethal level may exceed 50 mg/m3

, since 

exposure to this concentration of o-cresol for 1 month had no effect on mouse mortality (Uzhdavini et al. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

CRESOLS 23 

3. HEALTH EFFECTS 

1972). Clinical signs that preceded death in acute experiments included irritation of mucous membranes 

and neuromuscular excitation that progressed from tremors to clonic convulsions. 

3.2.1.2 Systemic Effects 

No studies were located regarding gastrointestinal, hematological, musculoskeletal, or dermal effects in 

humans or animals following inhalation exposure to cresols. 

Respiratory Effects. When inhaled as a concentrated aerosol, o-cresol is a respiratory irritant in 

humans; however, the minimal exposure level and duration associated with irritation have not been 

reliably documented. Following brief exposures to 6 mg/m3

, 8 out of 10 subjects complained of mucosal 

irritation symptoms including dryness, nasal constriction, and throat irritation (Uzhdavini et al. 1972). 

Signs of respiratory irritation have been reported in animals acutely exposed to cresol vapors and 

aerosols, although the levels associated with irritation have not been reliably documented (Campbell 

1941; Uzhdavini et al. 1972). Mucosal irritation, as shown by parotid gland secretions, occurred in cats 

during 30-minute exposures to 5–9 mg/m3 of o-cresol (Uzhdavini et al. 1972). An assortment of 

respiratory effects, including inflammation and irritation of the upper respiratory tract, pulmonary edema, 

and hemorrhage and perivascular sclerosis in the lungs were seen in animals exposed to 9–50 mg/m3 of 

o-cresol 2–6 hours/day for ≥1 month (Uzhdavini et al. 1972). 

Cardiovascular Effects. No studies were located regarding cardiovascular effects in humans 

following inhalation exposure to cresols. 

Heart muscle degeneration was reported in mice exposed to 50 mg/m3 of o-cresol 2 hours/day for 1 month 

(Uzhdavini et al. 1972). Mice were probably exposed to an aerosol. Exposure levels were not reliably 

documented. 

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

exposure to cresols. 

Fatty degeneration and centrilobular necrosis were observed in the livers of mice that died following 

acute exposure to o-cresol; the mean lethal concentration was 178 mg/m3

. Exposure to 9 mg/m3 for 
 

 

 

 

 

CRESOLS 24 

3. HEALTH EFFECTS 

4 months interfered with liver function in rats, as shown by increased susceptibility to hexanol narcosis 

(Uzhdavini et al. 1972). 

Renal Effects. No studies were located regarding renal effects in humans following inhalation 

exposure to cresols. 

Blood was found in the urine of mice acutely exposed to o-cresol; the mean lethal concentration was 

178 mg/m3 (Uzhdavini et al. 1972). Necropsy and histopathologic examination of the mice that died 

following exposure revealed edema and swelling of the glomeruli, degeneration of the tubular epithelium, 

and perivascular hemorrhage. 

Ocular Effects. No studies were located regarding ocular effects in humans following inhalation 

exposure to cresols. 

Eye irritation was noted in mice briefly exposed to highly concentrated cresylic acid (a mixture of cresol 

isomers and other phenolic solvents that boils above 204 C) vapors; however, the exact exposure 

concentrations associated with irritation were not documented (Campbell 1941). 

3.2.1.3 Immunological and Lymphoreticular Effects 

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

exposure to cresols. 

3.2.1.4 Neurological Effects 

No studies were located regarding neurological effects in humans following inhalation exposure to 

cresols. 

Neurologic effects in animals acutely exposed to cresol aerosols have been reported (Uzhdavini et al. 

1972). The effects include mild nervous excitation, muscle twitching accompanied by general fatigue, 

and clonic convulsions. The exposure concentrations associated with these effects have not been reliably 

documented; however, they may occur at levels approximating 178 mg/m3 during a single exposure. 

Prolonged exposure (2 hours/day for 1 month) to a lower concentration of o-cresol aerosol (50 mg/m3

) 

reportedly produced degeneration of nerve cells and glial elements in mice (Uzhdavini et al. 1972). The 
 

 

 

 

 

 

 

 

 

CRESOLS 25 

3. HEALTH EFFECTS 

severity of these changes was not discussed, however, and no further details were provided. The 

exposure concentration associated with this effect was not reliably documented. 

No information was located regarding the following effects of cresols in humans following inhalation 

exposure: 

3.2.1.5 Reproductive Effects 

3.2.1.6 Developmental Effects 

3.2.1.7 Cancer 

3.2.2 Oral Exposure 

3.2.2.1 Death 

Ingestion of cresols can be fatal to humans. Fatalities were described in several case reports involving 

ingestion of cresol-containing disinfectants. A 37-year-old woman died 4 days after swallowing about 

250 mL of a disinfectant described as 50% cresols in a mixture of linseed oil, potassium hydroxide, and 

water. Death was caused by acute intravascular hemolysis, which resulted in multiple thrombosis and 

renal failure (Chan et al. 1971). The lethal dose was roughly 2 g/kg of cresols (only about one-half of 

which was actually absorbed). The same report described the case of a woman who recovered after 

drinking a smaller amount of the same disinfectant (approximately 100 mL). The urine of both women 

contained glucuronides of cresol metabolism. A woman who swallowed between 500 and 750 mL of a 

concentrated cresol mixture died from cardiac arrest 26 hours later (Labram and Gervais 1968). Among 

the 52 cases of cresol poisoning reported by Isaacs (1922), two patients died, both within 0.5 hours of 

drinking a disinfectant purported to contain 25–50% cresols. Similarly, Monma-Ohtaki et al. (2002) 

reported that ingestion of a large volume of a saponated cresol solution caused the death of a man in about 

15 minutes. A woman who drank a disinfectant suspected of containing cresols died 5 days later (Dellal 

1931). There was little corrosion in the throat so it is probable that not much disinfectant was swallowed. 

The cause of death was thought to be acute hemorrhagic degeneration of the pancreas, which may or may 

not have been related to cresol consumption. Bruce et al. (1976) also described two cases of ingestion of 

cresols that ended in death; in both cases, there was significant injury to the gastrointestinal tract. 

LD50 values in rats were 1,350, 1,800, and 2,020 mg/kg for o-, p-, and m-cresol, respectively, for 10% 

solutions in olive oil (Deichmann and Witherup 1944). LD50 values of 121, 242, and 207 mg/kg were 

reported for undiluted o-, m-, and p-cresol, respectively, in rats (EI du Pont 1969). Hypoactivity, tremors, 
 

 

 

 

 

 

 

CRESOLS 26 

3. HEALTH EFFECTS 

convulsions, salivation, and dyspnea were signs commonly seen preceding death (EI du Pont 1969). 

Acute LD50 values for various cresylic acid formulations in mice ranged from 500 to 2,050 mg/kg 

(Campbell 1941). Although LD50 values were not determined in other species, minimum lethal values 

were available for a few species; the small number of animals in these studies, however, limits the 

reliability of these data. In rabbits, minimum lethal values from ingestion ranged from 620 to 

1,400 mg/kg for the three isomers (Deichmann and Witherup 1944). In mink, the minimum lethal value 

of o-cresol by gavage was 200 mg/kg, and in ferrets, it was 400 mg/kg (Hornshaw et al. 1986). 

Dietary administration of 4,480 mg/kg/day of o-cresol to male mice or 5,000 mg/kg/day to female mice 

for 10 days resulted in the death of 2/5 males and 1/5 females (NTP 1992b). Doses of 4,710 or 

4,940 mg/kg/day of m-cresol killed 2/5 males and 2/5 female mice, respectively, in a 6-day period (NTP 

1992b). A diet containing 30,000 ppm of p-cresol (The National Toxicology Program [NTP] did not 

estimate doses, but were probably 4,000–5,000 mg/kg/day) caused the death of 4/5 male and 5/5 female 

mice within 1 week in this diet. In the cases of o- and m-cresol, necropsy of the dead animals did not 

reveal any notable histopathological changes. In the case of p-cresol, lesions were considered secondary 

to moribund condition or stress, except for liver and kidney necrosis and bone marrow hypocellularity, 

which could have been related to p-cresol (NTP 1992b). Exposure of male F-344 rats or female B6C3F1 

mice to up to 720 and 1,040 mg/kg/day, respectively, in the diet for 2 years did not affect survival rates 

(NTP 2008). 

Mortality data were also available for pregnant rats (Tyl 1988a) and rabbits (Tyl 1988b) given cresols by 

gavage repeatedly during gestation in studies of developmental toxicity. Both o- and p-cresol produced 

mortality among rats given 450 mg/kg/day, whereas m-cresol did not (Tyl 1988a). In rabbits, p-cresol 

appeared to produce a dose-related increase in mortality at 50–100 mg/kg/day. No deaths occurred in 

rabbits exposed to o- or m-cresol (Tyl 1988b). 

Exposure to o-, p-, or m-cresol at 450 mg/kg/day by oral gavage produced 12–60% mortality in adult 

male and female rats in two-generation reproduction studies. The elevated mortality occurred in both the 

F0 and F1 generation adults (Neeper-Bradley and Tyl 1989a, 1989b; Tyl and Neeper-Bradley 1989). In 

13-week oral gavage studies of systemic toxicity in rats, elevated mortality resulted only from exposure to 

o-cresol at 600 mg/kg/day (EPA 1988b); in these studies, p- and m-cresol failed to produce mortality at 

450–600 mg/kg/day (EPA 1988c, 1988d). 
 

 

 

 

 

 

 

 

 

 

 

 

 

CRESOLS 27 

3. HEALTH EFFECTS 

All reliable LD50 and LOAEL values for death in each species and duration category are recorded in 

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

3.2.2.2 Systemic Effects 

The highest NOAEL values and all reliable LOAEL values for systemic effects of each type in each 

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

Respiratory Effects. Diffuse necrosis of the bronchial epithelium was noted in a woman who died 

after drinking 500–750 mL of a concentrated cresol mixture (Labram and Gervais 1968). This effect was 

thought to have occurred prior to death. Edema and hemorrhage were also observed, but may have 

occurred secondary to death. Adhesions and fluid were found in the lungs of a woman who died after 

drinking a disinfectant suspected of containing cresols (Dellal 1931). 

Hyperplastic or metaplastic lesions in the respiratory epithelium have been observed in rats orally 

exposed to cresols for intermediate durations. Epithelial metaplasia of the trachea has been reported to 

occur in Sprague-Dawley male and female rats treated by gavage with 600 mg/kg/day of p-cresol for 

13 weeks (EPA 1988c). Fischer-344 rats exposed to doses of up to approximately 2,600 mg/kg/day of 

o-cresol or m-cresol in the diet for 28 days had no noticeable histological alterations in tissues of the 

respiratory tract, including nasal tissues (NTP 1992b). However, exposure of males to ≥835 mg/kg/day or 

females to ≥770 mg/kg/day of p-cresol, or of males to ≥261 mg/kg/day or females to ≥95 mg/kg/day of a 

mixture of m- and p-cresol (58/41%) induced dose-related (incidence and severity) hyperplasia of the 

nasal respiratory epithelium (NTP 1992b). This suggests that p-cresol is more potent than the other 

isomers in inducing this type of lesion. The corresponding NOAELs were 256 and 242 mg/kg/day for 

p-cresol and 90 and 27 mg/kg/day for the mixture. In a 13-week dietary study in rats, similar lesions were 

seen in males at ≥123 mg/kg/day of the cresol mixture and in females at ≥254 mg/kg/day (NTP 1992b). 

A NOAEL for males was not identified; the NOAEL for females was 131 mg/kg/day. Neither m-cresol 

nor p-cresol alone was tested in the 13-week study. The lesions were observed at the most anterior 

portions of the nasal septum, dorsal arch, and medial aspect of the nasal turbinates. The hyperplasia was 

characterized by increased number of goblet cells and pseudogland formation due to the infolding of the 

hyperplastic cells. The incidence data for nasal lesions in male and female rats exposed for 13 weeks 

were analyzed via a benchmark dose approach to derive points of departure for deriving an intermediateduration oral MRL for cresols. 
35

1350

37

2020

39

1800

81

242

84

121

87

207

172

1050

287

4480

Table 3-1 Levels of Significant Exposure to Cresols - Oral 

Exposure/ LOAEL 

Duration/ 

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

ACUTE EXPOSUREDeath 

1 Rat once 

(Wistar) (GO) 

2 Rat once 

(Wistar) (GO) 

3 Rat once 

(Wistar) (GO) 

4 Rat once 

(albino) (G) 

5 Rat once 

(albino) (G) 

6 Rat once 

(albino) (G) 

7 Mouse once 

(NS) (GW) 

8 Mouse 2 wk 

ad lib (B6C3F1) (F) 

1350 2020 1800 

242 121 207 

1050 

4480 M 

(LD50, 10% solution in 

olive oil) 

(LD50, 10% solution in 

olive oil) 

(LD50, 10% solution in 

olive oil) (LD50, undiluted) (LD50, undiluted) (LD50, undiluted) 

(LD50) 

(2/5 males and 1/5 

females died before day 10) 

Reference Chemical Form 

Deichmann and Witheruortho Deichmann and Witherumeta Deichmann and Witherupara EI du Pont 1969 meta EI du Pont 1969 ortho EI du Pont 1969 para Campbell 1941 mix NTP 1992b ortho 
295

4710

133

100

142

175 45045030

175

450

450

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

9 Mouse 

(B6C3F1) 

10 Rabbit 

(New Zealand) 

Systemic 

11 Rat 

(SpragueDawley) 

Exposure/ LOAEL 

Duration/ 

Frequency 

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

2 wk ad lib (F) 

4710 M (2/5 males and 2/5 

females died before day 6) 

Gd 6-18 (GO) 100 (5/14 deaths; 0/28 in controls) Gd 6-15 1 x/d (GO) 

Resp Hepatic Bd Wt 

175 F 450 F 

30 F 

450 F (audible respiration) 175 F (12% decreased body 

weight gain) 

450 F (47% decreased body 

weight gain during treatment) 

Other 450 F (15% reduced food 

intake during treatment) 

Reference Chemical Form 

NTP 1992b meta Tyl 1988b para Tyl 1988a ortho 
147

175 450450175

450

450

152

175 450450175

450

175

450

129

5 501005 50100

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

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

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

12 Rat 

(SpragueDawley) 

Gd 6-15 1 x/d (GO) 

Resp 175 F 450 F (labored respiration) Tyl 1988a 

meta 

Hepatic Bd Wt 

450 F 175 F 450 F (46% decreased body 

weight gain durng treatment) 

Other 450 F (13% reduced food 

intake during treatment) 

13 Rat 

(SpragueDawley) 

Gd 6-15 1 x/d (GO) 

Resp 175 F 450 F (labored respiration) Tyl 1988a 

para 

Hepatic Bd Wt 

450 F 175 F 450 F (40% decreased body 

weight gain during treatment) 

Other 175 F 450 F (25% decreased food 

intake during treatment) 

14 Rabbit 

(New Zealand) 

Gd 6-18 1 x/d (GO) 

Resp 5 F 50 F (audible respiration) Tyl 1988b 

ortho 

Hepatic Ocular Bd Wt 

100 F 

5 F 

100 F 

50 F (ocular discharge) 
132

5 501005 50100

137

5 501005 50100

229

50 600

234

50 600

238

50 450

139

175

450

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

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

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

15 Rabbit 

(New Zealand) 

Gd 6-18 1 x/d (GO) 

Resp 5 50 (labored respiration) Tyl 1988b 

meta 

Hepatic Ocular Bd Wt 

100 

5 

100 

50 (ocular discharge 

16 Rabbit 

(New Zealand) 

Gd 6-18 1 x/d (GO) 

Resp 5 F 50 F (labored breathing) Tyl 1988b 

para 

Neurological 

17 Rat 

(CD) 

2 wk 7 d/wk (GO) 

Hepatic Ocular Bd Wt 

100 F 

5 F 

100 F 

50 F (ocular discharge) 

50 (CNS stimulation) 600 (convulsions) TRL 1986 

ortho 

18 Rat 

(CD) 

2 wk 7 d/wk (GO) 

50 (CNS stimulation) 600 (convulsions) TRL 1986 

para 

19 Rat 

(CD) 

2 wk 7 d/wk (GO) 

50 (CNS stimulation) 450 (convulsions) TRL 1986 

meta 

20 Rat 

(SpragueDawley) 

Gd 6-15 1 x/d (GO) 

175 450 (ataxia, tremors, 

hypoactivity) 

Tyl 1988a ortho 
144

175

450

149

175

450

126

5 50

134

5 50

15

50 100

17

200

141

450

146

450

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

Exposure/ 

Duration/ 

Frequency 

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

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

Gd 6-15 1 x/d (GO) 

175 450 (ataxia, tremors 

hypoactivity) 

Tyl 1988a meta 

Gd 6-15 1 x/d (GO) 

175 450 (ataxia, tremors 

hypoactivity) 

Tyl 1988a para 

Gd 6-18 1 x/d (GO) 

5 50 (hypoactivity) Tyl 1988b 

ortho 

Gd 6-18 1 x/d (GO) 

5 50 (hypoactivity) Tyl 1988b 

para 

once (G) 50 100 (incoordination) Hornshaw et al. 1986 ortho 

once (G) Gd 6-15 1 x/d (GO) 

450 

200 (incoordination) Hornshaw et al. 1986 

ortho Tyl 1988a ortho 

Gd 6-15 1 x/d (GO) 

450 Tyl 1988a 

meta 

a 

Key to 

Figure 

21 22 23 24 25 26 

Species 

(Strain) 

Rat (SpragueDawley) Rat (SpragueDawley) Rabbit (New Zealand) Rabbit (New Zealand) Mink (NS) Ferret (NS) 

Reproductive 

27 Rat 

(SpragueDawley) 

28 Rat 

(SpragueDawley) 
151

450

128

100

131

100

136

100

272

1000

140

175

450

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

29 Rat 

(SpragueDawley) 

30 Rabbit 

(New Zealand) 

31 Rabbit 

(New Zealand) 

32 Rabbit 

(New Zealand) 

Developmental 

33 Rat 

(SpragueDawley) 

34 Rat 

(SpragueDawley) 

Exposure/ 

Duration/ 

Frequency 

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

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

Gd 6-15 1 x/d (GO) 

450 Tyl 1988a 

para 

Gd 6-18 1 x/d (GO) 

100 Tyl 1988b 

ortho 

Gd 6-18 1 x/d (GO) 

100 Tyl 1988b 

meta 

Gd 6-18 1 x/d (GO) 

100 Tyl 1988b 

para 

Gd 11 once (G) 

1000 Kavlock 1990 

para 

Gd 6-15 1 x/d (GO) 

175 450 (increased incidence of 

skeletal variations) 

Tyl 1988a ortho 
145

450

150

175

450

127

50 100

130

100

135

100

221

600

250

450

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

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

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

35 Rat 

(SpragueDawley) 

Gd 6-15 1 x/d (GO) 

450 Tyl 1988a 

meta 

36 Rat 

(SpragueDawley) 

Gd 6-15 1 x/d (GO) 

175 450 (increased incidence of 

skeletal variations) 

Tyl 1988a para 

37 Rabbit 

(New Zealand) 

Gd 6-18 1 x/d (GO) 

50 100 (delayed ossification) Tyl 1988b 

ortho 

38 Rabbit 

(New Zealand) 

Gd 6-18 1 x/d (GO) 

100 Tyl 1988b 

meta 

39 Rabbit 

(New Zealand) 

Gd 6-18 1 x/d (GO) 

INTERMEDIATE EXPOSURE Death 

40 Rat 

(SpragueDawley) 

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

100 

600 (death of 19 females and 

9 males out of 30 rats/sex) 

Tyl 1988b para EPA 1988b ortho 

41 Rat 

(CD) 

10 wk 5 d/wk (GO) 

450 (death of 8/25 males and 

5/25 females) 

Neeper-Bradley and Typara 
255

450

245

450

225

600600600600600600600600600175

600

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

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

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

42 Rat 

(CD) 

10 wk 5 d/wk (GO) 

450 (death of 7 males and 5 

females out of 25/sex) 

Neeper-Bradley and Tymeta 

43 Rat 

(CD) 

10-11 wk 5 d/wk (GO) 

450 (32-60% mortality in F0 

and F1 adults) 

Tyl and Neeper-Bradley ortho 

Systemic 

44 Rat 

(SpragueDawley) 

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

Resp 600 EPA 1988b 

ortho 

Cardio 600 Gastro 600 Hemato 600 Musc/skel Hepatic Renal 

600 

600 600 

Endocr 600 Ocular 600 Bd Wt 175 M 600 M (11% decreased body 

weight gain) 
217

175

600

60060050

175

600175

60050

600600175

600

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

a 

Key to Species Frequency NOAEL Less Serious Serious Reference 

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

45 Rat 

(SpragueDawley) 

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

Resp Cardio Gastro Hemato 

175 

600 

600 

50 F 

600 175 F 

Musc/skel Hepatic 

600 

175 600 

Renal Endocr Ocular Bd Wt 

600 600 175 M 

50

(epithelial metaplasia in 

trachea) 

(6-8% decreased red 

blood cell count and hemoglobin) 

(increased SGOT, SGPT; 

inflammation) 

(nephropathy) 

600 M (21% decreased body 

weight gain) 

EPA 1988c para 
210

45045045045045045045045045050

150

270

100010001000300

1000

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

Exposure/ 

Duration/ 

a 

Key to Species Frequency 

Figure (Strain) (Route) 

46 Rat 

(SpragueDawley) 

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

47 Rat 

(SpragueDawley) 

28 d 1 x/d (GO) 

System 

Resp 

Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr Ocular Bd Wt Hemato 

Hepatic Renal Bd Wt 

LOAEL 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

450 EPA 1988d 

meta 

450 

450 450 450 

450 450 

450 450 

50 M 150 M (22% decreased body 

weight gain) 

1000 Koizumi et al. 2003 

meta 

1000 1000 

300 1000 F (11% reduced final body 

weight) 
254

175

450

259

175

450

273

2610261026102610266

861

266

861

26102610881

2510

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

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

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

48 Rat 

(CD) 

10-11 wk 5 d/wk (GO) 

Bd Wt 175 M 450 M (13% reduced final body 

weight) 

Neeper-Bradley and Typara 

49 Rat 

(CD) 

10 wk 5 d/wk (GO) 

Bd Wt 175 M 450 M (15% decreased final 

body weight) 

Neeper-Bradley and Tymeta 

50 Rat 

(Fischer- 344) 

28 d ad lib (F) 

Resp 2610 M NTP 1992b 

ortho 

Cardio 2610 M Gastro 2610 M Musc/skel Hepatic 

2610 M 

266 M 861 M (25% increase absolute 

liver weight and 23% in relative) 

Renal 266 M 861 M (15% increase in 

absolute kidney weight and 13% in relative) 

Endocr 2610 M Dermal 2610 M Bd Wt 881 F 2510 F (12% reduction in final 

body weight) 
277

2470247024702470252

870

247024702470862

2310

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

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

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

51 Rat 

(Fischer- 344) 

28 d ad lib (F) 

Resp 2470 M NTP 1992b 

meta 

Cardio 2470 M Gastro 2470 M Musc/skel Hepatic 

2470 M 

252 M 870 M (16% increase in 

absolute and relative liver weight) 

Renal 2470 M Endocr 2470 M Dermal 2470 M Bd Wt 862 F 2310 F (16% reduced final body 

weight) 
281

242

770

21802180770

2060

218083

242

218021802180835

2060 2180

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

a 

Key to 

Figure 

Species 

(Strain) 

Frequency 

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

52 Rat 

(Fischer- 344) 

28 d ad lib (F) 

Resp 242 F 770 F (respiratory nasal 

epithelium hyperplasia) 

Cardio 2180 M Gastro 2180 M Hemato 770 F 2060 F (bone marrow 

hypocellularity) 

Musc/skel 2180 M Hepatic 83 F 242 F (16% increase absolute 

liver weight) 

Renal 2180 M Endocr 2180 M Dermal 2180 M Bd Wt 835 M 2060 F (16% reduced final body 

weight) 

Serious Reference 

(mg/kg/day) Chemical Form 

NTP 1992b para 

2180 M (30% reduced final body 

weight) 
285

27

95

260090

261

886

2570

2600261

877

260090

261

2600877

2600

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

Exposure/

Duration/

a Frequency Key to Species (Route) Figure (Strain) System 

53 Rat 28 d Resp ad lib (Fischer- 344) 

(F) 

Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr Dermal Bd Wt 

LOAEL 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

27 F 95 F (hyperplasia in NTP 1992b 

respiratory nasal mix epithelium) 

2600 M 

90 M 261 F (hyperplasia and 

hyperkeratosis of esophageal epithelium) 

886 M 2570 M (bone marrow 

hypocellularity) 

2600 M 

261 M 877 M (16-20% increase in 

absolute and relative liver weight) 

2600 M 

90 M 261 M (increased colloid in 

thyroid follicular cell) 

2600 M 

877 M 2600 M (18% reduced final body 

weight) 
305

202820282028513

1021

2028247

510

2028202820281021

2024

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

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

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

54 Rat 

(Fischer- 344) 

13 wk ad lib (F) 

Resp 2028 M NTP 1992b 

ortho 

Cardio 2028 M Gastro 2028 M Hemato 513 F 1021 F (bone marrow 

hypocellularity) 

Musc/skel Hepatic 

2028 M 

247 M 510 M (10-12% increase in 

absolute and relative liver weight) 

Renal 2028 M Endocr 2028 M Dermal 2028 M Bd Wt 1021 F 2024 F (15% reduced final body 

weight) 
309

123

20502050991

2014

2050241

486

2050254

509

2050991

2014

249

175

450

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

Exposure/ 

Duration/ 

a 

Key to Species Frequency 

Figure (Strain) (Route) 

55 Rat 13 wk 

ad lib (Fischer- 344) (F) 

56 Rat 10 wk 

5 d/wk (CD) (GO) 

System 

Resp 

Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr Dermal Bd Wt Bd Wt 

LOAEL 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

b

123 M (3/10 with minimal 

hyperplasia in the nasal respiratory epithelium vs. 0/10 in controls) 

NTP 1992b mix 

2050 F 2050 F 

991 M 2014 M (bone marrow 

hypocellularity) 

2050 F 

241 M 486 M (11-12% increase in 

absolute and relative liver weight) 

2050 F 

254 F 509 F (increased colloid in 

thyroid follicular cells) 

2050 F 

991 M 2014 M (17% reduced final body 

weight) 

175 M 450 M (10% decreased final 

body weight) 

Tyl and Neeper-Bradley ortho 
286

1650 448050005000500050005000500050001650

4480

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

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

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

57 Mouse 

(B6C3F1) 

28 d ad lib (F) 

Resp 1650 M 4480 M (rapid breathing) NTP 1992b 

ortho 

Cardio 5000 F Gastro 5000 F Musc/skel Hepatic Renal 

5000 F 5000 F 5000 F 

Endocr 5000 F Dermal 5000 F Bd Wt 1650 M 4480 M (28% reduction in final 

weight) 
289

651 208049404940494049404940494049401730

4710

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

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

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

58 Mouse 

(B6C3F1) 

28 d ad lib (F) 

Resp 651 F 2080 F (labored respiration) NTP 1992b 

meta 

Cardio 4940 F Gastro 4940 F Musc/skel Hepatic Renal 

4940 F 4940 F 4940 F 

Endocr 4940 F Dermal 4940 F Bd Wt 1730 M 4710 M (21% reduction in final 

weight) 
296

50

163

1590159015901590564

1590

159015901590469

1410

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System 

59 Mouse 

(B6C3F1) 

28 d ad lib (F) 

Resp 

Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr Dermal Bd Wt 

LOAEL 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

50 M 163 M (3/5 with minimal NTP 1992b 

hyperplasia of nasal para respiratory epithelium vs. 0/5 in controls) 

1590 F 1590 F 1590 F 1590 F 

564 F 1590 F (15-20% increase in 

relative and absolute liver weight) 

1590 F 1590 F 1590 F 

469 M 1410 M (17% reduced final body 

weight) 
301

200

604

473047301490

4530

4730604

1880

473047301490 4530471

1490 4530

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System 

60 Mouse 

(B6C3F1) 

28 d ad lib (F) 

Resp 

Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr Dermal Bd Wt 

LOAEL 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

NTP 1992b 

200 F 604 F (3/5 with minimal 

hyperplasia of the nasal mix respiratory epithelium vs. 0/5 in controls) 

4730 F 4730 F 1490 M 4530 M (bone marrow 

hypocellularity) 

4730 F 

604 F 1880 F (30% increase in 

absolute and relative liver weight) 

4730 F 4730 F 1490 M 4530 M (alopecia) 

471 M 1490 M (10% reduced final body 4530 M (27% reduction in final 

weight) weight) 
313

320532051723

2723

32053205794

1723

3205320532051723

2723

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System 

61 Mouse 

(B6C3F1) 

13 wk ad lib (F) 

Resp 

Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr Dermal Bd Wt 

LOAEL 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

NTP 1992b 

3205 F 

ortho 

3205 F 1723 M 2723 M (forestomach epithelial 

hyperplasia) 

3205 F 3205 F 

794 M 1723 M (17-19% increase in 

absolute and relative liver weight) 

3205 F 3205 F 3205 F 1723 M 2723 M (16% reduced final body 

weight) 
317

402

776

1693169316931693402

776

1693169316931693

240

1415

1415

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

Exposure/ 

Duration/ 

a 

Key to Species Frequency 

Figure (Strain) (Route) 

62 Mouse 

(B6C3F1) 

13 wk ad lib (F) 

63 Hamster 

(Golden Syrian) 

20 wk ad lib (F) 

System 

Resp 

Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr Dermal Bd Wt Gastro Hepatic 

LOAEL 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

402 M 776 M (4/10 with minimal 

hyperplasia of the nasal respiratory epithelium vs. 1/10 in controls) 

NTP 1992b mix 

1693 F 1693 F 1693 F 1693 F 

402 M 776 M (12% increase in 

absolute and relative liver weight) 

1693 F 1693 F 1693 F 1693 F 

1415 M (mild to moderate 

forestomach hyperplasia) 

Hirose et al. 1986 para 

1415 M 
22

400400400400400400

27

320320320320320

320

222

600

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

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

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

64 Ferret 

(NS) 

28 d (F) Resp 400 Hornshaw et al. 1986 ortho 

Cardio Hemato 

400 

400 

Hepatic Renal 

400 400 

Bd Wt 400 

65 Mink 

(NS) 

28 d (F) Resp 320 Hornshaw et al. 1986 ortho 

Cardio Hemato 

320 

320 

Hepatic Renal 

320 320 

Immuno/ Lymphoret 

66 Rat 

(SpragueDawley) 

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

Bd Wt 

600 

320 F (weight loss) 

EPA 1988b ortho 
214

600

207

450

274

2610

278

2470

282

2180

306

2028

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

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

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

67 Rat 

(SpragueDawley) 

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

600 EPA 1988c 

para 

68 Rat 

(SpragueDawley) 

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

450 EPA 1988d 

meta 

69 Rat 

(Fischer- 344) 

28 d ad lib (F) 

2610 M NTP 1992b 

ortho 

70 Rat 

(Fischer- 344) 

28 d ad lib (F) 

2470 M NTP 1992b 

meta 

71 Rat 

(Fischer- 344) 

28 d ad lib (F) 

2180 M NTP 1992b 

para 

72 Rat 

(Fischer- 344) 

13 wk ad lib (F) 

2028 M NTP 1992b 

ortho 
310

2050

323

2600

291

5000

292

4940

297

1590

302

4730

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

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

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

73 Rat 

(Fischer- 344) 

13 wk ad lib (F) 

2050 F NTP 1992b 

mix 

74 Rat 

(Fischer- 344) 

28 d ad lib (F) 

2600 M NTP 1992b 

mix 

75 Mouse 

(B6C3F1) 

28 d ad lib (F) 

5000 F NTP 1992b 

ortho 

76 Mouse 

(B6C3F1) 

28 d ad lib (F) 

4940 F NTP 1992b 

meta 

77 Mouse 

(B6C3F1) 

28 d ad lib (F) 

1590 F NTP 1992b 

para 

78 Mouse 

(B6C3F1) 

28 d ad lib (F) 

4730 F NTP 1992b 

mix 
314

3205

318

1693

223

175 600

215

175 600

208

150 450

271

300 1000

251

30 175

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

79 Mouse 

(B6C3F1) 

80 Mouse 

(B6C3F1) 

Neurological 

81 Rat 

(SpragueDawley) 

82 Rat 83 Rat 84 Rat 

(SpragueDawley) 

85 Rat 

(CD) 

Exposure/ 

Duration/ 

Frequency 

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

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

13 wk ad lib (F) 

3205 F NTP 1992b 

ortho 

13 wk ad lib (F) 

1693 F NTP 1992b 

mix 

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

175 600 (coma, convulsions) EPA 1988b 

ortho 

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

175 600 (convulsions, coma) EPA 1988c 

para 

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

150 450 (lethargy, tremors) EPA 1988d 

meta 

28 d 1 x/d (GO) 

300 1000 (salivation and tremors) Koizumi et al. 2003 

meta 

10 wk 5 d/wk (GO) 

30 175 (perioral wetness) Neeper-Bradley and Ty

para 
256

30 175

275

2610

280

2470

284

2180

307

2028

311

2050

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

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

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

86 87 

Rat (CD) 

10 wk 5 d/wk (GO) 

Rat (Fischer- 344) 

28 d ad lib (F) 

30 

2610 M 

175 (perioral wetness) Neeper-Bradley and Ty

meta NTP 1992b ortho 

88 Rat 

(Fischer- 344) 

28 d ad lib (F) 

2470 M NTP 1992b 

meta 

89 Rat 

(Fischer- 344) 

28 d ad lib (F) 

2180 M NTP 1992b 

para 

90 Rat 

(Fischer- 344) 

13 wk ad lib (F) 

2028 M NTP 1992b 

ortho 

91 Rat 

(Fischer- 344) 

13 wk ad lib (F) 

2050 F NTP 1992b 

mix 
324

2600

226

50 450

231

50 600

236

50 450

246

30 175

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

a 

Key to 

Figure 

Species 

(Strain) 

Frequency 

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

92 Rat 

(Fischer- 344) 

28 d ad lib (F) 

2600 M 

93 Rat 

(CD) 

13 wk 7 d/wk (GO) 

50 (CNS stimulation) 450 (convulsions) 

94 Rat 

(CD) 

13 wk 7 d/wk (GO) 

50 (CNS stimulation) 600 (convulsions) 

95 Rat 

(CD) 

13 wk 7 d/wk (GO) 

50 (hypoactivity) 450 (convulsions) 

96 Rat 

(CD) 

10-11 wk 5 d/wk 6-9 wk 7 d/wk (GO) 

30 175 (ataxia, hypoactivity) 

Reference Chemical Form 

NTP 1992b mix TRL 1986 ortho TRL 1986 para TRL 1986 meta Tyl and Neeper-Bradley ortho 
288

1650 4480

294

651 2080

300

469 1410

1590

303

1490 4530

315

3205

319

1693

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

97 Mouse 

(B6C3F1) 

98 Mouse 

(B6C3F1) 

99 Mouse 

(B6C3F1) 

100 Mouse 

(B6C3F1) 

101 Mouse 

(B6C3F1) 

102 Mouse 

(B6C3F1) 

Exposure/ 

Duration/ 

Frequency 

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

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

28 d ad lib (F) 

1650 M 4480 M (lethargy and tremors) NTP 1992b 

ortho 

28 d ad lib (F) 

651 F 2080 F (lethargy) NTP 1992b 

meta 

28 d ad lib (F) 

469 M 

c

1410 M (lethargy) 1590 F 

NTP 1992b para 

28 d ad lib (F) 

1490 M 4530 M (lethargy) NTP 1992b 

mix 

13 wk ad lib (F) 

3205 F NTP 1992b 

ortho 

13 wk ad lib (F) 

1693 F NTP 1992b 

mix 
224

600

216

600

209

450

253

450

258

450

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

Reproductive 

103 Rat 

(SpragueDawley) 

104 Rat 

(SpragueDawley) 

105 Rat 

(SpragueDawley) 

106 Rat 

(CD) 

107 Rat 

(CD) 

Exposure/ 

Duration/ 

Frequency 

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

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

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

600 EPA 1988b 

ortho 

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

600 EPA 1988c 

para 

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

450 EPA 1988d 

meta 

10 wk 5 d/wk (GO) 

450 Neeper-Bradley and Ty

para 

10 wk 5 d/wk (GO) 

450 Neeper-Bradley and Ty

meta 
276

2610

279

2470862

2310

283

2180770

2060

308

2028

312

2014254

509

325

2600

a 

Key to 

Figure 

108 109 110 111 112 113 

Exposure/

Duration/

Frequency Species (Route) (Strain) 

Rat(Fischer- 344)Rat(Fischer- 344)Rat(Fischer- 344)Rat(Fischer- 344)Rat(Fischer- 344)Rat(Fischer- 344)

28 d ad lib (F) 28 d ad lib (F) 28 d ad lib (F) 13 wk ad lib (F) 13 wk ad lib (F) 28 d ad lib (F) 

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

LOAEL 

System 

NOAEL 

(mg/kg/day) 

2610 M 2470 M 

c

862 F 

2180 M 

c

770 F 

2028 M 2014 M 

c

254 F 

2600 M 

Less Serious Serious 

(mg/kg/day) (mg/kg/day) 

2310 F (mild uterine atrophy in 

4/5 females) 

2060 F (mild to moderate uterine 

atrophy) 

509 F (lengthened estrous

cycle)

Reference Chemical Form 

NTP 1992b ortho NTP 1992b meta NTP 1992b para NTP 1992b ortho NTP 1992b mix NTP 1992b mix 
248

450

321

660

290

4480763

1670

293

47102080

4940

298

1590

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

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

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

114 Rat 

(CD) 

10 wk 5 d/wk (GO) 

450 Tyl and Neeper-Bradley 

ortho 

115 Mouse 

(CD-1) 

14 wk ad lib (F) 

660 NTP 1992a 

ortho 

116 Mouse 

(B6C3F1) 

28 d ad lib (F) 

4480 M 

c

763 F 

1670 F (mild atrophy of the 

uterus in 5/5 mice) 

NTP 1992b ortho 

117 Mouse 

(B6C3F1) 

28 d ad lib (F) 

4710 M 

c

2080 F 

4940 F (mild to moderate 

atrophy of mammary gland, uterus, and ovaries) 

NTP 1992b meta 

118 Mouse 

(B6C3F1) 

28 d ad lib (F) 

1590 F NTP 1992b 

para 
304

4730

316

27231663

3205

320

1693

322

1390

1682

30

105

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

119 Mouse 

(B6C3F1) 

120 Mouse 

(B6C3F1) 

121 Mouse 

(B6C3F1) 

122 Mouse 

(CD-1) 

123 Mink 

(NS) 

Exposure/ 

Duration/ 

Frequency 

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

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

28 d ad lib (F) 

4730 F NTP 1992b 

mix 

13 wk ad lib (F) 

2723 M 

c

1663 F 

3205 F (lengthened estrous 

cycle) 

NTP 1992b ortho 

13 wk ad lib (F) 

1693 F NTP 1992b 

mix 

14 wk ad lib (F) 

1390 1682 (increased cumulative 

days to litter) 

NTP 1992c mix 

6 mo (F) 105 Hornshaw et al. 1986 ortho 
269

30

100

252

175

450

257

175

450

247

175

450

326

1390

1682

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

Developmental 

124 Rat 

(SpragueDawley) 

125 Rat 

(CD) 

126 Rat 

(CD) 

127 Rat 

(CD) 

128 Mouse 

(CD-1) 

Exposure/ LOAEL 

Duration/ 

Frequency 

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

18 d 1 x/d pnd 4-21 (GO) 

30 100 (tremors under contact 

stimulus) 

10 wk 5 d/wk (GO) 

175 450 (reduced viability of F1 

generation) 

10 wk 5 d/wk (GO) 

175 450 (reduced viability of F1 

generation) 

10 wk 5 d/wk (GO) 

175 450 (reduced viability of F1 

generation) 

14 wk ad lib (F) 

1390 1682 (decreased number of 

live pups/litter) 

Reference Chemical Form 

Koizumi et al. 2003 meta Neeper-Bradley and Typara Neeper-Bradley and Tymeta Tyl and Neeper-Bradley ortho NTP 1992c mix 
327

123

720720720230

720

230

720

720720720230

720

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

LOAEL 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

123 M (17/50 with minimal NTP 2008 

hyperplasia of the nasal mixed respiratory epithelium, 3/50 in controls) 

720 M 720 M 720 M 230 M 720 M (increased incidence of 

eosinophilic foci) 

230 M 720 M (transitional epithelial 

hyperplasia of the renal pelvis) 

720 M 720 M 720 M 230 M 720 M (final body weight 

reduced 15%) 

Exposure/ 

Duration/ 

a 

Key to Species Frequency 

Figure (Strain) (Route) 

CHRONIC EXPOSURE Systemic 

129 Rat 2 yr 

ad lib (Fischer- 344) (F) 

System 

Resp 

Cardio Gastro Musc/skel Hepatic Renal Endocr Dermal Ocular Bd Wt 
332

100

104010401040300

1040

1040

100

10401040100

300 1040

328

720

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

Exposure/ 

Duration/ 

a 

Key to Species Frequency 

Figure (Strain) (Route) 

130 Mouse 2 yr 

ad lib (B6C3F1) (F) 

Immuno/ Lymphoret 

131 Rat 2 yr 

ad lib (Fischer- 344) (F) 

System 

Resp 

Cardio Gastro Musc/skel Hepatic Renal Endocr Dermal Ocular Bd Wt 

LOAEL 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

d

100 F (42/50 with minimal 

bronchiolar hyperplasia, 0/50 in controls) 

NTP 2008 mixed 

1040 F 1040 F 1040 F 

300 F 1040 F (increased eosinophilic 

foci) 

1040 F 

100 F (follicular degeneration in 

thyroid gland) 

1040 F 1040 F 

100 F 300 F (11% reducton in final 

body weight) 

1040 F (24% reduction in final 

body weight) 

720 M NTP 2008 

mixed 
333

1040

329

720

335

1040

330

720

334

1040

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

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

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

132 Mouse 

(B6C3F1) 

2 yr ad lib (F) 

1040 F NTP 2008 

mixed 

Neurological 

133 Rat 

(Fischer- 344) 

2 yr ad lib (F) 

720 M NTP 2008 

mixed 

134 Mouse 

(B6C3F1) 

2 yr ad lib (F) 

1040 F NTP 2008 

mixed 

Reproductive 

135 Rat 

(Fischer- 344) 

2 yr ad lib (F) 

720 M NTP 2008 

mixed 

136 Mouse 

(B6C3F1) 

2 yr ad lib (F) 

1040 F NTP 2008 

mixed 
336

1040

Table 3-1 Levels of Significant Exposure to Cresols - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

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

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

Cancer 

137 Mouse 

(B6C3F1) 

2 yr ad lib (F) 

NTP 2008 mixed 

1040 F (CEL: squamous cell 

papilloma in forestomach, 0/50, 1/50, 1/49, 10/50) 

a The number corresponds to entries in Figure 3-1. b Used to derive an intermediate-duration oral minimal risk level (MRL) of 0.1 mg/kg/day; the MRL was derived by dividing the BMDL10 of 13.94 mg/kg/day by an u100 (10 for animal to human extrapolation and 10 to protect sensitive subpopulations). c Differences in levels of health effects and cancer effects between male and females are not indicated in Figure 3-1. Where such differences exist, only the levels most sensitive gender are presented. d Used to derive a chronic-duration oral minimal risk level (MRL) of 0.1 mg/kg/day; the MRL was derived by dividing the LOAEL of 100 mg/kg/day by an uncertainty for animal to human extrapolation, 10 for use of a LOAEL, and 10 for human variability). ad lib = ad libitum; Bd Wt = body weight; BMDL = below minimum detectable limits; Cardio = cardiovascular; CNS = central nervous system; d = day(s); Endocr = efeed; F = Female; (G) = gavage; Gastro = gastrointestinal; gd = gestational day; (GO) = gavage in oil; (GW) = gavage in water; hemato = hematological; hr = hour(sImmuno/Lymphoret = immunological/lymphoreticular; LD50 = lethal dose, 50% kill; LOAEL = lowest-observed-adverse-effect level; M = male; mo = month(s); Muscmusculo/skeletal; NOAEL = no-observed-adverse-effect level; NS = not specified; occup = occupational; pnd = post-natal day; Resp = respiratory; SGOT = serum goxaloacetic transaminase; SGPT = serum glutamic pyruvic transaminase; x = time(s); wk = week(s) 
Death 

Respiratory Hepatic Ocular Body Weight 

Figure 3-1 Levels of Significant Exposure to Cresols - Oral
	

Acute (≤14 days)
	

Systemic 

CRESOLS

mg/kg/day 

10000 

9m m

8m o

2r m

3r p

1r o

7m mx 1000 

11r o 12r m 13r p 11r o 12r m 13r p 11r o 12r m 13r p

4r m
 

6r p
 

11r o 12r m 13r p 11r o 12r m 13r p

5r o
 

100
	 10h p 14h o 15h m 16h p 14h o 15h m 16h p

14h o 15h m 16h p 14h o 15h m 16h p

11r o

10 

14h o 15h m 16h p 14h o 15h m 16h p

1 

3. HEALTH EFFECTS

c-Cat 

d-Dog

r-Rat

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

f-Ferret e-Gerbil 

s-Hamster 

g-Guinea Pig 

m-meta 

o-ortho n-Mink

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 

mx-mixed 

p-para 

66
Other 

Neurological Reproductive Developmental 

10000 

Figure 3-1 Levels of Significant Exposure to Cresols - Oral (Continued)

Acute (≤14 days) 

Systemic 

CRESOLS

mg/kg/day 

1000 33r p

17r o 18r p

11r o 12r m 13r p 19r m 20r o 21r m 22r p 27r o 28r m 29r p 34r o 35r m 36r p

26f o

13r p 20r o 21r m 22r p 34r o 36r p

100 25n o 30h o 31h m 32h p 37h o 38h m 39h p

25n o 17r o 18r p 19r m 23h o 24h p 37h o

10 

23h o 24h p

1 

3. HEALTH EFFECTS

c-Cat 

d-Dog

r-Rat

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

f-Ferret e-Gerbil 

s-Hamster 

g-Guinea Pig 

m-meta 

o-ortho n-Mink

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 

mx-mixed 

p-para 

67
Death 

Respiratory Cardiovascular Gastrointestinal 

Figure 3-1 Levels of Significant Exposure to Cresols - Oral (Continued)
 

Intermediate (15-364 days)
	

Systemic 

CRESOLS

mg/kg/day 

10000 

57m o 57m o 58m m 58m m

60m mx 60m mx 57m o

61m o 61m o

50r o 61m o50r o 53r mx

58m m 51r m 51r m

52r p

55r mx

57m o 54r o 54r o

61m o 62m mx 62m mx

59m p 59m p

63s p

1000
	 62m mx
 52r p

58m m

60m mx 40r o 44r o 45r p 44r o 45r p 44r o

41r p 42r m 43r o 46r m 46r m

62m mx 64f o 64f o

65n o 65n o

52r p
 

60m mx
 

59m p
 45r p

55r 

100 53r mx

59m p

53r mx

10 

1 

0.1 

3. HEALTH EFFECTS

c-Cat 

d-Dog

r-Rat

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

f-Ferret e-Gerbil 

s-Hamster 

g-Guinea Pig 

m-meta 

o-ortho n-Mink

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 

mx-mixed 

p-para 

68
Gastrointestinal 

Hematological Musculoskeletal Hepatic 

Figure 3-1 Levels of Significant Exposure to Cresols - Oral (Continued)
 

Intermediate (15-364 days)
	

Systemic 

CRESOLS

mg/kg/day 

10000 

57m o 57m o 58m m

60m mx 60m mx

61m o 61m o

50r o 50r o 53r mx 53r mx 51r m 51r m

52r p 52r p

52r p 55r mx 55r mx 54r o 54r o 55r mx

62m mx 62m mx

59m p 59m p

60m mx 63s p

54r o 1000 47r m 55r mx

53r mx

52r p

45r p 44r o 44r o 45r p

54r o

46r m 46r m 46r m

64f o

65n o 65n o

53r mx

45r o

100 53r mx

45r o

10 

1 

0.1 

3. HEALTH EFFECTS

c-Cat 

d-Dog

r-Rat

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

f-Ferret e-Gerbil 

s-Hamster 

g-Guinea Pig 

m-meta 

o-ortho n-Mink

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 

mx-mixed 

p-para 

69
Hepatic 

Renal Endocrine 

Figure 3-1 Levels of Significant Exposure to Cresols - Oral (Continued)
 

Intermediate (15-364 days)
	

Systemic 

CRESOLS

mg/kg/day 

10000 

57m o 57m o 58m m 58m m 58m m

60m mx 60m mx

61m o 61m o

50r o 53r mx 51r m

52r p

55r mx 54r o

60m mx

61m o 62m mx 62m mx

59m p 59m p 59m p

1000 47r m 47r m

53r mx 51r m 50r o 50r o

61m o 62m mx

60m mx 44r o 45r p 44r o 44r o 45r p

59m p

54r o

55r mx

46r m 46r m 46r m

62m mx 64f o 64f o

65n o

50r o 50r o 53r mx 51r m 54r o 52r p 55r mx

45r p

100 52r p

45r p

10 

1 

0.1 

3. HEALTH EFFECTS

c-Cat 

d-Dog

r-Rat

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

f-Ferret e-Gerbil 

s-Hamster 

g-Guinea Pig 

m-meta 

o-ortho n-Mink

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 

mx-mixed 

p-para 

70
Endocrine 

Dermal Ocular Body Weight 

Figure 3-1 Levels of Significant Exposure to Cresols - Oral (Continued)
 

Intermediate (15-364 days)
	

Systemic 

CRESOLS

mg/kg/day 

10000 

57m o 58m m

58m m

60m mx 60m mx 57m o

61m o

61m o

50r o 53r mx 51r m 51r m

52r p 52r p

55r mx 54r o 54r o

58m m 61m o 62m mx 62m mx 57m o

59m p

60m mx 60m mx 59m p

1000 47r m

44r o 45r p 44r o 45r p

55r mx

60m mx 59m p

46r m

65n o

47r m

53r mx 55r mx

44r o 45r p

46r m

100 53r mx

46r m

10 

1 

0.1 

3. HEALTH EFFECTS

c-Cat 

d-Dog

r-Rat

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

f-Ferret e-Gerbil 

s-Hamster 

g-Guinea Pig 

m-meta 

o-ortho n-Mink

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 

mx-mixed 

p-para 

71
Body Weight 

Immuno/Lymphor Neurological 

10000 

Figure 3-1 Levels of Significant Exposure to Cresols - Oral (Continued)
 

Intermediate (15-364 days)
	

Systemic
	

CRESOLS

mg/kg/day 

75m o 76m m

78m mx 100m mx 97m o

79m o 101m o

69r o 53r mx 74r mx 50r o 70r m

51r m

52r p 71r p

98m m 52r p 73r mx 72r o 54r o 55r mx

80m mx 102m mx 97m o

77m p

100m mx 99m p

54r o 1000 55r mx

50r o 53r mx 51r m

52r p

98m m

66r o 67r p 81r o

99m p

48r p 49r m 56r o 68r m

64f o

48r p 49r m 56r o 81r o

100 

10 

1 

0.1 

3. HEALTH EFFECTS

c-Cat 

d-Dog

r-Rat

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

f-Ferret e-Gerbil 

s-Hamster 

g-Guinea Pig 

m-meta 

o-ortho n-Mink

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 

mx-mixed 

p-para 

72
Neurological 

Reproductive 

Figure 3-1 Levels of Significant Exposure to Cresols - Oral (Continued)

Intermediate (15-364 days) 

mg/kg/day 

10000 

117m m

119m mx

120m o

87r o 108r o 92r mx 88r m

109r m

89r p

117m m

116m 

91r o

mx 90r o

121m mx 122m mx 120m o

118m p

122m mx
 

1000
	 84r m

109r m

110r p 116m o

115m o

82r p 94r p 103r o 104r p

83r m 93r o 95r m 105r m 106r p 107r m

84r m

82r p 85r p 86r m 96r o

83r m
 

100
	 123n o

93r o 94r p 95r m

85r p 86r m 96r o

10 

1 

0.1 

CRESOLS

3. HEALTH EFFECTS

c-Cat 

d-Dog

r-Rat

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

f-Ferret e-Gerbil 

s-Hamster 

g-Guinea Pig 

m-meta 

o-ortho n-Mink

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 

mx-mixed 

p-para 

73
Reproductive 

Developmental 

Figure 3-1 Levels of Significant Exposure to Cresols - Oral (Continued)
 

Intermediate (15-364 days)
	 CRESOLS

mg/kg/day 

10000 

113r mx

110r p 111r o

128m mx

128m mx

1000 

112r mx

114r o 125r p 126r m 127r o

112r mx

125r p 126r m 127r o

100 124r m

124r m

10 

1 

0.1 

3. HEALTH EFFECTS

c-Cat 

d-Dog

r-Rat

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

f-Ferret e-Gerbil 

s-Hamster 

g-Guinea Pig 

m-meta 

o-ortho n-Mink

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 

mx-mixed 

p-para 

74
Respiratory 

Cardiovascular Gastrointestinal Musculoskeletal Hepatic Renal Endocrine Dermal Ocular Body Weight Immuno/Lymphor Neurological Reproductive Cancer * 

 

 

Figure 3-1 Levels of Significant Exposure to Cresols - Oral (Continued)

Chronic (≥365 days) 

Systemic 

CRESOLS

mg/kg/day 

10000 

1000 

100 

10 

1 

0.1 

130m mx 130m mx 130m mx 130m mx 130m mx 130m mx 130m mx 130m mx 132m mx 134m mx 136m mx 137m mx 

129r mx 129r mx 129r mx 129r mx 129r mx 129r mx 129r mx 129r mx 129r mx 131r mx 133r mx 135r mx 

130m mx 130m mx 

129r mx 129r mx 129r mx 

129r mx 

130m mx 130m mx 130m mx 

*Doses represent the lowest dose tested per study that produced a tumorigenic 

response and do not imply the existence of a threshold for the cancer endpoint. 

3. HEALTH EFFECTS

c-Cat 

d-Dog

r-Rat

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

f-Ferret e-Gerbil 

s-Hamster 

g-Guinea Pig 

m-meta 

o-ortho n-Mink

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 

mx-mixed 

p-para 

75
 

 

 

 

 

 

 

 

 

 

 

 

CRESOLS 76 

3. HEALTH EFFECTS 

B6C3F1 mice also exhibited nasal changes following dietary treatment with p-cresol or the m/p-cresol 

mixture for 28 days (NTP 1992b). For p-cresol, the LOAEL in males and females was 163 and 

207 mg/kg/day, respectively, with corresponding NOAELs of 50 and 60 mg/kg/day. For the mixture, the 

respective LOAELs in males and females were 4,530 and 604 with corresponding NOAELs of 1,490 and 

200 mg/kg/day. Male mice dosed with 4,530 mg/kg/day of the cresol mixture also exhibited a significant 

increase in bronchiolar hyperplasia. In the 13-week study in mice with o-cresol and the cresol mixture, 

hyperplasia of the respiratory nasal epithelium was seen in males treated with 776 mg/kg/day, but not 

402 mg/kg/day, and in females at 1,693 mg/kg/day, but not 923 mg/kg/day of the cresol mixture. No 

such lesions were seen in mice dosed with o-cresol in doses of up to 2,700–3,200 mg/kg/day for 

13 weeks. 

The respiratory system was also a target for m/p-cresol in male Fischer rats (females not tested) and 

female B6C3F1 mice (males not tested) in a 2-year dietary study (NTP 2008). In rats, the response with 

the lowest threshold appeared to be hyperplasia of the respiratory epithelium of the nose, which occurred 

with an incidence of 3/50, 17/50, 31/50, and 47/50 in rats dosed with mean time-weighted average (TWA) 

doses of 0, 70, 320, and 720 mg/kg/day, respectively; severity was minimal to mild. The incidence in the 

low-dose group (17/50, 34%) was very similar to that reported in the 13-week study (NTP 1992b) (3/10, 

30%) in male rats that received mean daily doses of 123 mg/kg/day during the 13 weeks of the study. 

Since the mean dose received by the low-dose rats during the first 13 weeks of the 2-year study was 

123 mg/kg/day (from a table in the NTP report providing mean weekly doses during the first 13 weeks), it 

means that the lesions were already established by week 13 of the 2-year study and did not increase in 

severity. Therefore, the value listed as a LOAEL in the LSE table is 123 mg/kg/day, the true mean dose 

during the first 13 weeks, rather than the low TWA dose of 70 mg/kg/day for the entire duration of the 

chronic study. Other nasal lesions observed in rat included squamous metaplasia of the nasal epithelium, 

hyperplasia of the goblet cell, and inflammation of the nose. In mice, the most sensitive response was 

hyperplasia of the bronchiole of the lung, occurring with incidences of 0/50, 42/50, 44/49, and 47/50 in 

mice dosed with mean TWA doses of 0, 100, 300, and 1,040 mg/kg/day, respectively. Hyperplasia of the 

bronchiole of the lung was not a lesion reported in mice in the 13-week NTP (1992b) study. Dose-related 

elevated incidences of respiratory epithelium hyperplasia were also reported at 300 and 1,040 mg/kg/day 

in mice (NTP 2008). The LOAEL of 100 mg/kg/day for bronchiole hyperplasia in female mice exposed 

for 2 years was used to derive a chronic-duration oral MRL for cresols. 
 

 

 

 

 

 

 

 

 

 

 

CRESOLS 77 

3. HEALTH EFFECTS 

Pregnant rats (Tyl 1988b) and rabbits (Tyl 1988a) exposed to o-, p-, and m-cresol were reported to have 

audible respiration and labored breathing. These effects may be of a neurologic origin, rather than a 

direct effect on the respiratory system (Section 3.2.2.4). 

Cardiovascular Effects. A woman who swallowed 500–750 mL of a concentrated cresol mixture 

exhibited tachycardia with polymorphic ventricular extra-systoles shortly after exposure (Labram and 

Gervais 1968). This was followed within 26 hours by ventricular fibrillation and cardiac arrest. 

In rats exposed to o-cresol (EPA 1988b), p-cresol (EPA 1988c), or m-cresol (EPA 1988d) at levels up to 

600 mg/kg/day for 13 weeks by gavage, histological examination of the heart revealed no changes that 

indicated an adverse effect on the heart. A 28-day dietary study reported no significant histopathological 

effects in the heart or aorta of rats dosed with up to approximately 2,600 mg/kg/day of each cresol isomer 

or with a mixture (58/41%) of m- and p-cresol (NTP 1992b). A similar lack of effects was reported in 

rats following 13 weeks of treatment with approximately 2,000 mg/kg/day of o-cresol or the cresol 

mixture in the diet (NTP 1992b). 

In mice, treatment for 28 days with up to approximately 5,000 mg/kg/day of o-cresol, m-cresol, or the 

m/p-cresol mixture or 1,590 mg/kg/day of p-cresol had no significant effect on the gross or microscopic 

appearance of the heart or aorta (NTP 1992b). Similar effects were reported in mice dosed with up to 

3,200 mg/kg/day of o-cresol or 1,693 mg/kg/day of the m/p-cresol mixture for 13 weeks (NTP 1992b). 

The data available suggest that the cardiovascular system is not a sensitive target for cresol toxicity. 

No gross or microscopic alterations were observed in the heart of male rats and female mice administered 

mean doses of up to 720 and 1,040 mg/kg/day m/p-cresol, respectively, via the diet for 2 years (NTP 

2008). 

Gastrointestinal Effects. Mouth and throat burns, abdominal pain, and vomiting were common 

symptoms of cresol poisoning among 52 patients who drank between 4 and 120 mL of a disinfectant 

containing 25–50% mixed cresols (Isaacs 1922). These effects were also seen in a man who swallowed 

approximately 250 mL of a concentrated cresol mixture in a suicide attempt (Jouglard et al. 1971). 

Hemorrhagic degeneration of the pancreas was the cause of death in a woman who swallowed a 

disinfectant suspected of containing cresols. It was not clear, however, if this effect was actually 

produced by the disinfectant or was due to a pre-existing condition (little disinfectant was taken) (Dellal 

1931). In a man who ingested an unknown amount of cresol, gastrointestinal endoscopy performed 
 

 

 

 

 

 

 

 

CRESOLS 78 

3. HEALTH EFFECTS 

10 hours later revealed dark red corrosive injuries on the esophagus and stomach wall (Hayakawa 2002). 

Diffuse erosions in the gastrointestinal tract have been observed in subjects who drank saponated cresol 

solutions containing about 50% cresol (Bruce et al. 1976; Kamijo et al. 2003; Wu et al. 1998; Yashiki et 

al. 1990). 

Rats exposed to cresols in doses up to 600 mg/kg/day for 13 weeks by gavage in corn oil did not have 

gastrointestinal lesions (EPA 1988b, 1988c, 1988d). However, dietary administration of p-cresol in doses 

of approximately 1,415 mg/kg/day for 20 weeks produced an increased incidence of mild and moderate 

hyperplasia of the forestomach of hamsters (Hirose et al. 1986). Rats treated for 28 days with up to 

approximately 2,200–2,400 mg/kg/day of each cresol isomer in the diet showed no significant alterations 

in the gastrointestinal tract. However, doses ≥260 mg/kg/day of m/p-cresol mixture (58/41%) induced 

hyperplasia and hyperkeratosis of the esophageal epithelium in male and female rats (NTP 1992b); the 

NOAEL was 90–95 mg/kg/day. Higher doses (2,500–2,600 mg/kg/day) also induced hyperplasia in the 

epithelium of the forestomach. Longer treatments (13 weeks) with approximately 2,000 mg/kg/day of 

o-cresol or the cresol mixture had no significant effect on the gastrointestinal tract of rats (NTP 1992b). 

In mice, doses of up to near 5,000 mg/kg/day of o-, m-, or an m/p-cresol mixture had no significant effect 

on the gastrointestinal tract (NTP 1992b). Similarly, no increased incidence of gastrointestinal tract 

lesions occurred with up to 1,590 mg/kg/day of p-cresol; the highest dietary dose of p-cresol was not 

estimated by NTP (1992b) since it killed all the mice, but was probably near 5,000 mg/kg/day. The 

13-week studies in mice provided no evidence of gastrointestinal alterations following doses of 

approximately 1,500–1,700 mg/kg/day of the cresol mixture, but doses of 2,700–3,200 mg/kg/day of 

o-cresol induced minimal forestomach epithelial hyperplasia (NTP 1992b). 

No gross or microscopic alterations were observed in the gastrointestinal tract of male rats and female 

mice administered mean doses of up to 720 and 1,040 mg/kg/day m/p-cresol, respectively, via the diet for 

2 years (NTP 2008). 

Hematological Effects. Hematological effects were described in four people who ingested cresolcontaining products. One woman swallowed 100 mL of a disinfectant containing 50% mixed cresols, 

receiving a dose of approximately 1 g/kg (Chan et al. 1971). Methemoglobin was seen in the blood after 

1.5 hours, but was no longer detected after 6 hours. Some Heinz bodies were observed after 6 hours, but 

these disappeared after 2 days. A second woman who drank 250 mL of disinfectant (roughly 2 g/kg) 

experienced more serious effects. Methemoglobinemia and markedly reduced glutathione levels were 
 

 

 

 

 

 

 

CRESOLS 79 

3. HEALTH EFFECTS 

seen after 7 hours. After 3 days, the patient developed severe hemoglobinemia and hemoglobinuria, 

indicating that massive intravascular hemolysis had occurred; extensive Heinz body formation had also 

taken place. The patient died the next day, apparently from thrombus formation and kidney failure 

secondary to acute intravascular hemolysis (Chan et al. 1971). A marked increased in methemoglobin 

also was observed in a man 15 hours after he swallowed a cresol solution of unknown concentration 

(Minami et al. 1990). Heinz body formation, hemoglobinemia, hemoglobinuria, and hemolytic anemia 

were also seen in a man who drank 100 mL of penetrating oil containing 12% mixed cresols, receiving a 

dose of about 170 mg/kg (Cote et al. 1984). In addition, a man who swallowed approximately 250 mL of 

a concentrated cresol mixture developed severe hemolytic anemia during the second week following 

ingestion (Jouglard et al. 1971). Isaacs (1922) did not find abnormalities in the blood of any of 

52 patients who had ingested cresols, but the specific analyses performed were not reported. Low platelet 

count, which could have been due to disseminated intravascular congestion, was described in a man who 

drank an undetermined amount of cresol (Hayakawa 2002). Leukocytosis and hemolysis were reported in 

a man who drank 300 mL of a 50% saponated solution of cresols (Wu et al. 1998). The hematological 

effects of cresols appear to be due to both an oxidant effect on the cell contents and a direct effect on the 

red cell membrane (Chan et al. 1971). 

Severe hematological effects, such as those reported in humans, were not observed in animals exposed to 

cresols possibly because acute high-dose studies in animals did not investigate hematological effects. 

Mild decreases in red blood cells, blood hemoglobin concentrations, and hematocrit were reported in rats 

dosed by gavage with 175 mg/kg of p-cresol for 13 weeks (EPA 1988c), but the effects were not 

produced by the other isomers (EPA 1988b, 1988d). Mild and inconsistent changes in red blood cell 

count seen in mink were of questionable significance (Hornshaw et al. 1986). A study in rats reported 

increased incidence of moderate bone marrow hypocellularity following 28 days of a diet that provided 

approximately 2,000–2,200 mg/kg/day of p-cresol or 2,500–2,600 mg/kg/day of an m/p-cresol mixture 

(NTP 1992b); the NOAELs were near 800 mg/kg/day. Blood parameters were not monitored in this 

28-day study. Bone marrow hypocellularity also was reported in female rats treated with 

≥1,021 mg/kg/day of o-cresol for 13 weeks and in male and female rats treated with approximately 

2,100 mg/kg/day of m/p-cresol (NTP 1992b). Hematological parameters in the 13-week studies with both 

o-cresol and m/p-cresol were unremarkable, although there was a tendency to hemoconcentration in 

animals receiving the highest doses (>2,000 mg/kg/day) early in the study. 

Male mice treated for 28 days with 4,530 mg/kg/day of m/p-cresol showed mild to moderate bone marrow 

hypocellularity, but no such effect was seen at 1,490 mg/kg/day or in females treated with up to 
 

 

 

 

 

 

 

 

CRESOLS 80 

3. HEALTH EFFECTS 

4,730 mg/kg/day (NTP 1992b). Bone marrow hypocellularity also was observed in all mice treated with 

the highest dietary level of p-cresol, 30,000 ppm (NTP did not estimate daily doses at this level since all 

mice died), but not at estimated doses near 1,500 mg/kg/day (NTP 1992b). No significant hematological 

effects were reported in mice in the 13-week study with o-cresol (2,700–3,200 mg/kg/day) or m/p-cresol 

(1,500–1,700 mg/kg/day). 

Musculoskeletal Effects. No studies were located regarding musculoskeletal effects in humans 

following oral exposure to cresols. 

Cresols had no effect on the incidence of gross or microscopic lesions in the muscle or bone of rats given 

doses up to 600 mg/kg/day by gavage for 13 weeks (EPA 1988b, 1988c, 1988d). The NTP (1992b) 

dietary studies examined sternebrae and femurs of rats and mice and found no significant gross or 

microscopic alterations in these tissues. Maximal doses of all the cresols tested were approximately 

2,000–2,600 mg/kg/day in rats (28-day and 13-week studies), 4,500–5,000 mg/kg/day (28-day study in 

mice), 2,700–3,200 mg/kg/day (13-week in mice with o-cresol), and 1,500–1,600 mg/kg/day (13-week in 

mice with m/p-cresol). Skeletal muscle was not examined in the NTP (1992b) study. No gross or 

microscopic alterations were observed in bone (not specified) of male rats and female mice administered 

mean doses of up to 720 and 1,040 mg/kg/day m/p-cresol, respectively, via the diet for 2 years (NTP 

2008). 

Hepatic Effects. Moderate fatty degeneration was found in the liver of a woman who died after 

drinking 250 mL of a disinfectant, which contained 50% mixed cresols (Chan et al. 1971). The liver 

appeared normal in another woman who died after ingesting a disinfectant suspected of containing cresols 

(Dellal 1931). In a more recent case report, a woman who ingested 70 mL of a 50% cresol solution 

experienced a marked increase in serum aspartate aminotransferase (AST) and alanine aminotransferase 

(ALT) activities (more than 100-fold increase) after a 24-hour asymptomatic period (Hashimoto et al. 

1998). The hepatocellular injury was not severe enough to cause liver descompensation and there was no 

evidence of hepatic encephalopathy. Blood work done 22 days after the poisoning episode revealed 

normal serum AST and ALT values. Similar results have been reported in other cases of acute oral 

intoxication with cresols (Bruce et al. 1976; Hayakawa 2002; Kamijo et al. 2003). 

Following oral exposure of animals to cresols by gavage, increased relative liver weight and increased 

serum transaminase levels were reported. Relative liver weights in rats increased following gavage 

exposure to doses of 450 mg/kg/day of cresols during pregnancy (Tyl 1988a). Longer-term exposure to 
 

 

 

 

 

 

 

 

 

CRESOLS 81 

3. HEALTH EFFECTS 

levels as low as 5 mg/kg/day had the same effect in mink and ferrets (Hornshaw et al. 1986). However, in 

these studies, changes in liver weight were not accompanied by histological changes and may not have 

indicated adverse effects. Increased levels of serum AST and ALT were seen in female rats given 

600 mg/kg/day of p-cresol by gavage for 13 weeks and appeared to be correlated with the presence of 

hepatic inflammation (EPA 1988c). 

Dietary administration of approximately ≥700–800 mg/kg/day of o-, m-, or m/p-cresol to rats for 28 days 

resulted in increases (>10%) in absolute and relative liver weight (NTP 1992b). The NOAELs were 

approximately 260–270 mg/kg/day. For p-cresol, doses of 242 mg/kg/day caused a 16% increase in 

absolute liver weight, whereas 83 mg/kg/day produced an increase of only 6%. No significant gross or 

microscopic changes were seen in the liver in this series of experiments. In the 13-week rat study with 

o-cresol, absolute and relative liver weights were increased in males and females at ≥510 mg/kg/day. 

Clinical chemistry tests showed an increase in serum bile acids in females at ≥1,021mg/kg/day and in 

males at 2,028 mg/kg/day. However, there was no indication of liver necrosis or cholestasis, as serum 

ALT, 5'-nucleosidase, and alkaline phosphatase activities were not significantly affected. Furthermore, 

there were no gross or histological alterations in the liver even with the highest doses of 2,028 mg/kg/day. 

Similar results were reported for the m/p-cresol mixture. Clinical chemistry tests showed some alterations 

in enzymes activities, but no clear pattern or dose-relationships. Bile acids in serum were increased at 

study termination in females at 2,050 mg/kg/day and in males at 241 and 991 mg/kg/day. Gross necropsy 

and histopathology of the liver did not reveal any significant treatment-related alterations. Administration 

of mean doses of 720 mg m/p-cresol mixture/kg/day for 2 years male Fisher rats produced a significant 

increase in the incidence of eosinophilic foci in the liver of (NTP 2008). In rats dosed with 

≤230 mg/kg/day, the incidences were comparable to controls. 

In mice, treatment in the diet with up to 5,000 mg/kg/day (the highest dose tested) of o- or m-cresol for 

28 days caused mortality but did not induce significant histopathological effects on the liver (NTP 

1992b). Doses of 1,590 mg/kg/day of p-cresol increased absolute and relative liver weight (15–20%) in 

female mice, but caused no histopathology; no significant changes were seen at 564 mg/kg/day. Mice 

treated with a higher dose level of p-cresol (30,000 ppm in food, but doses were not estimated by NTP) 

that killed 9/10 mice by day 5 showed liver necrosis. The m/p-cresol mixture, at ≥1,880 mg/kg/day, 

increased absolute and relative liver weight in female mice, but there were no histological alterations even 

at the higher dose level of 4,730 mg/kg/day. In the 13-week study, o-cresol increased liver weight in 

males at ≥1,723 mg/kg/day, whereas the m/p-cresol mixture had the same effect at ≥776 mg/kg/day (NTP 

1992b). There were no treatment-related alterations in liver morphology in the 13-week study or in 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CRESOLS 82 

3. HEALTH EFFECTS 

clinical chemistry tests that would have indicated alterations in liver function. The only effect reported in 

female mice in the 2-year NTP (2008) bioassay with m/p-cresol was an increased incidence of 

eosinophilic foci in the liver at the 1,040 mg/kg/day dose level, but not at ≤300 mg/kg/day. 

While some hepatic parameters were affected by treatment with some cresol isomers, the overall database 

does not suggest that the liver is a particularly sensitive target for cresol toxicity. 

Renal Effects. Massive eosinophilic necrosis was found in the proximal tubule of a woman who died 

after drinking 500–750 mL of a concentrated cresol mixture (Labram and Gervais 1968). This effect was 

considered by the investigators to have occurred before death, and may have been due to the toxic action 

of cresol. Renal effects in a woman who drank 250 mL of a disinfectant (50% mixed cresols), and later 

died, consisted of fibrin clumps in the glomeruli and a moderate level of tubular degeneration, which 

could have been due to intravascular thrombosis (Chan et al. 1971). Mild congestion of the kidney was 

reported in a second woman who died following consumption of a disinfectant suspected of containing 

cresols (Dellal 1931). Greatly elevated blood urea nitrogen (BUN) and serum creatinine were reported in 

another case of ingestion of a saponated cresol solution (Wu et al. 1998). Among 52 patients with 

diagnosed cresol poisoning, there were signs of renal toxicity, including darkly colored urine, renal 

irritation, and in a few cases, reduced phenolsulphonephthalein output (Isaacs 1922). Bruce et al. (1976) 

observed lipofuscin deposits in the cells of many of the proximal convoluted tubules in a woman who 

died 2 hours after ingestion of an unknown quantity of Lysol®. 

Exposure of male rats to 600 mg/kg/day by gavage for 13 weeks induced a slight increase, which did not 

appear to be dose related, in the incidence of histological changes characteristic of chronic nephropathy 

(EPA 1988c). No such changes were seen in rats treated with comparable doses of o- or m-cresol and 

urinalyses provided no evidence for altered kidney function with any of the cresol isomers. Exposure of 

rats to m-, p-, or an m/p-cresol mixture in the diet for 28 days in doses of up to 2,200–2,600 mg/kg/day 

did not induce treatment-related alterations in gross or microscopic appearance of the kidneys (NTP 

1992b). Doses of ≥861 mg/kg/day of o-cresol increased absolute and relative kidney weight (13–15%) in 

male rats, whereas 266 mg/kg/day produced changes in kidney weight of ≤5% relative to controls. 

Kidney weight in females was not significantly altered. Histological examination of the kidneys did not 

reveal lesions. The 13-week study found no renal alterations in rats dosed with up to approximately 

2,000 mg/kg/day of o-cresol or the m/p-cresol mixture (NTP 1992b). In both cases, urinalyses provided 

no evidence of renal injury. Increased incidence of transitional epithelium hyperplasia (minimal to mild 

severity) of the renal pelvis (8/50 compared with 0/50 in controls) was reported in male rats that received 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

CRESOLS 83 

3. HEALTH EFFECTS 

mean doses of 720 mg m/p-cresol/kg/day for 2 years through the diet (NTP 2008); the NOAEL was 

230 mg/kg/day. 

Renal effects in mice in the NTP (1992b) studies were limited to kidney necrosis, which was observed in 

mice that died after being exposed to a diet containing 30,000 ppm p-cresol (dosed were not calculated by 

NTP, but were probably in the range of 4,000–5,000 mg/kg/day). p-Cresol in doses of 1,590 mg/kg/day 

had no significant effect on the kidneys in the 28-day study. The other isomers and the m/p-cresol 

mixture did not induce adverse kidney effects in doses of up to 4,000–4,500 mg/kg/day and neither did 

o-cresol (2,700–3,200 mg/kg/day) or m/p-cresol (1,500–1,700 mg/kg/day) in the 13-week study. No 

significant gross or microscopic alterations were reported in the kidneys from female mice dosed with up 

to 1,040 mg m/p-cresol in the diet for 2 years (NTP 2008). 

The available studies in animals do not suggest that the kidneys are a sensitive target for cresol toxicity. 

Endocrine Effects. No studies were located regarding endocrine effects in humans following oral 

exposure to cresols. 

Studies in animals do not suggest that endocrine organs are susceptible targets for cresol toxicity. A 

13-week gavage study with the three cresol isomers reported no treatment-related gross or microscopic 

alterations in the pituitary, thyroid, adrenals, and pancreas of rats treated with doses of up to 

450 mg/kg/day of m-cresol or 600 mg/kg/day of o- and p-cresol (EPA 1988b, 1988c, 1988d). 

Both the 28-day and 13-week dietary studies with cresol isomers and a cresol mixture conducted by NTP 

(1992b) examined the adrenals, pancreas, thyroid, parathyroid, and pituitary of rats and mice. The only 

treatment-related effect observed was an increase in colloid within the thyroid gland follicles in rats 

treated with an m/p-cresol mixture for 28 days and 13 weeks. The LOAEL and NOAEL in the 28-day 

were approximately 270 and 90 mg/kg/day, respectively, in males and females. In the 13-week study, the 

LOAEL for females was 509 mg/kg/day and for males 991 mg/kg/day; the corresponding NOAELs were 

254 and 486 mg/kg/day. NTP (1992b) noted that the biological significance of the lesions is uncertain 

because it was not seen with the individual isomers, nor was it associated with follicular cell hypertrophy 

and/or hyperplasia. The highest doses of the individual isomers tested in the rats were in the range of 

2,000–2,400 mg/kg/day. Mice treated for 28 days received doses of up to 5,000 mg/kg/day of cresols. 

Mice treated for 13 weeks received up to 3,200 mg/kg/day of o-cresol and 1,700 mg/kg/day of m/p-cresol. 

Administration of up to 720 mg m/p-cresol/kg/day to male rats via the diet for 2 years did not cause any 
 

 

 

 

 

 

 

 

 

 

CRESOLS 84 

3. HEALTH EFFECTS 

significant alteration in gross or microscopic appearance of the pancreas or of the adrenal, pituitary, 

parathyroid, and thyroid glands (NTP 2008). In female mice, administration of m/p-cresol for 2 years 

induced a significant increase in the incidence of mild follicular degeneration of the thyroid in all dosed 

groups (7/48, 24/48, 24/49, and 21/50 in the 0, 100, 300, and 1,040 mg/kg/day dose groups, respectively) 

(NTP 2008). The LOAEL of 100 mg/kg/day for mild follicular degeneration of the thyroid gland in 

female mice was used to derive a chronic oral MRL for cresols. 

Dermal Effects. No studies were located regarding dermal effects in humans following oral exposure 

to cresols. 

There were no gross or histological alterations in the skin of rats treated with cresol isomers for 28 days 

or 13 weeks in doses of 2,100–2,600 mg/kg/day (NTP 1992b). In mice, the only significant treatmentrelated effect was alopecia in males and females treated with 4,530 and 4,730 mg/kg/day, respectively, of 

m/p-cresol for 28 days. No such effect occurred in mice treated with up to 3,205 mg/kg/day of o-cresol or 

1,693 mg/kg/day of m/p-cresol for 13 weeks. No exposure-related histopathological changes in the skin 

were observed in rats and mice exposed up to 720 or 1,040 mg/kg/day, respectively, m/p-cresol in the diet 

for 2 years (NTP 2008). 

Ocular Effects. No studies were located regarding ocular effects in humans following oral exposure 

to cresols. 

Pregnant rabbits repeatedly given ≥50 mg/kg/day of the cresol isomers during gestation were found to 

have significant amounts of ocular discharge, some of which may have been due to hemorrhaging (Tyl 

1988b), but no gross or microscopic lesions of the eye were found in rats given cresols in doses of up to 

450 mg/kg/day of m-cresol or 600 mg/kg/day of o- or p-cresol by oral gavage for 13 weeks (EPA 1988b, 

1988c, 1988d; TRL 1986). No exposure-related histopathological changes in the eye were observed in 

rats and mice exposed up to 720 or 1,040 mg/kg/day, respectively, m/p-cresol in the diet for 2 years (NTP 

2008). 

Body Weight Effects. No studies were located regarding body weight effects in humans following 

oral exposure to cresols. 

In animals, a common response to oral exposure to cresols, particularly in oral gavage studies, was 

decreased growth, often associated with decreased food consumption (EPA 1988b, 1988c, 1988d; 
 

 

 

 

 

 

 

 

 

 

 

CRESOLS 85 

3. HEALTH EFFECTS 

Hornshaw et al. 1986; Koizumi et al. 2003; Neeper-Bradley and Tyl 1989a, 1989b; TRL 1986; Tyl 1988a; 

Tyl and Neeper-Bradley 1989). The effects were usually more pronounced during the early stages of the 

studies and, in almost all cases, were associated with significant reductions in food consumption. It 

should be mentioned also that the dose levels that reduced food consumption and body weight gain 

induced neurological effects such as hypoactivity, incoordination, and tremors. Reduced body weight 

gain was also observed in the dietary studies in rats and mice, generally at the highest dose levels tested 

(i.e., ≥2,000 mg/kg/day) and was almost always associated with reduced food consumption (NTP 1992b). 

Whether the latter is due to poor palatability or other reason is unknown since pair-fed groups were not 

utilized. 

Final body weight in male rats treated with 720 mg m/p-cresol/kg/day in the diet for 2 years was 15% 

lower than in controls (NTP 2008), the NOAEL was 230 mg/kg/day. In the same study, final body 

weight of female mice dosed with 300 and 1,040 mg m/p-cresol/kg/day was reduced 11 and 24%, 

respectively, relative to controls. Food consumption was not significantly affected in either species 

throughout the study. 

Metabolic Effects. Marked metabolic acidosis (pH 7.058) was reported in a man who drank an 

undetermined amount of cresol (Hayakawa 2002). Similar observations were made by Kamijo et al. 

(2003) in a man who drank about 150 mL of a saponated cresol solution containing about 50% cresol. No 

explicit mention of adverse metabolic effects was made in other reports of ingestion of cresols. 

There is no evidence that cresols induced metabolic effects at the doses tested in the animal studies 

available. 

3.2.2.3 Immunological and Lymphoreticular Effects 

No studies were located regarding immunological effects in humans following oral exposure to cresols. 

The only immunological end points examined in animal studies were weight and gross and microscopic 

appearance of the spleen and thymus and occasionally, lymph nodes. Spleen weight was unaffected by 

28-day exposure to o-cresol in the feed at doses up to 400–720 mg/kg/day in ferrets and 320– 

480 mg/kg/day in mink (Hornshaw et al. 1986). Similarly, no effect was seen on spleen weight in a 

reproduction study in which mink were exposed to 105–190 mg/kg/day of o-cresol in the feed for 

6 months (Hornshaw et al. 1986). Absolute spleen weight was decreased (approximately 18%) in male 
 

 

 

 

 

 

 

 

 

 

 

 

CRESOLS 86 

3. HEALTH EFFECTS 

rats given 600 mg/kg/day of p-cresol by gavage for 13 weeks, but relative spleen weight was unaffected 

and no lesions were found; neither weight nor morphological appearance of the thymus or mandibular 

lymph nodes was significantly altered (EPA 1988c). No significant alterations were seen in these tissues 

in rats given similar doses of o- or m-cresol (EPA 1988b, 1988d). Studies in rats and mice exposed to 

cresol isomers and a mixture of m- and p-cresol for 28 days or 13 weeks also found no significant 

histological alterations in lymphoreticular organs and tissues (NTP 1992b). Maximal doses in mice were 

near 5,000 mg/kg/day and in rats near 2,600 mg/kg/day. Similar results were reported in the 2-year study 

with maximal doses of m/p-cresol of 720 mg/kg/day in male rats and 1,040 mg/kg/day in female mice 

(NTP 2008). None of the studies mentioned above conducted tests of immunocompetence. 

These NOAELs for lymphoreticular effects are presented in Table 3-1 and plotted in Figure 3-1. 

3.2.2.4 Neurological Effects 

Neurological effects have frequently been noted following oral exposure to cresols. A woman who drank 

approximately 100 mL of a disinfectant, which consisted of roughly 50% mixed cresols, was 

semiconscious after 2 hours. A second woman, who swallowed about 250 mL of the same disinfectant, 

was in a deep coma after 2 hours. She regained consciousness 10 hours later (Chan et al. 1971). A 

woman who swallowed 500–750 mL of a concentrated cresol mixture fell into a deep coma within 1 hour 

(Labram and Gervais 1968). Coma was a common feature of cresol poisoning among 52 patients studied 

by Isaacs (1922). The author noted that unconsciousness could occur very soon after exposure and could 

last 14 hours or more. 

A series of neurological effects, including hypoactivity and lethargy, excess salivation, dyspnea, 

incoordination, muscle twitches and tremors, convulsions, and coma, have been reported in animals 

acutely exposed to cresols by gavage (Deichmann and Witherup 1944; Hornshaw et al. 1986; TRL 1986; 

Tyl 1988a, 1988b). The lowest dose at which neurological effects were reported was 50 mg/kg/day, 

which produced hypoactivity and labored respiration in pregnant female rabbits repeatedly dosed with 

o- or p-cresol during gestation (Tyl 1988b). In rats, effects such as hypoactivity and rapid labored 

respiration were seen at 50 mg/kg/day for all three isomers (TRL 1986). More serious effects, such as 

convulsions, were seen at 450 mg/kg/day or higher (TRL 1986). 

A detailed oral neurotoxicity study of intermediate duration was performed on rats using all three cresol 

isomers administered by gavage for 13 weeks (TRL 1986). A host of clinical observations indicative of 
 

 

 

 

 

 

 

CRESOLS 87 

3. HEALTH EFFECTS 

neurotoxicity (including hypoactivity, rapid labored respiration, excessive salivation, and tremors) was 

reported at doses of 50 mg/kg/day or higher for all three isomers. However, the results of a number of 

neurobehavioral tests designed to assess demeanor and motor and reflex activity (testing was done 6 times 

throughout the 13 weeks prior to dosing) showed only sporadic differences with controls and/or 

alterations were not dose-related. No brain weight changes or histopathologic lesions in the brain or other 

nervous tissues were found for any isomer. Convulsions were reported at 450 mg/kg/day or higher (TRL 

1986). More recently, salivation and tremors were reported in young rats treated by gavage with 

1,000 mg/kg/day m-cresol, but not 300 mg/kg/day, for 28 days (Koizumi et al. 2003). Other studies of 

prolonged oral exposure to cresols by gavage had similar findings (EPA 1988b, 1988c, 1988d; Hornshaw 

et al. 1986; Neeper-Bradley and Tyl 1989a, 1989b; Tyl and Neeper-Bradley 1989). The only 

intermediate-duration gavage studies to determine NOAEL values for neurological effects were the 

two-generation reproduction studies in rats (Neeper-Bradley and Tyl 1989a, 1989b; Tyl and NeeperBradley 1989). Neurological NOAEL values of 30 mg/kg/day were reported for all three cresol isomers 

in these studies. However, tests for neurobehavioral effects were not performed. None of the studies 

mentioned above observed treatment-related gross or microscopic alterations in the brain, spinal cord, or 

sciatic nerve. 

In the intermediate-duration dietary studies in rats and mice conducted by NTP (1992b), the most 

common adverse clinical signs of neurological impairment observed were lethargy and occasionally 

tremors, and were seen only in mice. Male and female mice dosed with 4,400–5,000 mg/kg/day of 

o-cresol for 28 days showed lethargy and tremors; these signs were not seen at 1,700 mg/kg/day. Female 

mice, but not males, exposed to 2,080 mg/kg/day of m-cresol for 28 days also exhibited lethargy. 

Lethargy was also seen in male mice dosed with 1,410 mg/kg/day of p-cresol and in male and female 

mice dosed with 4,530–4,730 mg/kg/day of the m/p-cresol mixture. These results indicate that, at least 

for the end points of lethargy and tremors, mice are more sensitive than rats. Gross and microscopic 

examination of the brain of rats and mice in the NTP (1992b) study did not reveal any treatment-related 

lesions. Similar negative observations were reported in male rats and female mice dosed with up to 

720 and 1,040 mg/kg/day m/p-cresol, respectively, in the diet for 2 years (NTP 2008). 

The highest NOAEL values and all reliable LOAEL values for neurological effects in each species and 

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

 

 

 

 

 

 

 

 

CRESOLS 88 

3. HEALTH EFFECTS 

3.2.2.5 Reproductive Effects 

No studies were located regarding reproductive effects in humans following oral exposure to cresols. 

Developmental toxicity studies in which pregnant rats (Tyl 1988a) and rabbits (Tyl 1988b) were exposed 

to cresols by gavage during gestation reported no effects on the reproductive parameters investigated 

(e.g., number of ovarian corpora lutea, number of implantation sites, number of viable fetuses), even at 

maternally toxic doses. Two-generation reproduction studies in rats (up to 450 mg/kg/day of each isomer 

by gavage) and mink (up to 105 mg/kg/day dietary o-cresol for 6 months) also failed to detect adverse 

effects on reproductive function or lesions in reproductive tissues (Hornshaw et al. 1986; Neeper-Bradley 

and Tyl 1989a, 1989b; Tyl and Neeper-Bradley 1989). These studies also included doses producing 

maternal toxicity. No histopathological lesions and only mild organ weight changes of doubtful 

significance were reported in the reproductive organs of animals exposed to up to 600 mg/kg/day of 

cresols by gavage for 13 weeks (EPA 1988b, 1988c, 1988d). 

The NTP (1992b) study evaluated changes in weight and histopathology of reproductive organs of males 

and females, as well as sperm parameters and duration of the estrous cycle, of Fisher-344 rats and 

B6C3F1 mice exposed via the diet to cresol isomers and to a mixture of m- and p-cresol. The only 

significant effects observed in rats in 28-day experiments included mild to moderate uterine atrophy in 

females dosed with 2,310 mg/kg/day of m-cresol or 2,060 mg/kg/day of p-cresol. In the 13-week study, 

doses of ≥509 of m/p-cresol lengthened the estrous cycle in females and doses of 1,024 and 

2,050 mg/kg/day induced minimal to mild uterine atrophy. No significant effects were seen in male rats 

dosed with up to 2,200–2,600 mg/kg/day of cresols. In mice, 28 days of dosing with 1,670 mg/kg/day of 

o-cresol produced mild atrophy of the uterus, whereas 4,940 mg/kg/day of m-cresol induced mild to 

moderate atrophy of the mammary glands, uterus, and ovaries. Neither p-cresol nor the m/p-cresol 

mixture adversely affected the reproductive end points in mice in the 28-day study. A 13-week regimen 

of 3,205 mg/kg/day of o-cresol lengthened the estrous cycle in mice, and doses of up to 1,500– 

1,700 mg/kg/day of m/p-cresol did not induce any significant alterations in males or females. Treatment 

of male rats and female mice with up to 720 and 1,040 m/p-cresol/kg/day, respectively, in the diet for 

2 years did not induce any significant alterations in the gross or microscopic morphology of reproductive 

organs (NTP 2008). 

Two studies have evaluated the effects of o-cresol and a mixture of m/p-cresol on reproductive function 

end points in CD-1 mice using a continuous breeding protocol (NTP 1992a, 1992c). End points evaluated 
 

 

 

 

 

 

 

CRESOLS 89 

3. HEALTH EFFECTS 

included fertility, mean number of litters per pair, live litter size, weight and histopathology of 

reproductive organs, vaginal cytology, and sperm parameters. Both studies started with a 14-week 

cohabitation period in which males and females received the test material in the diet. The highest doses 

during this period were 660 mg/kg/day for o-cresol and 1,682 mg/kg/day for m/p-cresol. No significant 

alterations were observed with o-cresol at any stage of the study. However, the highest dose of 

m/p-cresol significantly decreased the number of live pups/litter and increased the cumulative days to 

litter; a dose level of 1,390 mg/kg/day was a NOAEL. To determine which sex was the affected sex 

during the cohabitation period, a 1-week crossover mating trial was conducted, but the results indicated 

that either sex could have been affected. In neither study was fertility affected. In addition, sperm 

parameters and gross and microscopic morphology of reproductive organs were not affected by treatment 

with the cresols. 

NOAEL and LOAEL values for reproductive effects derived from these studies are recorded in Table 3-1 

and plotted in Figure 3-1. 

3.2.2.6 Developmental Effects 

No studies were located regarding developmental effects in humans following oral exposure to cresols. 

Developmental effects have been reported in animals given cresols, but only at maternally toxic doses. 

Maternal effects in rats dosed by gavage on gestation days 6–15 (audible respiration, reduced body weight 

gain, reduced food consumption, ataxia, tremors, and hypoactivity) occurred at 450 mg/kg/day (Tyl 

1988a). At this dose, both o- and p-cresol produced slight fetotoxicity (increased incidences of dilated 

lateral ventricles in the brain and minor skeletal variations, respectively), but had no effect on 

malformation incidence or gestation parameters (e.g., the number of implantations per litter or fetal body 

weight per litter). No effects of any kind were seen at lower doses. m-Cresol had no effect on gestation 

parameters, fetotoxicity, or the incidence of malformations, even at maternally toxic doses (Tyl 1988a). 

An additional study in which rats were dosed only on gestation day 11 with up to 1,000 mg/kg of p-cresol 

reported no significant effects on post-implantation loss, litter size, viability, or postnatal weight of the 

offspring, even when maternal toxicity was evident at doses ≥410 mg/kg (Kavlock 1990). Slight maternal 

toxicity in the form of decreased weight gain was also observed at the 1,682 mg/kg/day dose level. In 

rabbits dosed on gestation days 6–18 with up to 100 mg/kg/day of each isomer, maternal effects, such as 

audible respiration, ocular discharge, and hypoactivity, were seen following exposure to o- or p-cresol at 

50 mg/kg/day (Tyl 1988b). At 100 mg/kg/day, o-cresol produced slight fetotoxicity (increased incidences 
 

 

 

 

 

 

 

 

 

 

 

 

CRESOLS 90 

3. HEALTH EFFECTS 

of subepidermal hematoma on the head and poorly ossified sternebrae), but no other effects at any dose. 

Neither p- nor m-cresol produced any developmental effects in this study (Tyl 1988b). 

Fetotoxicity was also observed at parentally-toxic doses in two-generation reproduction studies. Rats 

treated by gavage with 450 mg/kg/day of o- and p-cresol for 10 weeks before mating produced F1 

offspring that had reduced body weight 4–6 weeks after birth. This dose also produced overt toxicity in 

the parents (Neeper-Bradley and Tyl 1989a; Tyl and Neeper-Bradley 1989). In contrast to the results of 

the developmental toxicity studies discussed above, m-cresol was the most potent developmental toxicant 

among the cresols in the two-generation studies. This isomer reduced pup survival during lactation when 

administered by gavage at the high dose of 450 mg/kg/day (Neeper-Bradley and Tyl 1989b). Parental 

toxicity manifested as reduced body weight gain was reported at the low dose of 30 mg/kg/day. 

Decreased number of live pups/litter (F1) was reported in a 2-generation reproductive study in mice 

exposed to 1,682 mg/kg/day of an m/p-cresol mixture for 14 weeks, but not at 1,390 mg/kg/day (NTP 

1992c). 

The comparative susceptibility of newborn and young rats to m-cresol was studied by Koizumi et al. 

(2003). Neonates were treated by gavage with up to 300 mg/kg/day m-cresol from postnatal day 4 to 21, 

whereas 5-week-old rats were dosed with up to 1,000 mg/kg/day for 28 days. Most neonates exhibited 

deep respiration, hypersensitivity on handling, and tremors under contact stimulus at 300 mg/kg/day. 

Final body weight also was significantly reduced at this dose level. Tremors also occurred in few 

neonates at 100 mg/kg/day, but no clinical signs were seen at 30 mg/kg/day. No significant alterations 

were reported in clinical chemistry, hematology, gross or microscopic pathology (major organs and 

tissues), or physical development and sexual maturation. In the young rats, clinical signs such as 

salivation, tremors, and reduced weight gain were observed at 1,000 mg/kg/day, but there were no 

significant alterations in clinical chemistry, hematology, or histopathological changes at this dose level. 

A dose level of 300 mg/kg/day m-cresol was a NOAEL in 5-week-old rats, whereas 30 mg/kg/day was a 

NOAEL in neonates. 

NOAEL and LOAEL values derived from these studies are recorded in Table 3-1 and plotted in 

Figure 3-1. 

3.2.2.7 Cancer 

No studies were located regarding cancer in humans following oral exposure to cresols. 
 

 

 

 

 

 

 

 

 

 

 

 

CRESOLS 91 

3. HEALTH EFFECTS 

In an intermediate-duration study, a diet that provided approximately 1,415 mg/kg/day of p-cresol for 

20 weeks produced an increased incidence of mild to moderate forestomach hyperplasia in hamsters, 

suggesting that this cresol isomer may have the potential to act as a promoter of forestomach 

carcinogenesis in this species (Hirose et al. 1986). However, promotion potential was not tested directly. 

However, p-cresol did not produce forestomach hyperplasia in rats treated with the chemical in the diet 

(2% or approximately 2,140 mg/kg/day) for an unspecified period of time (Altmann et al. 1986), but rats 

are generally less sensitive than hamsters to inducers of forestomach lesions. In mice, simultaneous 

administration of 1 mg of o-cresol and 1 mg of benzo[a]pyrene twice daily by gavage for up to 30 weeks 

increased the incidence and malignancy of forestomach tumors and shortened their latency relative to 

benzo[a]pyrene alone (Yanysheva et al. 1993). However, administration of o-cresol before or after 

benzo[a]pyrene decreased the carcinogenicity of the latter substance. 

A recently conducted 2-year feeding study with a mixture of m- and p-cresol (60%/40%) found no 

evidence of neoplastic effects in male Fischer-344 rats (females were not tested) that received mean doses 

of up to 720 mg/kg/day of the test material (NTP 2008). However, NTP (2008) determined that a slight 

nonstatistically significant increase (p=0.121) in the incidence of renal tubule adenoma constituted an 

equivocal finding. In female B6C3F1 mice (males were not tested) that received mean doses of 

approximately 0, 100, 300, or 1,040 mg/kg/day, the incidence of squamous cell papilloma of the 

forestomach was significantly increased (p<0.001) in the high dose group (0/50, 1/50, 1/49, 10/50). No 

other significant neoplastic effect was reported in mice. 

The EPA (IRIS 2008) has classified the three cresol isomers in Group C, “possible human carcinogens,” 

based on inadequate human data and limited data in animals (the assessment is dated 10/89). The 

assessment was based on an increased incidence of skin papillomas in mice in an initiation-promotion 

study and on the fact that the cresol isomers produced positive results in genetic toxicity studies both 

alone and in combination. Based on updated guidelines for carcinogen assessment (EPA 2005c), cresols 

fall in the category of chemicals for which there is “inadequate information to assess carcinogenic 

potential.” EPA did not derive quantitative estimates of carcinogenic risk for cresols (IRIS 2008). EPA’s 

assessment of cresols’ carcinogenicity was conducted before the results of the NTP (2008) study became 

available. 
 

 

 

 

 

 

 

 

 

 

CRESOLS 92 

3. HEALTH EFFECTS 

3.2.3 Dermal Exposure 

3.2.3.1 Death 

There are two case reports of people who died following dermal exposure to cresols. In one case, a 

1-year-old baby had 20 mL of a cresol derivative (90% mixed cresols in water) spilled on his head, 

covering about 7% of his body surface. The baby died in coma within 4 hours (Green 1975). Assuming 

the baby weighed approximately 10 kg, the lethal dose in this case can be estimated to have been roughly 

2 g/kg if all the cresol was absorbed, but was probably less since the infant’s head was washed with soap 

and water 5 minutes after the spill. In the other case, a man fell into a vat of a cresylic acid derivative 

(cresol content unknown) and suffered burns on 15% of the body surface. Anuria was evident after 

36 hours and blood urea content rose steadily during the following days. The patient fell into a coma on 

the 9th day, and death occurred on the 10th day (Cason 1959). Dermal absorption of cresol also appears 

to have been responsible for the death of a man who worked with an antiseptic solution containing 

concentrated mixed cresols for 2 days prior to becoming ill (Larcan et al. 1974). 

In rabbits, dermal LD50 values for cresols were 890, 300, 2,830, and 2,000 mg/kg for o-, p-, m-, and mixed 

cresols, respectively (Vernot et al. 1977). These values are recorded in Table 3-2. Based on these 

LD50 values, p-cresol appears to be more toxic dermally than o-cresol, with m-cresol being the least toxic 

of the three isomers. 

3.2.3.2 Systemic Effects 

No studies were located regarding cardiovascular or musculoskeletal effects in humans or animals 

following dermal exposure to cresols. 

Respiratory Effects. Hemorrhagic pulmonary edema was found at necropsy in a 1-year-old baby 

who died after having 20 mL of a cresol-containing product spilled on his head (Green 1975). Liu et al. 

(1999) reported a case of a woman who suffered acute respiratory failure following chemical burns 

caused by skin contact with a saponated solution of mixed cresols. 

No studies were located regarding respiratory effects in animals following dermal exposure to cresols. 

Gastrointestinal Effects. No lesions were found in the gastrointestinal tract of a 1-year-old baby 

who died after dermal exposure to a cresol-containing product (Green 1975). 
59 mg/kg/day

60 mg/kg/day61 mg/kg/day62 mg/kg/day63 mg/kg/day64 mg/kg/day65 mg/kg/day66 mg/kg/day

Table 3-2 Levels of Significant Exposure to Cresols - Dermal 

Exposure/ 

Duration/ 

LOAEL 

Species 

(Strain) 

Frequency 

(Route) System NOAEL Less Serious Serious 

Reference Chemical Form 

ACUTE EXPOSURE 

Death 

Rabbit 1 d 

24 hr/d 2000 

mg/kg/day 

(LD50) Vernot et al. 1977 

mix 

Rabbit 1 d 

24 hr/d 890 

mg/kg/day 

(LD50) Vernot et al. 1977 

ortho 

Rabbit 1 d 

24 hr/d 2830 

mg/kg/day 

(LD50) Vernot et al. 1977 

meta 

Rabbit 1 d 

24 hr/d 300 

mg/kg/day 

(LD50) Vernot et al. 1977 

para 

Systemic 

Rabbit 1 d 

4 hr/d Dermal 147 

mg/kg/day 

(skin corrosion) Vernot et al. 1977 

mix 

Rabbit 1 d 

4 hr/d Dermal 147 

mg/kg/day 

(skin corrosion) Vernot et al. 1977 

ortho 

Rabbit 1 d 

4 hr/d Dermal 147 

mg/kg/day 

(skin corrosion) Vernot et al. 1977 

meta 

Rabbit 1 d 

4 hr/d Dermal 147 

mg/kg/day 

(skin corrosion) Vernot et al. 1977 

para 

d = day(s); hr = hour(s); LD50 = lethal dose, 50% kill; LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level 
 

 

 

 

 

 

 

 

CRESOLS 94 

3. HEALTH EFFECTS 

No studies were located regarding gastrointestinal effects in animals following dermal exposure to 

cresols. 

Hematological Effects. Hematological effects in a man apparently exposed to cresol dermally while 

working with an antiseptic solution containing concentrated mixed cresols, included methemoglobinemia 

with massive hemolysis and the presence of numerous large Heinz bodies in the blood (Larcan et al. 

1974). Similar effects have been reported following oral exposure to cresols (see Section 3.2.2.2). 

No studies were located regarding hematological effects in animals following dermal exposure to cresols. 

Hepatic Effects. Necropsy revealed extensive centrilobular to mid-zonal liver necrosis in a 1-year-old 

baby who had 20 mL of a cresol derivative spilled on his head (Green 1975). 

No studies were located regarding hepatic effects in animals following dermal exposure to cresols. 

Renal Effects. A 1-year-old baby who died after a cresol derivative was spilled on his head had 

congested and swollen kidneys that were damaged by tubular necrosis (Green 1975). A man who fell into 

a vat containing a cresylic acid derivative developed anuria after 36 hours and experienced a steady 

increase in blood urea levels for 10 days until he died (Cason 1959). Anuria was also seen in a man who 

apparently absorbed cresol through the skin while working with an antiseptic solution containing 

concentrated mixed cresols (Larcan et al. 1974). Acute polyuric renal failure was described in a man who 

accidentally spilled with m-cresol onto both legs and face (Evers et al. 1994). 

No studies were located regarding renal effects in animals following dermal exposure to cresols. 

Dermal Effects. Corrosive damage to the skin has been reported in humans dermally exposed to 

cresols (Cason 1959; Green 1975; Herwick and Treweek 1933; Klinger and Norton 1945; Pegg and 

Campbell 1985). In one patient, disfiguring scars remained visible 1 year after exposure (Herwick and 

Treweek 1933). However, no reaction to cresol was noted when it was applied to the skin as a 1% 

solution in alcohol (Reimann 1933). 

Cresols are also strong skin irritants in animals. All three cresol isomers, either alone or in combination, 

are severely irritating to rabbit skin, producing visible and irreversible tissue destruction (Vernot et al. 
 

 

 

 

 

 

 

 

 

 

CRESOLS 95 

3. HEALTH EFFECTS 

1977). Some cresylic acids produced induration and discoloration of the skin in rats (Campbell 1941). 

All reliable LOAEL values for acute dermal effects in rabbits are recorded in Table 3-2. 

In a study of intermediate duration, dermal application of 0.5% p-cresol for 6 weeks produced permanent 

depigmentation of the skin and hair of mice (Shelley 1974). A caustic effect on the skin was noted in one 

strain of mouse, but not another. Neither o- nor m-cresol produced any color change in the mice. The 

investigator suggested that only p-cresol was active because it mimics the structure of tyrosine, the amino 

acid present in melanin, so that tyrosinase acts on it, liberating free radicals that damage melanocytes. 

NOAEL and LOAEL values were not derived from this study because the applied dose was not reported. 

3.2.3.3 Immunological and Lymphoreticular Effects 

No studies were located regarding immunological effects in humans or animals following dermal 

exposure to cresols. 

3.2.3.4 Neurological Effects 

Neurological effects were seen in two people who were accidentally exposed to mixed cresols on the skin 

and later died. A 1-year-old baby who had 20 mL of a cresol derivative spilled on his head was 

unconscious within 5 minutes; autopsy revealed swelling and congestion of the brain (Green 1975). A 

man who fell into a vat containing a cresylic acid derivative and received burns on 15% of his body fell 

into a coma 9 days later (Cason 1959). A man who survived a 5–6-hour immersion of his hands in a 

concentrated cresylic acid solution experienced persistent eye watering, followed by pain on the side of 

his face and, ultimately, marked facial paralysis (Klinger and Norton 1945). 

Only one study reported neurological effects in animals following dermal exposure to cresols. Rapid, 

shallow breathing and convulsions were observed in rats 5–30 minutes after covered dermal application 

of 1.0–3.5 mL/kg of certain cresylic acid formulations (Campbell 1941). Other formulations had no 

effect. These convulsions stopped after a few hours in the rats that survived. 
 

 

 

 

 

 

 

 

 

CRESOLS 96 

3. HEALTH EFFECTS 

No studies were located regarding the following health effects in humans or animals after dermal 

exposure to cresols: 

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 following dermal exposure to cresols. 

Cresols have not been evaluated for ability to induce cancer when applied to the skin of animals. 

However, a study of skin tumor promotion by cresols was located (Boutwell and Bosch 1959). Mice 

were given a single dermal application of 9,10-dimethyl-1,2-benzanthracene (DMBA), a cancer initiator, 

followed by application of 20% solutions of o-, p-, or m-cresol in benzene twice a week for 12 weeks. 

This level of cresols exposure proved to be acutely toxic, producing relatively high nontumor-related 

mortality. Consequently, all tumor results were based on number of survivors (14–20 per group). 

Promotion with cresols led to increases in the average number of skin papillomas per mouse and the 

percentage of exposed mice with at least one papilloma. o-Cresol was the most potent isomer, and 

p-cresol the least. Carcinomas were not observed following cresols exposure, although the observed 

papillomas have the potential to develop into carcinomas. A problem with the study was use of benzene, 

a known carcinogen, as the solvent for the cresols. However, benzene controls in the cresols experiment 

did not develop papillomas, and neither did benzene controls in four parallel series of experiments (a few 

papillomas were observed in a fifth benzene control group). Therefore, the results of this study showing 

that all three cresol isomers are capable of promoting skin tumors initiated by DMBA appear to be valid. 

3.3 GENOTOXICITY 

The genotoxic effects of cresols have been well studied. In vitro genotoxicity assays on o-, p-, and 

m-cresol are shown in Table 3-3. Results were uniformly negative in Salmonella assays with or without 

metabolic activation (Douglas et al. 1980; Florin et al. 1980; Haworth et al. 1983; Kubo et al. 2002; NTP 

1992b; Pepper, Hamilton & Scheetz 1981; Pool and Lin 1982) and mixed in in vitro studies using 

mammalian cells (Brusick 1988a, 1988b, 1988c; Cifone 1988a, 1988b, Gaikwad and Bodell 2001; 

Hamaguchi and Tsutsui 2000; Hikiba et al. 2005; Li et al. 2005; Miyachi and Tsutsui 2005; Murli 1988, 

Pepper, Hamilton & Scheetz 1980, 1981). Positive results were reported in assays for chromosomal 
 

 

 

 

 

 

 

 

 

 

CRESOLS 

3. HEALTH EFFECTS 

97 

Table 3-3. Genotoxicity of Cresols In Vitro 

Species (test 

system) End point 

Results 

With 

activation 

Without 

activation References Isomer 

Prokaryotic organisms: 

Salmonella Reverse mutation – – Douglas et al. 1980; o, p, m, 1:1:1 

typhimurium on Florin et al. 1980; mixture of o, 

plates Haworth et al. 1983; p, m 

Kubo et al. 2002; 

Pepper, Hamilton & 

Scheetz 1980, 1981; 

Pool and Lin 1982 

Eukaryotic organisms: 

Mammalian cells: 

CHO cells Chromosomal + + Murli 1988 o, p 

aberrations 

CHO cells Chromosomal – – Murli 1988 m 

aberrations 

CHO cells Sister chromatid + + Pepper, Hamilton & o, 1:1:1 

exchange Scheetz 1980, 1981 mixture of o, 

p, m 

Mouse Cell transformation + No data	 Pepper, Hamilton & 1:1:1 mixture 

BALB/C-313 cells Scheetz 1980 of o, p, m 

Mouse Cell transformation No data + Brusick 1988b p 

BALB/C-313 cells 

Mouse Cell transformation – –	 Brusick 1988a, o, m 

BALB/C-313 cells	 1988b, Pepper ,
 

Hamilton & Scheetz 

1981; Sernav 1989b
 

L5178Y mouse Forward mutation + (+)	 Pepper, Hamilton & 1:1:1 mixture 

lymphoma cells Scheetz 1980 of o, p, m 

L5178Y mouse Forward mutation – – Cifone 1988a; o, p, m 

lymphoma cells Pepper, Hamilton & 

Scheetz 1981
 

Mouse spermatid DNA damage No data + Li et al. 2005 o
 

Primary rat Unscheduled DNA No data – Pepper, Hamilton & o
 

hepatocytes synthesis Scheetz 1981 

Rat hepatocytes DNA adduct – + Gaikwad and Bodell p
 

formation 2001
 

Freshly cultured Unscheduled DNA No data – Cifone 1988b m
 

rat hepatocytes synthesis
 

Human peripheral Semiconservative/ No data (+) Daugherty and p
 

lymphocytes repair DNA	 Franks 1986 

Human peripheral DNA damage No data + Li et al. 2005 o
 

lymphocytes
 

HL-60 cells DNA adduct – + Gaikwad and Bodell p
 

formation	 2001 
 

 

 

CRESOLS 98 

3. HEALTH EFFECTS 

Table 3-3. Genotoxicity of Cresols In Vitro 

Results 

Species (test 

system) 

Syrian hamster 

kidney cells 

SHE cells 

End point 

SV40 induction 

Chromosomal 

aberrations 

With 

activation 

No data 

+ 

Without 

activation 

(+) 

+ 

References 

Moore and Coohill 

1983 

Hikiba et al. 2005 

Isomer 

m 

m 

SHE cells 

SHE cells 

Cultured human 

fibroblasts 

Unscheduled DNA 

synthesis 

Sister chromatid 

exchange 

Sister chromatid 

exchange 

+ 

No data 

No data 

– 

+ 

– 

Hamaguchi and 

Tsutsui 2000 

Miyachi and Tsutsui 

2005 

Cheng and 

Kligerman 1984 

m 

m 

o, p, m 

– = negative result; + = positive result; (+) = weakly positive; CHO = Chinese hamster ovary; 

DNA = deoxyribonucleic acid; SHE = Syrian hamster embryo 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

CRESOLS 99 

3. HEALTH EFFECTS 

aberrations for o- and p- cresol, but not for m-cresol in Chinese hamster cells (Murli 1988), while 

m-cresol produced positive results for chromosomal aberrations in Syrian hamster embryo cells (Hikiba et 

al. 2005). There was a positive result for sister chromatid exchange for o-cresol and for a mixture of o-, 

p-, and m-cresol in Chinese hamster ovary cells (Pepper, Hamilton & Scheetz 1980, 1981), and Syrian 

hamster embryo cells (Miyachi and Tsutsui 2005), which is in contrast to negative results for sister 

chromatid exchange in human fibroblasts for the o-, p-, and m-isomers (Cheng and Kligerman 1984). 

p-Cresol, and a mixture of the o-, p-, and m-cresol, also produced cell transformation in mouse 

BALB/C-3T3 cells (Brusick 1988b; Pepper, Hamilton & Scheetz 1980), while o- and m-cresol did not 

(Brusick 1988a, 1988b; Pepper, Hamilton & Scheetz 1981; Sernav 1989b). 

A 1:1:1 mixture of the three cresol isomers was positive in tests for forward mutation in mouse lymphoma 

cells (Pepper, Hamilton & Scheetz 1980), but negative for each isomer tested individually (Cifone 1988a; 

Pepper, Hamilton & Scheetz 1981). Assays were negative for increased DNA synthesis in rat hepatocytes 

for o- and m-cresols (Cifone 1988b; Pepper, Hamilton & Scheetz 1981), and positive in Syrian hamster 

embryo cells with activation for m-cresol (Hamaguchi and Tsutsui 2000) and in human peripheral 

lymphocytes for p-cresol (Daugherty and Franks 1986). DNA damage was found in mouse spermatid and 

human peripheral lymphocytes in assays testing o-cresol (Li et al. 2005), as was DNA adduct formation in 

rat hepatocytes and HL-60 cells incubated with p-cresol (Gaikwad and Bodell 2001). A weak positive 

result was reported for SV40 induction in Syrian hamster kidney cells (Moore and Coohill 1983). 

Positive results obtained in some human and animal in vitro tests suggest that cresols have some ability to 

react with DNA, and may be clastogenic under certain circumstances. 

Results from in vivo genotoxicity assays on o-, p-, and m-cresol are shown in Table 3-4. Studies of the 

genotoxicity of cresols in animals in vivo reported negative results for dominant lethal, chromosomal 

aberrations and mouse bone marrow, alveolar macrophages, and regenerating liver cells in vivo (Cheng 

and Kligerman 1984; Ivett 1989a, 1989b, 1989c; Sernav 1989a, 1989b). Treatment of male and female 

B6C3F1 mice with up to 2,723 or 3,205 mg/kg/day o-cresol, respectively, for 13 weeks did not increase 

the incidence of micronuclei in peripheral blood erythrocytes (NTP 1992b). Similar negative results were 

reported in male and female mice dosed with up to 1,513 or 1,693 mg/kg/day m/p-cresol, respectively 

(NTP 1992b). However, micronucleus frequency was increased in bone marrow from male mice injected 

twice intraperitoneally with 20, 40, or 80 mg/kg o-cresol (Li et al. 2005). Although o-, p-, and m-cresol 

and a 1:1:1 mixture of the three cresol isomers gave some indication of genotoxic activity in in vitro 

assays with mammalian cells, most in vivo assays were negative, with one exception. Overall, cresols do 

not seem to pose a genotoxic threat to humans under normal environmental exposure conditions. 
 

 

 

 

CRESOLS 100 

3. HEALTH EFFECTS 

Table 3-4. Genotoxicity of Cresols In Vivo 

Results 

Species (test With Without 

system) End point activation activation References Isomer 

Eukaryotic organisms (in vivo): 

Mouse Dominant lethal No data – Ivett 1989a, 1989b o, p 

Mouse Chromosomal aberrations (bone No data – Ivett 1989b m 

marrow) 

Mouse Sister chromatid exchange (bone No data – Cheng and o, p, m 

marrow, alveolar macrophages, Kligerman 1984 

and regenerating liver cells) 

Mouse Micronucleus frequency No data + Li et al. 2005 o 

Mouse Micronucleus frequency No data – NTP 1992b o, m/p 

Drosophila Sex-linked recessive lethal No data – Sernav 1989a, o, p 

melanogaster 1989b 

– = negative result; + = positive result 
 

 

 

 

 

 

 

 

 

 

CRESOLS 101 

3. HEALTH EFFECTS 

3.4 TOXICOKINETICS 

Cresols can be absorbed following inhalation, oral, and dermal exposure by humans and animals. Most of 

the evidence of absorption in humans is indirect, derived from cases of accidental dermal contact with 

these substances or accidental or intentional ingestion. Limited data from workers exposed to airborne 

cresols provide evidence of absorption by inhalation, although dermal absorption could have also 

occurred. Quantitative data are not available. Little is known about distribution of cresols in humans. In 

a fatal case of dermal intoxication, cresols were found in the brain and liver. Studies in animals dosed by 

oral gavage with a single dose of m- or p-cresol indicate that cresols can distribute rapidly into many 

organs and tissues. Cresols undergo oxidative metabolism in the liver and are rapidly eliminated, mostly 

in the urine, as sulfate or glucuronide conjugates. A study showed that human and rat liver microsomes in 

vitro metabolized p-cresol in a similar manner. However, the relevance of the available toxicokinetics 

information in animals to toxicokinetics of cresols in humans is unknown. 

3.4.1 Absorption 

p-Cresol is normally found in the body where it is generated from protein breakdown. p-Cresol is one of 

the metabolites of the amino acid tyrosine and of phenylalanine. Tyrosine and phenylalanine are 

converted to 4-hydroxyphenylacetic acid by intestinal bacteria. 4-Hydroxyphenylacetic acid is further 

decarboxylated to p-cresol, which is absorbed from the intestine and excreted in the urine as conjugates 

(De Smet et al. 1997; Vanholder et al. 1999). De Smet et al. (1998a) reported a mean concentration of 

8.6 μmol/L of p-cresol (0.93 mg/L) in serum from healthy subjects. 

3.4.1.1 Inhalation Exposure 

No studies were located regarding the rate and extent of absorption in humans following inhalation 

exposure to cresols. 

The absorption of cresols following inhalation exposure in animals has not been quantified, but can be 

assumed to occur, since mortality and other effects have been reported in animals following exposure 

(Campbell 1941; Kurlyandskiy et al. 1975; Uzhdavini et al. 1972). 
 

 

 

 

 

 

 

 

 

 

CRESOLS 102 

3. HEALTH EFFECTS 

3.4.1.2 Oral Exposure 

No studies were located regarding the rate and extent of absorption in humans following oral exposure to 

cresols. However, it can be assumed that cresol are absorbed orally based on the many reports of adverse 

effects in subjects who ingested cresols accidentally or intentionally (i.e., Chan et al. 1971; Hashimoto et 

al. 1998; Kamijo et al. 2003; Labram and Gervais 1968). 

In a study in rabbits administered all three cresol isomers by oral gavage under fasting conditions, from 

65 to 84% of the administered dose was recovered in the urine within 24 hours, indicating that at least that 

amount had been absorbed (Bray et al. 1950). When p-cresol was administered 1–2 hours after the 

rabbits were fed, the rabbits exhibited less toxic effects than when given the compound under fasting 

conditions, indicating that the gastrointestinal contents retarded the absorption of p-cresol (Bray et al. 

1950). A recent study showed that after a single gavage dose of a cresol soap solution (p- and m-cresol) 

to rats, 50% of the administered dose disappeared from the gastric contents in 15 minutes, and almost all 

of the administered cresol disappeared within 8 hours (Morinaga et al. 2004). In blood, the unconjugated 

concentrations of p- and m-cresol decreased rapidly for 2 hours after peaking 30 minutes after dosing. No 

unconjugated cresols could be detected after 4 hours. The p-cresol glucuronide in blood was always 

higher than the p-cresol sulfate, whereas the concentration of m-cresol sulfate was consistently higher 

than the m-cresol glucuronide. Based on the fact that the concentrations of the unconjugated cresols in 

liver and spleen were much higher than those in blood over a monitoring period of 8 hours, Morinaga et 

al. (2004) suggested that cresol administered by oral gavage diffuses directly through the gastric and 

small intestinal walls. 

3.4.1.3 Dermal Exposure 

The occurrence of coma, death, and systemic effects in two humans dermally exposed to cresols (Cason 

1959; Green 1975) indicates that these compounds can be absorbed through the skin. In another case of 

accidental dermal exposure to cresols, Fuke et al. (1998) reported that the concentrations of unconjugated 

p-cresol, sulfate, and glucuronide in the serum collected 2 hours after exposure were 15.7, 21.3, and 

38.6 μg/mL, respectively. The respective concentrations of m-cresol were 31.4, 17.0, and 82.9 μg/mL; 

the exposure amount was unknown so that the extent of absorption could not be estimated. An in vitro 

study of the permeability of human skin to cresols found that these substances had permeability 

coefficients greater than that for phenol, which is known to be readily absorbed across the skin in humans 

(Roberts et al. 1977). 
 

 

 

 

 

 

 

 

CRESOLS 103 

3. HEALTH EFFECTS 

No studies were located regarding the rate and extent of absorption in animals following dermal exposure 

to cresols. 

3.4.2 Distribution 

3.4.2.1 Inhalation Exposure 

No studies were located regarding the extent of distribution in humans or animals following inhalation 

exposure to cresols. 

3.4.2.2 Oral Exposure 

No studies were located regarding the distribution of cresols in humans following oral exposure. 

The distribution of m- and p-cresol has been studied in rats (Morinaga et al. 2004). Rats received a single 

gavage dose of a mixture of m- and p-cresol soap solution (100 mg p-cresol, 160 mg m-cresol/kg) and 

conjugated and unconjugated cresols were determined in tissues at various times up to 8 hours after 

dosing. The concentrations of unconjugated m- and p-cresol in liver and spleen were always much higher 

than in blood and higher than the sulfate or glucuronide metabolites in those organs. The unconjugated 

concentrations of both cresols in brain, lung, and muscle were similar to those in blood. The 

concentration of glucuronidated cresols were always highest in the kidney followed by the liver. 

Comparison of the concentration of glucuronide and sulfate conjugates in tissues showed that the 

glucuronide was always higher than the sulfate for both p- and m-cresol, particularly in the liver and 

kidneys. In all tissues, m-cresol sulfate was always higher than p-cresol sulfate, suggesting a slightly 

different metabolic disposition for these two isomers. 

3.4.2.3 Dermal Exposure 

Cresols were identified in the blood (12 mg/100 mL), liver, and brain of a 1-year-old baby who died 

4 hours after 20 mL of a cresol derivative was spilled on his head (Green 1975). 

No studies were located regarding the extent of distribution in animals following dermal exposure to 

cresols. 
 

 

 

 

 

 

 

 

 

CRESOLS 104 

3. HEALTH EFFECTS 

3.4.2.4 Other Routes of Exposure 

In rats administered a single intravenous dose of 3 mg/kg of p-cresol, the concentration of p-cresol in 

blood 5 minutes after dosing was 6.7 mg/L and decreased gradually to 0.6 mg/L near 240 minutes after 

dosing (Lesaffer et al. 2001). The half-life of p-cresol in serum was 1.5 hours (twice as long as 

creatinine) and its total clearance was 23.2 mL/minute/kg (3 times that of creatinine). Also, the volume of 

distribution of p-cresol was 5 times that of creatinine; however, renal clearance of p-cresol 

(4.8 mL/minute/kg) was about half that of creatinine. Similar results were reported in a subsequent paper 

from the same group of investigators (Lesaffer et al. 2003a). 

3.4.3 Metabolism 

No studies were located regarding metabolism in humans following exposure to cresols. 

A few studies reported on the metabolism of cresols in animals. Cresols in the urine are found primarily 

as sulfate and glucuronide conjugates. In the urine of rabbits, 60–72% of the orally administered dose 

was recovered as ether glucuronide, and 10–15% was recovered as ethereal sulfate (Bray et al. 1950). A 

similar result was obtained in an earlier study in rabbits in which 14.5–23.5% of the orally administered 

dose was found conjugated with sulfate in the urine (Williams 1938). For simple phenols such as cresols, 

the proportions of the conjugates are known to vary with dose and to differ from one species to the next. 

In the study by Bray et al. (1950), hydroxylation of a small percentage (3%) of the administered dose to 

2,5-dihydroxytoluene (conjugated) occurred for both o- and m-cresol. No hydroxylation occurred for 

p-cresol, but p-hydroxybenzoic acid (both free and conjugated) was detected in the urine. Only 1–2% of 

the administered dose was found as unconjugated free cresol in the urine. A study in rats showed that 

m-cresol is preferentially metabolized to sulfate, and p-cresol to glucuronide (Morinaga et al. 2004). 

Studies by Thompson and coworkers (Thompson et al. 1994, 1995, 1996) and Yan et al. (2005) have 

provided more detailed information on the metabolism of cresols and the role of metabolism in 

hepatotoxicity (the role of metabolism on hepatotoxicity is discussed in Section 3.5.2). Using rat liver 

microsomes and precision-cut liver slices, Thompson et al. (1995) demonstrated that p-cresol formed 

monoglutathione conjugates with a structure consistent with the formation of a quinone methide 

intermediate. The latter may be formed in two successive one electron oxidation steps by cytochrome 

P-450 (Koymans et al. 1993). Using human liver microsomes Yan et al. (2005) confirmed that the 

activation of p-cresol by oxidation forms a reactive quinone methide which formed a conjugate, 
 

 

 

 

 

 

 

 

 

 

 

 

CRESOLS 105 

3. HEALTH EFFECTS 

glutationyl-4-methyphenol. In addition, a new pathway was identified consisting of aromatic oxidation 

leading to the formation of 4-methyl-o-hydroquinone which is further oxidized to 4-methyl[1,2]benzoquinone. The latter formed three adducts with glutathione, but the predominant was found to be 

3-(glutathione-S-yl)-5-methyl o-hydroquinone. It was also found that 4-hydroxybenzylalcohol, a major 

metabolite formed by oxidation of the methyl group in liver microsomes, was further converted to 

4-hydroxybenzaldehyde. Experiments with recombinant P-450s demonstrated that the formation of the 

quinone methide intermediate was mediated by several P-450s including CYP2D6, 2C19, 1A2, 1A1, and 

2E1. The ring oxidation pathway was found to be mediated primarily by the CYP2E1 and to a lesser 

extent by CYP1A1, 1A2, and 2D6. Formation of 4-hydroxybenzaldehyde was catalyzed by 1A2 and also 

1A1 and 2D6. Human liver microsomes formed the same adducts as rat liver microsomes suggesting that 

the metabolism of p-cresol is similar in humans and rats. The metabolic pathway for p-cresol proposed 

by Yan et al. (2005) is shown in Figure-3-2. 

3.4.4 Elimination and Excretion 

3.4.4.1 Inhalation Exposure 

Studies of subjects occupationally exposed to cresols have demonstrated that cresols are eliminated in the 

urine. Workers employed in the distillation of the high temperature phenolic fraction of tar excreted 

p-and o-cresol in the urine at rates of 2.4 and 3.3 mg/hour, respectively (Bieniek 1994). The highest 

concentrations in urine were found during the first 2 hours after the end of the work shift. A study of 

76 men working at a coke plant where the geometric mean concentrations of o-, m-, and p-cresol in the 

breathing zone air were 0.09, 0.13, and 0.13 mg/m3

, respectively, reported that the corresponding 

concentrations in hydrolyzed urine were 16.74, 16.74, and 0.53 mg/g creatinine (Bieniek 1997). 

3.4.4.2 Oral Exposure 

No studies were located regarding excretion in humans following oral exposure to cresols. 

Following oral exposure to cresols in rabbits, 65–84% of the dose was excreted in the urine within 

24 hours, mostly as ethereal glucuronides and sulfates (Bray et al. 1950). 

3.4.4.3 Dermal Exposure 

No studies were located regarding excretion in humans or animals following dermal exposure to cresols. 
 

CRESOLS	 106 

3. HEALTH EFFECTS 

Figure 3-2. Bioactivation Pathways of p-Cresol in Human Liver Microsomes 

H2 

GS C CH3

SG 

OH 

O OH OH 

6-(glutathione-S-yl)­

5-methy hydroquinone 

CH2

2D6, 2E1 

2C19, 

1A2 

2E1 

CH3 

CH3	 

GSH 

CH3 CH3
 

GS
 

OH O OH 

OH OH O OH 

p-cresol 4-methyl-hydroquinone	 4-methyl-[1,2] 4-(glutathione-S-yl)­ benzoquinone
 

GSH 

5-methyl hydroquinone 

GB 

CH3 H2C HC 

OH	 OH 

GS OH 

OH 

OH OH 3-(glutathione-S-yl)-5-methyl quinone 

Source: adapted from Yan et al. 2005 
 

 

 

 

 

 

 

 

CRESOLS 107 

3. HEALTH EFFECTS 

3.4.4.4 Other Routes of Exposure 

Intravenous injection of a single dose of p-cresol to rats resulted in approximately 23% of the injected 

dose being excreted in the urine as parent compound within 240 minutes, the duration of the experiment 

(Lesaffer et al. 2001). As indicated in Section 3.4.2.4, the total clearance of p-cresol largely exceeded its 

renal clearance, which led Lesaffer et al. (2001) to suggest the presence of extra-renal elimination routes 

for p-cresol, namely, exsorption from the blood compartment into the gastrointestinal tract, biotransformation, or excretion via the bile. A subsequent study from the same group of investigators showed 

that in rats, 64% of an intravenous dose of p-cresol (9.6 mg/kg) was excreted as p-cresylglucuronide 

(Lesaffer et al. 2003b). When the glucuronide and the unconjugated p-cresol were combined, 

approximately 85% of the injected dose was recovered in the urine. 

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

Physiologically based pharmacokinetic (PBPK) models use mathematical descriptions of the uptake and 

disposition of chemical substances to quantitatively describe the relationships among critical biological 

processes (Krishnan et al. 1994). PBPK models are also called biologically based tissue dosimetry 

models. PBPK models are increasingly used in risk assessments, primarily to predict the concentration of 

potentially toxic moieties of a chemical that will be delivered to any given target tissue following various 

combinations of route, dose level, and test species (Clewell and Andersen 1985). Physiologically based 

pharmacodynamic (PBPD) models use mathematical descriptions of the dose-response function to 

quantitatively describe the relationship between target tissue dose and toxic end points. 

PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to 

delineate and characterize the relationships between: (1) the external/exposure concentration and target 

tissue dose of the toxic moiety, and (2) the target tissue dose and observed responses (Andersen and 

Krishnan 1994; Andersen et al. 1987). These models are biologically and mechanistically based and can 

be used to extrapolate the pharmacokinetic behavior of chemical substances from high to low dose, from 

route to route, between species, and between subpopulations within a species. The biological basis of 

PBPK models results in more meaningful extrapolations than those generated with the more conventional 

use of uncertainty factors. 
 

 

 

 

 

 

 

 

CRESOLS 108 

3. HEALTH EFFECTS 

The PBPK model for a chemical substance is developed in four interconnected steps: (1) model 

representation, (2) model parameterization, (3) model simulation, and (4) model validation (Krishnan and 

Andersen 1994). In the early 1990s, validated PBPK models were developed for a number of 

toxicologically important chemical substances, both volatile and nonvolatile (Krishnan and Andersen 

1994; Leung 1993). PBPK models for a particular substance require estimates of the chemical substancespecific physicochemical parameters, and species-specific physiological and biological parameters. The 

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

equations that describe the pharmacokinetic processes. Solving these differential and algebraic equations 

provides the predictions of tissue dose. Computers then provide process simulations based on these 

solutions. 

The structure and mathematical expressions used in PBPK models significantly simplify the true 

complexities of biological systems. If the uptake and disposition of the chemical substance(s) are 

adequately described, however, this simplification is desirable because data are often unavailable for 

many biological processes. A simplified scheme reduces the magnitude of cumulative uncertainty. The 

adequacy of the model is, therefore, of great importance, and model validation is essential to the use of 

PBPK models in risk assessment. 

PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the 

maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994). 

PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in 

humans who are exposed to environmental levels (for example, levels that might occur at hazardous waste 

sites) based on the results of studies where doses were higher or were administered in different species. 

Figure 3-3 shows a conceptualized representation of a PBPK model. 

If PBPK models for cresols 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. 

No PBPK models have been developed for cresols. 
 

CRESOLS 109 

3. HEALTH EFFECTS 

Figure 3-3. 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 

Vmax Km 

GI 

Tract 

Feces 

Urine

Note: This is a conceptual representation of a physiologically based pharmacokinetic (PBPK) model for a 

hypothetical chemical substance. The chemical substance is shown to be absorbed via the skin, by inhalation, or by 

ingestion, metabolized in the liver, and excreted in the urine or by exhalation. 

Source: adapted from Krishnan et al. 1994 
 

 

 

 

 

 

 

 

 

 

 

 

CRESOLS 110 

3. HEALTH EFFECTS 

3.5 MECHANISMS OF ACTION 

3.5.1 Pharmacokinetic Mechanisms 

Absorption. No specific information was located regarding the mechanism of absorption of cresols. 

However, in a study in rats administered a cresol soap solution (m- and p-cresol) via a gastric tube, the 

concentration of free cresols in liver and spleen were much higher than those in blood at all times after 

dosing (up to 8 hours) (Morinaga et al. 2004). This led the investigators to suggest that cresol 

administered via a stomach tube diffuses directly though the gastric and small intestinal walls, which 

according to Morinaga et al. (2004), would explain the very high concentration of unconjugated cresols 

found in the liver and also in the spleen, which is adjacent to the stomach. Whether this also happens 

following ingestion of cresols mixed in food or in water is not known. 

Distribution. No specific information was located regarding how cresols are transported in blood, but 

it is reasonable to assume that they may be bound to albumin, the most important binding protein for 

many acidic and basic drugs (Mabuchi and Nakahashi 1988). In a study of healthy subjects and patients 

with chronic renal failure, no free p-cresol could be detected in the blood of healthy subjects, 100% was 

protein-bound (De Smet et al. 1998a). No information was located for o- or m-cresol. 

Metabolism. The limited information available summarized in Section 3.4.3 indicates that cresols 

undergo conjugation with sulfate and glucuronic acid and also form oxidative metabolites. However, 

there is virtually no information on possible shifts between these reactions that could be dose-dependent, 

dependent on the availability of co-substrates in the conjugation reactions, or related to different enzyme 

activity levels across areas of the liver, as occurs with structurally similar chemicals (i.e., phenol). The 

role of metabolism on the toxicity of cresols is discussed in Section 3.5.2. 

Excretion. Cresols are excreted in the urine as glucuronides and sulfates. However, based on the 

observation that the total clearance of p-cresol largely exceeded its renal clearance in rats administered 

p-cresol intravenously, Lesaffer et al. (2001) suggested the presence of extra-renal elimination routes for 

p-cresol, namely, exsorption (reverse absorption or secretion) from the blood compartment into the 

gastrointestinal tract, biotransformation, or excretion via the bile. Exsorption from the blood 

compartment into the gastrointestinal tract may be plausible for unbound p-cresol, a relatively small 

molecule, but not for protein-bound p-cresol, which is how 100% of p-cresol is normally found in the 

blood (De Smet et al. 1998a). No pertinent information was located for o- or m-cresol. 
 

 

 

 

 

 

 

 

 

 

 

CRESOLS 111 

3. HEALTH EFFECTS 

3.5.2 Mechanisms of Toxicity 

Limited information is available regarding the mechanism(s) of toxicity of cresols. Cresols are irritant 

and corrosive at high concentrations as evidenced by numerous cases of accidental dermal exposure or 

accidental or intentional ingestion of cresols. Much like phenol, cresols impair the stratum corneum and 

produce coagulation necrosis by denaturating and precipitating proteins. 

The role of metabolism in the toxicity of cresol has been studied by Thompson and coworkers (Thompson 

et al. 1994, 1995, 1996). Using lactate dehydrogenase (LDH) leakage or intracellular potassium as 

indices of toxicity in precision-cut rat liver slices as a test system, they showed that p-cresol was the most 

toxic of the three isomers. Similar results were obtained in liver slices from rats pretreated with 

phenobarbital, an inducer of cytochrome P-450; however, in this case, the toxicity of each isomer relative 

to control was increased compared to untreated slices. On a molar basis, p-cresol was 5–10 times more 

toxic than o- or m-cresol in the LDH leakage test. Incubation with the thiol precursor N-acetylcysteine or 

inhibition of cytochrome P-450 with metyrapone inhibited the toxicity of p-cresol, whereas depletion of 

glutathione increased the toxicity of p-cresol. These treatments had little effect on the toxicity of o- or 

m-cresol, suggesting a somewhat different mechanism of action, at least in the test system used. 

Furthermore, p-cresol rapidly depleted intracellular levels of glutathione, while the other isomers did it to 

a lesser extent. In the absence of glutathione, the major metabolite of p-cresol was p-hydroxybenzyl 

alcohol, which caused no observable toxicity to the liver slices. In the presence of glutathione, the 

amount of p-hydroxybenzyl alcohol was reduced by about 30% and the new product formed was 

confirmed to be a glutathione conjugate formed via the formation of a reactive quinone methide 

intermediate. The reactive intermediate bound covalently to protein in slices and in microsomal 

preparations. A metabolic pathway for p-cresol proposed by Yan et al. (2005) is shown in Figure 3-2. 

A study by Kitagawa (2001) suggested that liver mitochondria may be a target for the liver toxicity of 

cresols based on results that indicated that these compounds inhibited mitochondrial respiration and 

induced or accelerated swelling of the mitochondria. However, it is difficult to relate the results from 

these studies in vitro to the observations of little or no alterations in the liver of animals dosed with 

cresols for extended periods of time (NTP 1992b). 

Many studies in which the animals were dosed with cresols by oral gavage reported adverse neurological 

signs ranging from lethargy to tremors and convulsions (EPA 1988b, 1988c; TRL 1986; Tyl 1988a, 

1988b). Dietary studies reported occasional tremors only at the highest doses administered. The 
 

 

 

 

 

 

 

CRESOLS 112 

3. HEALTH EFFECTS 

mechanism by which cresols induced these effects is unknown. Studies in rats have reported that cresols 

induce changes in neurotransmitter levels in the brain (Calderón-Guzmán et al. 2005) and in activities of 

some enzymes (DeWolf et al. 1988; Savolainen 1979). Calderón-Guzmán et al. (2005) also suggested 

that cresols may increase lipid peroxidation and change membrane fluidity in rat brain. Studies have also 

reported neurophysiological changes in animals exposed to cresols. Mattsson et al. (1989) observed 

excitation of somatosensory evoked potentials and changes in the EEG in rats following intravenous 

administration of o-cresol. Mohammadi et al. (2001) reported that o-cresol, but not m-cresol, activated 

GABAA receptors expressed in transformed human embryonic kidney cells. If such an effect were to 

occur in the intact animal, it may result in decreased activity and sedation since GABA normally mediates 

inhibitory neural activity. Whether any of these putative mechanisms of neurological effects are involved 

in the effects observed following oral dosing of animals, particularly by gavage, is unknown. Cresols 

could be acting at multiple sites including sites at the periphery. 

3.5.3 Animal-to-Human Extrapolations 

Cresols are irritants and corrosive in high concentrations and will produce similar effects on the skin and 

mucosal surfaces of humans and animals. Other than death and neurological effects, which have been 

reported both in humans and animals exposed to high amounts of cresols, it is difficult to predict other 

health outcomes in humans based on observations in animals. The metabolism of cresols seems to be 

similar in humans and rats based on the fact that both species excrete sulfate and glucuronide conjugation 

products in the urine. Furthermore, Yan et al. (2005) showed that bioactivation patterns for p-cresol in 

human and rat liver microsomes lead to the same reactive intermediates and glutathione adducts. While 

this and other studies (Thompson et al. 1994, 1995) served to construct a toxicity ranking for cresol 

isomers in hepatocytes in vitro, extrapolation to other toxicities would be pure speculation and 

inappropriate. 

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS 

Recently, attention has focused on the potential hazardous effects of certain chemicals on the endocrine 

system because of the ability of these chemicals to mimic or block endogenous hormones. Chemicals 

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

terminology to describe such effects remains controversial. The terminology endocrine disruptors, 

initially used by Thomas and Colborn (1992), was also used in 1996 when Congress mandated the EPA to 

develop a screening program for “...certain substances [which] may have an effect produced by a 
 

 

 

 

 

 

 

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naturally occurring estrogen, or other such endocrine effect[s]...”. To meet this mandate, EPA convened a 

panel called the Endocrine Disruptors Screening and Testing Advisory Committee (EDSTAC), and in 

1998, the EDSTAC completed its deliberations and made recommendations to EPA concerning endocrine 

disruptors. In 1999, the National Academy of Sciences released a report that referred to these same types 

of chemicals as hormonally active agents. The terminology endocrine modulators has also been used to 

convey the fact that effects caused by such chemicals may not necessarily be adverse. Many scientists 

agree that chemicals with the ability to disrupt or modulate the endocrine system are a potential threat to 

the health of humans, aquatic animals, and wildlife. However, others think that endocrine-active 

chemicals do not pose a significant health risk, particularly in view of the fact that hormone mimics exist 

in the natural environment. Examples of natural hormone mimics are the isoflavinoid phytoestrogens 

(Adlercreutz 1995; Livingston 1978; Mayr et al. 1992). These chemicals are derived from plants and are 

similar in structure and action to endogenous estrogen. Although the public health significance and 

descriptive terminology of substances capable of affecting the endocrine system remains controversial, 

scientists agree that these chemicals may affect the synthesis, secretion, transport, binding, action, or 

elimination of natural hormones in the body responsible for maintaining homeostasis, reproduction, 

development, and/or behavior (EPA 1997). Stated differently, such compounds may cause toxicities that 

are mediated through the neuroendocrine axis. As a result, these chemicals may play a role in altering, 

for example, metabolic, sexual, immune, and neurobehavioral function. Such chemicals are also thought 

to be involved in inducing breast, testicular, and prostate cancers, as well as endometriosis (Berger 1994; 

Giwercman et al. 1993; Hoel et al. 1992). 

Based on the available information, there is no evidence that cresols are endocrine disruptors in humans 

and little evidence in animals. A 28-day dietary study reported mild uterine atrophy in female rats dosed 

with 2,310 mg/kg/day of m-cresol or 2,060 mg/kg/day of p-cresol (NTP 1992b). Comparable doses of 

o-cresol or an m/p-cresol mixture were without significant effect. A 13-week treatment with the 

≥509 mg/kg/day m/p-cresol in the diet significantly lengthened the estrous cycle of rats, and doses of 

1,024 and 2,050 mg/kg/day induced minimal to mild uterine atrophy (NTP 1992b). In mice, exposure to 

≥1,670 mg/kg/day of o-cresol for 28 days also induced mild atrophy of the uterus, and 4,940 mg/kg/day 

of m-cresol induced mild to moderate atrophy of the mammary gland, uterus, and ovaries (NTP 1992b). 

In addition, doses of 3,205 mg/kg/day of o-cresol for 13 weeks lengthened the estrous cycle in female 

mice. In these studies, there was no biologically significant effect on males’ reproductive organs or on 

sperm parameters. In the 2-year bioassay, doses of up to 720 and 1,040 mg/kg/day m/p-cresol, 

respectively, did not induce and significant alterations in gross or microscopic morphology of 

reproductive organs (NTP 2008). 
 

 

 

 

 

 

 

CRESOLS 114 

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Multiple-generation reproductive studies that administered cresols by oral gavage (Neeper-Bradley and 

Tyl 1989a, 1989b; Tyl and Neeper-Bradley 1989) or through the diet (NTP 1992a, 1992c) have provided 

no evidence of endocrine-mediated alterations on reproduction or development. 

In standard developmental toxicity studies in rats and rabbits, cresols have induced slight fetotoxicity, but 

only at maternally toxic doses (Tyl 1988a, 1988b). A study that treated newborn rats with m-cresol by 

gavage from postnatal day 4 through 21 reported noticeable clinical signs (tremors, hypersensitivity) with 

the highest dose tested, 300 mg/kg/day, but there were no alterations in the physical development or 

sexual maturation of the pups (Koizumi et al. 2003). 

A study in which embryos of rats were incubated in vitro with p-cresol observed increased incidence of 

structural abnormalities such as hind limb bud absence and tail defects, but there is no evidence that this 

was endocrine-mediated (Oglesby et al. 1992). Additional information from studies in vitro is limited. 

Nishihara et al. (2000) reported that p-cresol tested positive and o-cresol 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 more than 10% of the activity of 10-7 M 17β-estradiol. Neither o-cresol nor 

p-cresol showed androgenic activity (agonist or antagonist) in stably transfected CHO-K1 cell lines, 

which expressed the androgen receptor (AR) and a AR-responsive luciferase gene reporter (Araki et al. 

2005; Satoh et al. 2005). 

Collectively, the available evidence does not suggest that cresols represent a hazard due to properties of 

endocrine disrupters, although a few cases of mild atrophy of female reproductive organs and lengthening 

of estrous cycle in rats and mice were reported for cresols, but generally at relatively high doses. 

3.7 CHILDREN’S SUSCEPTIBILITY 

This section discusses potential health effects from exposures during the period from conception to 

maturity at 18 years of age in humans, when all biological systems will have fully developed. Potential 

effects on offspring resulting from exposures of parental germ cells are considered, as well as any indirect 

effects on the fetus and neonate resulting from maternal exposure during gestation and lactation. 

Relevant animal and in vitro models are also discussed. 
 

 

 

 

 

 

 

CRESOLS 115 

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Children are not small adults. They differ from adults in their exposures and may differ in their 

susceptibility to hazardous chemicals. Children’s unique physiology and behavior can influence the 

extent of their exposure. Exposures of children are discussed in Section 6.6, Exposures of Children. 

Children sometimes differ from adults in their susceptibility to hazardous chemicals, but whether there is 

a difference depends on the chemical (Guzelian et al. 1992; NRC 1993). Children may be more or less 

susceptible than adults to health effects, and the relationship may change with developmental age 

(Guzelian et al. 1992; NRC 1993). Vulnerability often depends on developmental stage. There are 

critical periods of structural and functional development during both prenatal and postnatal life, and a 

particular structure or function will be most sensitive to disruption during its critical period(s). Damage 

may not be evident until a later stage of development. There are often differences in pharmacokinetics 

and metabolism between children and adults. For example, absorption may be different in neonates 

because of the immaturity of their gastrointestinal tract and their larger skin surface area in proportion to 

body weight (Morselli et al. 1980; NRC 1993); the gastrointestinal absorption of lead is greatest in infants 

and young children (Ziegler et al. 1978). Distribution of xenobiotics may be different; for example, 

infants have a larger proportion of their bodies as extracellular water, and their brains and livers are 

proportionately larger (Altman and Dittmer 1974; Fomon 1966; Fomon et al. 1982; Owen and Brozek 

1966; Widdowson and Dickerson 1964). The infant also has an immature blood-brain barrier (Adinolfi 

1985; Johanson 1980) and probably an immature blood-testis barrier (Setchell and Waites 1975). Many 

xenobiotic metabolizing enzymes have distinctive developmental patterns. At various stages of growth 

and development, levels of particular enzymes may be higher or lower than those of adults, and 

sometimes unique enzymes may exist at particular developmental stages (Komori et al. 1990; Leeder and 

Kearns 1997; NRC 1993; Vieira et al. 1996). Whether differences in xenobiotic metabolism make the 

child more or less susceptible also depends on whether the relevant enzymes are involved in activation of 

the parent compound to its toxic form or in detoxification. There may also be differences in excretion, 

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 
 

 

 

 

 

 

 

 

 

 

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alveoli being less developed, which results in a disproportionately smaller surface area for alveolar 

absorption (NRC 1993). 

There are no studies that specifically address the health effects of exposure to cresols in children; 

therefore, it is unknown whether children differ from adults in their susceptibility to health effects from 

cresols. Only one study was located that compared the effects of m-cresol administered by gavage in 

newborn rats and young rats (Koizumi et al. 2003). Newborn rats exhibited adverse neurological signs at 

approximately one third the doses that affected young rats. It is unknown whether this reflects differences 

in pharmacokinetics or on other aspects of m-cresol action. Data on the effects of cresols in adults are 

derived almost exclusively from cases of accidental or intentional ingestion of cresol solutions (i.e., Chan 

et al. 1971; Hayakawa 2002; Isaacs 1922; Jouglard et al. 1971; Kamijo et al. 2003; Minami et al. 1990; 

Wu et al. 1998) or accidental dermal exposure (i.e., Cason 1959; Pegg and Campbell 1985). In some of 

these cases, death occurred. Exposure to these amounts of cresols produced corrosion at the points of 

contact including the skin and gastrointestinal tract. Similar effects would be expected in children 

exposed to high amounts of cresols. In fact, Green (1975) reported the death of a child after a cresol 

mixture was spilled on his head. 

There is no information regarding possible adverse developmental effects in humans exposed to cresols. 

Some studies in animals have reported fetotoxicity at dose levels that also produced maternal toxicity 

(Neeper-Bradley and Tyl 1989a, 1989b; Tyl 1988a, 1988b; Tyl and Neeper-Bradley 1989). For the most 

part, cresols have been negative in genotoxicity tests in vivo. Therefore, it is unlikely that parental 

exposure would result in adverse childhood development or cancer development as a result of cresol 

exposures to parental germ cells. 

There is no information regarding pharmacokinetics of cresols in children. A study of the metabolism of 

p-cresol in human liver microsomes showed that both phase I and phase II metabolic enzymes are 

involved in the biotransformation of p-cresol and that the metabolism of p-cresol in humans and rats is 

similar (Yan et al. 2005). That study and others (Thompson et al. 1994, 1995) have provided evidence 

that, at least in rats, phase I enzymes increase the liver toxicity of p-cresol in vitro, whereas conjugation 

reactions decreased the toxicity. To the extent that some of these enzymes are developmentally regulated, 

the metabolism, and consequently the toxicity of cresols in immature humans may be different than in 

adults. However, since the causative agent of cresols toxicity is still unknown, trying to predict how 

immature enzymatic systems could affect the toxicity of cresols in developing humans would be pure 
 

 

 

 

 

 

 

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speculation at this time. It is not known whether cresols can cross the placenta and there are no reports on 

levels of cresols in maternal milk. 

There are no biomarkers of exposure or effect for cresols that have been validated in children or in adults 

exposed as children. No relevant studies were located regarding interactions of cresols with other 

chemicals in children or adults. 

No information was located regarding pediatric-specific methods for reducing peak absorption following 

exposure to cresols, reducing body burden, or interfering with the mechanism of action for toxic 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 biomarker of exposure is a xenobiotic 

substance or its metabolite(s) or the product of an interaction between a xenobiotic agent and some target 

molecule(s) or cell(s) that is measured within a compartment of an organism (NAS/NRC 1989). The 

preferred biomarkers of exposure are generally the substance itself, substance-specific metabolites in 

readily obtainable body fluid(s), or excreta. However, several factors can confound the use and 

interpretation of biomarkers of exposure. The body burden of a substance may be the result of exposures 

from more than one source. The substance being measured may be a metabolite of another xenobiotic 

substance (e.g., high urinary levels of phenol can result from exposure to several different aromatic 

compounds). Depending on the properties of the substance (e.g., biologic half-life) and environmental 

conditions (e.g., duration and route of exposure), the substance and all of its metabolites may have left the 

body by the time samples can be taken. It may be difficult to identify individuals exposed to hazardous 

substances that are commonly found in body tissues and fluids (e.g., essential mineral nutrients such as 

copper, zinc, and selenium). Biomarkers of exposure to cresols are discussed in Section 3.8.1. 

Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an 

organism that, depending on magnitude, can be recognized as an established or potential health 

impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of 
 

 

 

 

 

 

 

 

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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 cresols are discussed in Section 3.8.2. 

A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism's ability 

to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic or 

other characteristic or a preexisting disease that results in an increase in absorbed dose, a decrease in the 

biologically effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are 

discussed in Section 3.10, Populations That Are Unusually Susceptible. 

3.8.1 Biomarkers Used to Identify or Quantify Exposure to Cresols 

No biomarkers that uniquely implicate exposure to cresols have been identified in humans or animals. 

Cresols are formed from the commonly found amino acid tyrosine, and occur naturally in human and 

animal tissues, fluids, and urine. Cresols are also formed as minor metabolites of toluene, and an 

increased presence of o-cresol in the body could be due to exposure to this substance, although toluene or 

hippuric acid in the urine seem to be more reliable indicators of occupational exposure to toluene than 

o-cresol (De Rosa et al. 1987; Fustinoni et al. 2007). The use of cresols as a biomarker of exposure to 

cresol would require a considerable elevation to exceed biological background levels and potential 

confounding from conversion of other environmental agents. There is some evidence that the presence of 

o-cresol in urine can be used as a biomarker for phenol exposure. A study of workers at a coke plant 

involved in the tar-distillation process found a statistically significant correlation (p<0.001) between low 

concentrations of o-cresol in breathing-zone air and end-of-shift urine samples (Bieniek 1997). Urinary 

levels of o-cresol were also found to be significantly higher in the urine of workers employed in the 

distillation of carbolic oil than in nonexposed workers (Bieniek 1994). 

p-Cresol has been found to form adducts with DNA in in vitro systems and it has been suggested that this 

property might provide a biomarker to assess occupational exposure to toluene (Gaikwad and Bodell 

2001, 2003). 
 

 

 

 

 

 

 

 

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3.8.2 Biomarkers Used to Characterize Effects Caused by Cresols 

No biomarkers of effects caused by cresols have been identified in humans or animals. Data on human 

exposure to cresols are derived mainly from cases of acute accidental or intentional exposure to high 

amounts of cresol, which usually caused external burns and corrosive necrosis of the gastrointestinal tract. 

Generally, these types of exposures also involved liver and kidney alterations as well as other nonspecific 

pathologies. 

3.9 INTERACTIONS WITH OTHER CHEMICALS 

Cresols are irritant and corrosive by impairing the stratum corneum and producing coagulation necrosis 

by denaturating and precipitating proteins, which explains the toxic effects at the sites of contact (i.e., 

skin, mucosal surfaces). However, there is no information on other mechanisms of toxicity for cresols. 

Studies with liver cells in vitro suggested that metabolic activation of cresols by microsomal enzymes 

might produce toxic reactive intermediates (Thompson et al. 1994). It is plausible that exposure to 

substances that induce P-450 isozymes involved in the metabolism of cresols may increase the toxicity of 

cresols. Similar outcomes could occur by simultaneous exposure to cresols and substances that decrease 

phase II metabolic reactions. However, there is no experimental evidence to support these assumptions. 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 

A susceptible population will exhibit a different or enhanced response to cresols than will most persons 

exposed to the same level of cresols in the environment. Reasons may include genetic makeup, age, 

health and nutritional status, and exposure to other toxic substances (e.g., cigarette smoke). These 

parameters result in reduced detoxification or excretion of cresols or compromised function of organs 

affected by cresols. Populations who are at greater risk due to their unusually high exposure to cresols are 

discussed in Section 6.7, Populations with Potentially High Exposures. 

Some groups have been identified that might exhibit increased vulnerability to the effects of cresols. 

There is very limited evidence that individuals with glucose-6-phosphate dehydrogenase (G6PD) 

deficiency may have increased susceptibility to hematological effects of cresols; the increase in 

methemoglobin formation and decrease in glutathione levels were more pronounced in blood taken from 

subjects with G6PD deficiency than in blood taken from normal subjects following exposure of the blood 

to a disinfectant containing 50% cresols in vitro (Chan et al. 1971). 
 

 

 

 

 

 

 

 

 

 

 

CRESOLS 120 

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Patients with chronic renal failure constitute another group with increased susceptibility to p-cresol. In 

these patients, the concentration of p-cresol in the blood is 10 times higher than in healthy subjects due to 

both overgrowth of intestinal bacteria responsible for p-cresol production and reduced renal clearance. 

Free serum concentrations of p-cresol were shown to predict mortality in hemodialysis patients 

(Bammens et al. 2006). It has also been suggested that p-cresol decreases endothelial proliferation and 

wound repair in uremic patients, thus contributing to the immune defect in these patients (Dou et al. 2002, 

2004). In a prospective longitudinal study, the concentrations of p-cresol were higher in 

hypoalbuminemic individuals than in those with normal albumin, and free p-cresol was related to 

hospitalization for infection (De Smet et al. 2003b). 

3.11 METHODS FOR REDUCING TOXIC EFFECTS 

This section will describe clinical practice and research concerning methods for reducing toxic effects of 

exposure to cresols. 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 cresols. 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 

cresols: 

Ellenhorn MJ, ed. 1997. Ellenhorn’s medical toxicology. Diagnosis and treatment of human poisoning. 

2nd ed. Baltimore, MD: Williams and Wilkins. 

Haddad LM, Shannon MW, Winchester JF. 1998. Clinical management of poisoning and drug overdose. 

3rd ed. Philadelphia, PA: W.B. Saunders Company. 

Leikin JB, Paloucek FP. 2002. Leikin and Paloucek’s poisoning and toxicology handbook. 3rd ed. 

Hudson, OH: Lexi-Comp, Inc. 

3.11.1 Reducing Peak Absorption Following Exposure 

For ingestion exposure, water or milk should be given if the patient is alert and has an intact gag reflex. 

Activated charcoal and a cathartic can then be administered orally or by gastric tube. Because cresol is 

corrosive and may cause seizures, emesis should not be induced. If the eyes have been exposed, they 

should be thoroughly irrigated as soon as possible with running water or saline. If the skin has been 

exposed, it should be flushed promptly with copious amounts of water or undiluted polyethylene glycol 
 

 

 

 

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followed by thorough washing with soap or mild detergent and water (Bronstein and Currance 1988; 

Haddad et al. 1998; HSDB 2008; Leikin and Paloucek 2002; Stutz and Janusz 1988). 

3.11.2 Reducing Body Burden 

Procedures that might decrease the toxicity of cresols present in the bloodstream have not been identified. 

Although supporting data were not located, it is possible that elimination of cresols from the blood would 

be enhanced by alkaline diuresis, which would increase the proportion of cresols existing in the ionized 

state, thereby reducing reabsorption of cresols by the kidney tubules. 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects 

No specific procedures have been developed to interfere with the mechanism of action of cresols. 

Treatment of individuals intoxicated with cresols is mainly supportive. Exposed individuals with 

evidence of central nervous system depression or seizures should be evaluated for the presence of some 

other underlying disorder. Diazepam or phenobarbital may be administered to alleviate seizures. 

Supplemental oxygen can also be administered. If pulmonary edema occurs, conventional therapy should 

be given. Methylene blue may be administered for treatment of methemoglobinemia. Additional 

information regarding the treatment of individuals exposed to cresols may be obtained from Bronstein and 

Currance 1988; Haddad et al. 1998; HSDB 2008; Leikin and Paloucek 2002; and Stutz and Janusz 1988. 

3.12 ADEQUACY OF THE DATABASE 

Section 104(I)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of cresols is available. Where adequate information is not 

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

initiation of a program of research designed to determine the health effects (and techniques for developing 

methods to determine such health effects) of cresols. 

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 
 

 

 

 

 

 

CRESOLS 122 

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that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

3.12.1 Existing Information on Health Effects of Cresols 

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to 

cresols are summarized in Figure 3-4. The purpose of this figure is to illustrate the existing information 

concerning the health effects of cresols. Each dot in the figure indicates that one or more studies provide 

information associated with that particular effect. The dot does not necessarily imply anything about the 

quality of the study or studies, nor should missing information in this figure be interpreted as a “data 

need”. A data need, as defined in ATSDR’s Decision Guide for Identifying Substance-Specific Data 

Needs Related to Toxicological Profiles (Agency for Toxic Substances and Disease Registry 1989), is 

substance-specific information necessary to conduct comprehensive public health assessments. 

Generally, ATSDR defines a data gap more broadly as any substance-specific information missing from 

the scientific literature. 

In the following discussion, the various forms of cresol are considered together, due to the similarity of 

their effects and the levels at which these effects occur. 

Cresols are irritants and have corrosive properties following exposure to high concentrations by any route 

of exposure. Therefore, the skin and mucosal membranes are targets for cresol toxicity. The existing 

information on the health effects of cresols in humans comes almost entirely from case reports of people 

who accidentally or intentionally swallowed cresol-containing substances or had these substances spilled 

on them. The single exception was an inhalation study of mucosal irritation in humans. Acute oral or 

dermal exposure to high amounts of cresol caused serious systemic effects and even death in humans. 

A limited number of studies of inhalation exposure in animals tried to determine lethal levels or evaluated 

systemic and neurologic end points. A much greater number of studies in animals have been conducted 

by the oral route. Evaluation of the oral database suggests that a distinction should be made between 

studies by oral gavage and dietary studies based on differences on end points affected and threshold 

levels. Cresols are much more toxic when administered by oral gavage than when given in the diet. The 

difference is most likely related to differences in pharmacokinetics between the two means of 

administration. Animals exposed to cresols by gavage often showed adverse neurological signs and 

decreased weight gain associated with decreased food consumption. Oral gavage studies evaluated 
 

CRESOLS 123 

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Figure 3-4. Existing Information on Health Effects of Cresols 

Death 

Acute 

Intermediate

Chronic 

Immunologic/Lymphoretic

Neurologic

Reproductive

Developmental

Genotoxic

Cancer 

Systemic 

Human 

Inhalation 

Oral 

Dermal 

Death 

Acute 

Intermediate

Chronic 

Immunologic/Lymphoretic

Neurologic

Reproductive

Developmental

Genotoxic

Cancer 

Systemic 

Animal 

Inhalation 

Oral 

Dermal 

Existing Studies 
 

 

 

 

 

 

 

 

CRESOLS 124 

3. HEALTH EFFECTS 

reproductive, developmental, and neurological end points. Longer-term dietary studies examined 

systemic end points as well as reproductive, developmental, and carcinogenic effects. Studies of dermal 

exposure to cresols in animals generally looked at levels of lethality and irritation to the skin and eyes. 

One study of intermediate duration investigated dermal effects. A cancer-promotion study was also 

performed using dermally applied cresols. 

3.12.2 Identification of Data Needs 

Acute-Duration Exposure. Case reports of humans exposed to high doses of cresols, either orally or 

dermally, have provided acute toxicity information. Fatalities due to ingestion and dermal exposure have 

been described (Bruce et al. 1976; Cason 1959; Chan et al. 1971; Green 1975; Isaacs 1922; Labram and 

Gervais 1968; Monma-Ohtaki et al. 2002). Other effects reported in these acute high exposure scenarios 

include respiratory failure (Liu et al. 1999), tachycardia and ventricular fibrillation (Labram and Gervais 

1968), abdominal pain, vomiting, and corrosive lesions of the gastrointestinal tract (Hayakawa 2002; 

Isaacs 1922; Jouglard et al. 1971; Kamijo et al. 2003; Wu et al. 1998; Yashiki et al. 1990), methemoglobinemia (Chan et al. 1971; Minami et al. 1990), leukocytosis and hemolysis (Cote et al. 1984; Wu et 

al. 1998), hepatocellular injury (Chan et al. 1971; Hashimoto et al. 1998; Hayakawa 2002; Kamijo et al. 

2003), renal alterations (Chan et al. 1971; Isaacs 1922; Labram and Gervais 1968; Wu et al. 1998), skin 

damage (Cason 1959; Green 1975; Herwick and Treweek 1933; Klinger and Norton 1945; Pegg and 

Campbell 1985), metabolic acidosis (Hayakawa 2002; Kamijo et al. 2003), and unconsciousness (Chan et 

al. 1971; Isaacs 1922; Labram and Gervais 1968). Many of these effects may not have been caused 

directly by cresols, but represent secondary reactions to shock caused by external and internal burns. A 

single study in volunteers reported that brief exposures to 6 mg/m3 of o-cresol in the air caused respiratory 

tract irritation (Uzhdavini et al. 1972). 

Limited data on acute inhalation effects were available from only two studies (Campbell 1941; Uzhdavini 

et al. 1972) in which exposure involved mixtures of vapors and aerosols that provided insufficient 

information to estimate exposure levels reliably; therefore, an acute-duration inhalation MRL for cresols 

was not derived. Still, these studies provided some data on lethality of airborne cresols as well as 

information on the respiratory system (irritation), liver (fatty degeneration and necrosis), renal (tubular 

degeneration), and nervous system (excitation, fatigue, convulsions). Inhalation studies that use modern 

methodology to generate and control exposure atmospheres and that evaluate a wide range of end points 

may be considered in order to construct dose-response curves for acute inhalation exposure. However, 

under normal circumstances, acute inhalation exposure is generally not considered hazardous due to 
 

 

 

 

 

 

 

 

 

 

 

 

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cresols’ low vapor pressure and a distinct odor at <1 ppm (NTP 1992b). A study of acute dermal 

exposure of animals to cresols determined exposure levels that produce skin irritation and death (Vernot 

et al. 1977); it is unclear what new key information would be provided by additional dermal studies. All 

acute-duration oral studies in animals administered cresols by oral gavage, a dosing mode that, as 

discussed in Section 2.3, induces different effects than those observed in dietary studies and is not 

considered relevant for risk assessment. Oral gavage studies showed reduced body weight, neurotoxicity, 

fetotoxicity, and death in exposed animals (EPA 1988b, 1988c, 1988d; TRL 1986; Tyl 1988a, 1988b). 

No acute dietary or drinking water studies were located for cresols, and for that reason, no acute-duration 

oral MRLs were derived. Although drinking water studies would mimic exposure to contaminated water 

at or near a waste site, the solubility of cresols would limit the high doses to be around 2%. In addition, 

the odor and taste of cresols may pose potential palability problems. Therefore, acute-duration dietary 

studies are needed for defining targets and generating dose-response relationships for this exposure 

duration. 

Intermediate-Duration Exposure. No information is available regarding humans exposed to 

cresols for an extended period of time. One of the studies that provided acute-duration inhalation data 

also provided intermediate-duration inhalation data (Uzhdavini et al. 1972). Rodents exposed to cresols 

showed adverse respiratory, cardiovascular, hepatic, renal, and neurological effects, but the methods used 

at the time to generate and monitor the exposure atmospheres were inadequate to estimate exposure 

concentrations with any precision. Modern studies are needed to define targets of toxicity and to establish 

dose-response relationships. It would be important to determine whether the nasal lesions observed in 

rats and mice in the dietary study conducted by NTP (1992b) also appear in animals exposed by 

inhalation. If so, the intermediate-duration oral MRL for cresols (see below) may have to be revisited 

(this also applies for chronic-duration exposure). 

Oral gavage studies of intermediate duration in animals have been performed for all three cresol isomers, 

and have helped to identify the levels at which cresols produce neurological, respiratory, hepatic, renal, 

hematological, and body weight changes in orally exposed animals (EPA 1988b, 1988c, 1988d; TRL 

1986). However, gavage administration of cresols induces different effects than those observed in dietary 

studies and do not resemble human environmental exposure scenarios to cresols. Therefore, only dietary 

studies were considered for MRL derivation even though some LOAELs by gavage are lower than dietary 

LOAELs. NTP (1992b) tested the cresol isomers and a mixture of m- and p-cresol in 28-day and 13-week 

dietary studies in rats and mice. A comprehensive number of end points were examined and the critical 

effect was nasal lesions in both species exposed to p-cresol and m/p-cresol. The data from the 13-week 
 

 

 

 

 

 

 

 

 

 

 

 

 

CRESOLS 126 

3. HEALTH EFFECTS 

study in rats exposed to m/p-cresol were used to derive an intermediate-duration oral MRL for cresols. 

Additional intermediate oral studies do not seem necessary at this time since the NTP (1992b) study 

evaluated a comprehensive number of end points and cresols exhibited relatively little toxicity. Only one 

intermediate-duration dermal study in animals was located (Shelley 1974). People living near waste sites 

may be exposed to cresols in soil or dermally through water contaminated with cresols. Therefore, 

additional intermediate-duration dermal exposure studies are needed. 

Chronic-Duration Exposure and Cancer. No studies of chronic duration were found in humans. 

Information regarding chronic toxicity is important because people living near hazardous waste sites 

might be exposed to cresols for many years. A mixture of m/p-cresol was tested in male Fischer-344 rats 

and female B6C3F1 mice in a 2-year toxicity and carcinogenicity bioassay sponsored by NTP (NTP 

2008). Although the study is yet to be finalized, preliminary results confirmed the presence of nasal 

lesions reported in the 28-day and 13-week studies (NTP 1992b) and also observed increased incidences 

of bronchiolar hyperplasia and follicular degeneration of the thyroid gland in treated mice (0, 100, 300, 

and 1,040 mg/kg/day). The data for bronchiole hyperplasia and follicular degeneration of the thyroid 

gland in female mice exposed for 2 years were used to derive a chronic-duration oral MRL for cresols. 

Additional long-term studies do not seem necessary at this time. 

No studies were located regarding the carcinogenicity of cresols in humans. In a 2-year NTP-sponsored 

bioassay, an m/p-cresol mixture administered in the diet to male Fischer-344 rats and female B6C3F1 

mice induced a nonsignificant increase in the incidence of renal tubule adenoma in rats at 720 mg/kg/day, 

which was considered an equivocal finding of carcinogenicity by NTP (2008); no other neoplastic effects 

were reported in rats. In mice, treatment with 1,040 mg/kg/day m/p-cresol induced a significant increase 

in the incidence of squamous cell papilloma in the forestomach. Additional carcinogenicity bioassays do 

not seem necessary at this time. 

Genotoxicity. No data were located regarding the genotoxicity of cresols in humans in vivo. In vitro 

studies using cultured human cells were negative for sister chromatid exchange for all three isomers 

(Cheng and Kligerman 1984) and positive for unscheduled DNA synthesis for p-cresol (Daugherty and 

Franks 1986). Studies of the genotoxicity of cresols in animals in vivo reported negative results (Cheng 

and Kligerman 1984; Ivett 1989a, 1989b, 1989c; NTP 1992b; Sernav 1989a, 1989b) with the exception of 

one study (Li et al. 2005). Results were mixed in in vitro studies using mammalian cells (Brusick 1988a, 

1988b, 1988c; Cifone 1988a, 1988b; Murli 1988; Pepper, Hamilton & Scheetz 1980, 1981), and 

uniformly negative in Salmonella assays (Douglas et al. 1980; Florin et al. 1980; Haworth et al. 1983; 
 

 

 

 

 

CRESOLS 127 

3. HEALTH EFFECTS 

Kubo et al. 2002; NTP 1992b; Pepper, Hamilton & Scheetz 1981; Pool and Lin 1982). The positive 

results obtained in some human and animal in vitro tests suggest that cresols have some ability to react 

with DNA. It is unlikely that additional tests will provide new key information regarding the genotoxicity 

of cresols. 

Reproductive Toxicity. There are no data available regarding the reproductive effects of cresols in 

humans. Studies in animals do not suggest that reproductive end points are sensitive targets for cresols 

toxicity (EPA 1988b, 1988c, 1988d; Hornshaw et al. 1986; Neeper-Bradley and Tyl 1989a, 1989b; NTP 

1992a, 1992b, 1992c, 2008; Tyl and Neeper-Bradley 1989). The well-conducted dietary continuous 

breeding protocol studies in mice with o-cresol and m/p-cresol found no evidence of reproductive toxicity 

for o-cresol (NTP 1992a); m/p-cresol, at a dose that caused minor maternal toxicity, produced a decrease 

in the number of pups/litter and increased the cumulative days to litter, but did not affect other 

reproductive function end points (NTP 1992c). In the intermediate-duration dietary studies in rats and 

mice conducted by NTP (1992b), effects were limited to mild to moderate uterine atrophy and 

lengthening of the estrous cycle, generally at the highest dose levels tested. In the 2-year bioassay in male 

rats and female mice dosed with up to 720 and 1.040 mg m/p-cresol/kg/day, respectively, there were no 

gross or microscopic alterations in the reproductive organs (NTP 2008). There is no reason to believe that 

potential reproductive effects might be route-dependent. Additional studies do not seem warranted at this 

time. 

Developmental Toxicity. There are no data available regarding the developmental effects of cresols 

in humans. The developmental toxicity of cresols in animals was evaluated in a series of studies in which 

pregnant rats and rabbits were exposed by oral gavage to each cresol isomer (Neeper-Bradley and Tyl 

1989a, 1989b; Tyl 1988a, 1988b; Tyl and Neeper-Bradley 1989) and in pregnant mice exposed to 

o-cresol or m/p-cresol in the diet in continuous breeding protocol studies (NTP 1992a, 1992c). These 

studies generally reported mild fetotoxicity only at maternally toxic doses. Additional information was 

provided by a comparative study that observed tremors in newborn mice exposed to 100 mg/kg/day 

m-cresol on postnatal days 4–21, but none in adults exposed to up to 300 mg/kg/day for 28 days (Koizumi 

et al. 2003). The reason why this occurs is not known, but it is likely related to differences in the 

metabolic disposition of m-cresol between the two age groups. There is no indication that potential 

developmental effects of cresols could be route-dependent. Since the data from gestation exposure 

studies in animals indicate that developmental effects occur only at dose levels that affect the mother, 

further studies examining the potential developmental toxicity of cresols do not seem necessary at this 

time. 
 

 

 

 

 

 

 

 

 

 

 

 

 

CRESOLS 128 

3. HEALTH EFFECTS 

Immunotoxicity. No immunological effects were reported in case studies of human exposure. No 

significant alterations in weight or histology of lymphoreticular organs have been observed in animals 

following cresol exposure (EPA 1988b, 1988c, 1988d; Hornshaw et al. 1986; NTP 1992b, 2008). The 

information available does not suggest that the immune system is a target for cresol toxicity, but 

immunocompetence has not been evaluated. 

Neurotoxicity. A common feature of oral poisoning with cresols in humans is coma (Chan et al. 1971; 

Isaacs 1922; Labram and Gervais 1968). Accidental dermal exposure of a cresol derivative was fatal to a 

child (Green 1975) and produced facial paralysis in a man who spilled cresol on his face (Klinger and 

Norton 1945). Oral gavage studies in rodents often induced adverse clinical signs indicative of 

neurological impairment such as hypoactivity, excessive salivation, labored respiration, and tremors 

(Neeper-Bradley and Tyl 1989a, 1989b; TRL 1986; Tyl and Neeper-Bradley 1989). In no cases have 

gross or microscopic alterations of the brain, spinal cord, or sciatic nerve been observed. None of the 

clinical signs seen in oral gavage studies have been seen in dietary studies (NTP 1992b, 2008), or if seen, 

they have occurred at much higher dose levels than in oral gavage studies. This difference is probably 

related to the different disposition of cresols and metabolites between the two modes of oral dosing. The 

mechanism(s) by which cresols induce these effects is not known, but could include actions at both 

central and peripheral sites of the nervous system. There is no reason to believe that the neurotoxic 

effects of cresols are route-dependent. Studies aimed at elucidating these mechanisms of action would be 

informative, but from the point of view of hazard identification, the nervous system is not a sensitive 

target for cresols administered at environmentally relevant levels by relevant routes of exposure. 

Epidemiological and Human Dosimetry Studies. As previously mentioned, information about 

the effects of cresols in humans is derived mainly from case reports of accidental or intentional ingestion 

of cresol solutions or from accidental contact of cresol with the skin. Specific effects and references are 

mentioned under Acute-Duration Exposure. Doses were generally not available in the acute oral case 

reports, but Chan et al. (1971) estimated that roughly 2 g/kg may have caused the death of a woman. No 

group of the general population has been identified as having being exposed exclusively or predominantly 

to low levels of cresols for a long time. Based on data from long-term dietary studies in animals, it would 

be difficult to determine what specific end points to monitor in humans exposed to cresols since cresols 

caused relatively little systemic toxicity in the animal studies; hyperplastic or metaplastic lesions in the 

nasal respiratory epithelium were the most sensitive effects identified in rats and mice. 
 

 

 

 

 

 

 

 

 

CRESOLS 129 

3. HEALTH EFFECTS 

Biomarkers of Exposure and Effect. 

Exposure. No biomarkers of exposure to cresols have been identified. In fact, even the cresols 

themselves cannot be considered specific biomarkers for cresol exposure because they are also formed as 

breakdown products of toluene and tyrosine. However, if toluene exposure could be ruled out, then a 

high level of cresols or metabolites in the blood or urine would strongly suggest cresol exposure. 

p-Cresol was found to form adducts with DNA in in vitro systems (Gaikwad and Bodell 2001, 2003); 

however, even if it does the same in vivo, identification of adducts would not necessarily indicate 

exposure to cresols for the same reasons mentioned above. 

Effect. No specific biomarkers of effect have been identified for cresols. Since cresols are irritants and 

corrosive at high concentration, their main effects are at sites of contact (i.e., skin, respiratory, and 

gastrointestinal tract). Other effects observed in subjects exposed acutely to relatively high amounts of 

cresols (i.e., hepatic, renal, hematological, and metabolic) may be secondary to the external and internal 

injuries (burns) caused by cresols. It seems unlikely that specific biomarkers of effect will be identified 

for cresols. 

Absorption, Distribution, Metabolism, and Excretion. Case reports and a limited number of 

studies in animals suggest that cresols are well absorbed by all routes of exposure, although quantitative 

data are lacking. Only one study was located that provided information on the distribution of m- and 

p-cresol in rats following an oral gavage dose (Morinaga et al. 2004). Cresols were found to distribute 

widely among tissues and no specific organ seemed to preferentially accumulate cresols. The 

intermediate-duration oral MRL for cresols is based on nasal effects in rats administered the test material 

in the diet (NTP 1992b). Since there is the possibility that the lesions may be caused by inhalation of 

vapors of cresol from the food, a particularly valuable study would be to administer radiolabeled cresols 

by gavage and determine whether cresol-derived radioactivity appears disproportionately in the nasal 

epithelium. 

The basic metabolic reactions for cresols are known (Bray et al. 1950; Morinaga et al. 2004; Williams 

1938). The metabolism of p-cresol has been examined in more detail in rat liver microsomes and liver 

slices (Thompson et al. 1994, 1995, 1996; Yan et al. 2005). These studies suggested that a reactive 

intermediate plays a role in the toxicity of p-cresol on liver cells in vitro, but the relevance of this finding 

to studies in vivo is unknown since cresols exhibited little or no liver toxicity in dietary studies in rats and 

mice (NTP 1992b). 
 

 

 

 

 

 

 

 

CRESOLS 130 

3. HEALTH EFFECTS 

Lacking from the cresol database are studies comparing the pharmacokinetics of cresols administered by 

oral gavage and in the diet. This is important because the effects of cresols administered by gavage are 

different than those seen following dietary administration. Based on information on a similar chemical, 

phenol, it is likely that the toxicity of cresols correlate with peak blood concentration rather than with 

total dose, but this has not been experimentally demonstrated for cresols. Information on possible dose 

dependency of the phase II metabolism is also lacking. It would be valuable to know for the various 

isomers which conjugation reaction, with sulfate or glutathione, predominates at low and high doses, and 

at what level each reaction might become saturated. No PBPK models have been developed for cresols. 

Such models are needed for addressing interspecies issues related to saturable pathways associated with 

various dosing parameters such as ingestion from food or water, issues related to gavage dosing, and 

inhalation and dermal absorption. 

Comparative Toxicokinetics. The limited information available suggests that the metabolism of 

cresols is similar in humans and rats based on the fact that both species excrete sulfate and glutathione 

conjugation products in the urine. In addition, a recent study showed that bioactivation patterns for 

p-cresol in human and rat liver microsomes led to the same reactive intermediates and glutathione adducts 

(Yan et al. 2005). This information is insufficient to predict whether humans and animals will exhibit 

similar effects under similar exposure conditions, with the exception of portal-of-entry effects. However, 

it is unclear what practical information would provide additional comparative toxicokinetics studies given 

that cresols showed little systemic toxicity in animal studies when administered by an environmentally 

relevant route of exposure (other than nasal lesions) and no reports were found on humans exposed to 

cresols for long periods of time. 

Methods for Reducing Toxic Effects. Cresols are strong irritants and corrosive at high 

concentrations and, therefore, their main effects are on surfaces with which they come in contact, such as 

the skin, and respiratory and gastrointestinal epithelia. Cresols exhibited little systemic toxicity in a 

limited number of intermediate-duration dietary studies in animals; therefore, attempts to suggest studies 

to counteract a yet unknown mechanism of action seem impractical at this time. The treatment for high 

dermal or oral exposures to cresols is standard for chemical burns and mainly supportive. Development 

of new therapies for the treatment of skin burns will help subjects accidentally exposure to cresols and 

similar chemicals. 
 

 

 

 

 

 

 

 

 

CRESOLS 131 

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. 

There are no studies that specifically addressed exposure to cresols in children. Data on the effects of 

cresols in adults are derived almost exclusively from cases of accidental or intentional ingestion of cresol 

solutions (see above Acute-Duration Exposure for specific references). Exposure to these high amounts 

of cresols produced corrosion at the points of contact including the skin and gastrointestinal tract. Similar 

effects would be expected in children exposed to high amounts of cresols. There is no information on 

whether the developmental process is altered in humans exposed to cresols. Studies in animals suggest 

that fetotoxicity occurs only with doses of cresols that are also toxic to the mother (Neeper-Bradley and 

Tyl 1989a, 1989b; Tyl 1988a, 1988b; Tyl and Neeper-Bradley 1989) and further standard developmental 

toxicity studies do not appear necessary at this time. A study showed that newborn rats (exposed daily on 

postnatal days 4–21) were more sensitive to the neurological effects of bolus doses of cresols than young 

rats (exposed daily for 28 days) (Koizumi et al. 2003). This may be due to age-related differences in 

toxicokinetics. 

There are no data to evaluate whether toxicokinetics of cresols in children are different from adults. 

There is no information on whether cresols can cross the placenta and there are no studies on whether 

cresols can be transferred from mother to offspring through maternal milk. Research into the 

development of biomarkers of exposure for cresols would be valuable for both adults and children. There 

are no data on the interactions of cresols with other chemicals in children. There are no pediatric-specific 

methods to mitigate the effects of exposure to high amounts of cresols. Based on the information 

available, it is reasonable to assume that the supportive methods recommended for maintaining vital 

functions in adults, will also be applicable to children. 

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 cresols were identified in the Federal Research in Progress database 

(FEDRIP 2008). 
 

CRESOLS 132
 

3. HEALTH EFFECTS 

This page is intentionally blank. 
 

 

CRESOLS 133 

4. CHEMICAL AND PHYSICAL INFORMATION 

4.1 CHEMICAL IDENTITY 

Data pertaining to the chemical identity of cresols are listed in Table 4-1. 

4.2 PHYSICAL AND CHEMICAL PROPERTIES 

The physical and chemical properties of cresols are presented in Table 4-2. 
 

 

CRESOLS 134 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of Cresols 

o-, m-, 

Characteristics o-Cresol p-Cresol m-Cresol p-Cresol References 

Chemical name o-Cresol p-Cresol m-Cresol (o, m, p)-Cresol ChemID 2008 

Synonyms 2-Methylphenol; 4-Methylphenol; 3-Methylphenol Methylphenol; ChemID 2008; 

2-hydroxy­ 4-hydroxy­ 3-hydroxy­ hydroxytoluene; HSDB 2008; 

toluene; toluene; toluene; cresylic acid SANSS 1989 

o-cresylic acid p-cresylic acid m-cresylic acid 

Trade names No data No data No data No data 

Chemical C7H8O C7H8O C7H8O C7H8O ChemID 2008 

formula 

Chemical OH OH OH Mixture of three 

structure previous 

isomers 

Identification 

numbers: 

CAS registry 95-48-7 106-44-5 108-39-4 1319-77-3 ChemID 2008 

NIOSH GO6300000 GO6475000 GO61250000 GO5950000 SANSS 1989 

RTECS 

EPA F004; U052 F004; U052 F004; U052 F004; U052 HSDB 2008 

hazardous 

waste 

DOT/UN/NA/ UN 2022; UN 2022; UN 2022; UN 2022; HSDB 2008 

IMCO UN 3455; UN 3455; UN 3455; UN 3455; 

shipping UN 2076; UN 2076; UN 2076; UN 2076; 

IMO 6.1 IMO 6.1 IMO 6.1 IMO 6.1 

HSDB 1813 1814 1815 250 HSDB 2008 

NCI No data No data No data No data 

CAS = Chemical Abstracts Service; DOT/UN/NA/IMCO = Department of Transportation/United Nations/North 

America/Intergovernmental Maritime Consultive Organization; EPA = Environmental Protection Agency; 

HSDB = Hazardous Substance Data Bank; NCI = National Cancer Institute; NIOSH = National Institute for 

Occupational Safety and Health; RTECS = Registry of Toxic Effects of Chemical Substances 
 

 

 

 

CRESOLS 135 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of Cresols 

Property o-Cresol m-Cresol p-Cresol 

Mixture of o-, p-, 

and m-cresol References 

Molecular weight 108.14 108.14 108.14 108.14 O’Neil et al. 2001 

Color White crystals 

darken with 

age 

Colorless to 

yellowish 

No data Colorless, 

yellowish, 

brownish-yellow, or 

pinkish 

O’Neil et al. 2001 

Physical state Solid Liquid Solid Liquid O’Neil et al. 2001 

Melting point 30.944 °C 12.22 °C 34.739 °C 11–35 °C Lewis 2001; 

Riddick et al. 1986 

Boiling point 

1 atm 191.004 °C 202.32 °C 201.94 °C 191–203 °C Riddick et al. 1986 

10 mmHg 74.9 °C 86 °C 85.7 °C No data Lewis 2001; Lide 

2005 

Density (20 °C) 1.047 g/mL 1.034 g/mL 1.0341 g/mL 1.030–1.038 g/mL O’Neil et al. 2001 

Odor Phenol-like Phenol-like Phenol-like Phenol-like O’Neil et al. 2001 

Odor threshold 

Water No data 0.037 ppm No data No data Amoore and 

Hautala 1983 

Air No data 0.00028 ppm No data No data Amoore and 

Hautala 1983 

Solubility 

Water at 25 °C 25,950 ppm 22,700 ppm 21,520 ppm No data Yalkowsky et al. 

1987 

Organic solvents Alcohol, ether, 

acetone, 

benzene, 

chloroform, 

alkali 

hydroxides 

(aqueous) 

Alcohol, ether, 

acetone, 

benzene, 

chloroform, 

alkali 

hydroxides 

(aqueous) 

Alcohol, 

ether, 

acetone, 

benzene, 

chloroform, 

alkali 

hydroxides 

(aqueous) 

Alcohol, glycol, 

base 

Lewis 2001; Lide 

2005; O’Neil et al. 

2001 

Partition coefficients 

Log octanol/water 1.95 1.96 1.94 No data Hansch and Leo 

1985 

Log Koc 1.03 1.54 1.69 No data Artiola-Fortuny 

and Fuller 1982; 

Boyd 1982 

Vapor pressure 

25 °C 0.299 mmHg 0.138 mmHg 0.11 mmHg No data AIChE 1989,2000, 

Chao et al. 1983 
 

 

CRESOLS	 136 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of Cresols 

Mixture of o-, p-, 

Property o-Cresol m-Cresol p-Cresol and m-cresol References
 

Henry’s law constant 

atm/m3-molecule at 1.2x10-6 8.65x10-7 7.92x10-7 No data Gaffney et al. 

25 °C (calculated 1987; Hine and 

from vapor Mookerjee 1975 

pressure and 

water 

solubility) 

Flashpoint (closed 81 °C 85 °C 86 °C 82 °C Lewis 2001 

cup) 

Flammability limits 1.4% (lower) 1.1% (lower) 1.1% (lower) HSDB 2008 

Conversion factors 

ppm (v/v) to mg/m3	 4.50 4.50 4.50 4.50 Verschueren 1983 

in air (20 °C)
 

mg/m3 to ppm (v/v) 0.22 0.22 0.22 0.22 Verschueren 1983
 

in air (20 °C)
 

Bioconcentration 

factor 

Log BCF	 1.25 1.30 1.24 No data Freitag et al. 1985; 

(calculated (calculated Thomas 1982 

from Kow) from Kow) 

Explosive limits No data No data No data No data 
 

 

 

 

 

 

 

 

 

 

CRESOLS 137 

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

5.1 PRODUCTION 

Prior to World War II, multimillion pound quantities of cresols were produced annually in the United 

States, and domestic production and sales of cresols have steadily increased over the past several decades. 

In 1987, the national capacity for producing cresylics (compounds relating to cresols) was 208 million 

pounds per year (CMR 2004). More recent data indicate that the total U.S. production capacity for 

cresols, xylenols, and cresylics is approximately 470 million pounds (CMR 2004). Overall demand for 

cresols, xylenols, and cresylics was 340 million pounds in 2002, 365 million pounds in 2003, and is 

projected to increase to 385 million pounds by 2007 (CMR 2004). Information regarding the production 

levels of individual isomers and specific mixtures was unavailable. These production totals include data 

on the manufacture of cresylic acid and exclude information on cresol production by coke and gas-retort 

ovens. The commercial mixture of cresol isomers, in which the m-isomer predominates and contains 

<5% phenol, is sometimes referred to as cresylic acid (Windholz et al. 1983). However, cresylic acids 

generally are composed of cresols, phenols, and xylenols; they are defined as those mixtures in which 

over 50% will boil at temperatures above 204 °C (Lewis 2001). 

Cresols are used widely by industry. Information from the EPA's Toxic Release Inventory (TRI) on 

facilities that either manufactured or processed o-, m-, p-, or mixed isomers of cresols in 2004 is outlined 

in Tables 5-1 through 5-4, respectively. The TRI data should be used with caution since only certain 

types of facilities were required to report. This is not an exhaustive list. According to the 2005 Directory 

of Chemical Producers (SRI 2005), cresols are currently produced by five manufacturers in New York, 

Pennsylvania, Illinois, and Texas. Stanford Research Institute (SRI 2005) data for individual isomers and 

the mixture o-, p-, and m-isomers are included in Table 5-5. 

The oldest cresol production method used in the United States is through the recovery of fractional 

distillates from coal tars. Most domestic cresols are formed via catalytic and thermal cracking of naphtha 

fractions during petroleum distillation. Since 1965, quantities of coal tar and petroleum isolates have 

been insufficient to meet the rising demand. Consequently, several processes for the manufacture of the 

various isomers have been developed. One General Electric facility produces o-cresol at an annual 

capacity of 10,000 tons by the methylation of phenol in the presence of catalysts. The Sherman-Williams 

Company uses the toluene sulfonation process and maintains an annual capacity for p-cresol of 

15,000 tons. The Hercules Powder Company produced p-cresol until 1972 by the cymene-cresol process. 
 

 

 

 

CRESOLS 138 

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

Table 5-1. Facilities that Produce, Process, or Use o-Cresol 

Minimum Maximum 

Number of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

AL 4 0 999,999 1, 6, 9, 12, 13, 14 

AR 1 1,000 9,999 12 

CA 8 1,000 999,999 2, 3, 6, 7 

DE 1 10,000 99,999 6 

GA 4 100 99,999 2, 3, 6, 7, 8 

IL 12 100 9,999,999 1, 2, 3, 4, 6, 7, 12 

IN 9 100 99,999 1, 5, 7, 8, 10, 11, 12 

KS 1 100 999 12 

KY 11 0 999,999 2, 3, 6, 7, 8, 10, 11, 12 

LA 7 1,000 9,999,999 1, 2, 3, 6, 12, 13 

MI 1 1,000 9,999 7 

MO 4 100 99,999 9, 12 

MS 1 10,000 99,999 1, 3, 6 

NE 2 1,000 99,999 12 

NJ 6 1,000 999,999 6, 7, 9, 12 

NY 9 1,000 999,999 1, 5, 6, 7, 13 

OH 9 0 999,999 1, 3, 6, 7, 8, 12 

OK 2 100 999 6, 7 

PA 6 1,000 999,999 1, 4, 8, 9, 13 

RI 4 1,000 99,999 6, 7, 8 

SC 1 10,000 99,999 12 

TN 8 100 9,999,999 2, 3, 6, 8, 9, 11, 12 

TX 28 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13 

UT 2 10,000 999,999 1, 3, 4, 5, 6 

WI 4 1,000 999,999 6, 7 

AL 4 0 999,999 1, 6, 9, 12, 13, 14 

AR 1 1,000 9,999 12 

a

Post office state abbreviations used 

b

Amounts on site reported by facilities in each state 

c

Activities/Uses: 

1. Produce 6. Impurity 11. Chemical Processing Aid 

2. Import 7. Reactant 12. Manufacturing Aid 

3. Onsite use/processing 8. Formulation Component 13. Ancillary/Other Uses 

4. Sale/Distribution 9. Article Component 14. Process Impurity 

5. Byproduct 10. Repackaging 

Source: TRI05 2007 (Data are from 2005) 
 

 

 

 

 

CRESOLS 139 

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

Table 5-2. Facilities that Produce, Process, or Use m-Cresol 

Minimum Maximum 

Number of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

AR 2 100 9,999 12 

CA 3 0 999,999 4, 7 

FL 1 1,000 9,999 7, 8 

GA 3 10,000 999,999 2, 3, 6, 7, 10, 11 

IL 6 100 99,999 1, 5, 6, 10, 12, 13 

IN 16 100 999,999 2, 3, 6, 7, 8, 10, 11, 12 

KS 3 1,000 99,999 6, 12 

KY 10 1,000 999,999 1, 2, 3, 6, 8, 10, 11, 12 

LA 1 1,000 9,999 6 

MA 2 1,000 99,999 6, 11 

MI 2 10,000 99,999 6 

MO 8 100 999,999 1, 4, 8, 9, 10, 11, 12 

MS 4 100 999,999 6, 10 

NC 3 0 99,999 6, 10, 11, 12 

NJ 1 1,000 9,999 12 

NY 6 10,000 999,999 1, 5, 6, 9, 10, 13 

OH 6 100 999,999 1, 3, 5, 6, 7, 12 

OK 4 100 99,999 6, 7, 10 

PA 8 1,000 999,999 1, 4, 6, 8, 9, 13 

RI 3 10,000 99,999 6, 7, 8 

SC 4 10,000 9,999,999 6, 12 

TN 9 0 9,999,999 6, 7, 8, 9, 11, 12 

TX 19 0 9,999,999 1, 2, 3, 4, 5, 6, 8, 11, 12, 13, 14 

WI 1 10,000 99,999 7 

WV 1 100,000 999,999 6 

a

Post office state abbreviations used 

b

Amounts on site reported by facilities in each state c

Activities/Uses: 

1. Produce 6. Impurity 11. Chemical Processing Aid 

2. Import 7. Reactant 12. Manufacturing Aid 

3. Onsite use/processing 8. Formulation Component 13. Ancillary/Other Uses 

4. Sale/Distribution 9. Article Component 14. Process Impurity 

5. Byproduct 10. Repackaging 

Source: TRI05 2007 (Data are from 2005) 
 

 

 

 

CRESOLS 140 

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

Table 5-3. Facilities that Produce, Process, or Use p-Cresol 

Minimum Maximum 

Number of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

AL 5 100 999,999 1, 2, 6, 12, 13, 14 

AR 3 0 9,999 12 

AZ 1 1,000 9,999 7 

CA 3 1,000 9,999,999 1, 3, 6, 7 

CT 2 10,000 999,999 6 

GA 1 10,000 99,999 2, 3, 6, 7 

IL 7 1,000 9,999,999 1, 3, 4, 6, 7, 10, 12 

IN 13 0 999,999 2, 3, 7, 8, 10, 11, 12 

KS 5 100 999,999 2, 3, 6, 8, 12 

KY 9 1,000 999,999 2, 3, 6, 8, 10, 11, 12 

LA 12 0 999,999 1, 2, 3, 4, 5, 6, 12 

MO 9 100 999,999 1, 4, 8, 9, 10, 11, 12 

MS 1 1,000 9,999 10 

NC 4 1,000 99,999 6, 8, 10, 12 

NE 2 1,000 99,999 12 

NJ 6 1,000 999,999 2, 3, 6, 12 

NY 4 100 999,999 1, 5, 6, 12, 13 

OH 5 1,000 999,999 6, 12 

OK 3 100 99,999 6, 7, 10 

PA 8 100 999,999 1, 4, 6, 8, 9, 12, 13 

RI 2 10,000 99,999 6, 8 

SC 3 10,000 999,999 6, 12 

TN 8 0 49,999,999 7, 8, 9, 11, 12 

TX 17 0 9,999,999 1, 2, 4, 5, 6, 8, 11, 12, 13, 14 

WV 1 100,000 999,999 6 

a

Post office state abbreviations used 

b

Amounts on site reported by facilities in each state 

c

Activities/Uses: 

1. Produce 6. Impurity 11. Chemical Processing Aid 

2. Import 7. Reactant 12. Manufacturing Aid 

3. Onsite use/processing 8. Formulation Component 13. Ancillary/Other Uses 

4. Sale/Distribution 9. Article Component 14. Process Impurity 

5. Byproduct 10. Repackaging 

Source: TRI05 2007 (Data are from 2005) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CRESOLS 141 

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

Table 5-4. Facilities that Produce, Process, or Use Cresol (Mixed Isomers) 

Minimum Maximum 

Number of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

AL 25 0 999,999 1, 2, 3, 4, 5, 6, 7, 8, 12, 13, 14 

AR 17 0 99,999 1, 2, 3, 5, 6, 7, 8, 9, 12, 13 

CA 43 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14 

CT 6 100 9,999 1, 5, 7, 10, 11 

DE 5 10,000 99,999 1, 3, 5, 6, 7, 12 

FL 8 0 99,999 1, 5, 7, 8, 11, 12, 13 

GA 25 0 999,999 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13 

IA 1 100 999 7 

ID 5 0 999 1, 5, 13 

IL 36 1,000 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14 

IN 47 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

KS 9 1,000 999,999 1, 4, 5, 7, 10, 12, 13 

KY 27 0 9,999,999 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

LA 48 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14 

MA 3 1,000 99,999 2, 3, 6, 10, 11 

MD 7 0 999,999 1, 5, 12, 13 

ME 2 0 99 1, 5, 13 

MI 16 0 999,999 1, 4, 5, 6, 7, 12, 13 

MN 6 100 99,999 1, 2, 3, 4, 5, 6, 9, 11, 12, 13 

MO 24 0 999,999 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 14 

MS 23 0 999,999 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14 

NC 18 0 999,999 1, 2, 3, 5, 6, 7, 10, 11, 12, 13 

NE 2 1,000 99,999 12 

NH 6 1,000 999,999 2, 3, 7, 10, 11 

NJ 17 1,000 999,999 2, 3, 4, 6, 7, 9, 12 

NM 3 10,000 999,999 1, 2, 3, 7, 10, 12, 13 

NV 1 10,000 99,999 12 

NY 21 100 9,999,999 1, 2, 4, 5, 6, 7, 8, 9, 10, 12, 13 

OH 30 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

OK 6 1,000 999,999 1, 3, 4, 5, 6, 7, 9, 10, 13, 14 

OR 7 0 9,999,999 1, 2, 3, 5, 7, 9, 12, 13 

PA 27 0 9,999,999 1, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14 

PR 1 100 999 2, 3, 4, 7, 9 

RI 1 10,000 99,999 6 

SC 13 0 999,999 1, 2, 3, 5, 6, 7, 12, 13 

TN 14 0 999,999 1, 5, 6, 7, 9, 10, 11, 12, 13, 14 

TX 68 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

UT 12 1,000 999,999 1, 3, 4, 5, 6, 7, 9, 10, 12, 13 
 

 

 

CRESOLS 142 

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

Table 5-4. Facilities that Produce, Process, or Use Cresol (Mixed Isomers) 

Minimum Maximum 

Number of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

VA 10 0 999,999 1, 5, 10, 11, 12 

VI 1 100 999 2, 3, 4, 7, 9 

WA 24 0 9,999,999 1, 2, 3, 4, 5, 7, 12, 13, 14 

WI 6 0 999,999 1, 5, 6, 13 

WV 12 0 9,999,999 1, 2, 3, 4, 5, 6, 8, 12, 13 

WY 5 0 99,999 1, 4, 5, 6, 13 

a

Post office state abbreviations used 

b

Amounts on site reported by facilities in each state 

c

Activities/Uses: 

1. Produce 6. Impurity 11. Chemical Processing Aid 

2. Import 7. Reactant 12. Manufacturing Aid 

3. Onsite use/processing 8. Formulation Component 13. Ancillary/Other Uses 

4. Sale/Distribution 9. Article Component 14. Process Impurity 

5. Byproduct 10. Repackaging 

Source: TRI05 2007 (Data are from 2005) 
CRESOLS 143 

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

Table 5-5. Current U.S. Producers of Cresol 

Company Locationa Isomer 

Merisol Antioxidants, LLC Oil City, Pennsylvania m-cresol 

Merisol USA, LLC m-cresol 

m/p-cresol 

Houston, Texas o-cresol 

p-cresol 

(o,m,p)-cresol 

General Electric Company Selkirk, New York o-cresol 

PMC Specialties Group, Inc. Chicago, Illinois o-cresol 

Bell Flavors and Fragrances, Inc. Northbrook, Illinois p-cresol 

Source: Derived from SRI 2005 
 

 

 

 

 

 

 

CRESOLS 144 

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

This method is capable of producing p- or m-cresol from the corresponding cymene (isopropyltoluene). 

Alkaline chlorotoluene hydrolysis is used to formulate a cresol mixture with a high m-cresol content. 

However, information pertaining to domestic use of this process was unavailable (Fiege and Bayer 1987). 

5.2 IMPORT/EXPORT 

In 2007, 548,446 kg of cresol and cresol salts were imported from other countries netting 

$1,895,164 (OSITC 2008). The largest exporters of cresol and cresol salts to the United States were 

Spain and the United Kingdom with export amounts for 2005 of 165,040 and 822,170 kg, respectively. 

Money spent on the import of cresols and their salts to the United States has increased from $698,000 in 

2003 to $1,363,000 in 2004 and $2,754,000 in 2005 (USITC 2006). 

In 2007, 26,100,350 kg of cresol and cresol salts were exported to other countries netting 

$62,558,544 (OSITC 2008). The largest importers of cresol and cresol salts from the United States were 

China, Japan, the Netherlands, and the United Kingdom with export values for 2005 of 3,200,351; 

2,436,843; 6,317,298; and 6,140,655 kg, respectively. Money from export of cresols and their salts from 

the United States has increased from $29,736,000 in 2003 to $38,534,000 in 2004 and $47,280,000 in 

2005 (USITC 2006). 

5.3 USE 

A considerable amount of o-cresol is used directly as either a solvent or disinfectant. o-Cresol is also 

used as a chemical intermediate for a wide variety of products. o-Cresol is hydrogenated to 

2-methylcyclohexanol or 2-methylcyclohexanone, which are also solvents. Coumarin is made from the 

carbonate ester of o-cresol and is a deodorizing and odor-enhancing agent that also has pharmaceutical 

applications (Lewis 2001). Alkylation of o-cresol with propene gives 3-isopropyl-6-methylphenol 

(carvacrol). Carvacrol is used as an antiseptic and in fragrances (Windholz et al. 1983). o-Cresol also 

serves as an intermediate for the production of various antioxidants. Several dye intermediates are 

manufactured from o-cresol. o-Cresotinic acid, produced from o-cresol via the Kolbe synthesis, is used as 

a dye, a dye intermediate, and a pharmaceutical intermediate. Recently, an increasing proportion of 

o-cresol has been devoted to the formulation of epoxy-o-cresol novolak (ECN) resins. ECN resins are 

sealing materials for integrated circuits (silicon chips). o-Cresol is also used as an additive to phenolformaldehyde resins. The manufacture of certain herbicides and pesticides, including 4-chloro-2-methylphenoxyacetic acid (MCPA), 2-(4-chloro-2-methylphenoxy)-propionic acid (MCPP), γ(4-chloro­
 

 

 

 

 

CRESOLS 145 

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

2-methylphenoxy)-butyric acid (MCPB), and 4,6-dinitro-o-cresol (DNOC), is also dependent upon 

o-cresol (Fiege and Bayer 1987). 

p-Cresol is used largely in the formulation of antioxidants such as 2,6-di-tert-butyl-p-cresol (BHT), 

2,6-dicyclopentyl-p-cresol, 2,2'-methylene- or 2,2'-thiodiphenols, and Tinuvin 326. Tinuvin 326 absorbs 

ultraviolet (UV) light and is added to polyethylene and polypropylene films and coatings for protection 

against photodegradation. p-Cresol also has many applications in the fragrance and dye industries 

(O’Neil et al. 2001). Synthetic food flavors also contain p-cresol (Lewis 2001). p-Cresol carboxylic acid 

esters and anisaldehyde are used in perfumes (Lewis 2001). The latter is made from p-cresol methyl ether 

(Fiege and Bayer 1987). 

m-Cresol, either pure or mixed with p-cresol, is important in the production of contact herbicides such as 

O,O-dimethyl-O-(3-methyl-4-nitrophenyl)thionophosphoric acid (fenitrothion, Follithion, and Sumithion) 

and O,O-dimethyl-O-(3-methyl-4-methylthiophenyl)thionophosphoric acid ester (fenthion, Baytex, and 

Lebaycid) (Fiege and Bayer 1987). m-Cresol is also a precursor to the pyrethroid insecticides. 

Furthermore, many flavor and fragrance compounds, such as (-)-methanol and musk ambrette, are derived 

from m-cresol. Several important antioxidants are produced from m-cresol. m-Cresol is also used to 

manufacture an explosive, 2,4,6-nitro-m-cresol. 

Mixtures of m- and p-cresol often serve as disinfectants and preservatives (O’Neil et al. 2001). Because 

cresols are bactericides and fungicides, they are added to soaps as disinfectants. Crude cresols are used as 

wood preservatives. Tricresyl phosphate and diphenyl cresyl phosphate are produced from m- and 

p-cresol mixtures. These neutral phosphoric acid esters are used as flame-retardant plasticizers for 

polyvinylchloride (PVC) and other plastics, fire-resistant hydraulic fluids, additives for lubricants, and air 

filter oils. Cresol mixtures condensed with formaldehyde are important for modifying phenolic resins. 

However, the m-isomer content is critical to the mixture because m-cresol is the most reactive of the three 

isomers. Cresols are also used in paints and textiles. Mixtures of cresols are used as solvents for 

synthetic resin coatings such as wire enamels, metal degreasers, cutting oils, and agents to remove carbon 

deposits from combustion engines. Other uses of cresol mixtures include ore flotation and fiber treatment 

(Fiege and Bayer 1987; Windholz et al. 1983). 
 

 

CRESOLS 146 

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

5.4 DISPOSAL 

Cresols may be disposed of by landfill, land applications, biological waste water treatment, or 

incineration. In an activated sludge system, cresols exhibit a 96% reduction of the chemical oxygen 

demand and a biodegradation rate of 55 mg of oxygen/g/hour. Cresols may be disposed of in a rotary kiln 

incinerator with a temperature range of 820–1,600 °C and a residence time of seconds. Cresols may also 

be disposed of in a fluidized bed incinerator with a temperature range of 450–980 °C and a residence time 

of seconds (HSDB 2008). 
 

CRESOLS 147 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.1 OVERVIEW 

o-Cresol, m-cresol, p-cresol, and mixed cresols have been identified in at least 210, 22, 310, and 70 of the 

1,678 hazardous waste sites that have been proposed for inclusion on the EPA National Priorities List 

(NPL), respectively (HazDat 2006). However, the number of sites evaluated for cresols is not known. 

The frequency of these sites for o-, m-, p-, and mixed cresols can be seen in Figures 6-1, 6-2, 6-3, and 6-4, 

respectively. 

Cresols are widely occurring natural and anthropogenic products. Although cresols appear to be 

ubiquitous in the environment, their concentrations probably remain low due to their rapid removal rates 

in most environmental media. In air, cresols degrade rapidly because of reactions with photochemically 

produced hydroxyl radicals. Biodegradation is the dominant mechanism responsible for the fast 

breakdown of cresols in soil and water. Nevertheless, cresols may persist in extremely oligotrophic 

waters, in those with limited microbial communities, and/or those under anaerobic conditions, such as in 

some sediments and groundwater aquifers. 

Based on the available information, the most common route of exposure for the general population is 

inhalation. Cresols are constantly emitted to air via automobile exhaust; consequently, people who live in 

urban and suburban settings may be constantly exposed to low levels of cresols in the atmosphere. 

Cresols are also emitted to ambient air during the combustion of coal, wood, and municipal solid waste. 

Therefore, residents near coal- and petroleum-fueled electricity-generating facilities, municipal solid 

waste incinerators, and industries with conventional furnace operations or large-scale incinerators may be 

exposed to cresols in air. People in residential areas where homes are heated with coal, oil, or wood may 

also be exposed to cresols in air. High levels of cresol exposure can result from active and passive 

inhalation of cigarette smoke (Wynder and Hoffmann 1967). Therefore, people who smoke or live with 

smokers are exposed to higher concentrations of cresol in the air. 

6.2 RELEASES TO THE ENVIRONMENT 

The Toxics Release Inventory (TRI) data should be used with caution because only certain types of 

facilities are required to report (EPA 2005). This is not an exhaustive list. Manufacturing and processing 

facilities are required to report information to the TRI only if they employ 10 or more full-time 

employees; if their facility is included in Standard Industrial Classification (SIC) Codes 10 (except 1011, 




 

 

 

 

 

 

 

 

 

 

 

 

 

 

CRESOLS 152 

6. POTENTIAL FOR HUMAN EXPOSURE 

1081, and 1094), 12 (except 1241), 20–39, 4911 (limited to facilities that combust coal and/or oil for the 

purpose of generating electricity for distribution in commerce), 4931 (limited to facilities that combust 

coal and/or oil for the purpose of generating electricity for distribution in commerce), 4939 (limited to 

facilities that combust coal and/or oil for the purpose of generating electricity for distribution in 

commerce), 4953 (limited to facilities regulated under RCRA Subtitle C, 42 U.S.C. section 6921 et seq.), 

5169, 5171, and 7389 (limited S.C. section 6921 et seq.), 5169, 5171, and 7389 (limited to facilities 

primarily engaged in solvents recovery services on a contract or fee basis); and if their facility produces, 

imports, or processes ≥25,000 pounds of any TRI chemical or otherwise uses >10,000 pounds of a TRI 

chemical in a calendar year (EPA 2005). 

6.2.1 Air 

Estimated releases of 3,313 pounds (~1.5 metric tons) of o-cresol, 41.496 pounds (~19 metric tons) of 

m-cresol, 31,393 pounds (~14 metric tons) of p-cresol, and 932,106 pounds (~423 metric tons) of mixed 

isomers of cresol, to the atmosphere from 23, 28, 27, and 157 domestic manufacturing and processing 

facilities in 2005, accounted for about <1, 21, 21 and 72% of the estimated total environmental releases of 

o-cresol, m-cresol, p-cresol, and cresol mixed isomer from facilities required to report to the TRI (TRI05 

2007), respectively. These releases are summarized in Tables 6-1 through 6-4. 

A national emissions study conducted from 1990 to 1998 reported an estimated 11,000 tons/year released 

throughout the United States for all combined isomers of cresol (EPA 2000d). The emissions of total 

cresol isomers were 6,000 and 5,000 tons/year for urban and rural locations, respectively (EPA 2000d). 

Cresols are a group of widely distributed natural compounds formed as metabolites of microbial activity 

and excreted in the urine of mammals (Fiege and Bayer 1987). Cresols occur in various plant lipid 

constituents, including oils from jasmine, cassia, Easter lily, ylang ylang, and Yucca gloriosa flowers, 

peppermint, eucalyptus, and camphor. Oils from conifers, oaks, and sandalwood trees also contain 

cresols (Fiege and Bayer 1987). Volatilization of natural cresols from urine and transpiration of plants 

may release cresols to the air. Cresols are also a product of combustion and can be released to the 

atmosphere from natural fires associated with lightning, spontaneous combustion, and volcanic activity 

(McKnight et al. 1982). 

Cresols are natural components of crude oil and coal tar, from which they are recovered as fractional 

distillates. Cresols are also produced synthetically. The dominant anthropogenic sources for the release 
 

CRESOLS 153 

6. POTENTIAL FOR HUMAN EXPOSURE 

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

Use o-Cresola
 

Reported amounts released in pounds per yearb 

Total release 

On- and 

Statec RFd Aire Waterf UIg Landh Otheri On-sitej Off-sitek off-site 

AR 1 0 No data 0 0 0 0 0 0 

IL 2 10 No data 0 5 250 10 255 265 

KY 2 478 No data 0 0 0 478 0 478 

LA 2 4 0 0 0 0 4 0 4 

MO 1 10 No data 0 0 0 10 0 10 

NY 3 1,000 5 0 0 0 1,005 0 1,005 

OH 3 103 0 0 255 0 103 255 358 

TX 7 1,695 118 182,006 10 1 182,358 1,472 183,830 

WI 2 12 0 0 0 0 12 0 12 

Total 23 3,313 123 182,006 270 251 183,981 1,982 185,963 

a

The TRI data should be used with caution since only certain types of facilities are required to report. This is not an 

exhaustive list. Data are rounded to nearest whole number.
 b

Data in TRI are maximum amounts released by each facility.
 c

Post office state abbreviations are used.
 d

Number of reporting facilities.

e

The sum of fugitive and point source releases are included in releases to air by a given facility.
 f

Surface water discharges, waste water treatment-(metals only), and publicly owned treatment works (POTWs) (metal
 

and metal compounds).

g

Class I wells, Class II-V wells, and underground injection. h

Resource Conservation and Recovery Act (RCRA) subtitle C landfills; other on-site landfills, land treatment, surface 

impoundments, other land disposal, other landfills.

i

Storage only, solidification/stabilization (metals only), other off-site management, transfers to waste broker for
 

disposal, unknown

j

The sum of all releases of the chemical to air, land, water, and underground injection wells.

k

Total amount of chemical transferred off-site, including to POTWs.
 

RF = reporting facilities; UI = underground injection 

Source: TRI05 2007 (Data are from 2005) 
 

CRESOLS 154 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-2. Releases to the Environment from Facilities that Produce, Process, or
 

Use m-Cresola
 

Reported amounts released in pounds per yearb 

Total release 

On- and 

Statec RFd Aire Waterf UIg Landh Otheri On-sitej Off-sitek off-site 

IL 2 10 No data 0 5 250 10 255 265 

IN 6 28,159 No data 0 0 0 28,159 0 28,159 

KS 1 3 No data 0 0 0 3 0 3 

KY 1 785 No data 0 0 0 785 0 785 

MI 1 3 No data 0 0 0 3 0 3 

MO 2 270 0 0 0 0 270 0 270 

MS 1 2,400 No data 0 0 0 2,400 0 2,400 

NC 1 3 No data 0 0 0 3 0 3 

NY 1 255 5 0 0 0 260 0 260 

OH 1 1,144 0 0 500 0 1,144 500 1,644 

OK 1 0 No data 0 0 0 0 0 0 

SC 3 207 No data 0 0 0 207 0 207 

TN 1 1,414 No data 0 0 0 1,414 0 1,414 

TX 5 6,820 497 153,332 274 13 160,786 150 160,936 

WV 1 23 42 0 1 0 65 1 66 

Total 28 41,496 544 153,332 780 263 195,509 906 196,415 

a

The TRI data should be used with caution since only certain types of facilities are required to report. This is not an 

exhaustive list. Data are rounded to nearest whole number.
 b

Data in TRI are maximum amounts released by each facility.
 c

Post office state abbreviations are used.
 d

Number of reporting facilities.

e

The sum of fugitive and point source releases are included in releases to air by a given facility.
 f

Surface water discharges, waste water treatment-(metals only), and publicly owned treatment works (POTWs) (metal
 

and metal compounds).

g

Class I wells, Class II-V wells, and underground injection. h

Resource Conservation and Recovery Act (RCRA) subtitle C landfills; other on-site landfills, land treatment, surface 

impoundments, other land disposal, other landfills.

i

Storage only, solidification/stabilization (metals only), other off-site management, transfers to waste broker for
 

disposal, unknown

j

The sum of all releases of the chemical to air, land, water, and underground injection wells.

k

Total amount of chemical transferred off-site, including to POTWs.
 

RF = reporting facilities; UI = underground injection 

Source: TRI05 2007 (Data are from 2005) 
 

CRESOLS 155 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-3. Releases to the Environment from Facilities that Produce, Process, or
 

Use p-Cresola
 

Reported amounts released in pounds per yearb 

Total release 

On- and 

Statec RFd Aire Waterf UIg Landh Otheri On-sitej Off-sitek off-site 

AR 1 0 No data 0 0 0 0 0 0 

IL 2 10 No data 0 5 250 10 255 265 

IN 6 19,942 No data 0 0 0 19,942 0 19,942 

KY 1 478 No data 0 0 0 478 0 478 

LA 3 4,798 0 2,282 0 0 7,080 0 7,080 

MO 1 255 No data 0 0 0 255 0 255 

MS 1 1,500 No data 0 0 0 1,500 0 1,500 

NC 1 3 No data 0 0 0 3 0 3 

NJ 1 8 0 0 23 0 31 0 31 

NY 1 10 5 0 0 0 15 0 15 

OH 1 0 0 0 500 0 0 500 500 

OK 1 0 No data 0 0 0 0 0 0 

SC 1 16 No data 0 0 0 16 0 16 

TN 1 879 No data 0 0 0 879 0 879 

TX 5 3,494 249 114,939 138 3 118,751 72 118,823 

Total 27 31,393 254 117,221 666 253 148,960 827 149,787 

a

The TRI data should be used with caution since only certain types of facilities are required to report. This is not an 

exhaustive list. Data are rounded to nearest whole number.
 b

Data in TRI are maximum amounts released by each facility.
 c

Post office state abbreviations are used.
 d

Number of reporting facilities.

e

The sum of fugitive and point source releases are included in releases to air by a given facility.
 f

Surface water discharges, waste water treatment-(metals only), and publicly owned treatment works (POTWs) (metal
 

and metal compounds).

g

Class I wells, Class II-V wells, and underground injection. h

Resource Conservation and Recovery Act (RCRA) subtitle C landfills; other on-site landfills, land treatment, surface 

impoundments, other land disposal, other landfills.

i

Storage only, solidification/stabilization (metals only), other off-site management, transfers to waste broker for
 

disposal, unknown

j

The sum of all releases of the chemical to air, land, water, and underground injection wells.

k

Total amount of chemical transferred off-site, including to POTWs.
 

RF = reporting facilities; UI = underground injection 

Source: TRI05 2007 (Data are from 2005) 
CRESOLS 156 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-4. Releases to the Environment from Facilities that Produce, Process, or
 

Use Cresol (Mixed Isomers)a
 

Reported amounts released in pounds per yearb 

Total release 

On- and 

Statec RFd Aire Waterf UIg Landh Otheri On-sitej Off-sitek off-site 

AL 7 95,823 24 0 6 0 95,853 0 95,853 

AR 4 48,000 44 0 29 0 48,047 26 48,073 

CA 11 424 877 0 22 0 1,301 22 1,323 

DE 1 3 55,312 0 5 0 55,315 5 55,320 

FL 3 47,346 7 0 18 0 47,371 0 47,371 

GA 6 101,614 11 0 2 0 101,627 0 101,627 

ID 1 30,000 5 0 0 0 30,005 0 30,005 

IL 8 1,051 151 0 1,479 253 1,202 1,732 2,934 

IN 9 13,914 0 0 193 0 13,914 193 14,107 

KS 1 311 0 0 0 0 311 0 311 

KY 5 103,854 0 0 0 0 103,854 0 103,854 

LA 16 39,749 2,072 0 555 250 41,852 774 42,626 

MD 1 35,000 No data 0 0 0 35,000 0 35,000 

ME 2 73,719 14 0 1 0 73,734 0 73,734 

MI 2 28,073 517 0 2 21,202 28,592 21,202 49,794 

MN 1 797 No data 0 12 5 797 17 814 

MO 4 510 0 0 0 0 510 0 510 

MS 3 68,209 258 0 0 0 68,467 0 68,467 

NC 3 41,818 9 0 343 0 41,830 340 42,170 

NH 1 2,320 No data 0 0 0 2,320 0 2,320 

NJ 3 1,007 14 0 480 0 1,501 0 1,501 

NM 2 422 No data 0 0 529 422 529 951 

NY 5 5,650 385 0 0 7 6,035 7 6,042 

OH 7 557 0 0 752 18 557 770 1,327 

OK 2 500 0 0 0 8,669 500 8,669 9,169 

OR 1 0 No data 0 0 0 0 0 0 

PA 4 9,437 3 2,400 15 3,100 9,450 5,505 14,955 

SC 6 76,282 7 2 492 0 76,779 4 76,783 

TN 2 21,834 20 0 5 0 21,854 5 21,859 

TX 19 57,824 233 241,664 24 2 297,466 2,281 299,747 

UT 3 500 500 0 6,000 0 7,000 0 7,000 

VA 2 4,602 1 0 531 0 5,133 1 5,134 

WA 7 19,905 256 0 6 0 20,167 0 20,167 

WI 3 707 No data 0 0 0 707 0 707 

WV 1 93 No data 0 0 0 93 0 93 
 

 

CRESOLS 157 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-4. Releases to the Environment from Facilities that Produce, Process, or
 

Use Cresol (Mixed Isomers)a
 

Reported amounts released in pounds per yearb 

Total release 

On- and 

Statec RFd Aire Waterf UIg Landh Otheri On-sitej Off-sitek off-site 

WY 1 250 No data 0 0 0 250 0 250 

Total 157 932,106 60,721 244,066 10,971 34,035 1,239,817 42,082 1,281,899 

a

The TRI data should be used with caution since only certain types of facilities are required to report. This is not an 

exhaustive list. Data are rounded to nearest whole number.
 b

Data in TRI are maximum amounts released by each facility.
 c

Post office state abbreviations are used.
 d

Number of reporting facilities.

e

The sum of fugitive and point source releases are included in releases to air by a given facility.
 f

Surface water discharges, waste water treatment-(metals only), and publicly owned treatment works (POTWs) (metal
 

and metal compounds).

g

Class I wells, Class II-V wells, and underground injection. h

Resource Conservation and Recovery Act (RCRA) subtitle C landfills; other on-site landfills, land treatment, surface 

impoundments, other land disposal, other landfills.

i

Storage only, solidification/stabilization (metals only), other off-site management, transfers to waste broker for
 

disposal, unknown

j

The sum of all releases of the chemical to air, land, water, and underground injection wells.

k

Total amount of chemical transferred off-site, including to POTWs.
 

RF = reporting facilities; UI = underground injection 

Source: TRI05 2007 (Data are from 2005) 
 

 

 

 

 

 

 

 

 

 

 

 

CRESOLS 158 

6. POTENTIAL FOR HUMAN EXPOSURE 

of cresols to the atmosphere are fugitive or accidental emissions during the manufacture, use, transport, 

and storage of cresols or associated products of the coal tar and petroleum industries. 

Low levels of cresols are constantly emitted to the atmosphere in the exhaust from motor vehicle engines 

using petroleum based-fuels (Fraser et al. 1998; Hampton et al. 1982; Johnson et al. 1989; Seizinger and 

Dimitriades 1972). Using data collected from 7,060 vehicles entering a tunnel in Southern California, the 

emission rates (calculated as μg cresol emitted per liter of fuel consumed) of o-cresol, and m/p-cresol 

were calculated as 756.6 and 4,449.1 μg/L, respectively (Fraser et al. 1998). Cresols have been identified 

in stack emissions from municipal waste incinerators (Assmuth and Kalevi 1992; James et al. 1984; Jin et 

al. 1999; Junk and Ford 1980) and in emissions from the incineration of vegetable materials (Liberti et al. 

1983). Cresols have also been identified as a component of fly ash from coal combustion (Junk and Ford 

1980). Therefore, coal- and petroleum-fueled electricity-generating facilities are likely to emit cresols to 

the air. The combustion of wood (Hawthorne et al. 1988, 1989; Schauer et al. 2001) and cigarettes 

(Arrendale et al. 1982; Novotny et al. 1982) also emits cresols to the ambient air. Cresols are also formed 

in the atmosphere as a result of reactions between toluene and photochemically generated hydroxy 

radicals (Leone et al. 1985). 

6.2.2 Water 

Estimated releases of 123 pounds (~0.6 metric tons) of o-cresol, 544 pounds (~0.2 metric tons) of 

m-cresol, 254 pounds (~0.1 metric tons) of p-cresol, and 60,721 pounds (~28 metric tons) of mixed 

isomers of cresols to surface water from 23, 28, 27,and 157 domestic manufacturing and processing 

facilities in 2005, accounted for about 0.06, 0.2, 0.1, and 4.7% of the estimated total environmental 

releases of o-cresol, m-cresol, p-cresol, and cresol mixed isomer from facilities required to report to the 

TRI (TRI05 2007), respectively. These releases are summarized in Tables 6-1 through 6-4. 

Cresols are widely distributed natural compounds. As discussed above, they are formed as metabolites of 

microbial activity and are excreted in the urine of humans (Needham et al. 1984) as well as other 

mammals (Fiege and Bayer 1987). Cresols from human urine are biodegraded at municipal sewage 

treatment facilities prior to release to ambient waters. However, for combined septic and storm sewage 

systems, cresols may be released to surface waters during periods of precipitation when influent volumes 

exceed treatment plant capacities. Also, in rural and suburban areas where septic tanks are used (o- and 

m-cresols can resist anaerobic digestion), human excrement may be a nonpoint source release of cresols to 

groundwater. 
 

 

 

 

 

 

CRESOLS 159 

6. POTENTIAL FOR HUMAN EXPOSURE 

Low levels of cresols are constantly emitted in the exhaust from motor vehicle engines using 

petroleum-based fuels (Hampton et al. 1982; Johnson et al. 1989; Seizinger and Dimitriades 1972). 

Therefore, waterways used for transportation and recreation are likely to receive cresols from ship and 

motorboat traffic. Waste water effluents from coal gasification (Giabbai et al. 1985; Neufeld et al. 1985) 

and liquefaction facilities (Fedorak and Hrudey 1986), shale oil production sites (Dobson et al. 1985; 

Hawthorne and Sievers 1984), refineries (Cardwell et al. 1986; Snider and Manning 1982), and a poultry 

processing plant (Andelman et al. 1984) also may release cresols to surface waters. 

In general, cresols will degrade in surface waters very rapidly. However, cresols may persist in 

groundwater due to a lack of microbes and/or anaerobic conditions. Cresols are largely released to 

groundwater via landfills and hazardous waste sites. Tables 6-5 through 6-8 include monitoring data for 

these sources. 

Coal liquefaction and other waste water may contain elevated levels of cresols. Effluent from coal 

gasification facilities contained o-cresol at a concentration of 586 mg/L (Fedorak and Hrudey 1986). 

Waste water effluents from coal gasification facilities contained p-cresol at concentrations of 880 mg/L 

(Neufeld et al. 1985) and 5.12 mg/L (Pellizzari et al. 1979). A coal liquefaction and a shale oil waste 

water effluent contained p-cresol at concentrations of 420 mg/L (Fedorak and Hrudey 1986) and 

0.779 mg/L (Pellizzari et al. 1979), respectively. p-Cresol was emitted with the waste water of a poultry 

processing plant at concentrations ranging from 0.00214 to 0.0225 mg/L (Andelman et al. 1984). Waste 

water effluents from coal gasification facilities contained m-cresol at concentrations of 950 mg/L 

(Neufeld et al. 1985) and 2.67 mg/L (Pellizzari et al. 1979). A coal liquefaction and a shale oil waste 

water effluent contained m-cresol at concentrations of 1,230 mg/L (Fedorak and Hrudey 1986) and 

0.561 mg/L (Pellizzari et al. 1979), respectively. Waste water effluents from coal gasification plants 

located in North Dakota contained p- and m-cresol at a combined concentration of 1,840 mg/L (Giabbai et 

al. 1985). 

p- and m-Cresol were detected at a combined average concentration of 1.0 mg/L for three samples of 

retort water from a shale oil production facility (Hawthorne and Sievers 1984). o-Cresol was detected at 

an average concentration of 1.1 mg/L for three samples of retort water from a shale oil production facility 

(Hawthorne and Sievers 1984). 
 

 

 

 

 

 

 

CRESOLS 160 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-5. Detection of o-Cresol in the Groundwater of Hazardous Waste Sites 

and Landfills 

Sampling Number of Number 

Type/location dates samples positive Concentration Reference 

Waste sites, groundwater 

Hazardous waste/ No data No data No data 2.3 mg/L Weber and 

Buffalo, New York Matsumoto 1987 

Pine tar manufacturing/ No data No data No data 3.08 mg/L Drinkwater et al. 

Gainesville, Florida 1986 

Wood preserving/ March 1984 19 6 0.04–7.10 mg/L Goerlitz et al. 

Pensacola, Florida 1985 

Coal gasification/Hoe No data 3 3 63–6,600 μg/L Stuermer et al. 

Creek, Wyoming 1982 

Gas works Park/Seattle, December 10 2 1–10 μg/L Turney and 

Washington 1986 Goerlitz 1990 

American Creosote March 1990 No data No data 4.2 mg/L Middaugh et al. 

Works Facility/ 1991 

Pensacola, Florida 

Coal gasification/ No data 12 8 10–77 μg/L Johansen et al. 

Denmark 1997 

Samara River/Ukraine 1987–1990 No data No data 1–10 μg/L Goncharuk and 

(mine water) Milyukin 1999 

American Creosote March 1990 No data No data 0.0047 mg/L Middaugh et al. 

Works Facility/ 1991 

Pensacola, Florida 

(stream) 

Abandoned pine tar No data 11 11 0.3–5,200 mg/L McCreary et al. 

manufacturing plant/ 1983 

Gainesville, Florida 

Effluent water 

American Creosote March 1990 No data No data 10.95 mg/L Middaugh et al. 

Works Facility/ 1991 

Pensacola, Florida (feed 

water) 

American Creosote March 1990 No data No data 0.157 mg/L Middaugh et al. 

Works Facility/ 1991 

Pensacola, Florida 

(permeate water) 

Industrial effluent/ No data 4 1 418 μg/L Bethune et al. 

Managua, Nicaragua 1996 
 

 

 

CRESOLS 161 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-6. Detection of m-Cresol in the Groundwater of Hazardous Waste Sites 

and Landfills 

Sampling Number of Number 

Type/location dates samples positive Concentration Reference 

Waste sites, groundwater 

Wood preserving/ March 1984 19 4 0.05–13.73 mg/L Goerlitz at al. 

Pensacola, Florida 1985 

Infiltration of waste water, groundwater 

Municipal, secondary/ No data 2 1 0.02 μg/L Bedient et al. 

Port Devens, 1983; Hutchins 

Massachusetts et al. 1984 

Samara River/Ukraine 1987–1990 No data No data 2.5–4 μg/L Goncharuk and 

(mine water) Milyukin 1999 

Landfill, Groundwater 

Municipal/Southington, 1982–1983 No data No data 0.6 mg/L Sawhney and 

Connecticut Kozloski 1984 

Gas works Park/Seattle, December 10 1 1.5 mg/L Turney and 

Washington 1986 Goerlitz 1990 

American Creosote March 1990 No data No data 2.5 mg/L Middaugh et al. 

Works Facility/ 1991 

Pensacola, Florida 

American Creosote March 1990 No data No data 0.0031 mg/L Middaugh et al. 

Works Facility/ 1991 

Pensacola, Florida 

(stream) 

American Creosote March 1990 No data No data 11.3 mg/L Middaugh et al. 

Works Facility/ 1991 

Pensacola, Florida (feed 

water) 

American Creosote March 1990 No data No data 0.271 mg/L Middaugh et al. 

Works Facility/ 1991 

Pensacola, Florida 

(permeate water) 

Industrial effluent/ No data 4 1 349 μg/L Bethune et al. 

Managua, Nicaragua 1996 
 

 

 

 

CRESOLS 162 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-7. Detection of p-Cresol in the Groundwater of Hazardous Waste Sites 

and Landfills 

Sampling Number of Number 

Type/location dates samples positive Concentration Reference 

Waste sites, groundwater 

Hazardous waste/ No data No data No data 15 mg/L Weber and 

Buffalo, New York Matsumoto 1987 

Wood preserving/ March 1984 19 3 0.02–6.17 mg/L Goerlitz et al. 

Pensacola, Florida 1985 

Gas Works Park/Seattle, December 10 2 0.6 and 1.6 mg/L Turney and 

Washington 1986 Goerlitz 1990 

American Creosote March 1990 No data No data 2 mg/L Middaugh et al. 

Works Facility/ 1991 

Pensacola, Florida 

Landfill, groundwater 

Municipal/Southington, 1982–1983 No data No data 1.5 mg/L Sawhney and 

Connecticut Kozloski 1984 

Waste sites/surface 

water 

American Creosote March 1990 No data No data 0.0022 mg/L Middaugh et al. 

Works Facility/ 1991 

Pensacola, Florida 

(stream) 

Effluent water 

American Creosote March 1990 No data No data 8.5 mg/L Middaugh et al. 

Works Facility/ 1991 

Pensacola, Florida (feed 

water) 

American Creosote March 1990 No data No data 0.75 mg/L Middaugh et al. 

Works Facility/ 1991 

Pensacola, Florida 

(permeate water) 

Industrial effluent/ No data 4 2 166 μg/L Bethune et al. 

Managua, Nicaragua 1996 
 

 

CRESOLS 163 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-8. Detection of p- and m-Cresol in the Groundwater of Hazardous Waste
 

Sites and Landfills
 

Sampling Number of Number 

Type/location dates samples positive Concentration Reference 

Waste sites, groundwater 

Pine tar, manufacturing/ No data No data No data 5.17 mg/L Drinkwater et al. 

Gainesville, Florida 1986 

Coal gasification/Hoe No data 3 3 9.6–16.000 μg/L Stuermer et al. 

Creek, Wyoming 1982 

Abandoned pine tar No data 11 <0.3 0.3–2,900 μg/L McCreary et al. 

manufacturing plant/ 1983 

Gainesville, Florida 

Coal gasification/ No data 12 7 5–77 μg/L Johansen et al. 

Denmark 1997 

Landfill leachate/Sweden No data 3 3 34 μg/L Oman and 

Hynning 1993 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

CRESOLS 164 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.2.3 Soil 

Estimated releases of 270 pounds (~0.1 metric tons) of o-cresol, 780 pounds (~0.4 metric tons) of 

m-cresol, 666 pounds (~0.3 metric tons) of p-cresol, and 10,971 pounds (~5 metric tons) of mixed isomers 

of cresol to soils from 23, 28, 27, and 157 domestic manufacturing and processing facilities in 2005, 

accounted for about 0.1, 0.4, 0.4, and 0.9% of the estimated total environmental releases of o-cresol, 

m-cresol, p-cresol, and mixed isomers respectively, from facilities required to report to the TRI (TRI05 

2007). An additional 182,006 pounds (~83 metric tons) of o-cresol, 153,332 pounds (~70 metric tons) of 

m-cresol, 117,221 pounds (~53 metric tons) of p-cresol, and 244066 pounds (~111 metric tons) of mixed 

isomers of cresols constituting about 98, 78, 78, and 19% of the total environmental emissions for 

o-cresol, m-cresol, p-cresol, and mixed isomers respectively, were released via underground injection 

(TRI05 2007). These releases are summarized in Tables 6-1 through 6-4. 

Cresols can enter soil from the same types of natural sources as described above. In fact, microbial 

activity may be an important contributor of cresols to soil. Poultry manure reportedly contained p-cresol 

at an average concentration of 11.7 mg/kg (Yasuhara 1987). Consequently, natural cresols are constantly 

released to soils via excrement, exocellular secretions, and necromass of living and former living 

organisms, where they are expected to degrade rapidly (Section 6.3.2.3). Also, rural and suburban septic 

tanks and grazing animals on pasture lands may contribute relatively large amounts of cresols to soil. 

Cresols are released to soil at landfills and hazardous waste sites. In general, cresols will degrade in soil 

very rapidly. However, cresols may persist in soil under anaerobic conditions or due to the toxic effects 

of high concentrations of cresols or other associated compounds. Tables 6-5 through 6-8 include 

monitoring data for these sources. The land application of municipal sewage sludges that contain cresols 

may also release cresols to soil (Demirjian et al. 1984, 1987). 

6.3 ENVIRONMENTAL FATE 

6.3.1 Transport and Partitioning 

The transport and partitioning of an organic compound in the environment is a function of the physical 

and chemical properties of that compound and the site-specific characteristics of the environment (e.g., 

percentage soil organic matter). Based on the environmental correlations with physical properties 

(Thomas 1982), the physical and chemical properties of the three isomeric cresols are sufficiently similar 

to indicate that similar transport and partitioning processes will be important for each isomer in the 
 

 

 

 

 

CRESOLS 165 

6. POTENTIAL FOR HUMAN EXPOSURE 

environment. Therefore, their potential for partitioning between the various environmental compartments 

will be discussed collectively. 

In the atmosphere, the vapor pressure of the isomeric cresols, 0.11±0.30 mmHg at 25.5 C (AIChE 1989, 

2000; Chao et al. 1983), suggests that these compounds will exist predominantly in the vapor phase 

(Eisenreich et al. 1981) rather than being bonded to atmospheric particles. This is consistent with 

experimental studies that found all three isomers in the gas phase of urban air samples, but they were not 

present in the particulate samples collected at the same time (Cautreels and Van Cauwenberghe 1978) 

when the droplets are present, gas-phase creosote will predominantly be taken up. The relatively high 

water solubility of the cresol isomers, 21,520–25,950 mg/L (Yalkowsky et al. 1987), indicates that wet 

deposition may remove them from the atmosphere. This is confirmed by the detection of cresols in rain 

water (Section 6.4.2). The short atmospheric residence time expected for the cresols (Section 6.3.2.1) 

suggests that cresols will not be transported long distances from their initial point of release. 

Calculated soil adsorption coefficients (Koc) of 17.5–117 have been determined for the three isomeric 

cresols, and compare favorably with experimentally determined values ranging from 22 to 158 (Boyd 

1982; Koch and Nagel 1988). The estimated values were derived by regression analysis based on the 

inherent hydrophobicity (octanol/water partition coefficient [Kow]) of an organic compound. For the soils 

studied in these adsorption studies, this type of regression analysis successfully predicted the potential for 

the movement of cresols through soil, suggesting high to very high mobility in soil (Swann et al. 1983). 

The mobility of the isomeric cresols cannot be adequately described by considering their tendency to 

partition from water. The hydroxyl function of cresol is capable of forming relatively strong hydrogen 

bonds with active sites in the soil, and its mobility will depend on the degree in which these bonds are 

formed (Artiola-Fortuny and Fuller 1982; Boyd 1982; Southworth and Keller 1986). This was the 

rationale presented to explain large values obtained in laboratory experiments, which obtained Koc values 

for isomeric cresol ranging from 115 to 3,420 in a study of three different soils (Southworth and Keller 

1986). A Koc value near 3,000 would suggest only slight mobility in soil (Swann et al. 1983). The 

amount of hydrogen bonding to sites in the soil will be strongly influenced by the pH of the surrounding 

medium, the type of soil, its iron oxide content, anion exchange capacity, and amount of organic matter 

present. From the literature, one cannot make generalized trends as to which soils provide active bonding 

sites for the cresol isomers. For example, m-cresol adsorbed strongly to a high-clay-content soil 

(Southworth and Keller 1986), but not to two others (Luh and Baker 1970). 
 

 

 

 

 

 

CRESOLS 166 

6. POTENTIAL FOR HUMAN EXPOSURE 

In water, the isomeric cresols may eventually volatilize to the atmosphere, but volatilization is expected to 

be a slow process. Based on their Henry's law constants, which range from 1.2x10-6 to 

8.65x10-7 atm-m3

/molecule (Gaffney et al. 1987; Hine and Mookerjee 1975), the volatilization half-life 

from a model river 1 m deep, flowing at 1 m/sec, with a wind velocity of 3 m/sec can be estimated to 

range from approximately 30 to 41 days (Thomas 1982). 

Experimental bioconcentration factors (BCFs) of 14.1 for o-cresol (Sabljic 1987) and 19.9 for m-cresol 

(Freitag et al. 1982) indicate that the isomers of cresol will not bioconcentrate in fish and aquatic 

organisms to any significant extent. Also, cresols are not likely to bioconcentrate in humans. Similar to 

their behavior in soil, the isomeric cresols are not expected to adsorb to sediment and suspended organic 

matter, although the potential for this process exists. 

6.3.2 Transformation and Degradation 

All cresol isomers can be rapidly removed from environmental media. The dominant removal mechanism 

in air appears to be oxidation by hydroxyl radical during the day and nitrate radical at night, with halflives on the order of a day. In water under aerobic conditions, biodegradation will be the dominant 

removal mechanism; half-lives will be on the order of a day to a week. Under anaerobic conditions, 

biodegradation should still be important, but half-lives should be on the order of weeks to months. In soil 

under aerobic conditions, biodegradation is also important, with half-lives on the order of a week or less. 

6.3.2.1 Air 

Cresols degrade rapidly in air. Removal during the day is dominated by the reaction with hydroxyl 

radical (HO•), while nighttime removal is dominated by the nitrate radical. Reaction with other oxidants 

in air (e.g., ozone) will be much slower than reactions with hydroxyl or nitrate radical (Atkinson and 

Carter 1984). 

Hydroxyl radicals react with cresols by attacking the carbon bearing the hydroxyl group. Degradation 

products from this reaction include nitrocresols and products of ring opening such as pyruvic acid, 

acetaldehyde, formaldehyde, peroxyacetylnitrate, and nitrocresol (Atkinson et al. 1980; Grosjean 1984, 

1985). Products may vary, depending on whether the reaction takes place in the gas or particle phase 

(Grosjean 1984). Second-order rate constants for o-, p-, and m-cresol of 4.0x10-11, 4.4x10-11, and 

5.7x10-11 cm3 molecule-1 sec-1, respectively, were determined (Atkinson 1985). Using 5x105 molecules 
 

 

 

 

 

 

 

 

CRESOLS 167 

6. POTENTIAL FOR HUMAN EXPOSURE 

cm3 as an average tropospheric hydroxyl radical concentration (Atkinson 1985) and the reaction rate 

constants presented above, the atmospheric half-lives for o-, p-, and m-cresol were calculated to be 9.63, 

8.75, and 6.76 hours, respectively. 

At night, hydroxyl radical concentrations decrease and nitrate radical concentrations increase (Platt et al. 

1984), making nitrate radical reactions more important than hydroxyl radical reactions. Nitrate radicals 

attack cresols by removing the hydroxyl hydrogen, yielding a phenoxy radical. The average second-order 

rate constants for the reactions of o-, p-, and m-cresol and the nitrate radical are 1.01x10-11, 0.70x10-11 , 

and 1.08x10-11 cm3 molecule-1 sec-1, respectively (Atkinson et al. 1984; Carter et al. 1981). The half-lives 

for these reactions, assuming an average night-time nitrate radical concentration of 2.4x108 molecules 

cm3

, are 4.8, 4.5, and 6.9 minutes for o-, m-, and p-cresols, respectively (Atkinson et al. 1984; Carter et al. 

1981). 

In addition to degradation by hydroxyl and nitrate radicals, all three cresol molecules absorb small 

amounts of UV light with wavelengths above 290 nm (Sadtler 1960a, 1960b, 1966). Therefore, direct 

photolysis is also possible; however, the photolysis rate is slow compared to the rate of reaction with 

atmospheric radicals. 

6.3.2.2 Water 

Dilute cresols have been tested for biodegradability in numerous screening tests and sewage treatment 

plant simulation tests, as well as in surface water, groundwater, estuarine water, and sea water. Most tests 

indicate that the cresol isomers rapidly and completely degrade to simpler molecules under aerobic 

conditions in fresh water. Degradation is slower in salt water and under anaerobic conditions. 

All cresol isomers were found to degrade rapidly in biodegradation screening and sewage treatment plant 

simulation studies with half-lives between <24 hours and <7 days (Alexander and Lustigman 1966; 

Babeu and Vaishnav 1987; Baird et al. 1974; Chambers et al. 1963; EPA 1979; Heukelekian and Rand 

1955; Ludzack and Ettinger 1960; Lund and Rodriguez 1984; Malaney 1960; Malaney and McKinney 

1966; McKinney et al. 1956; Pauli and Franke 1972; Pitter 1976; Tabak et al. 1964; Young et al. 1968). 

In these studies, degradation was rapid with both acclimated and unacclimated inocula; initial 

concentrations ranged from 0.5 to >500 ppm. Degradation generally was slower at the higher 

concentrations; however, under sewage treatment plant conditions, high cresol concentrations can be 

degraded (e.g., Chudoba et al. [1968] reported >99% removal of starting material [4,448 ppm of p-cresol] 
 

 

 

 

 

CRESOLS 168 

6. POTENTIAL FOR HUMAN EXPOSURE 

in 3 days under sewage treatment plant conditions). The available screening tests indicate that the cresols 

are readily degraded by microorganisms and activated sludge. 

Very little information is available concerning the differences in the biodegradability of the cresol 

isomers. Based on the results of one study (Visser et al. 1977), biodegradability of their isomers appears 

to exist in the order: p-cresol > o-cresol > m-cresol. Aerobic degradation under these conditions appears 

to be fast, with the initial step being the rate-limiting step. No intermediate products have been reported 

using grab samples and the inoculum (EPA 1978; Spain and van Veld 1983). 

Aerobic biodegradation in salt water (estuarine and sea water) appears to be slower than in fresh water; 

insufficient information is available to estimate anaerobic degradation in salt water. Factors governing 

biodegradation of m- and p-cresol in salt water include spatial and temporal variations (e.g., salinity and 

temperature) (Bartholomew and Pfaender 1983; Palumbo et al. 1988; Pfaender and Bartholomew 1982a, 

1982b; Spain and van Veld 1983; van Veld and Spain 1983), substrate concentration (Palumbo et al. 

1988; Spain and van Veld 1983), and the presence or absence of sediment (van Veld and Spain 1983). 

Almost no information is available for o-cresol, although one biological oxygen demand (BOD) test in 

saline water suggested rapid degradation (Takemoto et al. 1981). 

In contrast to aerobic conditions, cresols do not appear to degrade rapidly in anaerobic fresh water 

sediments, although very little information is available. Horowitz et al. (1982) reported that the cresol 

isomers in anoxic sediments from Wintergreen Lake in Kalamazoo County, Michigan, had degradation 

times in excess of 29 weeks. The authors also stated that, as described above for anaerobic sludges, the 

m- and p-cresol isomers showed the most degradation, while o-cresol resisted degradation. 

In anaerobic groundwater samples and groundwater samples with aquifer materials, cresol isomers 

display the same pattern of degradation p-cresol > m-cresol > o-cresol, where p-cresol is the most readily 

biodegradable of the three isomers, seen in anaerobic sewage sludge experiments. Thomas et al. (1989) 

reported that o-cresol concentrations decreased, then increased, in a groundwater sample from a creosotecontaminated site. The authors suggested that o-cresol may be a metabolite of some other chemical 

present during the multi-component study. 

The degradation pathway of p-cresol in groundwater appears to proceed by oxidation of the methyl group 

to first give the corresponding benzaldehyde, then benzoic acid (Kuhn et al. 1988; Smolenski and Suflita 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

CRESOLS 169 

6. POTENTIAL FOR HUMAN EXPOSURE 

1987; Suflita et al. 1988, 1989). The hydroxybenzoic acid then can be either decarboxylated or 

dehydroxylated to phenol or benzoic acid, respectively. 

There are no hydrolyzable functional groups on cresol, so hydrolysis is not an important environmental 

fate process. In addition to biodegradation, chemical oxidation (including by superoxide, singlet oxygen, 

hydroxyl radical, and organic peroxy radicals) and photolysis may be removal pathways in the 

environment, but do not appear to be as fast as biodegradation under most conditions. Faust and Holgné 

(1987) reported that the irradiation of water containing fulvic acid produced a transient oxidant that 

oxidized o- and p-cresol. The transient radical was suggested to be an organic peroxy species. Irradiation 

of water without fulvic acid produced almost no degradation of p-cresol in 3 hours; the addition of fulvic 

acids caused rapid disappearance with half-times of about 50 minutes (EPA 1978). In water from 

Greifensee (a polluted, eutrophic, pre-alpine Swiss lake) at pH 8, calculated half-lives for the top meter of 

water (where light of the necessary wavelength is present) are 11 and 4.4 days for o- and p-cresol, 

respectively. Singlet oxygen is also produced by solar irradiation on natural waters and can react with 

cresols. A rate constant of 3.7x10-8 M-1 sec-1 for p-cresol reaction with singlet oxygen was produced in 

the laboratory by irradiation of water containing rose bengal (Scully and Hoigne 1987). Using a singlet 

oxygen concentration of 4x10-14 M (corresponding to the concentration in water at noon on a summer 

day), these authors calculated a half-life of 500 hours. EPA (1978) studied the direct photolysis of 

p-cresol in water. In pure water and using solar irradiation in April, EPA (1978) reported half-lives of 

approximately 35 days. 

While the above data indicate that oxidative and photolytic processes occur during degradation of cresols 

in water, it is difficult to estimate the half-lives for these under environmental conditions. Since 

environmental waters vary significantly in clarity (and hence, in their ability to transmit light), as well as 

their concentration of fulvic substances, half-lives are expected to vary considerably. Additionally, the 

absorbance of cresols changes with the pH of the water (EPA 1978). Thus, the amount of light absorbed 

at a specific wavelength by cresols will change with pH, as will the degradation rates. EPA (1978) 

estimated a half-life of p-cresol in environmental waters from direct photolysis of 300–400 days under 

summer light conditions. This, with the other estimates presented above, suggests that chemical oxidation 

from light-produced radicals and direct photolysis will not be a significant removal mechanism under 

most environmental conditions. 

In addition to oxidants generated by light, Stone (1987) reported that ferric iron [Fe(III)] and manganese 

[Mn(III/IV)] oxides are capable of oxidizing p-cresol. Fe(III) and Mn(III/IV) oxides are common species 
 

 

 

 

 

 

 

 

 

 

CRESOLS 170 

6. POTENTIAL FOR HUMAN EXPOSURE 

found in surface water particulate and soils, as well as in dust and ash. Rate constants for p-cresol ranged 

from 10-9 to 10-6 mol/L-min for pH of 7.8–4.2, respectively. In the environment and at low pH values, 

these species may oxidize cresols with half-lives on the order of several hours. 

6.3.2.3 Sediment and Soil 

Cresol degradation in soil has been reported by Medvedev and Davidov (1981a, 1981b), Namkoong et al. 

(1988), and Dobbins and Pfaender (1988). Dobbins and Pfaender (1988) and Namkoong et al. (1988) 

found that the data for cresol degradation fit first-order kinetics, but with very different rates. Dobbins 

and Pfaender (1988) found that CO2 from m-cresol degradation evolved slowly when m-cresol was 

incubated in water slurries of surface and subsurface soils from a pristine location. Degradation was 

followed by trapping radioactive carbon dioxide, and overall mass balances were performed by 

comparing radioactivity remaining in the soil with the trapped CO2. In surface soils, first-order rate 

constants based on CO2 evolution were 7.55x10-5–6.31x10-4 hour-1, which yields half-lives from 46 days 

to about 1 year. 

By contrast, Namkoong et al. (1988) reported a rapid degradation of all cresol isomers in surface soils 

from an uncultivated grassland site. Degradation was followed by analyzing for the parent substance, and 

first-order kinetics were followed. o-Cresol reportedly had a half-life of about 1.6 days, while p-cresol 

degraded too fast to allow measurement of a rate constant. m-Cresol reportedly had a half-life of about 

0.6 days. Medvedev and Davidov (1981a, 1981b) reported the same relative rates for the three isomers in 

a soil from the Soviet Union but did not report absolute rates. Times to disappearance in the soil were 

reportedly 16, 9, and 27 days for o-, p-, and m-cresol, respectively. These authors were unable to detect 

any secondary products from cresol metabolism. The differences in the rates reported by Namkoong et al. 

(1988) and Dobbins and Pfaender (1988) appear to be the result of the different analytical methods used. 

Namkoong et al. (1988) used gas chromatography to determine the rate of cresol disappearance, while 

Dobbins and Pfaender (1988) used CO2 evolution to determine the rate of carbon dioxide appearance. 

Thus, based on the available information, cresols degrade rapidly in soils, possibly becoming incorporated 

into soil microorganisms, but they mineralize slowly. Indeed, Dobbins and Pfaender (1988) noted that 

significant amounts of radioactivity were bound to the soil, which supports the explanation that cresols or 

cresol metabolites are incorporated. 
 

 

 

 

 

 

 

 

 

 

 

 

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6. POTENTIAL FOR HUMAN EXPOSURE 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 

Reliable evaluation of the potential for human exposure to cresols depends in part on the reliability of 

supporting analytical data from environmental samples and biological specimens. Concentrations of 

cresols 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 cresol 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 cresols in a 

variety of environmental media are detailed in Chapter 7. 

6.4.1 Air 

Monitoring data have not shown cresols to be widely occurring atmospheric pollutants. A national 

emissions study conducted from 1990 to 1998 reported an estimated ambient concentration average of 

31.7 ng/m3 (EPA 2000d). In an analysis of contaminants of the air in southern California in August 1987, 

background levels of p-cresol and o-cresol were found in concentrations of 0.02–0.07 and 0.09–0.30 ppb 

(Harley and Cass 1994). The National Ambient Volatile Organic Compounds (VOCs) Database, a 

compilation of published and unpublished air monitoring data from 1970 to 1987, contained very little 

information on the cresols (EPA 1988e). The database contained only information for o-cresol in sourcedominated atmospheres (air surrounding a facility or known release of the chemical in question). The 

median air concentration of o-cresol at source-dominated sites is 1.62 μg/m3 for 32 samples (EPA 1988e). 

The median atmospheric concentration of o-cresol (10 samples collected at three unspecified sites in the 

United States) was 1.5 μg/m3

, a range of 0.5–20 μg/m3 was reported for p-cresol (62 samples collected at 

11 unspecified sites in the United States), and m-cresol was not detected in any of the three samples 

studied (Kelly et al. 1994). On September 8–9, 1993, 46.77 and 90.53 ng/m3 of o-cresol and a mixture of 

p- and m-cresol, respectively, were detected in vapor-phase semivolatile organics over Southern 

California during a major photochemical smog event (Fraser et al. 1998). Cresol was detected in the 

ambient air of Upland, California; however, specific isomers were not identified (Kolber et al. 1981). 

All three isomers of cresol have been identified, but not quantified, in gas samples taken from various 

municipal landfills in southern Finland (Assmuth and Kalevi 1992). In coal gas effluent, p- and m-cresol 

were found in concentrations of 11.6 and 7.09 mg/L, respectively (Jin et al. 1999). p-Cresol was detected 

in the emissions at waste incineration plants in Germany at a concentration of 0.43 μg/m3 (Jay and 

Stieglitz 1995). p-Cresol was indentified in the air adjacent to municipal incinerators, waste collection 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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6. POTENTIAL FOR HUMAN EXPOSURE 

centers, and sewage treatment plants around Southampton, England in concentrations ranging from 

<0.1 to 24.5 μg/m3 (Leach et al. 1999). 

In a study of air emissions from burning pine, oak, and eucalyptus, o-cresol was detected in the gas phase 

for all three samples at concentrations of 89.6, 47.7, and 37.8 mg/kg wood burned, respectively, and in the 

particle phase of oak and eucalyptus at concentrations of 0.018 and 0.006 mg/kg wood burned, 

respectively. A mixture of p- and m-cresol was detected in the gas phase for pine, oak, and eucalyptus in 

concentrations of 380, 179, and 110 mg/kg wood burned, respectively, and in the particle phase of all 

three wood types at concentrations of 0.5, 0.21, and 0.055 mg/kg wood burned, respectively (Schauer et 

al. 2001). 

The absence of data does not necessarily indicate a lack of cresol emissions into ambient air. In general, 

cresols are highly reactive with hydroxyl and nitrate radicals in the day and night, respectively, and 

atmospheric half-lives for cresols are short. Scavenging by water may further reduce the atmospheric 

residence time of cresols (see Section 6.3.2.1). 

6.4.2 Water 

In a national study of organic contaminants in 139 U.S. streams located in 30 states from 1999 to 2000, 

p-cresol was detected in 24.7% of the samples taken with a maximum concentration of 0.54 μg/L and a 

mean concentration of 0.05 μg/L (Kolpin et al. 2002). In a study of public groundwater at superfund 

sites, o-cresol and p-cresol were detected with maximum concentrations of 390 and 150 μg/L, 

respectively; however, neither was detected in well fields or finished water from treatment plants (Canter 

and Sabatini 1994). 

o-Cresol was detected in fresh water samples from Spirit Lake, Washington, on August 7, 1980 and from 

South Fork Castle Lake and Smith Creek, Washington, on September 11, 1980 at unreported 

concentrations (McKnight et al. 1982). The presence of cresols attributed to the Mount St. Helens 

eruption on May 18, 1980 was most likely a result of incomplete combustion of plant materials 

(McKnight et al. 1982). Whether or not the cresols originated from wood fires or the actual eruption was 

not clarified. 

p-Cresol was detected in surface water with a frequency of occurrence of 1.5% and with a geometric 

mean concentration of 11 μg/L for positive samples (CLPSD 1988). p-Cresol was identified as a 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

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6. POTENTIAL FOR HUMAN EXPOSURE 

contaminant of mixed water and sediment samples from the Tennessee River (Gordon and Goodley 1971) 

at a concentration of 200 μg/L (Goodley and Gordon 1976). p-Cresol also was detected in fresh water 

samples from Spirit Lake, Washington, on August 7, 1980 at unreported concentrations (McKnight et al. 

1982). 

m-Cresol was detected with a frequency of occurrence of 0.9% in surface water (CLPSD 1988). In 

addition, m-cresol was listed as a contaminant of the St. Joseph River in the Lake Michigan Basin (Great 

Lakes Water Quality Board 1983). m-Cresol was detected in fresh water samples from Spirit Lake, 

Washington, on August 7, 1980 at unreported concentrations (McKnight et al. 1982). 

Industrial effluents are a source of groundwater exposure to cresols. While human exposure to these 

waters is unlikely, it is important to note these releases to groundwater. Unspecified isomers of cresol 

were detected from one of seven sample sites along the Delaware River at a concentration of 20 μg/L. 

This was a result of industrial waste water effluent discharged by the Philadelphia Northeast Sewage 

Treatment Plant, which discharges secondary effluent into the river (Hites 1979; Sheldon and Hites 1979). 

For Delaware River water from August 1976 to March 1977, the summer and winter average 

concentrations of unspecified isomers of cresols that were not traceable to any source were "not detected" 

and 2 μg/L, respectively; this suggested that rapid biodegradation prevents cresol detection during the 

warmer months (Sheldon and Hites 1978). 

Tables 6-5 through 6-8 summarize the literature data on cresols found in groundwater and their respective 

anthropogenic sources. 

Rain water at Portland, Oregon, contained o-cresol at concentrations ranging from 0.240 to 2.80 μg/L, 

with an average concentration of 1.02 μg/L for seven rainfalls between February 12, 1984 and 

April 12, 1984. In addition to this study, combined p- and m-cresol was detected in rain in Portland, 

Oregon at concentrations >1.1 μg/L (Grosjean 1991). Combined p- and m-cresol concentrations ranged 

from 0.380 to 2.00 μg/L, with an average concentration of >1.10 μg/L (Leuenberger et al. 1985). 

o-Cresol was detected in rain water from a rural site (Grepden, Switzerland) on April 3, 1986, at 

concentrations ranging from not detected to 1.3 μg/L. Combined p- and m-cresol concentrations ranged 

from 0.65 to 9.3 μg/L (Czuczwa et al. 1987). Combined p-and m-cresol were detected in rain and cloud 

water in Vosges Mountains in France at concentrations ranging from 0.47 to 2.23 μg/L (Levsen et al. 

1993). p- and m-Cresol were also detected in concentrations ranging from 0.6 to 3.6 μg/L in cloud water 

samples taken from Mt. Brocken in Germany during June 1994 (Luttke et al. 1999). p-Cresol was found 
 

 

 

 

 

 

 

 

 

 

 

 

 

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6. POTENTIAL FOR HUMAN EXPOSURE 

in snow samples from Finland, Moscow, and Siberia at concentrations 0.04, 0.004–0.06, and 0.29 μg/kg 

(Poliakova et al. 2000). o-Cresol was found in snow samples from Finland and Moscow in concentration 

of 0.07 and 0.03 μg/kg, respectively (Poliakova et al. 2000). 

Cresols are formed when various aromatic compounds are metabolized. Therefore, cresols are expected 

to be in municipal waste water. p-Cresol was detected in five of nine municipal waste water plants in 

western Virginia with concentrations ranging from 0.18 to 0.86 μg/sample (Dietrich et al. 1993). 

The absence of monitoring data does not necessarily indicate a lack of cresols in the environment. 

Cresols are widely occurring natural and anthropogenic products. However, biodegradation is probably 

the dominant mechanism responsible for the rapid removal of cresols from surface waters (see 

Section 6.3.2.2). Nevertheless, cresols may persist in extremely oligotrophic waters, in waters with 

limited microbial communities, and/or under anaerobic conditions such as in some sediments and 

groundwater aquifers. 

6.4.3 Sediment and Soil 

o-Cresol was detected in 3.7% of the soil samples in the Contract Laboratory Program Statistical 

Database (CLPSD) (CLPSD 1988). p- and m-Cresol were also detected with frequencies of occurrence of 

4.4 and 0.9%, and geometric mean concentrations of 257 and 1,105 μg/kg for the positive samples, 

respectively (CLPSD 1988). o-Cresol was detected at maximum concentrations of 12,000, 21,000, 

34,000, and 55,000 μg/kg in the soil of an abandoned pine tar manufacturing plant in Gainesville, Florida 

at four separate sites (McCreary et al. 1983). 

Cresols are an excretory product of mammals and an intermediate biotransformation product of natural 

aromatics such as lignin constituents (Fiege and Bayer 1987). Soil microorganisms are capable of 

metabolizing cresols, and any anthropogenic release of cresol, other than massive spills, is likely to be 

rapidly degraded in soil (Section 6.3.2.3). 

Cresols have been detected in various sediment samples. In Roane County, Tennessee, p-cresol was 

detected in two sediment samples at concentrations of 1,233 and 127 ppb. In a study of streambed 

sediment in 20 major river basins of the United States from 1992 to1995, p-cresol was identified in 37.8% 

of the sites with a maximum value of 4,800 μg/kg dry weight; however, 90% of the positive samples 

contained ≤430 μg/kg dry weight (Lopes and Furlong 2001). o- and p-Cresol were identified, but not 
 

 

 

 

 

 

 

 

 

 

 

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6. POTENTIAL FOR HUMAN EXPOSURE 

quantified, in sediment samples obtained from the Elbe River of the German Bight (Schwarzbauer et al. 

2000). 

6.4.4 Other Environmental Media 

As discussed above, cresols are widely distributed natural compounds. They are formed as metabolites of 

microbial activity and are excreted in the urine of animals. Various plant lipid constituents, including 

many oils, contain cresols. Cresols have also been detected in certain foods and beverages such as 

tomatoes, tomato ketchup, cooked asparagus, various cheeses, butter, oil, red wine, distilled spirits, raw 

and roasted coffee, black tea, smoked foods, tobacco, and tobacco smoke (Fiege and Bayer 1987). 

However, very few monitoring data for cresols in food were found in the literature. p-Cresol has been 

detected in fermented soybean curds at concentrations ranging from 52.0 to 67.3 μg/kg (Chung 1999) and 

o-cresol has been detected in big eyed herring fermented fish at a mean concentration of 18.6 μg/kg (Cha 

and Cadwallader 1995). 

Both o-cresol and p-cresol have been detected in eggs of birds of the Selenga river estuary in Lake Baikal, 

Russia, one of the largest fresh natural water sources in the world. Concentrations ranged from 208 to 

<10 μg/kg dry weight and from 540 to <10 μg/kg dry weight for o- and p-cresol, respectively (Lebedev et 

al. 1998). 

All three cresol isomers were identified as volatile emissions of fried bacon (Ho et al. 1983). Various 

brands of Scotch whiskey, whiskeys made outside of Scotland, cognac, armagnac, brandy other than 

cognac and armagnac, and white and dark rums contained cresol at concentrations of 0.01–0.20 ppm, 

0.01–0.07 ppm, trace to 0.02 ppm, trace to 0.02 ppm, trace to 0.02 ppm, and trace to 0.20 ppm, 

respectively (Lehtonen 1983). 

Cresols are emitted in cigarette smoke. The total concentration of o-cresol and combined m-cresol and 

p-cresol in cigarette smoke was reported to range from approximately 14 to 26 μg/cigarette and from 

41 to 82 μg/cigarette, respectively (Wynder and Hoffmann 1967). Depending upon the rate of ventilation, 

o-cresol was detected in cigarette smoke at levels of 7.1–37 μg/cigarette, while combined m-cresol and 

p-cresol isomers were emitted at a rate of 12.3–68 μg/cigarette (Singer et al. 2002). The average cresol 

concentration in a 45 cubic meter chamber after six cigarettes had been smoked ranged from 0.17 to 

3.9 μg/m3 depending on the brand and type of cigarette (Nelson et al. 1998). In another study, o-, m-, and 

p-cresol were emitted from mainstream cigarette smoke at mean rates of 3.31, 2.55, and 6.36 μg/cigarette, 
 

 

 

 

 

 

 

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6. POTENTIAL FOR HUMAN EXPOSURE 

respectively (Rustemeier et al. 2002). Under steady-state conditions in a furnished 50 cubic meter room, 

the exposure relevant emission factors (EREFs) of o-, m-, and p-cresol were 22–41, 16–35, and 32– 

72 μg/cigarette, respectively, depending upon the ventilation of the building (Singer et al. 2003). These 

EREFs measure not only the initial exposure to environmental tobacco smoke, but also the potential for 

exposure from the re-emission of chemicals from absorbing surfaces such as wallboard, carpeting, and 

other room furnishings. 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 

Inhalation exposure is likely to be the most common route of exposure for the general population to 

cresols. However, since cresols have a short residence time in both day- and night-time air; atmospheric 

levels are probably low despite their ubiquitous nature. 

Cresols have been identified as components of automobile exhaust (Hampton et al. 1982; Johnson et al. 

1989; Seizinger and Dimitriades 1972), and may volatilize from gasoline and diesel fuels used to power 

motor vehicles. Vehicular traffic in urban and suburban settings provides a constant source of cresols to 

the atmosphere. Hence, urban and suburban populations may be constantly exposed to atmospheric 

cresols. Cresols are also emitted to ambient air during the combustion of coal (Junk and Ford 1980), 

wood (Hawthorne et al. 1988, 1989), municipal solid waste (James et al. 1984; Junk and Ford 1980), and 

cigarettes (Arrendale et al. 1982; Novotny et al. 1982). Therefore, residents near coal- and petroleumfueled electricity-generating facilities, municipal solid waste incinerators, and industries with 

conventional furnace operations or large-scale incinerators may be exposed to cresols in air. People in 

residential areas where homes are heated with coal, oil, or wood may also be exposed to cresols in air. 

Exposure to cresol may occur in atmospheres containing toluene. Cresols are formed in the atmosphere 

during photochemical reactions between toluene and photochemically generated hydroxy radicals (Leone 

et al. 1985). 

Cigarette smoke is also a source of cresol exposure. One estimate indicated that an individual who 

smokes two packs of cigarettes a day may inhale 3 μg/day of total cresol (Wynder and Hoffmann 1967). 

Other estimates are somewhat higher; for instance, Nazaroff and Singer (2004) estimated that nonsmokers 

who live with a person who smokes nine cigarettes/day may inhale 2–5 μg/day of cresols through 

inhalation of second-hand smoke. 
 

 

 

 

 

 

 

 

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6. POTENTIAL FOR HUMAN EXPOSURE 

Ingestion of certain foods may be as prevalent or more prevalent a route of exposure than inhalation. 

However, more quantitative data on the occurrence of cresols in food would be required to make a 

comparison. Cresols have been detected in tomatoes and tomato ketchup, cooked asparagus, various 

cheeses, butter, and oil (Fiege and Bayer 1987). Beverages such as red wine and distilled spirits 

(Lehtonen 1983), raw and roasted coffee, and black tea contain cresols (Fiege and Bayer 1987). Fried 

(Ho et al. 1983), smoked, and barbecued foods also may contain cresols (Fiege and Bayer 1987). For 

people with groundwater wells near landfills or hazardous waste sites, drinking water may be an 

important source of exposure; individuals living near hazardous waste sites or cresol production facilities 

may also be exposed. Quantitative information for both foods and drinking water was lacking, and the 

respective average daily intakes were not calculated. 

Dermal contact to cresols may occur during recreational activities at natural waterways containing either 

naturally or anthropogenically generated cresols. However, cresols are expected to degrade rapidly in 

surface water and this is not likely to be a major source of exposure. 

According to the National Occupational Exposure Survey (NOES) conducted by NIOSH in the workplace 

between 1981 and 1983, 10,985 (483 are female), 21,313 (16,798 are female), 5,615 (1,174 are female), 

and 132,742 (28,184 are female) workers were potentially exposed to o-, p-, m-, and the mixture of 

isomers, respectively (NIOSH 1989). The NOES database does not contain information on the frequency, 

concentration, or duration of exposure of workers to any of the chemicals listed therein. These surveys 

provide estimates of the number of workers potentially exposed to the chemicals in the workplace. The 

most probable routes of occupational exposure are inhalation and dermal contact at places where cresols 

and/or cresol-containing compounds are produced or used. 

Very little information pertaining to occupational exposure to cresols was located in the literature. 

Occupational exposure to cresols has been documented in laboratories and coal gasification facilities 

(Needham et al. 1984), during paint and varnish application (Angerer and Wulf 1985), during application 

of insulation lacquers to copper wires, and in wood-preserving facilities (Nieminen and Heikkila 1986). 

During the creosote impregnation of wood, workers were exposed to cresol concentrations <0.1 mg/m3 

(Heikkila et al. 1987). Workers of a bench scale coal conversion process were exposed to atmospheric 

levels of cresols <0.1 ppm in 1981 and 1982 (Dreibelbis et al. 1985). 
 

 

 

 

 

 

 

 

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6. POTENTIAL FOR HUMAN EXPOSURE 

6.6 EXPOSURES OF CHILDREN 

This section focuses on exposures from conception to maturity at 18 years in humans. Differences from 

adults in susceptibility to hazardous substances are discussed in Section 3.7, Children’s Susceptibility. 

Children are not small adults. A child’s exposure may differ from an adult’s exposure in many ways. 

Children drink more fluids, eat more food, breathe more air per kilogram of body weight, and have a 

larger skin surface in proportion to their body volume. A child’s diet often differs from that of adults. 

The developing human’s source of nutrition changes with age: from placental nourishment to breast milk 

or formula to the diet of older children who eat more of certain types of foods than adults. A child’s 

behavior and lifestyle also influence exposure. Children crawl on the floor, put things in their mouths, 

sometimes eat inappropriate things (such as dirt or paint chips), and spend more time outdoors. Children 

also are closer to the ground, and they do not use the judgment of adults to avoid hazards (NRC 1993). 

No data regarding environmental cresol exposure in children were found. No reports or studies of cresol 

in baby food or breast milk were found. The most likely route of exposure to cresols for children is 

through inhalation of ambient air. Children who live in areas of high traffic or with adults who smoke are 

more likely to be exposed to cresols through inhalation. 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 

High levels of exposure to cresols are most likely to occur in occupational settings where cresols are 

either produced or used. Intake by inhalation or dermal contact is the most probable route of high 

exposure to cresols. Cigarette smokers or persons who reside with smokers are likely to be exposed to 

higher amounts of cresols than the nonsmoking general population 

People who work at manufacturing facilities that process coal or coal tar may have an increased risk for 

cresol exposure. In a study of 76 male workers aged 22–58 years of age employed at a coke plant in 

Poland, slightly elevated levels of o-cresol and m/p-cresol were detected in the urine of employees when 

compared to a group of 34 nonoccupationally exposed individuals (Bieniek 1997). The concentrations of 

o-cresol and m/p-cresol in the urine of subjects working in the high temperature tar distillation process 

were 0.54 and 18.14 mg/L, respectively, while the nonexposed control group had levels of 0.041 and 

14.38 mg/L for o-cresol and m/p-cresol, respectively (Bieniek 1997). The time-weighted geometric mean 

concentrations of o-cresol and m/p-cresol in the breathing zone at the plant were reported as 0.09 and 

0.13 mg/m3

, respectively (Bieniek 1997). 
 

 

 

 

 

 

 

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6. POTENTIAL FOR HUMAN EXPOSURE 

Workers at gas stations, or those involved in distillation of crude tar, oil, and other plants that produce 

cresols as side-products are likely to have increased exposure to cresols. However, there are no 

monitoring data to give the exact exposure. 

Cresols are metabolites of other aromatic compounds. o-Cresol is a metabolite of toluene and therefore, 

exposure to toluene may increase exposure to o-cresol. Toluene is a major component of glue. In a 

Japanese study, people who sniffed glue as a form of intoxication had a mean value of 7.31 mg o-cresol/g 

creatinine in their urine as opposed to 0.095 and 0.016 mg o-cresol/g creatinine for industrial workers and 

those who did not sniff glue (Yamazaki et al. 1992). Workers who were occupationally exposed to 

toluene at a median concentration of 284.4 mg/m3 in workplace air had a median urinary o-cresol level of 

2.1 mg/g creatinine (Angerer and Kramer 1997). Workers at a rotogravure printing plant, who were 

exposed to toluene at levels ranging from 8 to 496 mg/m3 in workplace air, had mean o-cresol urinary 

excretion levels ranging from 0.080 to 2.37 mmol o-cresol/mol creatinine (0.076–2.26 mg o-cresol/g 

creatinine) (Nise 1992). These o-cresol excretory levels were correlated with toluene exposure levels and 

smoking habits of the employees. 

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 cresols is available. Where adequate information is not 

available, ATSDR, in conjunction with NTP, is required to assure the initiation of a program of research 

designed to determine the health effects (and techniques for developing methods to determine such health 

effects) of cresols. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 
 

 

 

 

 

 

 

 

 

 

 

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6. POTENTIAL FOR HUMAN EXPOSURE 

6.8.1 Identification of Data Needs 

Physical and Chemical Properties. The physical and chemical properties necessary to estimate 

the fate and transport of cresols in the environment have been described for all isomers (AIChE 1989, 

2000; Amoore and Hautala 1983; Artiola-Fortuny and Fuller 1982; Boyd 1982; Chao et al. 1983; Freitag 

et al. 1985; Gaffney et al. 1987; Hansch and Leo 1985; Hine and Mookerjee 1975; Lewis 2001; Lide 

2005; Riddick et al. 1986; Verschueren 1983; Windholz et al. 1983; Yalkowsky et al. 1987). Knowledge 

of some of these properties was required to describe the fate and transport of cresols because adequate 

experimental data were not available. The database was sufficient to perform the necessary estimates 

(Thomas 1982). 

Production, Import/Export, Use, Release, and Disposal. According to the Emergency 

Planning and Community Right-to-Know Act of 1986, 42 U.S.C. Section 11023, industries are required 

to submit substance release and off-site transfer information to the EPA. The TRI, which contains this 

information for 2005, became available in May of 2007. This database is updated yearly and should 

provide a list of industrial production facilities and emissions. 

Current production volumes and demand for cresylics are available (CMR 2004; USITC 2006), as are 

historical and predictive production volume information (CMR 2004; USITC 2006). Information on the 

uses of cresols is available, including the use as a chemical intermediate and wood preservative. 

Information on the release of cresols to the environment (Andelman et al. 1984; Arrendale et al. 1982; 

Cardwell et al. 1986; Dobson et al. 1985; Fedorak and Hrudey 1986; Giabbai et al. 1985; Hampton et al. 

1982; Hawthorne and Sievers 1984; Hawthorne et al. 1988, 1989; James et al. 1984; Johnson et al. 1989; 

Junk and Ford 1980; Leone et al. 1985; Liberti et al. 1983; Neufeld et al. 1985; Novotny et al. 1982; 

Pellizzari et al. 1979; Seizinger and Dimitriades 1972; Snider and Manning 1982) from manufacturing, 

production, and use (TRI05 2007) and to the workplace, as well as their presence in foods and other 

natural sources, is available (Fiege and Bayer 1987; McKnight et al. 1982; Needham et al. 1984). 

Disposal methods are also well described. 

Environmental Fate. Information concerning the partitioning of cresols in the environment is 

available; cresols occur in all environmental media. Information on the transport of cresols in 

environmental media is also available; however, the confounding influence of pH on soil transport makes 

assessing soil leaching difficult. An extensive database is available describing the aerobic (Alexander and 

Lustigman 1966; Babeu and Vaishnav 1987; Baird et al. 1974; Chambers et al. 1963; EPA 1979; 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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6. POTENTIAL FOR HUMAN EXPOSURE 

Heukelekian and Rand 1955; Ludzack and Ettinger 1960; Lund and Rodriguez 1984; Malaney 1960; 

Malaney and McKinney 1966; McKinney et al. 1956; Pauli and Franke 1972; Pitter 1976; Tabak et al. 

1964; Young et al. 1968) and anaerobic (Battersby and Wilson 1988, 1989; Boyd et al. 1983; EPA 1981; 

Fedorak and Hrudey 1984; Horowitz et al. 1982; Wang et al. 1988, 1989) degradation of cresols in water. 

Data exist regarding the biodegradation of cresols in soils (Dobbins and Pfaender 1988; Medvedev and 

Davidov 1981a, 1981b; Namkoong et al. 1988). The atmospheric fate of cresol isomers is well described 

and suggests that cresols are rapidly degraded in air (Atkinson 1985; Atkinson et al. 1980, 1984; Carter et 

al. 1981; Grosjean 1984, 1985; Platt et al. 1984). No data needs are identified at this time. 

Bioavailability from Environmental Media. Case reports of people who have experienced cresol 

poisoning following oral and dermal exposure indicate that all cresols can be absorbed by these routes 

(Cason 1959; Chan et al. 1971; Green 1975). However, no information is available regarding oral or 

dermal absorption of cresols in water and soil matrices, or plant material. Studies in animals have shown 

that cresols can be absorbed from contaminated air by inhalation but have not attempted to quantify this 

absorption. Studies of absorption of cresols from air, water, soil, and plant material are required to 

determine the rate and extent of absorption from each of these media and comparison of the potential 

hazard posed by cresols contained in each. 

Food Chain Bioaccumulation. Few data are available describing the food chain bioaccumulation 

of cresols. The available experimental data (Freitag et al. 1985) are consistent with estimated values 

obtained from regression equations which suggest that it will not bioconcentrate to any significant extent 

(Thomas 1982). Information concerning the potential for biomagnification has not been described, 

although the log Kow values are small and biomagnification is expected to be insignificant. Therefore, no 

data needs exist at this time. 

Exposure Levels in Environmental Media. Reliable monitoring data for the levels of cresols in 

contaminated media at hazardous waste sites are needed so that the information obtained on levels of 

cresols in the environment can be used in combination with the known body burden of cresols to assess 

the potential risk of adverse health effects in populations living in the vicinity of hazardous waste sites. 

Cresol levels in groundwater (Bedient et al. 1983; Drinkwater et al. 1986; Goerlitz et al. 1985; Oliveira 

and Sitar 1985; Sawhney and Kozloski 1984; Stuermer et al. 1982; Weber and Matsumoto 1987) and 

surface water (CLPSD 1988; Great Lakes Water Quality Board 1983; Kolpin et al. 2002) are available. 

Data exist regarding the level of cresols in atmospheric samples including rain water and clouds (Fraser et 
 

 

 

 

 

 

CRESOLS 182 

6. POTENTIAL FOR HUMAN EXPOSURE 

al. 1998; Grosjean 1991; Kelly et al. 1994; Leuenberger et al. 1985; Levsen et al. 1993; Luttke et al. 

1999). Cresols have infrequently been identified in foods (Chung 1999; Fiege and Bayer 1987), as well 

as in soil and sediment samples (Lopes and Furlong 2001; McCreary et al. 1983). Continued monitoring 

data in air, water, soil, and foods is necessary in order to assess the potential for human exposure from 

environmental media. Of particular value would be more quantitative data on the cresol levels in various 

foods. 

Exposure Levels in Humans. Cresols are naturally occurring substances that are widely distributed 

in the environment. Humans excrete, on average, 87 mg of p-cresol per day in urine (Fiege and Bayer 

1987). Cresols may also be present as a result of the metabolic breakdown of other organic compounds, 

such as toluene (Needham et al. 1984). As such, positive detections of cresols in human biological 

samples do not necessarily indicate exposure solely to cresol. Information concerning the number of 

persons potentially exposed to cresols near waste sites and manufacturing, production, and use facilities, 

however, is not available. High production and widespread use make the potential for human exposure 

high. A data need exists to rigorously establish cresol exposure levels in humans. There are insufficient 

data regarding body burden of cresol, partially due to the rapid metabolism and lack of bioaccumulation. 

This information is necessary for assessing the need to conduct health studies on these populations. 

Exposures of Children. There are limited, if any, data relating to exposures of children to cresols. 

Some of the factors that would increase the risk of children exposure include living with a smoker, and 

living near gas stations, heavy traffic areas, and companies that use and/or produce cresol. A data need 

exists to establish cresol exposure in children. 

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 cresols were located. This substance is not 

currently one of the compounds for which a sub-registry has been established in the National Exposure 

Registry. The substance will be considered in the future when chemical selection is made for subregistries to be established. The information that is amassed in the National Exposure Registry facilitates 

the epidemiological research needed to assess adverse health outcomes that may be related to exposure to 

this substance. 
 

 

CRESOLS 183 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.8.2 Ongoing Studies 

The Federal Research in Progress (FEDRIP 2008) database provided no additional information of 

ongoing studies that may fill in some of the data needs identified in Section 6.8.1. 
CRESOLS 184
 

6. POTENTIAL FOR HUMAN EXPOSURE 

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CRESOLS 185 

7. ANALYTICAL METHODS 

The purpose of this chapter is to describe the analytical methods that are available for detecting, 

measuring, and/or monitoring cresols, its metabolites, and other biomarkers of exposure and effect to 

cresols. The intent is not to provide an exhaustive list of analytical methods. Rather, the intention is to 

identify well-established methods that are used as the standard methods of analysis. Many of the 

analytical methods used for environmental samples are the methods approved by federal agencies and 

organizations such as EPA and the National Institute for Occupational Safety and Health (NIOSH). Other 

methods presented in this chapter are those that are approved by groups such as the Association of 

Official Analytical Chemists (AOAC) and the American Public Health Association (APHA). 

Additionally, analytical methods are included that modify previously used methods to obtain lower 

detection limits and/or to improve accuracy and precision. 

7.1 BIOLOGICAL MATERIALS 

Numerous methods for the determination of o-, m-, and p-cresol in urine have appeared in the literature. 

o-Cresol in urine is often measured to determine exposure to toluene or other aromatic compounds, of 

which cresol is a metabolite (DeRosa et al. 1987). The analytical methods summarized in Table 7-1 are 

sufficiently sensitive to detect the individual isomers of cresol at a concentration that may cause concern 

for human health. Humans normally excrete 16–29 mg of p-cresol daily as a result of the breakdown of 

tyrosine (Needham et al. 1984). 

The isomers of cresol are excreted in the urine as their glucuronides and sulfates (Bieniek and Wilczok 

1986). To analyze for cresols directly, they must first be separated from the biological carrier. This is 

usually accomplished by heating a urine sample with a concentrated mineral acid for 30 minutes to 1 hour 

(Angerer and Wulf 1985; DeRosa et al. 1987; Needham et al. 1984; Yoshikawa et al. 1986). The transfer 

of cresol from the aqueous hydrolysate to an organic solvent is accomplished by simple extraction with a 

volatile organic solvent such as methylene chloride or ethyl ether. Concentration of the extract by gentle 

removal of the solvent prepares the sample for the analysis stage. 

The amount of cresol in the concentrated extract can then be determined by high performance liquid 

chromatography (HPLC) (DeRosa et al. 1987; Yoshikawa et al. 1986) or gas chromatography (GC) 

coupled to either a flame ionization detector (FID) or a mass spectrometer detection system (Angerer and 

Wulf 1985; Needham et al. 1984). Separation of the cresol isomers by GC is readily accomplished, and 

the use of an appropriate internal standard allows the determination of their concentrations. Although 
 

 

 

CRESOLS 186 

7. ANALYTICAL METHODS 

Table 7-1. Analytical Methods for Determining Cresols in Biological Materials 

Sample 

matrix Preparation method 

Analytical 

method 

Sample 

detection 

limit 

Percent 

recovery Reference Isomer 

Blood Acidification with HCl 

followed by centrifugation 

at 3,000 rpm, filter to 

isolate free cresol 

GC/MS 0.14 μg/mL 95.4 De Smet et al. 

1998 

p 

Blood Deprotonization with 2 mL 

acetonitrile, vortex, 

centrifugation at 1,000 rpm 

GC/MS 0.016 μg/mL >95 Boatto et al. 

2004 

o 

Urine Hydrolyze with sulfuric 

acid; extract with ethyl 

acetate 

GC/FID No data 78–97 Needham et al. 

1984 

o, m, p 

Urine Hydrolyze with HCl extract 

with isopropyl ether; 

remove solvent; dissolve 

residue in water; add 

B-cyclodextrin 

HPLC/UV 1 ppm 97–102 Yoshikawa et 

al. 1986 

o, m, p 

Urine Acidify; steam distill; 

extract with methylene 

chloride 

GC/MS No data No data Angerer and 

Wulf 1985 

o 

Urine Hydrolyze with sulfuric 

acid; extract with CH2Cl2; 

HPLC/UV No data No data DeRosa et al. 

1987 

o 

concentrate 

Urine Collect sample with 

thymol; hydrolyze with 

HCl; extract with ethyl 

ether 

GC/FID 2 μg/mL 94% NIOSH 1994b o 

Expired 

air 

Breath collected in Teflon 

bag; concentration on 

Tenax GC adsorbent; 

thermal desorption 

GC/MS No data No data Krotoszynski 

and O'Neill 

1982 

Not 

specified 

FID = flame ionization detector; GC = gas chromatography; HPLC = high performance liquid chromatography; 

MS = mass spectrometry; UV = ultraviolet spectroscopy 
 

 

 

 

 

 

 

 

 

 

CRESOLS 187 

7. ANALYTICAL METHODS 

exact detection limits were not given for the above GC methods, a concentration of 10 ppm appears to be 

readily determined. 

Reversed-phase chromatography columns have been used for the analysis of cresols with limited success. 

A reversed-phase support has been developed that allows complete separation of the three cresol isomers 

(Bassler and Hartwick 1989). Inclusion complexes of the cresols with ß-cyclodextrin cleanly separate the 

three isomers on commercially available columns (Yoshikawa et al. 1986). Detection limits down to 

1 ppm can be obtained by this method. 

In cases involving acute cresol poisoning, cresol levels in biological tissues or blood levels are 

occasionally determined (Boatto et al. 2004). Methods have been described that can determine the level 

of free (nonprotein bound) p-cresol (De Smet et al. 1998) and o-cresol (Boatto et al. 2004) in blood. 

These methods typically involve hydrolysis with hydrochloric acid or acetonitrile to separate cresol from 

proteins followed by centrifugation, solvent extraction, and analysis by GC/mass spectrometry (MS). 

The detection of cresol in the expired air of humans has been accomplished by techniques used routinely 

for the analysis of other organic compounds in this sample matrix (Krotoszynski and O'Neill 1982). In 

this technique, the subject’s breath is collected in a bag made of inert material. The sample is then 

concentrated by pumping the expired air through a sorbent tube that collects the organic compounds. The 

organics are liberated from the adsorbent tube by thermal desorption, which flushes the components of the 

mixture directly onto a GC. The amount of each cresol isomer is quantified by comparison of the signal 

strength to that of a suitable internal standard using a FID, and identification is accomplished by 

interpretation of the data provided by a mass spectrometer. No detection limits were given for this 

method. 

7.2 ENVIRONMENTAL SAMPLES 

Methods for determining cresols in environmental media are summarized in Table 7-2. Procedures for 

the determination of and o- and p-cresol in water, soil, and sediment samples at hazardous waste sites are 

outlined by EPA (2005a). The required quantitation limits for each of the isomeric cresols are 10 ppb for 

water samples and 330 ppb for soil and sediment samples in this monitoring program. 

For the determination of cresol in water, good laboratory practice (GLP) guidelines state that the aqueous 

sample be brought to pH 11 by the addition of sodium hydroxide (NaOH). The basic mixture is then 
 

 

 

 

 

CRESOLS 188 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Cresols in Environmental
 

Materials
 

Sample 

matrix Preparation method 

Analytical 

method 

Sample 

detection 

limit 

Percent 

recovery Reference Isomer 

Air Pump air through 

adsorbent tube, desorb 

with methanol 

HPLC/UV 0.3 ppt 90–110 Kuwata and 

Tanaka 1988 

o, m, p 

Air Aerodispersive 

enrichment into water 

HPLC/ED No data No data Vecera and 

Janák 1987 

o 

Air Samples collected on 

solid sorbent tube. 

HPLC/UV No data No data NIOSH 1994a o, m, p 

Desorb with methanol 

Air Sample collected on 

solid sorbent tube, 

desorb with methanol 

GC/FID No data No data NIOSH 1994b o, m, p 

Air Ambient air drawn 

through impingers 

containing 15 mL of 

0.1M NaOH 

HPLC/UV 1–5 ppbv >80 EPA 1986 o, m. p 

Phenolates solution 

adjusted to pH <4 with 

5% sulfuric acid and 

diluted with water 

Water Adjust pH to 2, extract 

with CH2Cl2, 

GC/MS No data No data EPA 2005a o, p 

concentrate 

Water Solvent extraction, 

liquid chromatography 

prefractionation 

GC/MS No data No data Hites 1979 Not 

specified 

Rain water None; direct injection 

onto ion exchange 

column 

HPLC/CD No data No data DOE 1985 o, m, p 

Rain water Acidify, extract with 

CH2Cl2, concentrate. 

methylate 

GC/MS No data >50 Kawamura and 

Kaplan 1986 

o, m, p 

Drinking 

water 

1-L sample is extracted 

using a solid phase 

extraction cartridge 

GC/MS 0.026 μg/L 85 EPA 2000b 

Method 528 

o 

Soil, air, 

water, 

Samples are prepared 

for analysis by GC/MS 

GC/MS Not 

applicable 

Not 

applicable 

EPA 1998 

Method 8270D 

o, m, p 

Water or 

leachate 

Aqueous liquid waste 

or leachate is directly 

injected into a reverse 

phase HPLC column 

HPLC/UV 2.6 mg/L 

(o-cresol) 

0.9 mg/L 

(m-cresol) 

2.1 mg/L 

(p-cresol) 

89 DOE 1997a 

Method 

OH100R 

o, m, p 
 

 

CRESOLS	 189 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Cresols in Environmental
 

Materials
 

Sample 

Sample Analytical detection Percent 

matrix	 Preparation method method limit recovery Reference Isomer 

Water	 The sample is GC/MS Not Not EPA 2001 o 

extracted at pH 12–13, applicable applicable Method 1625 

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 are 

collected and analyzed 

GC/MS 27 μg/L 

o-cresol 

96 DOE 1997b 

Method 

o, p 

via GC/MS 42 μg/L OM100R 

p-cresol 

Aqueous Samples are extracted GC/MS Not Not EPA 2000c o, m, p 

samples and cleaned up applicable applicable Method 8041A 

(according to sample 

matrix) and the solvent 

appropriately 

exchanged; the 

phenols are then 

determined with or 

without derivatization 

Effluent The sample is GC-MS Not Not EPA 2001b o,m,p 

Water extracted at pH 12–13, (Method applicable applicable 

then at pH <2 with 1625) 

methylene chloride 

using continuous 

extraction techniques; 

the extract is dried over 

sodium sulfate and 

concentrated to a 

volume of 1 mL 

Soil, sediment Extract sample with GC/MS 330 ppb No data EPA 2005a o, p 

CH2Cl2 using ultra 

sonic probe 

Bottom Wet sediment samples GC/MS 41.2 μg/Lkg 86 USGS 1995 p 

sediment were dried and Method 

compounds were 0-5130-95 

extracted using 

dichloromethane 

Water Water samples were GC/MS 0.27 μg/L 36 USGS 2002 p 

filtered using glass Method 

fiber filters; samples 0-1433-01 

were extracted using 

SPE cartridges 
 

 

 

 

 

CRESOLS	 190 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Cresols in Environmental
 

Materials
 

Sample 

Sample Analytical detection Percent 

matrix	 Preparation method method limit recovery Reference Isomer 

Sediment	 Extract rapidly stirred GC/MS No data No data Goodley and Not 

sediment slurry with Gordon 1976 specified 

CH2Cl2 or ether, 

concentrate 

Breathing air	 Draw air through HPLC/ED 8 μg/m3 No data Nieminen and o, m, p 

XAD-s adsorbent tube, Heikkila 1986 

acetonitrile desorption 

CD = conductivity detector; ED = electrochemical detector; GC = gas chromatography; HPLC = high performance 

liquid chromatography; MS = mass spectrometry; SPE = solid phase extraction; UV = ultraviolet detector 
 

 

 

 

 

 

 

CRESOLS 191 

7. ANALYTICAL METHODS 

extracted with methylene chloride either in a separatory funnel or a continuous liquid-liquid extractor. 

The aqueous phase is then acidified to pH 2 and reextracted with methylene chloride. This second extract 

is concentrated by evaporation and subjected to GC/mass spectrometry (MS) analysis for identification 

and quantification. 

In sediment and soil samples, the isomers of cresol are determined by transferring a small portion of the 

solid sample (1 g) to a vial and adding methylene chloride. The contaminants are extracted from the 

sample with the aid of an ultrasonic probe. The methylene chloride extract is filtered, concentrated, and 

subjected to GC/MS analysis for quantitation. 

No other standardized methods for the determination of the three isomers of cresol were located (EPA 

1988a). However, numerous methods for their determination have appeared in the open literature. 

Methods for the determination of cresols in ambient air (Kolber et al. 1981; Kuwata and Tanaka 1988; 

Vecera and Janák 1987), breathing air (Heikkila et al. 1987; Leuenberger et al. 1985; Nieminen and 

Heikkila 1986), surface water (Goodley and Gordon 1976; Hites 1979; McKnight et al. 1982; Sheldon 

and Hites 1979), groundwater (Goerlitz et al. 1985; Hutchins et al. 1984; Sawhney and Kozloski 1984; 

Stuermer et al. 1982) rain water (DOE 1985; Kawamura and Kaplan 1986; Leuenberger et al. 1985), and 

sediment samples (Goodley and Gordon 1976; Hites and Lopez-Avila 1980) are available. 

The greatest difference between these methods is the procedure used in the sample preparation step. This 

step of the analysis varies widely between experimental techniques and may involve the use of highly 

specialized equipment. After the sample preparation step, however, the consensus is that separation of the 

isomers is best accomplished by using either GC or HPLC. 

Cresols degrade rapidly in the environment (see Section 6.3.2). The degradation products are also 

removed rapidly. The products resulting from the degradation of the three isomers of cresol in the 

environment are not unique to these compounds. 

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 cresols is available. Where adequate information is not 

available, ATSDR, in conjunction with NTP, is required to assure the initiation of a program of research 
 

 

 

 

 

 

 

 

 

 

CRESOLS 192 

7. ANALYTICAL METHODS 

designed to determine the health effects (and techniques for developing methods to determine such health 

effects) of cresols. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

7.3.1 Identification of Data Needs 

Methods for Determining Biomarkers of Exposure and Effect. 

Exposure. There are no known biomarkers of exposure that are unique to cresols. In addition, o-cresol 

has been used as a biomarker of toluene exposure, and the isomers of cresol may appear as a result of 

exposure to other aromatic compounds (Needham et al. 1984). The methods presently available are 

capable of determining low levels of the cresol isomers in biological media, and background levels in the 

population could be established using existing techniques (Angerer and Wulf 1985; DeRosa et al. 1987; 

Krotoszynski and O'Neill 1982; Needham et al. 1984; Yoshikawa et al. 1986). Before a complete 

discussion on determining biomarkers of exposure for cresol can be undertaken, biomarkers unique to this 

compound must first be established. 

Effect. Correlations of exposure and resulting biological effects are confounded by the metabolic 

formation of cresol after exposure to other organic compounds. Although the analytical methods for 

determining cresol in biological materials appear to provide the necessary precision and accuracy, their 

reliability in determining biomarkers of exposure and effect cannot, at this time, be ascertained. Before a 

complete discussion on determining biomarkers of effect for cresol can be undertaken, biomarkers unique 

to this compound must first be established. 

Methods for Determining Parent Compounds and Degradation Products in Environmental 

Media. Numerous methods for the determination of cresol in environmental matrices have appeared in 

the literature (DOE 1985; EPA 2005a; Goodley and Gordon 1976; Hites 1979; Kawamura and Kaplan 

1986; Kuwata and Tanaka 1988; Nieminen and Heikkila 1986; Vecera and Janák 1987). These 

procedures are capable of both identifying areas that have been contaminated with cresol and determining 
 

 

 

 

 

 

 

 

 

CRESOLS 193 

7. ANALYTICAL METHODS 

if the contaminated areas constitute a concern for human health. Human exposure to cresol is likely to 

occur by inhalation or ingestion of contaminated water. Standardized methods for the determination of 

the isomeric cresols exist for both of these matrices. These methods are both reproducible and sensitive. 

In addition, acceptable methods for the determination of cresol in other environmental media have 

appeared in the literature. No data needs are identified at this time. 

Although the isomeric cresols degrade readily in the environment, their degradation products (Bayly and 

Wigmore 1973; Masunaga et al. 1983, 1986) are not unique to these compounds (see Section 6.3.2). As a 

result, the determination of these intermediates cannot be accurately extrapolated back to levels of cresol 

contamination in the environment. 

7.3.2 Ongoing Studies 

No information regarding ongoing studies was found as a result of a search of the Federal Research in 

Progress database (FEDRIP 2008). 

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 cresols and 

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 cresols and 

other phenolic compounds in urine. These methods use high-resolution gas chromatography and 

magnetic sector mass spectrometry, which give detection limits in the low parts per trillion (ppt) range. 
 

CRESOLS 194
 

7. ANALYTICAL METHODS 

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CRESOLS 195 

8. REGULATIONS AND ADVISORIES
 

International and national regulations and guidelines pertinent to human exposure to cresols are 

summarized in Table 8-1. 

ATSDR has derived an intermediate-duration oral MRL of 0.1 mg/kg/day for cresols based on an increase 

incidence of nasal lesions in male rats administered m/p-cresol in the diet for 13 weeks (NTP 1992b). 

The MRL was derived using benchmark modeling of incidence data for nasal lesions in male rats. 

Following EPA’s Benchmark Dose Guidance (EPA 2000a) to select a point of departure, a BMR of 10% 

was selected for the benchmark analysis of nasal lesion incidence data in male rats in the 13-week NTP 

(1992b) study. The BMD corresponding to a BMR of 10% extra risk is 55.89 mg/kg/day; the 

corresponding BMDL10 is 13.94 mg/kg/day. An uncertainty factor of 100 (10 for interspecies 

extrapolation and 10 for human variability) was applied to the BMDL10. 

ATSDR has derived a chronic-duration oral MRL of 0.1 mg/kg/day for cresols based on increased 

incidences of bronchiole hyperplasia of the lung and follicular degeneration of the thyroid gland in female 

mice administered m/p-cresol in the diet for 2 years. The MRL was derived using a LOAEL of 

100 mg/kg/day divided by an uncertainty factor of 1,000 (10 for use of a LOAEL, 10 for extrapolation 

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

EPA (IRIS 2008) has derived oral reference doses of 0.05 mg/kg/day for m- and o-cresol based on 

NOAELs of 50 mg/kg/day for decreased body weights and neurotoxicity (myoclonus, tremors, labored 

respiration) observed in Sprague-Dawley rats exposed by gavage for 90 days (TRL 1986) in an 

assessment conducted in 1989. An uncertainty factor of 100 (10 for interspecies and 10 for intraspecies 

variability) was applied to the NOAEL. 

The EPA (IRIS 2008) has classified m-cresol, o-cresol, and p-cresol as possible human carcinogens 

(Group C) based on inadequate human data and limited data in animals. The assessment was based on an 

increased incidence of skin papillomas in mice in an initiation-promotion study and on the fact that the 

cresol isomers produced positive results in genetic toxicity studies both alone and in combination. 

According to EPA’s updated criteria for assessing carcinogenicity of chemicals (EPA 2005c), cresols fall 

in the category of chemicals for which there is “inadequate information to assess carcinogenic potential.” 

The American Conference of Governmental Industrial Hygienists (ACGIH), International Agency for 
 

 

 

CRESOLS 196 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Cresols 

Agency Description Information Reference 

INTERNATIONAL 

Guidelines: 

IARC Carcinogenicity classification No data IARC 2004 

WHO Air quality guidelines No data WHO 2000 

Drinking water quality guidelines No data WHO 2004 

NATIONAL 

Regulations and 

Guidelines: 

a. Air 

ACGIH TLV (8-hour TWA), all isomersa 5 ppm ACGIH 2005 

EPA AEGL No data EPA 2006a 

Hazardous air pollutant, all isomers Yes EPA 2006c 

42 USC 7412 

NIOSH REL (10-hour TWA), all isomers 2.3 ppm NIOSH 2005 

IDLH, all isomers 250 ppm 

OSHA PEL (8-hour TWA) for general industry, 

all isomersb 

5 ppm OSHA 2005c 

29 CFR 1910.1000 

PEL (8-hour TWA) for construction 

industry, all isomersb 

5 ppm OSHA 2005b 

29 CFR 1926.55, 

Appendix A 

PEL (8-hour TWA) for shipyard 

industry, all isomersb 

5 ppm OSHA 2005a 

29 CFR 1915.1000 

b. Water 

EPA Designated as hazardous substances Yes EPA 2006b 

in accordance with Section 311(b)(2)(A) 40 CFR 116.4 

of the Clean Water Act, all isomers 

Drinking water standards and health No data EPA 2004 

advisories 

Reportable quantities of hazardous Yes EPA 2006f 

substances designated pursuant to 40 CFR 117.3 

Section 311 of the Clean Water Act, 

mixed cresols 

Water quality criteria for human health No data EPA 2006e 

c. Food 

FDA Bottled drinking water No data FDA 2005 

21 CFR 165.110 

d. Other 

ACGIH Carcinogenicity classification No data ACGIH 2005 

EPA Carcinogenicity classification IRIS 2008 

Cresol No data 

m-Cresol Group Cc 

o-Cresol Group Cc 

p-Cresol Group Cc 
 

 

 

 

 

 

 

 

 

 

 

 

CRESOLS 197 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Cresols 

Agency Description Information Reference 

NATIONAL (cont.) 

EPA RfC IRIS 2008 

Cresol No datad 

m-Cresol No datad 

o-Cresol No datad 

p-Cresol No datad 

RfD 

Cresol No data 

m-Cresol 0.05 mg/kg/day 

o-Cresol 0.05 mg/kg/day 

p-Cresol Withdrawn 

Identification and listing of hazardous U052 EPA 2006d 

waste, mixed cresols 40 CFR 261, 

Appendix VIII 

Superfund, emergency planning, and EPA 2006g 

community right-to-know 40 CFR 302.4 

Designated CERCLA hazardous Yes 

substance, all isomers 

Reportable quantity 100 pounds 

Effective date of toxic chemical 01/01/87 EPA 2006i 

release reporting, all isomers 40 CFR 372.65 

Extremely hazardous substances 1,000/10,000 pounds EPA 2006h 

and their threshold planning 40 CFR 355, 

quantities, o-cresol only Appendix A 

NTP Carcinogenicity classification No data NTP 2004 

a

Skin notation: refers to the potential significant contribution to the overall exposure by the cutaneous route, including 

mucous membranes and the eyes, either by contact with vapors, liquids, and solids.

b

Skin designation 

c

Group C: possible human carcinogen 

d

The health effects data for cresol, m-cresol, o-cresol, and p-cresol were reviewed by the U.S. EPA RfD/RfC Work 

Group and determined to be inadequate for the derivation of an inhalation RfC. 

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; EPA = Environmental Protection Agency; FDA = Food 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 Toxicology 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 average; USC = United States Code; WHO = World Health Organization 
 

 

 

 

CRESOLS 198 

8. REGULATIONS AND ADVISORIES 

Research on Cancer (IARC), and the National Toxicology Program (NTP) have not classified cresols for 

human carcinogenicity (ACGIH 2005; IARC 2004; NTP 2004). 

OSHA requires employers of workers who are occupationally exposed to cresol to institute engineering 

controls and work practices to reduce and maintain employee exposure at or below permissible exposure 

limit time-weighted average (PEL-TWA). The employer must use engineering and work practice controls 

to reduce exposures to or below an 8-hour TWA of 5 ppm for cresol and its isomers (OSHA 2006). Both 

NIOSH and ACGIH and have established guideline values that range from 2.3 to 5 ppm for cresol and its 

isomers (ACGIH 2005; NIOSH 2005). 

EPA regulates cresols and its isomers under the Clean Air Act (CAA) and the Clean Water Act (CWA) 

and has designated them as hazardous air pollutants (HAPs) and hazardous substances, respectively (EPA 

2006b, 2006c). EPA has established a reportable quantity (RQ) of 100 pounds (EPA 2006i). 
 

 

 

 

_______________________ 

CRESOLS 199 

9. REFERENCES
 

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Adlercreutz H. 1995. Phytoestrogens: Epidemiology and a possible role in cancer protection. Environ 

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Agency for Toxic Substances and Disease Registry. 1989. Decision guide for identifying substancespecific data needs related to toxicological profiles; Notice. Fed Regist 54(174):37618-37634. 

AIChE. 1989. o-, p-Cresols. C7H8O. In: Physical and thermodynamic properties of pure chemicals. 

American Institute of Chemical Engineers, Design Institute for Physical Property Data. Philadelphia, PA: 

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CRESOLS 227 

10. GLOSSARY 

Absorption—The taking up of liquids by solids, or of gases by solids or liquids. 

Acute Exposure—Exposure to a chemical for a duration of 14 days or less, as specified in the 

Toxicological Profiles. 

Adsorption—The adhesion in an extremely thin layer of molecules (as of gases, solutes, or liquids) to the 

surfaces of solid bodies or liquids with which they are in contact. 

Adsorption Coefficient (Koc)—The ratio of the amount of a chemical adsorbed per unit weight of 

organic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium. 

Adsorption Ratio (Kd)—The amount of a chemical adsorbed by sediment or soil (i.e., the solid phase) 

divided by the amount of chemical in the solution phase, which is in equilibrium with the solid phase, at a 

fixed solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per gram of soil or 

sediment. 

Benchmark Dose (BMD)—Usually defined as the lower confidence limit on the dose that produces a 

specified magnitude of changes in a specified adverse response. For example, a BMD10 would be the 

dose at the 95% lower confidence limit on a 10% response, and the benchmark response (BMR) would be 

10%. The BMD is determined by modeling the dose response curve in the region of the dose response 

relationship where biologically observable data are feasible. 

Benchmark Dose Model—A statistical dose-response model applied to either experimental toxicological 

or epidemiological data to calculate a BMD. 

Bioconcentration Factor (BCF)—The quotient of the concentration of a chemical in aquatic organisms 

at a specific time or during a discrete time period of exposure divided by the concentration in the 

surrounding water at the same time or during the same period. 

Biomarkers—Broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as markers of exposure, markers of effect, and markers of susceptibility. 

Cancer Effect Level (CEL)—The lowest dose of chemical in a study, or group of studies, that produces 

significant increases in the incidence of cancer (or tumors) between the exposed population and its 

appropriate control. 

Carcinogen—A chemical capable of inducing cancer. 

Case-Control Study—A type of epidemiological study that examines the relationship between a 

particular outcome (disease or condition) and a variety of potential causative agents (such as toxic 

chemicals). In a case-controlled study, a group of people with a specified and well-defined outcome is 

identified and compared to a similar group of people without outcome. 

Case Report—Describes a single individual with a particular disease or exposure. These may suggest 

some potential topics for scientific research, but are not actual research studies. 

Case Series—Describes the experience of a small number of individuals with the same disease or 

exposure. These may suggest potential topics for scientific research, but are not actual research studies. 
 

 

 

 

 

 

 

 

 

 

CRESOLS 228 

10. GLOSSARY 

Ceiling Value—A concentration of a substance that should not be exceeded, even instantaneously. 

Chronic Exposure—Exposure to a chemical for 365 days or more, as specified in the Toxicological 

Profiles. 

Cohort Study—A type of epidemiological study of a specific group or groups of people who have had a 

common insult (e.g., exposure to an agent suspected of causing disease or a common disease) and are 

followed forward from exposure to outcome. At least one exposed group is compared to one unexposed 

group. 

Cross-sectional Study—A type of epidemiological study of a group or groups of people that examines 

the relationship between exposure and outcome to a chemical or to chemicals at one point in time. 

Data Needs—Substance-specific informational needs that if met would reduce the uncertainties of human 

health assessment. 

Developmental Toxicity—The occurrence of adverse effects on the developing organism that may result 

from exposure to a chemical prior to conception (either parent), during prenatal development, or 

postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point 

in the life span of the organism. 

Dose-Response Relationship—The quantitative relationship between the amount of exposure to a 

toxicant and the incidence of the adverse effects. 

Embryotoxicity and Fetotoxicity—Any toxic effect on the conceptus as a result of prenatal exposure to 

a chemical; the distinguishing feature between the two terms is the stage of development during which the 

insult occurs. The terms, as used here, include malformations and variations, altered growth, and in utero 

death. 

Environmental Protection Agency (EPA) Health Advisory—An estimate of acceptable drinking water 

levels for a chemical substance based on health effects information. A health advisory is not a legally 

enforceable federal standard, but serves as technical guidance to assist federal, state, and local officials. 

Epidemiology—Refers to the investigation of factors that determine the frequency and distribution of 

disease or other health-related conditions within a defined human population during a specified period. 

Genotoxicity—A specific adverse effect on the genome of living cells that, upon the duplication of 

affected cells, can be expressed as a mutagenic, clastogenic, or carcinogenic event because of specific 

alteration of the molecular structure of the genome. 

Half-life—A measure of rate for the time required to eliminate one half of a quantity of a chemical from 

the body or environmental media. 

Immediately Dangerous to Life or Health (IDLH)—The maximum environmental concentration of a 

contaminant from which one could escape within 30 minutes without any escape-impairing symptoms or 

irreversible health effects. 

Immunologic Toxicity—The occurrence of adverse effects on the immune system that may result from 

exposure to environmental agents such as chemicals. 
 

 

 

 

 

 

 

 

 

CRESOLS 229 

10. GLOSSARY 

Immunological Effects—Functional changes in the immune response. 

Incidence—The ratio of individuals in a population who develop a specified condition to the total 

number of individuals in that population who could have developed that condition in a specified time 

period. 

Intermediate Exposure—Exposure to a chemical for a duration of 15–364 days, as specified in the 

Toxicological Profiles. 

In Vitro—Isolated from the living organism and artificially maintained, as in a test tube. 

In Vivo—Occurring within the living organism. 

Lethal Concentration(LO) (LCLO)—The lowest concentration of a chemical in air that has been reported 

to have caused death in humans or animals. 

Lethal Concentration(50) (LC50)—A calculated concentration of a chemical in air to which exposure for 

a specific length of time is expected to cause death in 50% of a defined experimental animal population. 

Lethal Dose(LO) (LDLo)—The lowest dose of a chemical introduced by a route other than inhalation that 

has been reported to have caused death in humans or animals. 

Lethal Dose(50) (LD50)—The dose of a chemical that has been calculated to cause death in 50% of a 

defined experimental animal population. 

Lethal Time(50) (LT50)—A calculated period of time within which a specific concentration of a chemical 

is expected to cause death in 50% of a defined experimental animal population. 

Lowest-Observed-Adverse-Effect Level (LOAEL)—The lowest exposure level of chemical in a study, 

or group of studies, that produces statistically or biologically significant increases in frequency or severity 

of adverse effects between the exposed population and its appropriate control. 

Lymphoreticular Effects—Represent morphological effects involving lymphatic tissues such as the 

lymph nodes, spleen, and thymus. 

Malformations—Permanent structural changes that may adversely affect survival, development, or 

function. 

Minimal Risk Level (MRL)—An estimate of daily human exposure to a hazardous substance that is 

likely to be without an appreciable risk of adverse noncancer health effects over a specified route and 

duration of exposure. 

Modifying Factor (MF)—A value (greater than zero) that is applied to the derivation of a Minimal Risk 

Level (MRL) to reflect additional concerns about the database that are not covered by the uncertainty 

factors. The default value for a MF is 1. 

Morbidity—State of being diseased; morbidity rate is the incidence or prevalence of disease in a specific 

population. 

Mortality—Death; mortality rate is a measure of the number of deaths in a population during a specified 

interval of time. 
 

 

 

 

 

 

 

 

CRESOLS 230 

10. GLOSSARY 

Mutagen—A substance that causes mutations. A mutation is a change in the DNA sequence of a cell’s 

DNA. Mutations can lead to birth defects, miscarriages, or cancer. 

Necropsy—The gross examination of the organs and tissues of a dead body to determine the cause of 

death or pathological conditions. 

Neurotoxicity—The occurrence of adverse effects on the nervous system following exposure to a 

chemical. 

No-Observed-Adverse-Effect Level (NOAEL)—The dose of a chemical at which there were no 

statistically or biologically significant increases in frequency or severity of adverse effects seen between 

the exposed population and its appropriate control. Effects may be produced at this dose, but they are not 

considered to be adverse. 

Octanol-Water Partition Coefficient (Kow)—The equilibrium ratio of the concentrations of a chemical 

in n-octanol and water, in dilute solution. 

Odds Ratio (OR)—A means of measuring the association between an exposure (such as toxic substances 

and a disease or condition) that represents the best estimate of relative risk (risk as a ratio of the incidence 

among subjects exposed to a particular risk factor divided by the incidence among subjects who were not 

exposed to the risk factor). An OR of greater than 1 is considered to indicate greater risk of disease in the 

exposed group compared to the unexposed group. 

Organophosphate or Organophosphorus Compound—A phosphorus-containing organic compound 

and especially a pesticide that acts by inhibiting cholinesterase. 

Permissible Exposure Limit (PEL)—An Occupational Safety and Health Administration (OSHA) 

allowable exposure level in workplace air averaged over an 8-hour shift of a 40-hour workweek. 

Pesticide—General classification of chemicals specifically developed and produced for use in the control 

of agricultural and public health pests. 

Pharmacokinetics—The dynamic behavior of a material in the body, used to predict the fate 

(disposition) of an exogenous substance in an organism. Utilizing computational techniques, it provides 

the means of studying the absorption, distribution, metabolism, and excretion of chemicals by the body. 

Pharmacokinetic Model—A set of equations that can be used to describe the time course of a parent 

chemical or metabolite in an animal system. There are two types of pharmacokinetic models: data-based 

and physiologically-based. A data-based model divides the animal system into a series of compartments, 

which, in general, do not represent real, identifiable anatomic regions of the body, whereas the 

physiologically-based model compartments represent real anatomic regions of the body. 

Physiologically Based Pharmacodynamic (PBPD) Model—A type of physiologically based doseresponse model that quantitatively describes the relationship between target tissue dose and toxic end 

points. These models advance the importance of physiologically based models in that they clearly 

describe the biological effect (response) produced by the system following exposure to an exogenous 

substance. 
 

 

 

 

 

 

 

 

 

 

 

CRESOLS 231 

10. GLOSSARY 

Physiologically Based Pharmacokinetic (PBPK) Model—Comprised of a series of compartments 

representing organs or tissue groups with realistic weights and blood flows. These models require a 

variety of physiological information: tissue volumes, blood flow rates to tissues, cardiac output, alveolar 

ventilation rates, and possibly membrane permeabilities. The models also utilize biochemical 

information, such as air/blood partition coefficients, and metabolic parameters. PBPK models are also 

called biologically based tissue dosimetry models. 

Prevalence—The number of cases of a disease or condition in a population at one point in time. 

Prospective Study—A type of cohort study in which the pertinent observations are made on events 

occurring after the start of the study. A group is followed over time. 

q1*—The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the 

multistage procedure. The q1* can be used to calculate an estimate of carcinogenic potency, the 

incremental excess cancer risk per unit of exposure (usually μg/L for water, mg/kg/day for food, and 

μg/m3 for air). 

Recommended Exposure Limit (REL)—A National Institute for Occupational Safety and Health 

(NIOSH) time-weighted average (TWA) concentration for up to a 10-hour workday during a 40-hour 

workweek. 

Reference Concentration (RfC)—An estimate (with uncertainty spanning perhaps an order of 

magnitude) of a continuous inhalation exposure to the human population (including sensitive subgroups) 

that is likely to be without an appreciable risk of deleterious noncancer health effects during a lifetime. 

The inhalation reference concentration is for continuous inhalation exposures and is appropriately 

expressed in units of mg/m3 or ppm. 

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

daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious 

effects during a lifetime. The RfD is operationally derived from the no-observed-adverse-effect level 

(NOAEL, from animal and human studies) by a consistent application of uncertainty factors that reflect 

various types of data used to estimate RfDs and an additional modifying factor, which is based on a 

professional judgment of the entire database on the chemical. The RfDs are not applicable to 

nonthreshold effects such as cancer. 

Reportable Quantity (RQ)—The quantity of a hazardous substance that is considered reportable under 

the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA). Reportable 

quantities are (1) 1 pound or greater or (2) for selected substances, an amount established by regulation 

either under CERCLA or under Section 311 of the Clean Water Act. Quantities are measured over a 

24-hour period. 

Reproductive Toxicity—The occurrence of adverse effects on the reproductive system that may result 

from exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related 

endocrine system. The manifestation of such toxicity may be noted as alterations in sexual behavior, 

fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of 

this system. 

Retrospective Study—A type of cohort study based on a group of persons known to have been exposed 

at some time in the past. Data are collected from routinely recorded events, up to the time the study is 

undertaken. Retrospective studies are limited to causal factors that can be ascertained from existing 

records and/or examining survivors of the cohort. 
 

 

 

 

 

CRESOLS 232 

10. GLOSSARY 

Risk—The possibility or chance that some adverse effect will result from a given exposure to a chemical. 

Risk Factor—An aspect of personal behavior or lifestyle, an environmental exposure, or an inborn or 

inherited characteristic that is associated with an increased occurrence of disease or other health-related 

event or condition. 

Risk Ratio—The ratio of the risk among persons with specific risk factors compared to the risk among 

persons without risk factors. A risk ratio greater than 1 indicates greater risk of disease in the exposed 

group compared to the unexposed group. 

Short-Term Exposure Limit (STEL)—The American Conference of Governmental Industrial 

Hygienists (ACGIH) maximum concentration to which workers can be exposed for up to 15 minutes 

continually. No more than four excursions are allowed per day, and there must be at least 60 minutes 

between exposure periods. The daily Threshold Limit Value-Time Weighted Average (TLV-TWA) may 

not be exceeded. 

Standardized Mortality Ratio (SMR)—A ratio of the observed number of deaths and the expected 

number of deaths in a specific standard population. 

Target Organ Toxicity—This term covers a broad range of adverse effects on target organs or 

physiological systems (e.g., renal, cardiovascular) extending from those arising through a single limited 

exposure to those assumed over a lifetime of exposure to a chemical. 

Teratogen—A chemical that causes structural defects that affect the development of an organism. 

Threshold Limit Value (TLV)—An American Conference of Governmental Industrial Hygienists 

(ACGIH) concentration of a substance to which most workers can be exposed without adverse effect. 

The TLV may be expressed as a Time Weighted Average (TWA), as a Short-Term Exposure Limit 

(STEL), or as a ceiling limit (CL). 

Time-Weighted Average (TWA)—An allowable exposure concentration averaged over a normal 8-hour 

workday or 40-hour workweek. 

Toxic Dose(50) (TD50)—A calculated dose of a chemical, introduced by a route other than inhalation, 

which is expected to cause a specific toxic effect in 50% of a defined experimental animal population. 

Toxicokinetic—The absorption, distribution, and elimination of toxic compounds in the living organism. 

Uncertainty Factor (UF)—A factor used in operationally deriving the Minimal Risk Level (MRL) or 

Reference Dose (RfD) or Reference Concentration (RfC) from experimental data. UFs are intended to 

account for (1) the variation in sensitivity among the members of the human population, (2) the 

uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating from 

data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using lowestobserved-adverse-effect level (LOAEL) data rather than no-observed-adverse-effect level (NOAEL) data. 

A default for each individual UF is 10; if complete certainty in data exists, a value of 1 can be used; 

however, a reduced UF of 3 may be used on a case-by-case basis, 3 being the approximate logarithmic 

average of 10 and 1. 

Xenobiotic—Any chemical that is foreign to the biological system 
 

 

 

 

 

 

CRESOLS A-1 

APPENDIX A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS 

The Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) [42 U.S.C. 

9601 et seq.], as amended by the Superfund Amendments and Reauthorization Act (SARA) [Pub. L. 99– 

499], requires that the Agency for Toxic Substances and Disease Registry (ATSDR) develop jointly with 

the U.S. Environmental Protection Agency (EPA), in order of priority, a list of hazardous substances most 

commonly found at facilities on the CERCLA National Priorities List (NPL); prepare toxicological 

profiles for each substance included on the priority list of hazardous substances; and assure the initiation 

of a research program to fill identified data needs associated with the substances. 

The toxicological profiles include an examination, summary, and interpretation of available toxicological 

information and epidemiologic evaluations of a hazardous substance. During the development of 

toxicological profiles, Minimal Risk Levels (MRLs) are derived when reliable and sufficient data exist to 

identify the target organ(s) of effect or the most sensitive health effect(s) for a specific duration for a 

given route of exposure. An MRL is an estimate of the daily human exposure to a hazardous substance 

that is likely to be without appreciable risk of adverse noncancer health effects over a specified duration 

of exposure. MRLs are based on noncancer health effects only and are not based on a consideration of 

cancer effects. These substance-specific estimates, which are intended to serve as screening levels, are 

used by ATSDR health assessors to identify contaminants and potential health effects that may be of 

concern at hazardous waste sites. It is important to note that MRLs are not intended to define clean-up or 

action levels. 

MRLs are derived for hazardous substances using the no-observed-adverse-effect level/uncertainty factor 

approach. They are below levels that might cause adverse health effects in the people most sensitive to 

such chemical-induced effects. MRLs are derived for acute (1–14 days), intermediate (15–364 days), and 

chronic (365 days and longer) durations and for the oral and inhalation routes of exposure. Currently, 

MRLs for the dermal route of exposure are not derived because ATSDR has not yet identified a method 

suitable for this route of exposure. MRLs are generally based on the most sensitive chemical-induced end 

point considered to be of relevance to humans. Serious health effects (such as irreparable damage to the 

liver or kidneys, or birth defects) are not used as a basis for establishing MRLs. Exposure to a level 

above the MRL does not mean that adverse health effects will occur. 

MRLs are intended only to serve as a screening tool to help public health professionals decide where to 

look more closely. They may also be viewed as a mechanism to identify those hazardous waste sites that 
 

CRESOLS A-2 

APPENDIX A 

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

the lack of precise toxicological information on the people who might be most sensitive (e.g., infants, 

elderly, nutritionally or immunologically compromised) to the effects of hazardous substances. ATSDR 

uses a conservative (i.e., protective) approach to address this uncertainty consistent with the public health 

principle of prevention. Although human data are preferred, MRLs often must be based on animal studies 

because relevant human studies are lacking. In the absence of evidence to the contrary, ATSDR assumes 

that humans are more sensitive to the effects of hazardous substance than animals and that certain persons 

may be particularly sensitive. Thus, the resulting MRL may be as much as 100-fold below levels that 

have been shown to be nontoxic in laboratory animals. 

Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the 

Division of Toxicology and Environmental Medicine, expert panel peer reviews, and agency-wide MRL 

Workgroup reviews, with participation from other federal agencies and comments from the public. They 

are subject to change as new information becomes available concomitant with updating the toxicological 

profiles. Thus, MRLs in the most recent toxicological profiles supersede previously published levels. 

For additional information regarding MRLs, please contact the Division of Toxicology and 

Environmental Medicine, Agency for Toxic Substances and Disease Registry, 1600 Clifton Road NE, 

Mailstop F-32, Atlanta, Georgia 30333. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CRESOLS A-3 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Cresols 

CAS Numbers: 95-48-7, 108-39-4, 106-44-5, 1319-77-3 

Date: July 2008 

Profile Status: Final Draft Post-Public Comment 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [X] Intermediate [ ] Chronic 

Graph Key: 55 

Species: Rat 

Minimal Risk Level: 0.1 [X] mg/kg/day [ ] ppm 

Reference: NTP. 1992b. NTP report on the toxicity studies of cresols (CAS Nos. 95-48-7, 108-39-4, 

106-44-5) in F344/N rats and B6C3F1 mice (feed studies). Research Triangle Park, NC: National 

Toxicology Program. NIH Publication No. 92-3128. NTP Tox 9. 

Experimental design: Groups of Fischer 344 rats (20/sex/group) were administered m/p-cresol (58.5% 

m-cresol, 40.9% p-cresol) in the diet at levels of 0, 1,880, 3,750, 7,500, 15,000, or 30,000 ppm for 

13 weeks (NTP 1992b). The corresponding doses of test compound estimated by the investigators were 

0, 123, 241, 486, 991, and 2,014 mg/kg/day for males and 0, 131, 254, 509, 1,024, and 2,050 mg/kg/day 

for females. End points evaluated included clinical signs, food consumption, organ weights, clinical 

chemistry and hematology, and gross and microscopic appearance of organs and tissues. Although the 

dose groups consisted of 20 rats of each sex, 10 males and 10 females were used for clinical chemistry, 

hematology, and urinalysis studies and the remaining 10 rats/sex/group were used in gross pathology, 

organ weight, and histopathological studies. 

Effect noted in study and corresponding doses: There were no deaths during the study. Final body 

weight in the 2,014/2,050 mg/kg/day males and females was reduced 17 and 12%, respectively, relative to 

controls. Food consumption was also reduced (about 10%) in this group during the first week of the 

study. Additionally, males and females in this group exhibited rough hair coat; females also had a thin 

appearance. Absolute and relative liver weights were significantly increased (11–12%) in males at 

486 mg/kg/day and in females at 1,024 mg/kg/day. Absolute and relative kidney weight were increased 

in males at 991 mg/kg/day. In general, hematology findings were unremarkable, although there was a 

tendency to hemoconcentration at 2,014/2,050 mg/kg/day early in the study. Clinical chemistry tests 

showed an increase in serum alanine aminotransferase (ALT) in males and females exposed to 

2,014/2,050 mg/kg/day and in sorbitol dehydrogenase (SDH) in males at 2,014 mg/kg/day only on day 5. 

Bile acids in serum were increased in females at 2,050 mg/kg/day on day 90 and at 241 and 

991 mg/kg/day in males also on day 90. There was no indication of renal injury as judged by the results 

of urinalyses. Significant histopathological changes included minimal bone marrow hypocellularity in 

males and females at 2,014/2,050 mg/kg/day, and increased colloid (minimal) in thyroid follicular cells in 

females at 509 mg/kg/day and in males at 15,000 ppm (991 mg/kg/day). An increased dose-related 

incidence and severity of hyperplasia and glandular hyperplasia of the nasal respiratory epithelium was 

observed in male and female rats. Severity was minimal at 123/131 mg/kg/day, mild at 

486/509 mg/kg/day, and moderate at 2,014/2,050 mg/kg/day. The lesions were located at the most 

anterior portions of the nasal septum, dorsal arch, and medial aspect of the nasal turbinates. The 

hyperplasia was characterized by increased number of goblet cells and pseudogland formation due to the 

infolding of the hyperplastic cells. The hyperplastic areas were associated with single cell necrosis. The 

incidences in males dosed with 0, 123, 241, 486, 991, and 2,014 mg/kg/day were 0/10, 3/10, 8/10, 10/10, 

8/10, and 10/10, respectively. A similar trend was seen in female rats, but 3/10 control females also 

exhibited hyperplasia (3/10, 1/10, 5/10, 9/10, 8/10, and 10/10 at 0, 131, 254, 509, 1,024, and 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CRESOLS A-4 

APPENDIX A 

2,050 mg/kg/day, respectively). The LOAELs for nasal lesions in male and female rats were 123 and 

254 mg/kg/day, respectively. The NOAEL in females was 131 mg/kg/day and no NOAEL was 

established in males. 

In the 28-day study with m/p-cresol in rats, the incidences of hyperplasia of the nasal respiratory 

epithelium in females dosed with 0, 27, 95, 268, 886, and 2,570 mg/kg/day were 0/5, 0/5, 3/4, 5/5, 5/5, 

and 5/5, respectively. However, data from the 13-week study are preferred for MRL derivation because 

of the longer duration and because only five rats/group were examined in the 28-day study. 

Data from the NTP (1992b) were considered adequate for analysis using the benchmark dose approach 

for MRL derivation. Benchmark dose models in the EPA Benchmark Dose Software (BMDS) 

(version 2.0) were fit to the incidence data for nasal lesions in male and female rats exposed to m/p-cresol 

in the diet for 13 weeks in order to determine potential points of departure for the MRL (details of the 

modeling are presented below). 

Dose and end point used for MRL derivation: BMDL10 of 13.94 mg/kg/day for nasal lesions in male rats. 

[ ] NOAEL [ ] LOAEL [ x ] BMDL10 

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? Conversion from 

diet to dose was done by the investigators. 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not 

applicable. 

Was a conversion used from intermittent to continuous exposure? No. 

Other additional studies or pertinent information that lend support to this MRL: Almost all of the 

information available on health effects from intermediate-duration oral exposure is derived from a 

comprehensive study in rats and mice administered the three cresol isomers and a cresol mixture for 

28 days and 13 weeks (NTP 1992b). There are also two multigeneration reproductive studies in mice 

dosed with o-cresol (NTP 1992a) and a cresol mixture (NTP 1992c). Evaluation of the results of these 

studies indicates that the most sensitive end point was the nasal respiratory epithelium of rats and mice 

dosed with p-cresol or an m/p-cresol mixture. No clear target of toxicity emerged for o- or m-cresol. The 

nasal lesions occurred in rats dosed with p-cresol for 28 days (≥770 mg/kg/day), in rats exposed to 

m/p-cresol for 28 days (≥95 mg/kg/day), in mice exposed to p-cresol for 28 days (≥163 mg/kg/day), in 

mice exposed to m/p-cresol for 28 days (≥604 mg/kg/day), in rats exposed to m/p-cresol for 13 weeks 

(≥123 mg/kg/day), and in mice exposed to m/p-cresol for 13 weeks (≥472 mg/kg/day). Other effects that 

occurred at higher doses included increases in liver and kidneys weights ( ≥240 mg/kg/day), bone marrow 

hypocellularity (≥2,000 mg/kg/day), and mild uterine atrophy (≥1,000 mg/kg/day) (NTP 1992b). Clinical 

tests of liver and kidney function were generally unremarkable and gross and microscopic evaluation of 

the liver and kidney showed no significant alterations (NTP 1992b). None of the intermediate-duration 

oral gavage studies examined the nasal respiratory epithelium of the animals, and neither did the two 

multigeneration reproductive dietary studies in mice (NTP 1992a, 1992c). 

Agency Contacts (Chemical Managers): Malcolm Williams, Ph.D.; John Risher, Ph.D.; Mike Fay, Ph.D. 
 

 

 

 

 

CRESOLS A-5 

APPENDIX A 

BENCHMARK MODELING OF NASAL RESPIRATORY LESIONS IN RATS 

Benchmark dose models in the EPA Benchmark Dose Software (BMDS version 2.0) were fit to the 

incidence data for nasal lesions in male and female rats exposed to m/p-cresol in the diet for 13 weeks in 

order to determine potential points of departure for the MRL. BMDL10s (i.e., 95% lower confidence 

limits on the model-estimated dose associated with a 10% extra risk for nasal lesions) calculated with the 

best-fitting models for each data set (see Tables A-1, A-2, and, A-3 and Figures A-1 and A-2) were 

13.9 mg/kg/day for males and 30.8 mg/kg/day for females. While this difference in benchmark dose may 

indicate that male rats are more sensitive than females, it also can be a statistical artifact of a rather small 

sample size, only 10 rats per group. The male rat data set was selected for determining the point of 

departure for MRL derivation in order to be public health protective. 

Table A-1. Incidence Data for Respiratory Epithelium Glandular Hyperplasia or 

Hyperplasia in Rats Exposed to m/p-Cresol in the Diet for 13 Weeks 

Dietary concentration (ppm) Dose (mg/kg/day) Incidence of nasal lesions 

Male 0 0 0/10 

1,880 123 3/10 

3,750 241 8/10 

7,500 486 10/10 

15,000 991 9/10 

30,000 2,014 10/10 

Female 0 0 3/10 

1,880 131 2/10 

3,750 254 6/10 

7,500 509 10/10 

15,000 1,024 8/10 

30,000 2,050 10/10 

Source: NTP 1992b 
 

 

CRESOLS A-6 

APPENDIX A 

Table A-2. Goodness-of-Fit Statistics and BMD10s and BMDL10s from Models
 

Fit to Incidence Data for Nasal Lesions in Male Rats 

Exposed to m/p-Cresol in the Diet for 13 Weeks
 

Model AIC X2 p valuea BMD10 (mg/kg/day) BMDL10 (mg/kg/day) 

Gamma 37.3167 0.1221 24.1138 16.7698 

Logistic 46.7819 0.0000 63.9362 42.8254 

Log-Logisticb 36.8962 0.2605 55.8863 13.9381 

Multistage 37.3167 0.1221 24.1138 16.7698 

Probit 49.738 0.0002 71.306 50.8541 

Log-probit 37.6831 0.2511 46.1987 26.6915 

Quantal-linear 37.3167 0.1221 24.1138 16.7698 

Weibull 37.3167 0.1221 24.1138 16.7698 

a

Values <0.1 fail to meet conventional goodness-of-fit criteria. b

Best-fitting model 

AIC = Akaike’s Information Criteria; BMD = benchmark dose; BMDL = lower confidence limit (95%) on the 

benchmark dose; p = p value from the Chi-squared test 

Source: NTP 1992b 
 

 

 

CRESOLS A-7 

APPENDIX A 

Table A-3. Goodness-of-Fit Statistics and BMD10s and BMDL10s from Models Fit
 

to Incidence Data for Nasal Lesions in Female Rats
 

Exposed to m/p-Cresol in the Diet for 13 Weeks
 

Model AIC X2 p valuea BMD10 (mg/kg/day) BMDL10 (mg/kg/day) 

Gamma 61.5191 0.0477 64.2166 30.9781 

Logistic 60.7552 0.0557 89.5533 60.4852 

Log-Logistic 60.0961 0.0487 98.7921 28.7889 

Multistageb 59.5988 0.1020 48.0244 30.7916 

Probit 61.2978 0.0600 98.0573 69.3757 

Log-probit 60.351 0.0591 99.9316 51.3824 

Quantal-linearb 59.5988 0.1020 48.0246 30.7916 

Weibull 61.5874 0.0505 52.5879 30.8181 

a

Values <0.1 fail to meet conventional goodness-of-fit criteria. b

Best-fitting model 

AIC = Akaike’s Information Criteria; BMD = benchmark dose; BMDL = lower confidence limit (95%) on the 

benchmark dose; p = p value from the Chi-squared test 

Source: NTP 1992b 
 

 

CRESOLS A-8 

APPENDIX A 

Figure A-1. Observed and Predicted Incidences of Nasal Lesions in Male Rats 

Exposed to m/p-Cresol in the Diet for 13 Weeks*

Log-Logistic Model with 0.95 Confidence Level 

0

 0.2

 0.4

 0.6

 0.8

 1

Fraction Affected 

BMDL BMD 

Log-Logistic 

0 500 1000 1500 2000
 

dose
 

10:36 07/16 2008
 

*BMDs and BMDLs indicated are for a 10% extra risk and are in units of mg/kg/day.
 

Source: NTP 1992b
 
 

 

 

 

CRESOLS A-9 

APPENDIX A 

Figure A-2. Observed and Predicted Incidences of Nasal Lesions in Female Rats 

Exposed to m/p-Cresol in the Diet for 13 Weeks*

Quantal Linear Model with 0.95 Confidence Level 

Fraction Affected 

1

 0.8

 0.6

 0.4

 0.2

 0 BMDL BMD 

Quantal Linear 

0 500 1000 1500 2000 

dose 

11:00 07/16 2008 

*BMDs and BMDLs Indicated are for a 10% extra risk and are in units of mg/kg/day. 

Source: NTP 1992b 

BMDs and BMDLs associated with 1, 5, 10, 20, and 30% extra risk were calculated with the best-fitting 

model of the male rat nasal lesion incidence data (see Table A-4). Following EPA’s Benchmark Dose 

Guidance (EPA 2000a) to select a point of departure, a benchmark response (BMR) of 10% was selected 

for the benchmark analysis of nasal lesion incidence data in male rats in the 13-week NTP (1992b) study. 

The BMD corresponding to a BMR of 10% extra risk is 55.89 mg/kg/day; the corresponding BMDL10 is 

13.94 mg/kg/day (see Table A-4). Applying an uncertainty factor of 100 (10 each for intra- and 

interspecies extrapolation) to the BMDL10 yields an intermediate-duration oral MRL of 0.1 mg/kg/day for 

m/p-cresol. 
 

 

 

 

 

 

 

 

 

CRESOLS A-10 

APPENDIX A 

Table A-4. Best-fitting Model Predictions for 1, 5, 10, 20, and 30% Extra Risk for
 

Incidence of Nasal Lesions Observed in Rats Exposed to
 

m/p-Cresol in the Feed for 13 Weeks
 

Best fitting model BMR (% extra risk) BMD (mg/kg/day) BMDL (mg/kg/day) 

Male: Log-Logistic 1 18.38 1.70 

5 39.52 7.26 

10 55.89 13.94 

20 81.41 28.08 

30 104.53 44.35 

Female: Quantal Linear 1 4.58 2.94 

5 23.38 14.99 

10 48.02 30.79 

20 101.71 65.21 

30 162.58 104.24 

Source: NTP 1992b 

All available dichotomous models in the EPA BMDS (version 2.0) were fit to the incidence data for nasal 

lesions (respiratory epithelium glandular hyperplasia or hyperplasia) in male and female rats exposed to 

m/p-cresol in the diet for 13 weeks (NTP 1992b) (Table A-1). Predicted doses associated with 30, 20, 10, 

5, and 1% extra risks were calculated. 

Male Rats 

As assessed by the chi-square goodness-of-fit test, several models in the software provided adequate fits 

to the data for the incidence of nasal lesions in male rats (x2 p value ≥0.1) (Table 2). Comparing across 

models, a better fit is indicated by a lower Aikake’s Information Criteria value (AIC) (EPA 2000a). The 

log-logistic model was determined to be the best-fitting model, as indicated by the AIC (Table A-2). 

Benchmark doses (BMDs and BMDLs) associated with an extra risk of 30, 20, 10, 5, and 1, calculated 

from the best fitting model, are shown in Table A-4. 

The form and parameters of the log-logistic model for the male rat data are as follows: 

P[response] = background + (1-background)/[1+EXP(-intercept-slope*Log(dose))]
 

background = 0;
 

intercept = -5.78913;
 

slope = 1.21882.
 

Female Rats 

As assessed by the chi-square goodness-of-fit test, only the quantal linear model (which was the similar to 

the 1-degree polynomial model) provided an adequate fit to the data for the incidence of nasal lesions in 

female rats (x2 p value ≥0.1). Therefore, the quantal linear model was determined to be the best-fitting 

model (Table 3). Benchmark doses (BMDs and BMDLs) associated with an extra risk of 30, 20, 10, 5, 

and 1%, calculated from the quantal linear model, are shown in Table A-4. 
 

CRESOLS A-11 

APPENDIX A 

The form and parameters of the quantal linear model for the female rat data are as follows: 

P[response] = background + (1-background)*[1-EXP(-slope*dose)] 

background = 0.318182; 

slope = 0.001321; 

Power = 1 (Specified) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CRESOLS A-12 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Cresols 

CAS Numbers: 95-48-7, 108-39-4, 106-44-5, 1319-77-3 

Date: July 2008 

Profile Status: Final Draft Post-Public Comment 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [ ] Intermediate [X] Chronic 

Graph Key: 130 

Species: Mice 

Minimal Risk Level: 0.1 [X] mg/kg/day [ ] ppm 

Reference: NTP. 2008. Toxicology and carcinogenesis studies of cresols (CAS No. 1319-77-3) in male 

F344/N rats and female B6C3F1 mice (feed studies). Research Triangle Park, NC: National Toxicology 

Program. TR-550. Draft technical report. 

Although the report has not yet been finalized by the NTP, a draft technical report has been reviewed by 

the NTP Board of Scientific Counselors Technical Reports Review Subcommittee, and a draft abstract, 

pathology tables, and survival and growth curves are available in the NTP web site 

(http://ntp.niehs.nih.gov/index.cfm?objectid=9B58ADF7-F1F6-975E-78A23152B1596409). 

Experimental design: Groups of female B6C3F1 mice (50/group) were administered m/p-cresol (60% 

m-cresol, 40% p-cresol) in the diet at levels of 0, 1,000, 3,000, or 10,000 ppm for 2 years (NTP 2008). 

The corresponding doses of test compound estimated by the investigators were approximately 0, 100, 

300, and 1,040 mg/kg/day. End points evaluated included clinical signs, food consumption, organ 

weights, and gross and microscopic appearance of organs and tissues at termination. 

Effect noted in study and corresponding doses: Dosing with m/p-cresol did not affect survival rate. Food 

consumption did not appear to vary significantly throughout the study. No significant treatment-related 

clinical signs were reported. At termination, body weight in the mid- and high-dose groups was 

significantly lower than controls (11 and 24%, respectively). Significant treatment-related, nonneoplastic effects included: minimal to moderate bronchiolar hyperplasia in the lung (0/50, 42/50/, 44/49, 

47/50); minimal to mild hyperplasia of the nasal respiratory epithelium (0/50, 0/50, 28/49, 21/50); mild 

follicular degeneration of the thyroid gland (7/48, 24/48, 24/49, 21/50); and increased eosinophilic foci in 

the liver (1/50, 0/50, 2/49, 12/50). NOAELs for bronchiolar hyperplasia and thyroid follicular 

degeneration were not established, and in both cases, the LOAEL was 100 mg/kg/day. 

Since the incidence data indicate that bronchiolar hyperplasia of the lung and follicular degeneration of 

the thyroid gland had lower thresholds than the liver or nasal effects, the former two responses were 

considered for analysis using the benchmark dose approach for MRL derivation. After inspection of the 

dose response data, the use of a LOAEL/NOAEL approach for MRL derivation was considered to be 

more appropriate than the use of benchmark dose analysis because of the steep increase in the response 

rates between the control group and the first exposure level. 

Dose and end point used for MRL derivation: LOAEL of 100 mg/kg/day for bronchiole hyperplasia of 

the lung and follicular degeneration of the thyroid gland in female mice. 

[ ] NOAEL [x] LOAEL [ ] BMDL10 
 

 

 

 

 

 

 

CRESOLS A-13 

APPENDIX A 

Uncertainty Factors used in MRL derivation: 

[x] 10 for extrapolation from animals to humans 

[x] 10 for human variability 

[x] 10 for use of a LOAEL 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? Conversion from 

diet to dose was done by the investigators. 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not 

applicable. 

Was a conversion used from intermittent to continuous exposure? No. 

Other additional studies or pertinent information that lend support to this MRL: The NTP (2008) is the 

only chronic-duration study with cresols available. The NTP (2008) also tested male F-344/N rats and the 

results showed that the most sensitive end point was the nasal respiratory epithelium, as in the shorterterm studies (NTP 1992b). Other less sensitive effects observed in rats included hyperplasia of the 

transitional epithelium of the renal pelvis, squamous metaplasia in the nasal respiratory epithelium, 

inflammation of the nose, and eosinophilic foci in the liver. The incidence of respiratory epithelium 

hyperplasia of minimal to mild severity was 3/50, 17/50, 31/50, and 47/50 in the control, low-, mid-, and 

high-dose groups, respectively. As discussed in Section 2.3, the data suggest that, over the range of doses 

used in the NTP (1992b, 2008) studies, exposure beyond 13 weeks had little or no effect on the incidence 

or severity of the nasal respiratory hyperplasia, indicating that the intermediate-duration MRL, which is 

based on incidence data for this lesion, should be protective of nasal lesions induced by chronic-duration 

exposure. This is supported by the fact that fitting the incidence data for nasal respiratory epithelium 

hyperplasia from the 2-year study to the same BMDS model (Log-Logistic) that provided the BMDL10 

used to derive the intermediate-duration oral MRL yields a BMDL10 for chronic exposure to m/p-cresol of 

13.9017 mg/kg/day, essentially the same as the BMDL10 of 13.9381 mg/kg/day used to derive the 

intermediate-duration oral MRL for m/p-cresol. 

Agency Contacts (Chemical Managers): Malcolm Williams, Ph.D.; John Risher, Ph.D.; Mike Fay, Ph.D. 
CRESOLS A-14
 

APPENDIX A 

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CRESOLS	 B-1 

APPENDIX B. USER'S GUIDE 

Chapter 1 

Public Health Statement 

This chapter of the profile is a health effects summary written in non-technical language. Its intended 

audience is the general public, especially people living in the vicinity of a hazardous waste site or 

chemical release. If the Public Health Statement were removed from the rest of the document, it would 

still communicate to the lay public essential information about the chemical. 

The major headings in the Public Health Statement are useful to find specific topics of concern. The 

topics are written in a question and answer format. The answer to each question includes a sentence that 

will direct the reader to chapters in the profile that will provide more information on the given topic. 

Chapter 2 

Relevance to Public Health 

This chapter provides a health effects summary based on evaluations of existing toxicologic, 

epidemiologic, and toxicokinetic information. This summary is designed to present interpretive, weightof-evidence discussions for human health end points by addressing the following questions: 

1.	 What effects are known to occur in humans? 

2.	 What effects observed in animals are likely to be of concern to humans? 

3.	 What exposure conditions are likely to be of concern to humans, especially around hazardous 

waste sites? 

The chapter covers end points in the same order that they appear within the Discussion of Health Effects 

by Route of Exposure section, by route (inhalation, oral, and dermal) and within route by effect. Human 

data are presented first, then animal data. Both are organized by duration (acute, intermediate, chronic). 

In vitro data and data from parenteral routes (intramuscular, intravenous, subcutaneous, etc.) are also 

considered in this chapter. 

The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using 

existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer 

potency or perform cancer risk assessments. Minimal Risk Levels (MRLs) for noncancer end points (if 

derived) and the end points from which they were derived are indicated and discussed. 

Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to public 

health are identified in the Chapter 3 Data Needs section. 

Interpretation of Minimal Risk Levels 

Where sufficient toxicologic information is available, ATSDR has derived MRLs for inhalation and oral 

routes of entry at each duration of exposure (acute, intermediate, and chronic). These MRLs are not 

meant to support regulatory action, but to acquaint health professionals with exposure levels at which 

adverse health effects are not expected to occur in humans. 
 

 

 

 

 

 

 

 

 

 

 

CRESOLS B-2 

APPENDIX B 

MRLs should help physicians and public health officials determine the safety of a community living near 

a chemical emission, given the concentration of a contaminant in air or the estimated daily dose in water. 

MRLs are based largely on toxicological studies in animals and on reports of human occupational 

exposure. 

MRL users should be familiar with the toxicologic information on which the number is based. Chapter 2, 

"Relevance to Public Health," contains basic information known about the substance. Other sections such 

as Chapter 3 Section 3.9, "Interactions with Other Substances,” and Section 3.10, "Populations that are 

Unusually Susceptible" provide important supplemental information. 

MRL users should also understand the MRL derivation methodology. MRLs are derived using a 

modified version of the risk assessment methodology that the Environmental Protection Agency (EPA) 

provides (Barnes and Dourson 1988) to determine reference doses (RfDs) for lifetime exposure. 

To derive an MRL, ATSDR generally selects the most sensitive end point which, in its best judgement, 

represents the most sensitive human health effect for a given exposure route and duration. ATSDR 

cannot make this judgement or derive an MRL unless information (quantitative or qualitative) is available 

for all potential systemic, neurological, and developmental effects. If this information and reliable 

quantitative data on the chosen end point are available, ATSDR derives an MRL using the most sensitive 

species (when information from multiple species is available) with the highest no-observed-adverse-effect 

level (NOAEL) that does not exceed any adverse effect levels. When a NOAEL is not available, a 

lowest-observed-adverse-effect level (LOAEL) can be used to derive an MRL, and an uncertainty factor 

(UF) of 10 must be employed. Additional uncertainty factors of 10 must be used both for human 

variability to protect sensitive subpopulations (people who are most susceptible to the health effects 

caused by the substance) and for interspecies variability (extrapolation from animals to humans). In 

deriving an MRL, these individual uncertainty factors are multiplied together. The product is then 

divided into the inhalation concentration or oral dosage selected from the study. Uncertainty factors used 

in developing a substance-specific MRL are provided in the footnotes of the levels of significant exposure 

(LSE) tables. 

Chapter 3 

Health Effects 

Tables and Figures for Levels of Significant Exposure (LSE) 

Tables and figures are used to summarize health effects and illustrate graphically levels of exposure 

associated with those effects. These levels cover health effects observed at increasing dose 

concentrations and durations, differences in response by species, MRLs to humans for noncancer end 

points, and EPA's estimated range associated with an upper- bound individual lifetime cancer risk of 1 in 

10,000 to 1 in 10,000,000. Use the LSE tables and figures for a quick review of the health effects and to 

locate data for a specific exposure scenario. The LSE tables and figures should always be used in 

conjunction with the text. All entries in these tables and figures represent studies that provide reliable, 

quantitative estimates of NOAELs, LOAELs, or Cancer Effect Levels (CELs). 

The legends presented below demonstrate the application of these tables and figures. Representative 

examples of LSE Table 3-1 and Figure 3-1 are shown. The numbers in the left column of the legends 

correspond to the numbers in the example table and figure. 
 

 

 

 

 

 

CRESOLS	 B-3 

APPENDIX B 

LEGEND 

See Sample LSE Table 3-1 (page B-6) 

(1)	 Route of Exposure. One of the first considerations when reviewing the toxicity of a substance 

using these tables and figures should be the relevant and appropriate route of exposure. Typically 

when sufficient data exist, three LSE tables and two LSE figures are presented in the document. 

The three LSE tables present data on the three principal routes of exposure, i.e., inhalation, oral, 

and dermal (LSE Tables 3-1, 3-2, and 3-3, respectively). LSE figures are limited to the inhalation 

(LSE Figure 3-1) and oral (LSE Figure 3-2) routes. Not all substances will have data on each 

route of exposure and will not, therefore, have all five of the tables and figures. 

(2)	 Exposure Period. Three exposure periods—acute (less than 15 days), intermediate (15– 

364 days), and chronic (365 days or more)—are presented within each relevant route of exposure. 

In this example, an inhalation study of intermediate exposure duration is reported. For quick 

reference to health effects occurring from a known length of exposure, locate the applicable 

exposure period within the LSE table and figure. 

(3)	 Health Effect. The major categories of health effects included in LSE tables and figures are 

death, systemic, immunological, neurological, developmental, reproductive, and cancer. 

NOAELs and LOAELs can be reported in the tables and figures for all effects but cancer. 

Systemic effects are further defined in the "System" column of the LSE table (see key number 

18). 

(4)	 Key to Figure. Each key number in the LSE table links study information to one or more data 

points using the same key number in the corresponding LSE figure. In this example, the study 

represented by key number 18 has been used to derive a NOAEL and a Less Serious LOAEL 

(also see the two "18r" data points in sample Figure 3-1). 

(5)	 Species. The test species, whether animal or human, are identified in this column. Chapter 2, 

"Relevance to Public Health," covers the relevance of animal data to human toxicity and 

Section 3.4, "Toxicokinetics," contains any available information on comparative toxicokinetics. 

Although NOAELs and LOAELs are species specific, the levels are extrapolated to equivalent 

human doses to derive an MRL. 

(6)	 Exposure Frequency/Duration. The duration of the study and the weekly and daily exposure 

regimens are provided in this column. This permits comparison of NOAELs and LOAELs from 

different studies. In this case (key number 18), rats were exposed to “Chemical x” via inhalation 

for 6 hours/day, 5 days/week, for 13 weeks. For a more complete review of the dosing regimen, 

refer to the appropriate sections of the text or the original reference paper (i.e., Nitschke et al. 

1981). 

(7)	 System. This column further defines the systemic effects. These systems include respiratory, 

cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, and 

dermal/ocular. "Other" refers to any systemic effect (e.g., a decrease in body weight) not covered 

in these systems. In the example of key number 18, one systemic effect (respiratory) was 

investigated. 

(8)	 NOAEL. A NOAEL is the highest exposure level at which no harmful effects were seen in the 

organ system studied. Key number 18 reports a NOAEL of 3 ppm for the respiratory system, 

which was used to derive an intermediate exposure, inhalation MRL of 0.005 ppm (see 

footnote "b"). 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CRESOLS	 B-4 

APPENDIX B 

(9)	 LOAEL. A LOAEL is the lowest dose used in the study that caused a harmful health effect. 

LOAELs have been classified into "Less Serious" and "Serious" effects. These distinctions help 

readers identify the levels of exposure at which adverse health effects first appear and the 

gradation of effects with increasing dose. A brief description of the specific end point used to 

quantify the adverse effect accompanies the LOAEL. The respiratory effect reported in key 

number 18 (hyperplasia) is a Less Serious LOAEL of 10 ppm. MRLs are not derived from 

Serious LOAELs. 

(10)	 Reference. The complete reference citation is given in Chapter 9 of the profile. 

(11)	 CEL. A CEL is the lowest exposure level associated with the onset of carcinogenesis in 

experimental or epidemiologic studies. CELs are always considered serious effects. The LSE 

tables and figures do not contain NOAELs for cancer, but the text may report doses not causing 

measurable cancer increases. 

(12)	 Footnotes. Explanations of abbreviations or reference notes for data in the LSE tables are found 

in the footnotes. Footnote "b" indicates that the NOAEL of 3 ppm in key number 18 was used to 

derive an MRL of 0.005 ppm. 

LEGEND 

See Sample Figure 3-1 (page B-7) 

LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the 

reader quickly compare health effects according to exposure concentrations for particular exposure 

periods. 

(13)	 Exposure Period. The same exposure periods appear as in the LSE table. In this example, health 

effects observed within the acute and intermediate exposure periods are illustrated. 

(14)	 Health Effect. These are the categories of health effects for which reliable quantitative data 

exists. The same health effects appear in the LSE table. 

(15)	 Levels of Exposure. Concentrations or doses for each health effect in the LSE tables are 

graphically displayed in the LSE figures. Exposure concentration or dose is measured on the log 

scale "y" axis. Inhalation exposure is reported in mg/m3 or ppm and oral exposure is reported in 

mg/kg/day. 

(16)	 NOAEL. In this example, the open circle designated 18r identifies a NOAEL critical end point in 

the rat upon which an intermediate inhalation exposure MRL is based. The key number 18 

corresponds to the entry in the LSE table. The dashed descending arrow indicates the 

extrapolation from the exposure level of 3 ppm (see entry 18 in the table) to the MRL of 

0.005 ppm (see footnote "b" in the LSE table). 

(17)	 CEL. Key number 38m is one of three studies for which CELs were derived. The diamond 

symbol refers to a CEL for the test species-mouse. The number 38 corresponds to the entry in the 

LSE table. 
CRESOLS	 B-5 

APPENDIX B 

(18)	 Estimated Upper-Bound Human Cancer Risk Levels. This is the range associated with the upperbound for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are derived 

from the EPA's Human Health Assessment Group's upper-bound estimates of the slope of the 

cancer dose response curve at low dose levels (q1*). 

(19)	 Key to LSE Figure. The Key explains the abbreviations and symbols used in the figure. 
SAMPLE

1 → Table 3-1. Levels of Significant Exposure to [Chemical x] – Inhalation

LOAEL (effect) Exposure 

Key to frequency/ NOAEL Less serious Serious (ppm)figurea Species duration System (ppm) (ppm) Re

234

→ INTERMEDIATE EXPOSURE 

5 6 7 8 9 10 

→ Systemic ↓ ↓ ↓ ↓ ↓ ↓

18 Rat 13 wk Resp 3b 10 (hyperplasia)

→ 5 d/wk Nit

6 hr/d

CHRONIC EXPOSURE 

Cancer 11

↓

38 Rat 18 mo 20 (CEL, multiple Wo

5 d/wk organs)7 hr/d

39 Rat 89–104 wk 10 (CEL, lung tumors, NT

5 d/wk nasal tumors)6 hr/d

40 Mouse 79–103 wk 10 (CEL, lung tumors, NT

5 d/wk hemangiosarcomas) 6 hr/d 

12 → a The number corresponds to entries in Figure 3-1. b Used to derive an intermediate inhalation Minimal Risk Level (MRL) of 5x10-3 ppm; dose adjusted for intermittent ex

by an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability). 

CRESOLS B-8
 

APPENDIX B 

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CRESOLS C-1 

APPENDIX C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS
 

ACGIH American Conference of Governmental Industrial Hygienists 

ACOEM American College of Occupational and Environmental Medicine 

ADI acceptable daily intake 

ADME absorption, distribution, metabolism, and excretion 

AED atomic emission detection 

AFID alkali flame ionization detector 

AFOSH Air Force Office of Safety and Health 

ALT alanine aminotransferase 

AML acute myeloid leukemia 

AOAC Association of Official Analytical Chemists 

AOEC Association of Occupational and Environmental Clinics 

AP alkaline phosphatase 

APHA American Public Health Association 

AST aspartate aminotransferase 

atm atmosphere 

ATSDR Agency for Toxic Substances and Disease Registry 

AWQC Ambient Water Quality Criteria 

BAT best available technology 

BCF bioconcentration factor 

BEI Biological Exposure Index 

BMD benchmark dose 

BMR benchmark response 

BSC Board of Scientific Counselors 

C centigrade 

CAA Clean Air Act 

CAG Cancer Assessment Group of the U.S. Environmental Protection Agency 

CAS Chemical Abstract Services 

CDC Centers for Disease Control and Prevention 

CEL cancer effect level 

CELDS Computer-Environmental Legislative Data System 

CERCLA Comprehensive Environmental Response, Compensation, and Liability Act 

CFR Code of Federal Regulations 

Ci curie 

CI confidence interval 

CL ceiling limit value 

CLP Contract Laboratory Program 

cm centimeter 

CML chronic myeloid leukemia 

CPSC Consumer Products Safety Commission 

CWA Clean Water Act 

DHEW Department of Health, Education, and Welfare 

DHHS Department of Health and Human Services 

DNA deoxyribonucleic acid 

DOD Department of Defense 

DOE Department of Energy 

DOL Department of Labor 

DOT Department of Transportation 

DOT/UN/ Department of Transportation/United Nations/ 

NA/IMCO North America/Intergovernmental Maritime Dangerous Goods Code 
 

 

CRESOLS 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 F1 first-filial generation 

FAO Food and Agricultural Organization of the United Nations 

FDA Food and Drug Administration 

FEMA Federal Emergency Management Agency 

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act 

FPD flame photometric detection 

fpm feet per minute 

FR Federal Register 

FSH follicle stimulating hormone 

g gram 

GC gas chromatography 

gd gestational day 

GLC gas liquid chromatography 

GPC gel permeation chromatography 

HPLC high-performance liquid chromatography 

HRGC high resolution gas chromatography 

HSDB Hazardous Substance Data Bank 

IARC International Agency for Research on Cancer 

IDLH immediately dangerous to life and health 

ILO International Labor Organization 

IRIS Integrated Risk Information System 

Kd adsorption ratio 

kg kilogram 

kkg metric ton Koc organic carbon partition coefficient Kow octanol-water partition coefficient 

L liter 

LC liquid chromatography 

LC50 lethal concentration, 50% kill 

LCLo lethal concentration, low 

LD50 lethal dose, 50% kill 

LDLo lethal dose, low 

LDH lactic dehydrogenase 

LH luteinizing hormone 

LOAEL lowest-observed-adverse-effect level 

LSE Levels of Significant Exposure 

LT50 lethal time, 50% kill 

m meter 

MA trans,trans-muconic acid 

MAL maximum allowable level 

mCi millicurie 

MCL maximum contaminant level 

MCLG maximum contaminant level goal 

MF modifying factor 
 

CRESOLS 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 Toxics Information Clearinghouse 

NATO North Atlantic Treaty Organization 

NCE normochromatic erythrocytes 

NCEH National Center for Environmental Health 

NCI National Cancer Institute 

ND not detected 

NFPA National Fire Protection Association 

ng nanogram 

NHANES National Health and Nutrition Examination Survey 

NIEHS National Institute of Environmental Health Sciences 

NIOSH National Institute for Occupational Safety and Health 

NIOSHTIC NIOSH's Computerized Information Retrieval System 

NLM National Library of Medicine 

nm nanometer 

nmol nanomole 

NOAEL no-observed-adverse-effect level 

NOES National Occupational Exposure Survey 

NOHS National Occupational Hazard Survey 

NPD nitrogen phosphorus detection 

NPDES National Pollutant Discharge Elimination System 

NPL National Priorities List 

NR not reported 

NRC National Research Council 

NS not specified 

NSPS New Source Performance Standards 

NTIS National Technical Information Service 

NTP National Toxicology Program 

ODW Office of Drinking Water, EPA 

OERR Office of Emergency and Remedial Response, EPA 

OHM/TADS Oil and Hazardous Materials/Technical Assistance Data System 

OPP Office of Pesticide Programs, EPA 

OPPT Office of Pollution Prevention and Toxics, EPA 

OPPTS Office of Prevention, Pesticides and Toxic Substances, EPA 

OR odds ratio 

OSHA Occupational Safety and Health Administration 

OSW Office of Solid Waste, EPA 

OTS Office of Toxic Substances 

OW Office of Water 

OWRS Office of Water Regulations and Standards, EPA 

PAH polycyclic aromatic hydrocarbon 
 

 

CRESOLS 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 Toxic Effects of Chemical Substances 

SARA Superfund Amendments and Reauthorization Act 

SCE sister chromatid exchange 

SGOT serum glutamic oxaloacetic transaminase 

SGPT serum glutamic pyruvic transaminase 

SIC standard industrial classification 

SIM selected ion monitoring 

SMCL secondary maximum contaminant level 

SMR standardized mortality ratio 

SNARL suggested no adverse response level 

SPEGL Short-Term Public Emergency Guidance Level 

STEL short term exposure limit 

STORET Storage and Retrieval 

TD50 toxic dose, 50% specific toxic effect 

TLV threshold limit value 

TOC total organic carbon 

TPQ threshold planning quantity 

TRI Toxics Release Inventory 

TSCA Toxic Substances Control Act 

TWA time-weighted average 

UF uncertainty factor 

U.S. United States 

USDA United States Department of Agriculture 

USGS United States Geological Survey 

VOC volatile organic compound 

WBC white blood cell 

WHO World Health Organization 
 

CRESOLS C-5 

APPENDIX C 

> greater than 

≥ greater than or equal to 

= equal to 

< less than 

≤ less than or equal to 

% percent 

α alpha 

β beta 

γ gamma 

δ delta 

μm micrometer 

μg microgram q1

* cancer slope factor 

– negative 

+ positive 

(+) weakly positive result 

(–) weakly negative result 
CRESOLS C-6
 

APPENDIX C 

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CRESOLS D-1 

APPENDIX D. INDEX
 

absorbed dose............................................................................................................................................118
 

adrenals .......................................................................................................................................................83
 

adsorbed....................................................................................................................................................165
 

adsorption..................................................................................................................................................165
 

aerobic............................................................................................................................... 166, 167, 168, 180
 

alanine aminotransferase (see ALT) ..................................................................................................... 17, 80
 

ALT (see alanine aminotransferase) ............................................................................................... 17, 80, 81
 

ambient air ................................................................................................ 147, 158, 171, 172, 176, 178, 191
 

anaerobic................................................................................... 147, 158, 159, 164, 166, 167, 168, 174, 181
 

androgen receptor......................................................................................................................................114
 

anemia.........................................................................................................................................................79
 

aspartate aminotransferase (see AST).........................................................................................................80
 

AST (see aspartate aminotransferase)................................................................................................... 80, 81
 

bioaccumulation................................................................................................................................ 181, 182
 

bioconcentration factor .............................................................................................................................166
 

biodegradation............................................................................... 9, 146, 166, 167, 168, 169, 173, 174, 181
 

biomarker .................................................................................................................................. 117, 118, 192
 

biomarkers................................................................................................. 117, 118, 119, 129, 131, 185, 192
 

blood cell count...........................................................................................................................................79
 

body weight effects.....................................................................................................................................84
 

breast milk....................................................................................................................................... 5, 10, 178
 

cancer............................................................................................................................ 90, 96, 115, 116, 124
 

carcinogen..................................................................................................................................... 91, 96, 197
 

carcinogenic .............................................................................................................. 12, 13, 21, 91, 124, 195
 

carcinogenicity.................................................................................................................... 91, 126, 195, 198
 

carcinomas ..................................................................................................................................................96
 

cardiovascular ......................................................................................................................... 23, 77, 92, 125
 

cardiovascular effects............................................................................................................................ 23, 77
 

chromosomal aberrations............................................................................................................................99
 

clearance ........................................................................................................................... 104, 107, 110, 120
 

death........................................................ 4, 21, 22, 23, 25, 26, 27, 77, 82, 92, 102, 112, 116, 122, 125, 128
 

deoxyribonucleic acid (see DNA)...............................................................................................................98
 

dermal effects.................................................................................................................... 23, 84, 94, 95, 124
 

developmental effects ................................................................................. 15, 25, 89, 90, 96, 116, 127, 131
 

DNA (see deoxyribonucleic acid)........................................................................... 97, 98, 99, 118, 126, 129
 

endocrine............................................................................................................................. 83, 112, 113, 114
 

endocrine effects .........................................................................................................................................83
 

estrogenic ..................................................................................................................................................114
 

fetus...........................................................................................................................................................114
 

gastrointestinal effects .................................................................................................................... 77, 92, 94
 

general population................................................................................................. 9, 117, 128, 147, 176, 178
 

genotoxic......................................................................................................................................... 21, 96, 99
 

genotoxicity........................................................................................................................... 96, 99, 116, 126
 

groundwater .................. 2, 3, 9, 147, 158, 159, 160, 161, 162, 163, 167, 168, 172, 173, 174, 177, 181, 191
 

half-life...................................................................................................................... 104, 117, 166, 169, 170
 

hematological effects ........................................................................................................ 78, 79, 80, 94, 119
 

hepatic effects ................................................................................................................................. 23, 80, 94
 

hydrolysis.................................................................................................................................. 144, 169, 187
 

hydroxyl radical ................................................................................................................ 147, 166, 167, 169
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CRESOLS D-2 

APPENDIX D 

immune system .........................................................................................................................................128
 

immunological .................................................................................................................. 21, 24, 85, 95, 128
 

immunological effects............................................................................................................. 24, 85, 95, 128
 

Kow ............................................................................................................................................ 136, 165, 181
 

LD50........................................................................................................................................... 14, 25, 27, 92
 

lymphoreticular................................................................................................................................... 86, 128
 

metabolic effects .........................................................................................................................................85
 

micronuclei .................................................................................................................................................99
 

milk ....................................................................................................................................... 5, 117, 120, 131
 

musculoskeletal effects ......................................................................................................................... 80, 92
 

neoplastic ...................................................................................................................................... 19, 91, 126
 

neurobehavioral................................................................................................................................... 87, 113
 

neurological effects............................................................................... 14, 24, 85, 86, 87, 95, 112, 125, 131
 

neurophysiological....................................................................................................................................112
 

neurotransmitter ........................................................................................................................................112
 

ocular effects......................................................................................................................................... 24, 84
 

pharmacodynamic.....................................................................................................................................107
 

pharmacokinetic........................................................................................ 107, 108, 109, 115, 116, 122, 130
 

photolysis.......................................................................................................................................... 167, 169
 

placenta ............................................................................................................................................. 117, 131
 

rate constant ...................................................................................................................... 166, 167, 169, 170
 

renal effects..................................................................................................................................... 24, 82, 94
 

reproductive effects........................................................................................................... 25, 88, 89, 96, 127
 

respiratory effects............................................................................................................................ 23, 27, 92
 

salivation..................................................................................................................... 11, 26, 86, 87, 90, 128
 

solubility ................................................................................................................................... 125, 136, 165
 

systemic effects................................................................................................... 11, 15, 23, 27, 92, 102, 122
 

T3................................................................................................................................................................28
 

thyroid................................................................................................................... 4, 12, 17, 19, 83, 126, 195
 

toxicokinetic............................................................................................................ 14, 21, 16, 101, 130, 131
 

tremors ................................................................ 11, 14, 23, 25, 85, 86, 87, 89, 90, 111, 114, 127, 128, 195
 

tumors ................................................................................................................................................... 91, 96
 

vapor phase ...............................................................................................................................................165
 

vapor pressure ..................................................................................................................... 16, 125, 136, 165
 

volatilization .............................................................................................................................................166