TOXICOLOGICAL PROFILE FOR
 

DI(2-ETHYLHEXYL)PHTHALATE
 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
 

Public Health Service
 

Agency for Toxic Substances and Disease Registry
 

September 2002 
DI(2-ETHYLHEXYL)PHTHALATE 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. 
DI(2-ETHYLHEXYL)PHTHALATE iii 

UPDATE STATEMENT
 

Toxicological profiles are revised and republished as necessary, but no less than once every three years. 

For information regarding the update status of previously released profiles, contact ATSDR at: 

Agency for Toxic Substances and Disease Registry
 

Division of Toxicology/Toxicology Information Branch
 

1600 Clifton Road NE, E-29
 

Atlanta, Georgia 30333
 

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

and views expressed in this toxicological profile resides with ATSDR. 

Administrator 

Agency for Toxic Substances and 

Disease Registry 
vi 

*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 October 25,2001 

(66 FR 54014). 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); and 

October 21, 1999 (64 FR 56792). Section 104(i)(3) of CERCLA, as amended, directs the Administrator 

of ATSDR to prepare a toxicological profile for each substance on the list. 
 

 

DI(2-ETHYLHEXYL)PHTHALATE vii 

QUICK REFERENCE FOR HEALTH CARE PROVIDERS 

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

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

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

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

answers to often-asked questions. 

Primary Chapters/Sections of Interest 

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

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

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

the general health effects observed following exposure. 

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

and assesses the significance of toxicity data to human health. 

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

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

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

reported in this section. 

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

the clinical setting. Please refer to the Public Health Statement to identify 

general health effects observed following exposure. 

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

issues: 

Section 1.6 How Can (Chemical X) Affect Children?
 

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

Section 3.7 Children’s Susceptibility
 

Section 6.6 Exposures of Children
 

Other Sections of Interest: 

Section 3.8 Biomarkers of Exposure and Effect 

Section 3.11 Methods for Reducing Toxic Effects 

ATSDR Information Center 

Phone: 1-888-42-ATSDR or (404) 498-0110 Fax: (404) 498-0057 

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

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

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

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

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

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

Toxicity; and numerous chemical-specific case studies. 
DI(2-ETHYLHEXYL)PHTHALATE 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, 55 West Seegers Road, Arlington Heights, IL 

60005 • Phone: 847-818-1800 • FAX: 847-818-9266. 
DI(2-ETHYLHEXYL)PHTHALATE ix 

CONTRIBUTORS 

CHEMICAL MANAGER(S)/AUTHORS(S): 

Stephanie Miles-Richardson, D.V.M., Ph.D. 

ATSDR, Division of Toxicology, Atlanta, GA 

Stephen Bosch, M.S. 

Steven Swarts, Ph.D. 

Fernando Llados, Ph.D. 

D. Anthony Gray, Ph.D.
 

Syracuse Research Corporation, Syracuse, NY
 

THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS: 

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

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

end points. 

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

substance-specific minimal risk levels (MRLs), reviews the health effects database of each 

profile, and makes recommendations for derivation of MRLs. 

3.	 Data Needs Review. The Research Implementation Branch reviews data needs sections to assure 

consistency across profiles and adherence to instructions in the Guidance. 

DI(2-ETHYLHEXYL)PHTHALATE xi 

PEER REVIEW 

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

1.	 Daland R. Juberg, Ph.D. 

Principal 

International Center for Toxicology and Medicine 

139 Greenway Road 

Rochester, NY 14610 

2.	 James E. Klaunig, Ph.D. 

Director, Division of Toxicology 

Professor of Toxicology 

Indiana University School of Medicine 

135 Bennington Drive 

Zionsville, IN 46077 

3.	 James E. Trosko, Ph.D. 

Professor of Pediatrics and Human Development 

Michigan State University 

246 National Food Safety Toxicology Center 

East Lansing, MI 48824 

These experts collectively have knowledge of DEHP'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. A list of databases reviewed and 

a list of unpublished documents cited are also included in the administrative record. 

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. 

 

 

DI(2-ETHYLHEXYL)PHTHALATE xiii 

CONTENTS
 

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

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

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

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

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

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

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

1.1 	 WHAT IS DEHP? ...................................................... 1 
 

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

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

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

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

1.6	 HOW CAN DEHP AFFECT CHILDREN? .................................. 6
 

1.7	 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO DEHP? ........ 7
 

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

EXPOSED TO DEHP? .................................................. 8 
 

1.9	 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE 

TO PROTECT HUMAN HEALTH? ........................................ 8
 

1.10 	 WHERE CAN I GET MORE INFORMATION? ............................. . 9
 

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

2.1	 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO DI(2­

ETHYLHEXYL)PHTHALATE IN THE UNITED STATES .................... 11 
 

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

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

3. HEALTH EFFECTS .............................................................. 21 
 

3.1	 INTRODUCTION ..................................................... 21 
 

3.2	 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE ............ 21 
 

3.2.1	 Inhalation Exposure ............................................. 23 
 

3.2.1.1 Death .................................................. 23 
 

3.2.1.2 Systemic Effects ......................................... 23 
 

3.2.1.3 Immunological and Lymphoreticular Effects ................... 24 
 

3.2.1.4 Neurological Effects ...................................... 28 
 

3.2.1.5 Reproductive Effects ...................................... 28 
 

3.2.1.6 Developmental Effects ..................................... 28 
 

3.2.1.7 Cancer ................................................. 28 
 

3.2.2	 Oral Exposure .................................................. 29 
 

3.2.2.1 Death .................................................. 29 
 

3.2.2.2 Systemic Effects ......................................... 29 
 

3.2.2.3 Immunological and Lymphoreticular Effects ................... 81 
 
 

 

 

DI(2-ETHYLHEXYL)PHTHALATE xiv 

3.2.2.4 Neurological Effects ...................................... 81 
 

3.2.2.5 Reproductive Effects ...................................... 82 
 

3.2.2.6 Developmental Effects ..................................... 86 
 

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

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

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

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

3.2.3.3 Immunological and Lymphoreticular Effects ................... 93 
 

3.2.3.4 Neurological Effects ...................................... 93 
 

3.2.3.5 Reproductive Effects ...................................... 93 
 

3.2.3.6 Developmental Effects ..................................... 93 
 

3.2.3.7 Cancer ................................................. 93 
 

3.3 	 GENOTOXICITY ..................................................... 93 
 

3.4 	 TOXICOKINETICS .................................................. 102 
 

3.4.1 	 Absorption ................................................... 104 
 

3.4.1.1 Inhalation Exposure ...................................... 104 
 

3.4.1.2 Oral Exposure .......................................... 104 
 

3.4.1.3 Dermal Exposure ........................................ 105 
 

3.4.2 	 Distribution ................................................... 106 
 

3.4.2.1 Inhalation Exposure ...................................... 106 
 

3.4.2.2 Oral Exposure .......................................... 106 
 

3.4.2.3 Dermal Exposure ........................................ 107
 

3.4.2.4 Other Routes of Exposure ................................. 108 
 

3.4.3 	 Metabolism ................................................... 109 
 

3.4.4 	 Elimination and Excretion ....................................... 111 
 

3.4.4.1 Inhalation Exposure ...................................... 111 
 

3.4.4.2 Oral Exposure .......................................... 111 
 

3.4.4.3 Dermal Exposure ........................................ 112 
 

3.4.4.4 Other Routes of Exposure ................................. 112
 

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

Models ...................................................... 113 
 

3.5	 MECHANISMS OF ACTION ........................................... 120 
 

3.5.1 	 Pharmacokinetic Mechanisms ..................................... 120 
 

3.5.2 	 Mechanisms of Toxicity ......................................... 121 
 

3.5.3	 Animal-to-Human Extrapolations .................................. 134
 

3.6	 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS ....... 136
 

3.7	 CHILDREN’S SUSCEPTIBILITY ....................................... 139
 

3.8	 BIOMARKERS OF EXPOSURE AND EFFECT ............................ 145
 

3.8.1	 Biomarkers Used to Identify or Quantify Exposure to DEHP ............ 146
 

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

3.9	 INTERACTIONS WITH OTHER CHEMICALS ............................ 148
 

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

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

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

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

3.11.3 Interfering with the Mechanism of Action for Toxic Effects ............. 154
 

3.12	 ADEQUACY OF THE DATABASE ..................................... 155
 

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

3.12.2 Identification of Data Needs ...................................... 158
 

3.12.3 Ongoing Studies ............................................... 170
 
 

 

 

DI(2-ETHYLHEXYL)PHTHALATE xv 

4. CHEMICAL AND PHYSICAL INFORMATION ...................................... 172
 

4.1 CHEMICAL IDENTITY ............................................... 172
 

4.2 PHYSICAL AND CHEMICAL PROPERTIES ............................. 172
 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL ............................ 176
 

5.1 PRODUCTION ...................................................... 176
 

5.2 IMPORT/EXPORT ................................................... 179
 

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

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

6. POTENTIAL FOR HUMAN EXPOSURE ........................................... 182
 

6.1 OVERVIEW ........................................................ 182
 

6.2 RELEASES TO THE ENVIRONMENT ................................... 184
 

6.2.1 Air .......................................................... 184
 

6.2.2 Water ........................................................ 188
 

6.2.3 Soil ......................................................... 188
 

6.3 ENVIRONMENTAL FATE ............................................ 190
 

6.3.1 Transport and Partitioning ....................................... 190
 

6.3.2 Transformation and Degradation .................................. 192
 

6.3.2.1 Air ................................................... 192
 

6.3.2.2 Water ................................................. 192
 

6.3.2.3 Sediment and Soil ....................................... 193
 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT .......... 193
 

6.4.1 Air .......................................................... 194
 

6.4.2 Water ........................................................ 195
 

6.4.3 Sediment and Soil .............................................. 196
 

6.4.4 Other Environmental Media ...................................... 197
 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE ............. 199
 

6.6 EXPOSURES OF CHILDREN .......................................... 203
 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES ................ 209
 

6.8 ADEQUACY OF THE DATABASE ..................................... 210
 

6.8.1 Identification of Data Needs ...................................... 210
 

6.8.2 Ongoing Studies ............................................... 213
 

7. ANALYTICAL METHODS ....................................................... 215
 

7.1 BIOLOGICAL MATERIALS ........................................... 215
 

7.2 ENVIRONMENTAL SAMPLES ........................................ 218
 

7.3 ADEQUACY OF THE DATABASE ..................................... 221
 

7.3.1 Identification of Data Needs ...................................... 221
 

7.3.2 Ongoing Studies ............................................... 222
 

8. REGULATIONS AND ADVISORIES .............................................. 223
 

9. REFERENCES ................................................................. 231
 

10. GLOSSARY .................................................................. 285
 

APPENDICES 

A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS ................... A-1 
 
DI(2-ETHYLHEXYL)PHTHALATE xvi 

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

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

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

DI(2-ETHYLHEXYL)PHTHALATE xvii 

LIST OF FIGURES
 

3-1. Levels of Significant Exposure to DEHP - Inhalation ................................... 27 
 

3-2. Levels of Significant Exposure to DEHP - Oral ....................................... 60 
 

3-3. Peroxisomal Fatty Acid Metabolism ................................................ 71 
 

3-4. DEHP Metabolites ............................................................. 103 
 

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

Hypothetical Chemical Substance ................................................ 115 
 

3-6. Existing Information on Health Effects of DEHP ..................................... 156
 

6-1. Frequency of NPL Sites with DEHP Contamination ................................... 183
 

 

DI(2-ETHYLHEXYL)PHTHALATE xix 

LIST OF TABLES
 

3-1. Levels of Significant Exposure to DEHP - Inhalation ................................... 25 
 

3-2. Levels of Significant Exposure to DEHP - Oral ....................................... 30 
 

3-3. Genotoxicity of DEHP In Vivo .................................................... 95 
 

3-4. Genotoxicity of DEHP In Vitro .................................................... 98 
 

3-5. Tissue:Blood Partition Coefficients Used in the Keys et al. (1999) Model .................. 118 
 

3-6. Physiological Parameter Values Used in the Keys et al. (1999) Model .................... 119 
 

3-7. Ongoing Studies on the Health Effects of DEHP ..................................... 171
 

4-1. Chemical Identity of DEHP ...................................................... 173
 

4-2. Physical and Chemical Properties of DEHP ......................................... 174
 

5-1. Facilities that Produce, Process, or Use DEHP ....................................... 177
 

6-1. Releases to the Environment from Facilities that Produce, Process, or Use DEHP ........... 185
 

6-2. Concentration of DEHP in Categories of Household Waste ............................. 200
 

6-3. Types of Industries Using DEHP-containing Products ................................. 204
 

7-1. Analytical Methods for Determining DEHP in Biological Materials ...................... 217
 

7-2. Analytical Methods for Determining DEHP in Environmental Samples ................... 219
 

8-1. Regulations and Guidelines Applicable to DEHP ..................................... 225
 

DI(2-ETHYLHEXYL)PHTHALATE 1 

1. PUBLIC HEALTH STATEMENT
 

This public health statement tells you about di(2-ethylhexyl) phthalate (DEHP) and the effects of 

exposure. 

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

the nation. These sites make up the National Priorities List (NPL) and are the sites targeted for 

long-term federal cleanup activities. DEHP has been found in at least 737 of the 1,613 current or 

former NPL sites. However, the total number of NPL sites evaluated for DEHP is not known. 

As more sites are evaluated, the sites at which DEHP is found may increase. This information is 

important because exposure to DEHP may harm you and because these sites may be sources of 

exposure. 

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

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

exposure. You are 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 DEHP, many factors determine whether you’ll 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 the other chemicals you’re exposed to and your age, sex, diet, family 

traits, lifestyle, and state of health. 

1.1 WHAT IS DEHP? 

DEHP, which is an abbreviation for di(2-ethylhexyl) phthalate, is a manufactured chemical that 

is commonly added to plastics to make them flexible. Other names for this compound are 

dioctyl phthalate (DOP) and bis(2-ethylhexyl) phthalate (BEHP). (Note that di-n-octyl 

phthalate, however, is the name for a different chemical.) Trade names used for DEHP include 

Platinol DOP, Octoil, Silicol 150, Bisoflex 81, and Eviplast 80. DEHP is a colorless liquid with 

almost no odor. It does not evaporate easily, and little will be present in the air even near 
DI(2-ETHYLHEXYL)PHTHALATE 2 

1. PUBLIC HEALTH STATEMENT 

sources of production. It dissolves more easily in materials such as gasoline, paint removers, and 

oils than it does in water. It is present in many plastics, especially vinyl materials, which may 

contain up to 40% DEHP, although lower levels are common. DEHP is present in plastic 

products such as wall coverings, tablecloths, floor tiles, furniture upholstery, shower curtains, 

garden hoses, swimming pool liners, rainwear, baby pants, dolls, some toys, shoes, automobile 

upholstery and tops, packaging film and sheets, sheathing for wire and cable, medical tubing, 

and blood storage bags. Additional information on the properties of DEHP and its uses is found 

in Chapters 4 and 5. 

1.2 WHAT HAPPENS TO DEHP WHEN IT ENTERS THE ENVIRONMENT? 

DEHP can enter the environment through releases from factories that make or use DEHP and 

from household items containing it. Over long periods of time, it can move out of plastic 

materials into the environment. Therefore, DEHP is widespread in the environment; about 

291,000 pounds were released in 1997 from industries. It is often found near industrial settings, 

landfills, and waste disposal sites. A large amount of plastic that contains DEHP is buried at 

landfill sites. DEHP has been found in groundwater near waste disposal facilities. 

When DEHP is released to soil, it usually attaches strongly to the soil and does not move very 

far away from where it was released. When DEHP is released to water, it dissolves very slowly 

into underground water or surface waters that contact it. It takes many years before DEHP in 

buried or discarded materials disappears from the environment. Because DEHP does not 

evaporate easily, normally very little goes into the air. DEHP in air will bind to dust particles 

and will be carried back down to earth through gravity and rain or snow. Indoor releases of 

DEHP to the air from plastic materials, coatings, and flooring in home and work environments, 

although small, can lead to higher indoor levels than are found in the outdoor air. 

DEHP can break down in the presence of other chemicals to produce mono(2-ethylhexyl)­

phthalate (MEHP) and 2-ethylhexanol. Many of the properties of MEHP are like those of 

DEHP, and therefore its fate in the environment is similar. In the presence of oxygen, DEHP in 

water and soil can be broken down by microorganisms to carbon dioxide and other simple 
DI(2-ETHYLHEXYL)PHTHALATE 3 

1. PUBLIC HEALTH STATEMENT 

chemicals. DEHP does not break down very easily when deep in the soil or at the bottom of 

lakes or rivers where there is little oxygen. It can be found in small amounts in fish and other 

animals, and some uptake by plants has been reported. You will find additional information on 

the fate of DEHP in the environment in Chapters 5 and 6. 

1.3 HOW MIGHT I BE EXPOSED TO DEHP? 

You can be exposed to DEHP through air, water, or skin contact with plastics that have DEHP in 

them. Food may also contain DEHP, but it is not certain how much. 

It is not clear, but it is likely that a little DEHP is transferred by skin contact with plastic clothing 

or other articles that contain DEHP. Exposure through this route is expected to be low since 

plastic articles of clothing, like raincoats, do not have direct contact with your skin, and transfer 

is probably very low even if they do touch you. 

You may be exposed to DEHP through drinking water, but it is not known how common this is. 

If you drink water from a well located near a landfill or waste site, you may be exposed to 

higher-than-average levels of DEHP. 

You can breathe in DEHP that has been released to the environment. The average air level of 

DEHP is very low, less than 2 parts of DEHP per trillion parts of air (ppt) in cities and industrial 

areas. DEHP levels in the indoor air in a room with recently installed flooring could be higher 

than levels in the outdoor air. Workers in factories that make or use DEHP also breathe in 

higher-than-average levels of this compound. 

DEHP also can enter your body during certain medical procedures, and medical exposures are 

likely to be greater than any environmental exposures. Blood products that are stored in plastic 

bags and used for transfusions contain from 4.3 to 1,230 parts of DEHP per million parts of 

blood (ppm). Other plastic medical products also release DEHP. Flexible tubing used to 

administer fluids or medication can transfer DEHP to the patient. The plastic tubing used for 

kidney dialysis frequently contains DEHP and causes DEHP to enter the patient's blood. DEHP 
DI(2-ETHYLHEXYL)PHTHALATE 4 

1. PUBLIC HEALTH STATEMENT 

also is present in the plastic tubing of respirators and is carried from it to the lungs. Additional 

information concerning sources of exposure to DEHP is found in Chapter 6. 

1.4 HOW CAN DEHP ENTER AND LEAVE MY BODY? 

DEHP enters your body when you eat food or drink water containing this material or when you 

breathe in contaminated air. Small amounts of DEHP might enter your body by skin contact 

with plastics, but scientists are fairly certain that very little enters this way. Most DEHP that 

enters your body in food, water, or air is taken up into the blood from the intestines and lungs. 

DEHP can be introduced directly into your bloodstream if you get a blood transfusion, receive 

medicines through flexible plastic tubing, or have dialysis treatments. 

After DEHP is ingested, most of it is rapidly broken down in the gut to MEHP and 

2-ethylhexanol. Breakdown is much slower if DEHP enters your blood directly by way of a 

transfusion. Although some MEHP is absorbed into the bloodstream from the gut, MEHP is 

poorly absorbed, so that much of ingested DEHP leaves the body in the feces. The compounds 

that do enter the blood travel through the bloodstream to your liver, kidneys, testes, and other 

tissues, and small amounts might become stored in your fat and could possibly be secreted in 

breast milk. Most of the DEHP, MEHP, and 2-ethylhexanol leaves your body within 24 hours in 

the urine and feces. Additional information on the uptake, metabolism, and excretion of DEHP 

is found in Chapter 3. 

1.5 HOW CAN DEHP AFFECT MY HEALTH? 

To protect the public from the harmful effects of toxic chemicals and to find ways to treat people 

who have been harmed, scientists use many tests. 

One way to see if a chemical will hurt people is to learn how the chemical is absorbed, used, and 

released by the body; for some chemicals, animal testing might be necessary. Animal testing 

might also be used to identify health effects such as cancer or birth defects. Without laboratory 

animals, scientists would lose a basic method to get information needed to make wise decisions 
DI(2-ETHYLHEXYL)PHTHALATE 5 

1. PUBLIC HEALTH STATEMENT 

to protect public health. Scientists have the responsibility to treat research animals with care and 

compassion. Laws today protect the welfare of research animals, and scientists must comply 

with strict animal care guidelines. 

DEHP, at the levels found in the environment, is not expected to cause adverse health effects in 

humans. A man who voluntarily swallowed 10 g (approximately 0.4 ounces) of DEHP had 

stomach irritation and diarrhea. Most of what we know about the health effects of DEHP comes 

from studies of rats and mice that were given DEHP in their food, or the DEHP was placed in 

their stomach with the aid of a tube through their mouth. In most of these studies, the amounts 

of DEHP given to the animals were much higher than the amounts found in the environment. 

Rats and mice appear to be particularly sensitive to some of the effects of DEHP. Thus, because 

certain animal models may not apply to humans, it is more difficult to predict some of the health 

effects of DEHP in humans using information from these studies. 

Breathing DEHP does not appear to have serious harmful effects. Studies in rats have shown 

that DEHP in the air has no effect on lifespan or the ability to reproduce. As mentioned 

previously, almost no DEHP evaporates into air. You probably will not have any health effects 

from skin contact with DEHP because it cannot be taken up easily through the skin. 

Short-term oral exposures to levels of DEHP much higher than those found in the environment 

interfered with sperm formation in mice and rats. These effects were reversible, but sexual 

maturity was delayed when the animals were exposed before puberty. Short-term exposures to 

low levels of DEHP appeared to have no effect on male fertility. 

Studies of long-term exposures in rats and mice have shown that high oral doses of DEHP 

caused health effects mainly in the liver and testes. These effects were induced by levels of 

DEHP that are much higher than those received by humans from environmental exposures. 

Toxicity of DEHP in other tissues is less well characterized, although effects in the thyroid, 

ovaries, kidneys, and blood have been reported in a few animal studies. The potential for kidney 

effects is a particular concern for humans because this organ is exposed to DEHP during dialysis 

and because structural and functional kidney changes have been observed in some exposed rats. 
DI(2-ETHYLHEXYL)PHTHALATE 6 

1. PUBLIC HEALTH STATEMENT 

Since changes in the kidneys of long-term dialysis patients might be due to the underlying 

kidney disease, and kidney changes have not been consistently seen in animals exposed to 

DEHP, the significance of the rat kidney changes is not clear. 

Humans absorb and breakdown DEHP in the body differently than rats and mice. Therefore, 

many of the effects seen in rats and mice after exposures to DEHP might not occur in humans 

and higher animals like monkeys (primates). More information on the health effects of DEHP is 

found in Chapters 2 and 3. 

No studies have evaluated the potential for DEHP to cause cancer in humans. Eating high doses 

of DEHP for a long time resulted in liver cancer in rats and mice. 

The Department of Health and Human Services (DHHS) has determined that DEHP may 

reasonably be anticipated to be a human carcinogen. EPA has determined that DEHP is a 

probable human carcinogen. These determinations were based entirely on liver cancer in rats 

and mice. The International Agency for Research on Cancer (IARC) has recently changed its 

classification for DEHP from “possibly carcinogenic to humans” to “cannot be classified as to its 

carcinogenicity to humans,” because of the differences in how the livers of humans and primates 

respond to DEHP as compared with the livers of rats and mice. 

1.6 HOW CAN DEHP AFFECT CHILDREN? 

This section discusses potential health effects from exposures during the period from conception 

to maturity at 18 years of age in humans. 

Children can be exposed to DEHP if they eat food or drink water contaminated with DEHP or if 

they breathe in the chemical from ambient or indoor air. Small children can also be exposed by 

sucking on or skin contact with plastic objects (toys) and pacifiers that contain DEHP, as well as 

by ingestion of breast milk containing DEHP. Children also can be exposed to DEHP if they 

undergo certain medical procedures that require the use of flexible tubing such as that used to 
DI(2-ETHYLHEXYL)PHTHALATE 7 

1. PUBLIC HEALTH STATEMENT 

administer fluids or medication to the patient. However, there is no conclusive evidence of 

adverse health effects in children exposed to DEHP in any of these ways. 

In studies of pregnant mice and rats orally exposed to large doses of DEHP, effects on the 

development of the fetus, including birth defects and even fetal death, were observed. 

Researchers observed alterations in the structure of bones and of parts of the brain, and in the 

liver, kidney, and testes of the young animals. These harmful effects suggested that DEHP or 

some of its breakdown products passed across the placenta and reached the fetus. Therefore, 

humans exposed to sufficiently high levels of DEHP during pregnancy could possibly have 

babies with low birth weights and/or skeletal or nervous system developmental problems, but 

this is not certain. Studies in animals also have shown that DEHP or some of its breakdown 

products can pass from mother to babies via the breast milk and alter the development of the 

young animals. This could also happen in humans because DEHP has been detected in human 

milk. 

We do not know whether children differ from adults in their susceptibility to health effects from 

DEHP. However, studies suggest that young male animals are more susceptible than older ones 

to the adverse effects of DEHP on the sex organs. 

More information regarding children’s health and DEHP can be found in Section 3.7, Children’s 

Susceptibility. 

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

If your doctor finds that you have been exposed to significant amounts of DEHP, ask whether 

your children might also be exposed. Your doctor might need to ask your state 

health department to investigate. As discussed in Section 1.8, tests for DEHP only provide a 

measure of recent exposure to the chemical. 

DEHP is used in many products that are made from plastic, but especially a plastic known as 

polyvinyl chloride (PVC) or vinyl. When it is found in products, DEHP is at a higher level when 
DI(2-ETHYLHEXYL)PHTHALATE 8 

1. PUBLIC HEALTH STATEMENT 

that product is new. Less is found in products that are old. Items made from PVC include many 

plastic toys, some plastic furniture, car and furniture upholstery, shower curtains, some garden 

hoses, tablecloths, and some flooring (vinyl flooring). Not all PVC products contain DEHP, but 

it is found in many products. Because DEHP might be in some toys, there is a concern that 

children chewing on such toys might be exposed. One study has shown that DEHP can go from 

plastics to laboratory-simulated saliva. 

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

EXPOSED TO DEHP? 

The most specific test that can be used to determine if you have been exposed to DEHP is the 

measurement of MEHP and other breakdown chemicals in your urine or blood. This test only 

provides a measure of recent exposure, since DEHP is rapidly broken down into other substances 

and excreted from your body. You also could be tested for another breakdown product (phthalic 

acid), but this test would not be specific for DEHP. One or 2 days after exposure, your feces 

could be tested for the presence of DEHP metabolites. These tests are not routinely available 

through health care providers. More information on medical tests for DEHP is found 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. Federal agencies that develop regulations for toxic 

substances include the Environmental Protection Agency (EPA), the Occupational Safety and 

Health Administration (OSHA), and the Food and Drug Administration (FDA). 

Recommendations provide valuable guidelines to protect public health but cannot be enforced by 

law. Federal organizations that develop recommendations for toxic substances include the 

Agency for Toxic Substances and Disease Registry (ATSDR) and the National Institute for 

Occupational Safety and Health (NIOSH). 
DI(2-ETHYLHEXYL)PHTHALATE 9 

1. PUBLIC HEALTH STATEMENT 

Regulations and recommendations can be expressed in not-to-exceed levels in air, water, soil, or 

food that are usually based on levels that affect animals; then they are adjusted to help protect 

people. Sometimes these not-to-exceed levels differ among federal organizations because of 

different exposure times (an 8-hour workday or a 24-hour day), the use of different animal 

studies, or other factors. 

Recommendations and regulations are also periodically updated as more information becomes 

available. For the most current information, check with the federal agency or organization that 

provides it. Some regulations and recommendations for DEHP include the following: 

Several federal guidelines regulate DEHP in consumer products, drinking water, and the work 

environment. FDA limits the types of food packaging materials that can contain DEHP. EPA 

limits the amount of DEHP in drinking water to 6 parts of DEHP per billion parts of water 

(6 ppb). EPA requires that spills of 100 pounds or more of DEHP to the environment be 

reported to the agency. The average concentration of DEHP in workplace air is limited by 

OSHA to 5 milligrams of DEHP per cubic meter (mg/m3

) of air over an 8-hour workday. The 

short-term (15-minute) exposure limit is 10 mg/m3. The guidelines established by the American 

Conference of Governmental Industrial Hygienists (ACGIH) for the workplace are the same as 

the OSHA regulations. More information on government regulations pertaining to DEHP is 

found in 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 

Agency for Toxic Substances and Disease Registry 

Division of Toxicology 

1600 Clifton Road NE, Mailstop E-29 

Atlanta, GA 30333 

Web site: http://www.atsdr.cdc.gov 

* Information line and technical assistance 
DI(2-ETHYLHEXYL)PHTHALATE 10 

1. PUBLIC HEALTH STATEMENT 

Phone: 1-888-42-ATSDR (1-888-422-8737)
 

Fax: 1-404-498-0057
 

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

clinics specialize in recognizing, evaluating, and treating illnesses resulting from exposure to 

hazardous substances. 

* To order toxicological profiles, contact 

National Technical Information Service
 

5285 Port Royal Road
 

Springfield, VA 22161
 

Phone: 1-800-553-6847 or 1-703-605-6000
 
DI(2-ETHYLHEXYL)PHTHALATE 11 

2. RELEVANCE TO PUBLIC HEALTH 

2.1	 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO DI(2-ETHYLHEXYL)-

PHTHALATE IN THE UNITED STATES 

Di(2-ethylhexyl)phthalate, commonly referred to as DEHP, is predominantly used as a plasticizer in the 

production of flexible polyvinyl chloride (PVC) products. At least 95% of DEHP produced is used as a 

plasticizer for PVC. PVC is made flexible by addition of plasticizers and is used in many common items 

such as wall coverings, tablecloths, floor tiles, furniture upholstery, shower curtains, garden hoses, 

swimming pool liners, rainwear, baby pants, dolls, toys, shoes, automobile upholstery and tops, 

packaging film and sheet, sheathing for wire and cable, medical tubing, and blood storage bags. 

Numerous nonplasticizer uses of DEHP have been reported; however, it is not clear to what extent these 

uses are, or have ever been, important. Because of concerns regarding potential health effects from 

DEHP exposure, many toy manufacturers have discontinued use of DEHP in their products. The use of 

DEHP in domestically produced baby teethers and rattles has been discontinued, and DEHP is also no 

longer used as a plasticizer in plastic food wrap products. 

DEHP is a widely used chemical that enters the environment predominantly through disposal of industrial 

and municipal wastes in landfills and, to a much lesser extent, volatilization into air (from industrial and 

end uses of DEHP), carried in waste water from industrial sources of DEHP, and within effluent from 

municipal waste water treatment plants. It tends to sorb strongly to soils and sediments and to 

bioconcentrate in aquatic organisms. Biodegradation is expected to occur under aerobic conditions. 

Sorption, bioaccumulation, and biodegradation are likely to be competing processes, with the dominant 

fate being determined by local environmental conditions. When DEHP is present in the environment, it is 

usually at very low levels. It is very difficult to determine these low levels accurately since DEHP is a 

ubiquitous laboratory contaminant, and laboratory contamination may cause false positives to be reported 

in the literature. 

The principal route of human exposure to DEHP is oral. Most of the available monitoring data are old 

and may not represent current exposures, especially since the uses of DEHP have changed over the last 

20 years. Even so, some recent estimates for the average total daily individual ambient exposures to 

DEHP of 3–30 )g/kg/day (in a 70-kg adult) have been proposed. These intake approximations indicate 

that the general population is exposed to DEHP at levels that are 3–4 orders of magnitude lower than 

those observed to cause adverse health effects in animal studies (see Section 2.2). Occupational 
DI(2-ETHYLHEXYL)PHTHALATE 12 

2. RELEVANCE TO PUBLIC HEALTH 

exposures may be significant, but the highest exposures to DEHP result from medical procedures such as 

blood transfusions (upper bound limit of 8.5 mg/kg/day) or hemodialysis (upper bound limit of 

0.36 mg/kg/day), during which DEHP may leach from plastic equipment into biological fluids. 

Exposures of neonatal children to DEHP can be especially high as a result of some medical procedures. 

For example, upper-bound doses of DEHP have been estimated to be as high as 2.5 mg/kg/day during 

total parenteral nutrition (TPN) administration and 14 mg/kg/day during extracorporeal membrane 

oxygenation (ECMO) procedures. 

People residing near hazardous waste disposal sites or municipal landfills may be subject to higher than 

average levels of DEHP in ambient air and drinking water. Even so, the concentrations of DEHP in these 

media will be greatly limited by the low volatility and water solubility of DEHP, and subpopulations 

living in the vicinity of hazardous waste sites are much less highly exposed than those exposed to DEHP 

during medical procedures. DEHP is included in the priority list of hazardous substances identified by 

ATSDR and the EPA, and has been found in at least 733 of the 1,613 current or former NPL sites. 

However, the number of NPL sites evaluated for DEHP is not known. As more sites are evaluated, the 

sites at which DEHP is found may increase. 

2.2 SUMMARY OF HEALTH EFFECTS 

The health effects of DEHP are well studied in animals, particularly by the oral route, but there is a 

paucity of data in humans by any route of exposure. Information on the oral toxicity of DEHP in humans 

is limited to gastrointestinal symptoms (mild abdominal pain and diarrhea) in two individuals who 

ingested a single large dose of the compound. Studies in rats, mice, and other rodent species show that 

DEHP has a low order of acute oral toxicity, with some data indicating that young animals are more 

susceptible than adults. Numerous repeated dose oral studies in rats and mice have clearly established 

that the main targets of DEHP toxicity are the liver and testes. Toxicity of DEHP in other tissues is less 

well characterized, although effects in the thyroid, ovaries, kidneys, and blood have been reported in a 

few studies. In contrast to the findings in rats and mice, non-human primates appear to be relatively 

insensitive to the hepatic and testicular effects of DEHP. Manifestations of testicular toxicity in rats and 

mice include loss of spermatogenesis and decreased fertility. A more limited data set indicates that longterm oral exposure to DEHP can also cause adverse reproductive effects in female rats and mice. There is 

sufficient evidence showing that DEHP is fetotoxic and teratogenic in rodents, inducing a range of effects 

that includes abnormal development of the male reproductive tract following perinatal exposure. DEHP 

has been extensively tested for genotoxicity in a variety of in vitro and in vivo microbial and mammalian 
 

DI(2-ETHYLHEXYL)PHTHALATE 13 

2. RELEVANCE TO PUBLIC HEALTH 

assay systems with results that are predominately negative or misinterpreted as positive. The weight of 

evidence indicates that DEHP is not genotoxic, but exerts multiple effects by an epigenetic mechanism 

that can alter the expression of genes in cells. Sustained long-term oral exposure to DEHP is 

hepatocarcinogenic in rats and mice, but the mechanism by which liver cancer (and liver toxicity) is 

induced in these species does not appear to be operative in humans. 

Limited information is available on the health effects of DEHP in humans or animals following inhalation 

or dermal exposure. Regarding effects of inhalation, lung disorders resembling hyaline membrane 

disease were observed during the fourth week of life in three children who had received respiratory 

ventilation via PVC tubing as preterm infants. Although interpretation of these findings is complicated 

by confounding variables such as compromised health status of the preterm infants, the available 

information suggests that the lung disorders were related to DEHP released from the walls of the 

respiratory tubing. One inhalation study in rats that were intermittently exposed to DEHP aerosol for 

28 days reported increased lung and liver weights and histological changes in the lungs that were reversed 

following cessation of exposure. Two inhalation studies found no evidence of DEHP-induced 

reproductive or developmental toxicity in rats. One dermal study found no indications of skin irritation or 

sensitization in humans, skin irritation in rabbits, or ocular irritation in rabbits. 

Additional information on the main health effects of DEHP is discussed below. Because its effects are 

exerted in animals in a dose-related manner, exhibit threshold responses, and are not necessarily relevant 

to humans due to rodent-specific mechanisms, and concentrations of DEHP in the environment are almost 

certain to be well below effect thresholds, ambient levels exposure are not expected to be toxicologically 

significant, even in the vicinity of hazardous waste sites. DEHP therefore is not expected to pose a 

serious public health concern for the vast majority of the population. 

Hepatotoxicity and Liver Cancer. Acute, intermediate, and chronic oral exposures to DEHP have 

profound effects in the rodent liver. Characteristic hepatic effects in rats and mice observed in numerous 

studies include hypertrophy and hyperplasia, beginning within 24 hours of exposure as reflected by 

induction of DNA synthesis and mitosis; proliferation of hepatic peroxisomes and, to a lesser extent, 

mitochondria and lysosomes; induction of peroxisome β-oxidation enzymes, with an accompanying 

increase in mitochondrial fatty acid oxidation; decreased cholesterol synthesis and degradation; induction 

of microsomal CYP4A-associated enzymes; altered concentrations of membrane proteins and lipids; 

increased production of H2O2 and reduction of H2O2-degrading enzymes; decreased liver glycogen; 

alterations in the morphology of the bile ducts; increases in malondialdehyde, conjugated dienes, and 
DI(2-ETHYLHEXYL)PHTHALATE 14 

2. RELEVANCE TO PUBLIC HEALTH 

lipofuscin deposits, indicating increased cellular concentration of free radical oxygen due to insufficient 

catalase; possible increased 8-hydroxydeoxy-guanosine in hepatic DNA; and eventual appearance of 

precancerous altered cell foci, nodules, and tumors. 

It is generally believed that many of these liver effects are mediated through transcriptional activation of 

the peroxisome proliferator-activated receptor α (PPARα). The conclusion that the hepatic effects of 

DEHP are largely due to peroxisome proliferation is supported by findings that increased cell 

proliferation, hypertrophy, induction of peroxisomal and microsomal fatty acid-oxidizing enzymes, 

increased fatty acyl-CoA oxidase activity, excess production of hydrogen peroxide, decreased plasma 

lipid levels, and expression and activation of PPARα are common effects among structurally unrelated 

chemicals and drugs inducing peroxisome proliferation. As discussed in Section 3.5.2 Mechanisms of 

Toxicity, there are marked species differences in hepatic peroxisome proliferation. In particular, although 

human liver has low expression of PPARα, the characteristic effects of rodent peroxisome proliferators 

have not been observed in humans, either in liver biopsies from humans exposed to peroxisome 

proliferators, or in human hepatocytes exposed to peroxisome proliferators in vitro. The overall evidence 

indicates that most of the hepatic effects observed in DEHP-exposed rodents, including liver cancer, 

result from a mechanism that does not operate in humans. 

It is well documented that long-term oral exposure to DEHP causes cancer of the liver in both rats and 

mice. There is no evidence that DEHP is genotoxic or a liver tumor initiator in rats and mice, although it 

does appear to have tumor promotion activity. Based on the findings from one of the cancer studies, an 

NTP bioassay, EPA classified DEHP in Group B2 (probable human carcinogen) and derived a cancer risk 

value (q1*) of 1.4x10-2 (mg/kg/day)-1. Based largely on the same findings, the U.S. Department of Health 

and Human Services suggests that it is reasonable to consider DEHP as a human carcinogen. IARC 

recently (2001) updated its cancer classification of DEHP from Group 2B (possibly carcinogenic to 

humans) to Group 3 (not classifiable as to its carcinogenicity to humans). In making its overall 

evaluation of the carcinogenicity of DEHP to humans, IARC took into consideration that (1) DEHP 

produces liver tumors in rats and mice by a non-DNA-reactive mechanism involving peroxisome 

proliferation, (2) peroxisome proliferation and hepatocellular proliferation have been demonstrated under 

the conditions of the carcinogenicity studies of DEHP in rats and mice, and (3) peroxisome proliferation 

has not been documented either in human hepatocyte cultures exposed to DEHP or in the liver of 

nonhuman primates. Based on these three lines of evidence, IARC concluded that the mechanism by 

which DEHP increases the incidence of hepatocellular tumors in rats and mice is not relevant to humans. 

This conclusion is based on the assumption that peroxisome proliferation is the mechanism causing liver 
 

DI(2-ETHYLHEXYL)PHTHALATE 15 

2. RELEVANCE TO PUBLIC HEALTH 

cancer. The peroxisome proliferation mechanism of DEHP hepatocarcingenicity in rodents seems to be 

threshold-based and the NOEL for peroxisome proliferation in rats and mice is in the range of 

20–25 mg/kg/day. Although there is a real difference in the induction of peroxisome proliferation ability 

between rats/mice and humans, peroxisome proliferation might only be correlated with, but not be the 

actual mechanism of, tumor promotion. 

Even though studies have shown that DEHP can cause liver cancer in rats and mice, the mechanism data 

suggests that these findings may not be relevant to the probability of DEHP causing cancer in humans. 

Reproductive and Developmental Toxicity. No studies were located regarding reproductive 

effects of DEHP in humans. There are multiple studies in adult rats in which oral exposure to DEHP 

decreased the weights of the testes, prostate, seminal vesicles, and epididymis, and caused atrophy and 

degeneration of the seminiferous tubules with consequent altered sperm measures and reduced fertility. 

Testicular effects were induced in rats at doses as low as 37.6 mg/kg/day for 13 weeks, 50 mg/kg/day for 

30 days, and 14 mg/kg/day for 102 weeks. The testicular damage was more severe in young male rats 

than in older rats, and appeared to be reversible if DEHP was withdrawn from the diet before sexual 

maturity was reached. Oral exposure to DEHP similarly induced testicular atrophy in mice, and mating of 

exposed male and female mice in a continuous breeding study resulted in significantly reduced number of 

litters and live births. Few reproductive studies of DEHP have been conducted in nonrodent species. 

Available data in monkeys suggest that non-human primates are less sensitive than rodents to the 

testicular effects of DEHP. As discussed in Section 2.3, decreased fertility and testicular toxicity are the 

bases of the intermediate- and chronic-duration minimal risk levels (MRLs) for oral exposure to DEHP. 

Few studies have investigated the reproductive toxicity of DEHP in female animals. When female mice 

were exposed to a dietary dose of 420 mg/kg/day DEHP for 105 days and mated with unexposed males, 

combined weights of the ovaries, oviducts, and uterus were reduced, and no litters were produced. When 

female mice exposed to 14 or 140 mg DEHP/kg/day were mated with males given these same doses, there 

was a dose-related decline in the number of litters, live pups per litter, and live pup weight. Short-term 

gavage exposure to a very high level of DEHP (2,000 mg/kg/day), particularly with respect to possible 

human exposure, had clear effects on estradiol synthesis, manifested as decreased serum estradiol levels 

and anovulatory cycles and polycystic ovaries, in female rats. These data indicate that oral exposure to 

DEHP can affect reproductive processes in female rodents. 
DI(2-ETHYLHEXYL)PHTHALATE 16 

2. RELEVANCE TO PUBLIC HEALTH 

No studies were located regarding developmental toxicity in humans exposed to DEHP. Oral exposure to 

doses as low as 375 mg DEHP/kg/day during gestation and lactation altered development of the 

reproductive system in male rat offspring. A variety of effects were observed in androgen-sensitive 

tissues of young male rats, including reduced (female-like) anogenital distance and permanent nipples, 

vaginal pouch, penile morphological abnormalities, hemorrhagic and undescended testes, testicular and 

epididymal atrophy or agenesis, and small to absent sex accessory glands. These morphological effects, 

as well as reduced fetal and neonatal testosterone levels and adult sexual behavioral changes in male rats 

following gestational and lactational exposure, are consistent with an antiandrogenic action of DEHP. 

Function as well as development of the reproductive system were adversely affected in male offspring of 

rats that were orally exposed to DEHP in a two-generation study. The changes in the development, 

structure, and function of the male reproductive tract observed in various studies indicate that effects of 

DEHP on reproduction and development are interrelated. 

Most of the developmental toxicity evaluations of DEHP are traditionally designed studies in which 

physical development was evaluated just prior to birth in pups of rodents that were orally exposed during 

gestation only. These studies clearly show that gestational exposure to DEHP was embryotoxic and 

teratogenic in rats and mice. A range of effects were observed including intrauterine deaths, skeletal and 

cardiovascular malformations, neural tube closure defects, increased perinatal mortality, and 

developmental delays. 

2.3 MINIMAL RISK LEVELS 

A minimal risk level (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. MRLs are not intended to define clean-up or action levels. Additional 

background information on MRLs is provided in Appendix A. 
 

DI(2-ETHYLHEXYL)PHTHALATE 17 

2. RELEVANCE TO PUBLIC HEALTH 

Inhalation MRLs 

No inhalation MRLs were derived for DEHP due to inadequate data for this route of exposure. As 

summarized in Section 2.2, the inhalation database for DEHP is essentially limited to two studies in rats 

that found some reversible effects in the lungs and liver following exposure for 28 days and no evidence 

for reproductive or developmental toxicity (Klimisch et al. 1991; Merkle et al. 1988). 

Oral MRLs 

An MRL was not derived for acute-duration oral exposure (#14 days) to DEHP due to insufficient data on 

male reproductive effects, a known critical end point based on longer duration studies. In particular, 

derivation of an acute oral MRL is precluded by a lack of dose-response information on development of 

the male reproductive system in offspring acutely exposed during gestation and/or lactation. As 

previously discussed in Reproductive and Developmental Toxicity (Section 2.2, Summary of Health 

Effects), morphological and other effects in androgen-sensitive tissues, as well as reduced fetal and 

neonatal testosterone levels and adult sexual behavioral changes, have been observed in male rat offspring 

exposed to DEHP during gestation and lactation for intermediate durations of exposure. 

• An MRL of 0.1 mg/kg/day was derived for intermediate-duration oral exposure (15–364 days) to 

DEHP. 

This MRL is lower than the previous intermediate-duration MRL derived in the 1993 profile but is based 

on a more appropriate end point. Refer to Chapter 8 for additional information. 

The intermediate MRL is based on a no-observed-adverse-effects level (NOAEL) of 14 mg/kg/day for 

decreased fertility in a mouse reproductive toxicity study (Lamb et al. 1987). A continuous breeding 

protocol was used in which pairs of mice were exposed to DEHP in the diet at doses of 0, 14, 140, or 

420 mg/kg/day for up to 126 days. There were 20 breeding pairs in each exposed group and 40 pairs in 

the control group. No reproductive effects were observed at 14 mg/kg/day. Fertility was reduced at 

140 mg/kg/day, as shown by reductions in number of litters per pair, number of live pups per litter, and 

proportion of live pups, indicating that this dose is the lowest-observed-adverse effects level (LOAEL). 

Exposure to 420 mg/kg/day caused complete infertility during the continuous breeding part of the study 

(0/18 fertile pairs). Fertility was also profoundly reduced in crossover mating trials conducted in the 

420 mg/kg/day mice (lower doses not tested) at the end of the continuous breeding phase of the study. 

The crossover study involved mating high dose mice of each sex to unexposed mice of the opposite sex to 
DI(2-ETHYLHEXYL)PHTHALATE 18 

2. RELEVANCE TO PUBLIC HEALTH 

determine the affected sex; near to complete infertility occurred in both sexes (0/16 fertile females and 

4/20 fertile males). Other effects included reduced combined testis, epididymis, and prostate weights, 

reduced percentages of motile sperm and abnormal sperm, and reduced sperm concentration in the males, 

and reduced combined weight of ovaries, oviducts, and uterus in the females. Essentially all of the highdose males had some degree of bilateral atrophy of the seminiferous tubules, but no exposure-related 

reproductive histopathology was observed in the females. Considering the reduced fertility and 

reproductive organ weights in the high-dose females, there is evidence that reproductive performance was 

impaired in both sexes at 420 mg/kg/day. Because the crossover mating study was only conducted at the 

high dose level, the reduced fertility observed at the 140 mg/kg/day LOAEL is not necessarily due to 

reproductive toxicity in both sexes. 

Other studies have established that testicular toxicity is a critical effect of DEHP. It is well documented 

that oral exposure to DEHP in adult rats and mice causes decreased weights of the testes, prostate, 

seminal vesicles, and epididymis, atrophy and degeneration of the seminiferous tubules, and/or altered 

sperm measures and reduced fertility (David et al. 2000a; Dostal et al. 1988; Ganning et al. 1991; Gray 

and Butterworth 1980; Gray and Gangolli 1986; Kluwe et al. 1982a; Lamb et al. 1987; Oishi 1986, 1994; 

Parmar et al. 1987, 1995; Price et al. 1987; Sjoberg et al. 1986a, 1986b). The lowest reproductive effect 

levels in these studies are a NOAEL and LOAEL for testicular histopathology of 3.7 and 38 mg/kg/day, 

respectively, in rats exposed for 90 days (Poon et al. 1997), and 5.8 and 29 mg/kg/day, respectively, in 

rats exposed for 104 weeks (David et al. 2000a). Because the 14 mg/kg/day NOAEL in the critical study 

(Lamb et al. 1987) is higher than the NOAELs of 3.7 and 5.9 mg/kg/day (David et al. 2000a; Poon et al. 

1997), and is based on an assessment of fertility rather than histological examination without evaluation 

of reproductive function, the 14 mg/kg/day NOAEL is the most appropriate basis for derivation of the 

intermediate-duration MRL. 

Gestational and lactational exposure to DEHP has adversely affected the morphological development of 

the reproductive system, as well as caused reduced fetal and neonatal testosterone levels and adult sexual 

behavioral changes, in male rat offspring (Arcadi et al. 1998; Gray et al. 1999, 2000; Moore et al. 2001; 

Parks et al. 2000). One of these studies (Arcadi et al. 1998) was used as the basis of a provisional 

intermediate-duration oral MRL in a previous draft of the DEHP toxicological profile (i.e., the Draft for 

Public Comment). In the Arcadi et al. (1998) study, severe testicular histopathological changes were 

observed at 21–56 days of age in male offspring of rats that were exposed to DEHP in the drinking water 

at reported estimated doses of 3.3 or 33 mg/kg/day throughout pregnancy and continuing during postnatal 

days 1–21. The 3.3 mg/kg/day dose was classified as a serious LOAEL and was used to derive a MRL of 
DI(2-ETHYLHEXYL)PHTHALATE 19 

2. RELEVANCE TO PUBLIC HEALTH 

0.01 mg/kg/day by using an uncertainty factor of 300 (10 for the use of a LOAEL, 10 for interspecies 

extrapolation, and 3 for human variability). A component factor of 3 was used for human variability 

because DEHP was administered during the most sensitive period during development. The MRL was 

provisional because it was derived from a serious LOAEL, which is not conventional ATSDR 

methodology. The Arcadi et al. (1998) study is now judged to be inadequate for MRL derivation because 

the NTP-CERHR Expert Panel on DEHP (NTP 2000) concluded that the effect levels are reliable and are 

unsuitable for identifying a LOAEL. In particular, NTP (2000) found that (1) the methods used to verify 

and characterize the administered doses were not clearly described or completely reported, and could not 

be resolved, and (2) the study authors did not reconcile their blood DEHP concentration data with other 

studies. 

The intermediate MRL of 0.1 mg/kg/day was derived by dividing the 14 mg/kg/day reproductive NOAEL 

by an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human 

variability). Additional information regarding the derivation of this MRL, including evidence supporting 

selection of the uncertainty factor, is provided in Appendix A. 

• An MRL of 0.06 mg/kg/day was derived for chronic-duration oral exposure ($365 days) to 

DEHP. 

The chronic MRL is based on a NOAEL of 5.8 mg/kg/day for testicular pathology in male rats from a 

comprehensive chronic toxicity study (David et al. 2000a). Groups of 50–80 rats of both sexes were fed 

DEHP in the diet for up to 104 weeks. Reported average daily doses were 0, 5.8, 29, 147, or 789 mg/kg/ 

day in males and 0, 7.3, 36, 182, or 939 mg/kg/day in females. End points evaluated in all dose groups 

included clinical observations, food consumption, body and organ weights, and clinical pathology indices. 

Necropsy and histological examinations included the control and two highest dose groups after 78 weeks, 

the control and high-dose groups after 104 weeks, and target tissues and gross lesions from the remaining 

dose groups after 104 weeks. No exposure-related effects were observed at 5.8 mg/kg/day in the males or 

7.3 mg/kg/day in the females. Bilateral aspermatogenesis was significantly (p#0.05) increased in the 

higher dose male groups, indicating that the LOAEL for testicular effects is 29 mg/kg/day. The 

incidences of bilateral spermatogenesis were 37/64 (58%), 34/50 (64%), 43/55 (78%), 48/65 (74%), and 

62/64 (97%), showing a dose-related increase and consistency with a significant reduction in relative 

testes weight observed at 789 mg/kg/day (59% less than controls). Examinations at week 78 showed 

aspermatogenesis at 789,but not 147 mg/kg/day (no interim exams were performed in the lower dose 

groups), suggesting the possibility that the lesion was age- rather than treatment-related at 29 and 

147 mg/kg/day. Also observed in the high dose males was an increased incidence of castration cells in 
DI(2-ETHYLHEXYL)PHTHALATE 20 

2. RELEVANCE TO PUBLIC HEALTH 

the pituitary gland, which are promoted by reduced testosterone secretions from the testes. Other 

significant changes were essentially limited to the liver, including increased liver weights accompanied by 

increased peroxisome proliferation in both sexes at $147 mg/kg/day, spongiosis hepatis in males at 

$147 mg/kg/day, and hepatocellular neoplasms in males at $147 mg/kg/day and in females at 

939 mg/kg/day, but the mechanism for these hepatic effects is probably not relevant to humans as 

previously discussed in Hepatotoxicity and Liver Cancer (Section 2.2, Summary of Health Effects). A 

variety of renal changes were observed in all dose groups (e.g., increases in kidney weight, incidence and 

severity of mineralization of the renal papilla, and severity of normally occurring chronic progressive 

nephropathy and renal tubule pigmentation), but are unlikely to be toxicologically significant because 

they appeared to be age-related and/or species-specific. Body weight gain was significantly reduced 

throughout the study only in the high dose males and females (approximately 15% lower than controls at 

the end of the study). 

The chronic MRL of 0.06 mg/kg/day was derived by dividing the 5.8 mg/kg/day testicular NOAEL by an 

uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human variability). 

Additional information regarding the derivation of this MRL, including evidence supporting selection of 

the uncertainty factor, is provided in Appendix A. 
DI(2-ETHYLHEXYL)PHTHALATE 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 DEHP. 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 

lowest-observed-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the 

studies. Dose conversions, if necessary, were performed using EPA reference methodology. 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 
DI(2-ETHYLHEXYL)PHTHALATE 22 

3. HEALTH EFFECTS 

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

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

human health. 

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

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

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

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

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

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

Levels of exposure associated with carcinogenic effects (Cancer Effect Levels, CELs) of DEHP are 

indicated in Table 3-2 and Figure 3-2. Because cancer effects could occur at lower exposure levels, 

Figure 3-2 also shows a range for the upper bound of estimated excess risks, ranging from a risk of 1 in 

10,000 to 1 in 10,000,000 (10-4 to 10-7), as developed by EPA. 

Estimates of exposure levels posing minimal risk to humans (Minimal Risk Levels or MRLs) have been 

made for DEHP. An MRL is defined as an estimate of daily human exposure to a substance that is likely 

to be without an appreciable risk of adverse effects (noncarcinogenic) over a specified duration of 

exposure. MRLs are derived when reliable and sufficient data exist to identify the target organ(s) of 

effect or the most sensitive health effect(s) for a specific duration within a given route of exposure. 

MRLs are based on noncancerous health effects only and do not consider carcinogenic effects. MRLs can 

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

Appropriate methodology does not exist to develop MRLs for dermal exposure. 

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

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. 
DI(2-ETHYLHEXYL)PHTHALATE 23 

3. HEALTH EFFECTS 

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. A limited 

amount of information is available on health effects of DEHP in humans and essentially all of the 

significant levels of exposure that are presented in Tables 3-1 and 3-2 and Figures 3-1 and 3-2 are based 

on animal data. The LOAELs observed in animal studies cannot be directly extrapolated to humans, do 

not necessarily constitute levels of concern for humans, and are much higher than intake levels normally 

encountered by humans. As discussed in Chapter 6 (Section 6.5, Potential for Human Exposure), recent 

estimates of average total daily intake of DEHP from ambient exposures in the U.S. general population 

are in the range of 3–30 )g/kg/day (David 2000; Doull et al. 1996; Huber et al. 1996; Kohn et al. 2000; 

NTP 2000b; Tickner et al. 2001), which is 3–4 orders of magnitude lower than the lowest LOAELs in 

animals. Additional factors that may preclude the direct extrapolation or assumption of similar effects in 

animals and humans include the dose-related, species-specific, and route-specific nature of some of the 

effects, such as evidence indicating that most of the hepatic changes observed in DEHP-exposed rodents, 

including liver cancer, result from a mechanism that does not operate in humans (see Section 3.5, 

Mechanisms of Action). 

3.2.1 Inhalation Exposure 

3.2.1.1 Death 

No studies were located regarding lethality in humans after inhalation exposure to DEHP. 

Studies in animals suggest that DEHP has low toxicity when inhaled. No deaths occurred in rats exposed 

to 300 mg/m3

 for 6 hours/day for 10 days (Merkle et al. 1988) or hamsters exposed to 0.015 mg/m3 for 

their lifetime (Schmezer et al. 1988). At a concentration of 0.015 mg/m3

, DEHP is present as a vapor, 

while at 300 mg/m3

 it is an ultra fine aerosol. On the other hand, DEHP was found to be lethal to rats 

after 2–4 hours of exposure to a mist prepared by passing air through a heated sample of DEHP (Shaffer 

et al. 1945). The concentration of DEHP in the mist was not measured. 

3.2.1.2 Systemic Effects 

No studies were located regarding cardiovascular, gastrointestinal, musculoskeletal, renal, or 

dermal/ocular effects in humans or animals after inhalation exposure to DEHP. The systemic effects 

observed after inhalation exposure are discussed below. The highest NOAEL and all reliable LOAEL 
 

 

DI(2-ETHYLHEXYL)PHTHALATE 24 

3. HEALTH EFFECTS 

values from each reliable study for systemic effects in each species and duration category are recorded in 

Table 3-1 and Figure 3-1. 

Respiratory Effects. Unusual lung effects were observed during the fourth week of life in three 

children who were exposed to DEHP during mechanical ventilation as preterm infants (Roth et al. 1988). 

The effects clinically and radiologically resembled hyaline membrane disease, a disorder caused by 

insufficient surfactant production in the lungs of newborn infants. Although interpretation of these 

findings is complicated by the preexisting compromised health status of the preterm infants, the 

information indicates that the lung disorders were related to DEHP released from the walls of polyvinyl 

chloride (PVC) respiratory tubes. 

Increased lung weights accompanied by thickening of the alveolar septa and proliferation of foam cells 

were observed in male rats that were exposed to 1,000 mg/m3

 of DEHP aerosol for 6 hours/day, 

5 days/week for 4 weeks (Klimisch et al. 1991). These effects were reversible within an 8-week postexposure period. Females rats exposed to this concentration were not affected nor were animals of either 

sex at concentrations of 10 and 50 mg/m3

. 

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

exposure to DEHP. In male and female rats relative liver weights were increased by exposure to 

1,000 mg/m3

 administered as an aerosol 6 hours/day, 5 days/week for a 4-week period (Klimisch et al. 

1991). However, there was no evidence of peroxisome proliferation in thin slices of the livers examined 

under an electron microscope. Relative liver weights were not increased in animals examined 8 weeks 

after the last exposure to DEHP. 

3.2.1.3 Immunological and Lymphoreticular Effects 

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

to DEHP. 
Exposure/ 

Key toa Specie duration/ 

figure (strain) frequency 

ACUTE EXPOSURE 

Developmental 

1 Rat 10 d 

Table 3-1. Levelsof Significant Exposure to Di-(2-ethylhexy1)phthalate -

LOAEL 

NOAEL Less serious Serious 

System (mglm3) (mglm3) (mglm3) 

300 

Inhalation 

Reference 

Chemical Form 

Merkle et al. 1988 

w 

rn 

n 

n 

rn 

0 
Table 3-1. Levelsof Significant Exposure to Di-(2-ethylhexyl)phthalate - Inhalation (continued) h 

0 

x Exposure1 LOAEL -i

I 

Key toa Species duration/ NOAEL Less serious Serious Reference 

figure (strain) frequency System I

I (mgJm3) (mglm3) (mg/m3) Chemical Form 

INTERMEDIATE EXPOSURE 

Systemic 

2 Rat 28 d Resp 50 1000 (increased lung weight, Klimisch et al. 1991 

(wistar) 5 dlwk foam cell proliferation, 

6 hrld thickening of alveolar 

septa) 

Hepatic 50 1000 (increased relative liver 

weight) 

Reproductive 

3 Rat 28 d 1000 Klimisch et al. 1991 W

I (Wistar) 5 dlwk m 

6 hrld 5 - I

rn The number corresponds to entries in Figure 3-1. ll

2 

d = days; Gd = gestation day; hr = hour(s); LOAEL = lowest-observed-effect level; NOAEL = no-observed-adverse-effect level; Resp = respiratory; wk = week(s) -I

cn 

0 
10000 

rnglrn3 

1ooa 

1oc 

I( 

c-Cat 

d-Dog

r-Rat 

p-Pig

n-Cnw 

Figure 3-1. Levels of Significant Exposureto Di-(2-ethylhexyl)phthalate- Inhalation 

Acute (114 days) Intermediate (1 5-364 days) 

Systemic 

Olr 

02r 02r 

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

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

m-Mouse e-Gerbil (D LOAEL, Less Serious-Animals A LOAEL, Less Serious-Humans 

h-Rabbit s-Hamster 0NOAEL - Animals A NOAEL- Humans 

a-Sheen n-Giiinea Pia 

u 

I 

rn 

I

5 

rn 

n 

n 

rn

2 

v, 

LD50/LC50

: Minimal Risk Level 

: for effects 

other than 

Cancer 
DI(2-ETHYLHEXYL)PHTHALATE 28 

3. HEALTH EFFECTS 

3.2.1.4 Neurological Effects 

No studies were located regarding neurological effects in humans or animals after inhalation exposure to 

DEHP. 

3.2.1.5 Reproductive Effects 

No studies were located regarding reproductive effects in humans after inhalation exposure to DEHP. 

The fertility and mating performance of male rats was not effected by a 4-week exposure, 6 hours/day, 

5 days/week to a DEHP aerosol (10–1,000 mg/m3

) (Klimisch et al. 1991). Mating with unexposed 

females was carried out at 2 and 6 weeks after the end of DEHP exposure period. At sacrifice, there were 

no observable effects of DEHP on testicular structure. 

3.2.1.6 Developmental Effects 

No studies were located regarding developmental effects in humans after inhalation exposure to DEHP. 

In rats, there was no evidence of any treatment-related prenatal or postnatal developmental effects in the 

offspring of females exposed to up to 300 mg/m3

 DEHP (the highest dose tested) 6 hours/day during the 

period of organogenesis (gestation days 6–15) (Merkle et al. 1988). Newborn rats were evaluated for 

survival and several measures of neurological development (righting test on day 6, gripping reflex on 

day 13, pupillar reflex on day 20, and hearing test on day 21). These data indicated that there were no 

developmental effects when DEHP was present in the atmosphere during gestation. This NOAEL for 

developmental effects in rats is recorded in Table 3-1 and plotted in Figure 3-1. 

3.2.1.7 Cancer 

No studies were located regarding cancer in humans after inhalation exposure to DEHP. Lifetime 

exposure of hamsters to 0.015 mg/m3

 DEHP did not result in any significant increases in the incidence of 

tumors (Schmezer et al. 1988). Because the concentration in this study was very low, it is not possible to 

reach conclusions concerning whether or not higher concentrations might produce different results. 
DI(2-ETHYLHEXYL)PHTHALATE 29 

3. HEALTH EFFECTS 

3.2.2 Oral Exposure 

3.2.2.1 Death 

Single oral doses of up to 10 g DEHP are not lethal to humans (Shaffer et al. 1945), and no cases of death 

in humans after oral exposure to DEHP were located. These data indicate that DEHP is very unlikely to 

cause acute mortality in humans. This is supported by studies in rabbits and rats which indicate that 

single dose oral LD50 values are quite high (30,600–33,900 mg/kg) (Shaffer et al. 1945). To receive an 

equivalent dose, an adult human would have to consume about 41⁄2 pounds of DEHP. Some species seem 

to be more sensitive than others. Repeated administrations of 2,000 mg/kg/day DEHP (the only dose 

tested) was lethal to adult rabbits and guinea pigs when administered for up to 7 days, but not to adult 

mice and rats (Parmar et al. 1988). However, two doses of 2,000 mg DEHP/kg caused a high incidence 

of mortality in #21-day-old rats, but there were no deaths in 6-week-old or older rats, suggesting that age 

influences susceptibility to DEHP (Dostal et al. 1987a). Similar results regarding higher susceptibility to 

lethal doses among younger rats were reported by Parmar et al. (1994). Treatment of lactating female rats 

(postpartum days 1–7) with 5,000 mg DEHP/kg by gavage resulted in 25% mortality within 1 week of 

treatment, but no mortality occurred with #2,500 mg DEHP/kg (Cimini et al. 1994). In a 24-week 

feeding study, a diet that provided approximately 2,400 mg DEHP/kg/day induced 100% mortality in 

Sv/129 male mice after 16 weeks of dosing (Ward et al. 1998); at the time of death, mean body weights 

were approximately 50% that of controls, food consumption data were not provided. Survival was 

reduced in male F344 rats (12% less than controls) and male B6C3F1 mice (45% less than controls) that 

ingested 147 and 1,266 mg DEHP/kg/day in the diet, respectively, for up to 104 weeks (David et al. 

2000a, 2000b). The most frequent cause of death in the chronic studies was mononuclear cell leukemia in 

the rats and liver tumors in the mice. The LOAEL values for death in each species and duration category 

are recorded in Table 3-2 and plotted in Figure 3-2. 

3.2.2.2 Systemic Effects 

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

duration category are recorded in Table 3-2 and plotted in Figure 3-2. 
Exposure1 

duration/ 

~eyto“ Species frequency 

fig0re (Strain) (Specific route) 

ACUTE EXPOSURE 

Death 

1 Rat 7d 

(Fischer- 344) ppd 1-7 

1 xld 

(GO) 

2 Rat 5d 

(Sprague- 1 xld 

Dawley) (GO) 

Systemic 

7 Human 1 dose 

1xld 

(C) 

System 

Gastro 

Table 3-2. Levels of Significant Exposureto Di-(2-ethylhexy1)phthalate - Oral 

LOAEL 

NOAEL Less serious Serious 

(mg/kg/day) (WWdaY) (mgfltglday) 

5000 F (25% mortality within one 

week) 

1000 (68% mortality in 

14-1 8-day-old rats died after 

5 doses; older rats were less 

susceptible) 

2000 (10% mortality at 7 days in 

3-week-old rats; 0% in 

untreated or in treated older 

rats) 

30600 (LD,) 

2000 (50% mortality) 

33900 (LD,) 

71.4 143 (gastrointestinal distress) 

Reference 

Chemical Form 

Cimini et al. 1994 

Dostal et al. 1987a 

w 

I 

Parmar et al. 1994 rn

5

I 

rn 

n 

n 

rn

Shaffer et al. 1945 2

v) 

Parrnar et al. 1988 

Shaffer et al. 1945 

Shaffer et al. 1945 
Table 3-2. Levels of SignificantExposureto Di-(2-ethylhexyl)phthalate - Oral (continued) 

K~Ytoa 

figure 

Species 

(Strain) 

Exposure/

duration/ 

frequency 

(Specific route) System 

NOAEL 

(m@kg/day) 

Less serious 

(mgWday) 

LOAEL 

Serious 

(mg/kg/day) 

Reference 

Chemical Form 

8 Monkey 14d 

(Cynomotgus) 1 x/d 

(GI 

Hemato 

Hepatic 

500 M 

500 

Pugh et al. 2000 

Renal 500 

Bd Wt 500 

9 Monkey 

(Marmoset) 

14d 

1 x/d 

(GO) 

Hepatic 

Renal 2000 

2000 (20% increase in liver 

weight) 

Rhodes et al. 1986 

Bd Wt 2000 (70% reduction in body 

weight gain) w 

10 

11 

Rat 3d 

(Fischer- 344) 1 x/d 

(GO) 

Rat once 

(Fischer- 344) (GO) 

Hepatic 

Other 

Hepatic 

1200 

1200 

1500 

(altered liver lipid profile) 

(44% reduction in food 

consumption) 

(centrilobular necrosis or 

inflammation) 

Adinehzadeh and Reo 

1998 

Berman et al. 1995 

I

F 

I;i 

rn

24 

rn

2 

Endocr 5000 

12 Rat 14 d 

(Fischer- 344) 1x/d 

(GO) 

Hepatic 

Endocr 1500 

150 (18% increase in relative 

liver weight; incresed 

metosis) 

Berman et at. 1995 

13 Rat 7d 

(Fischer- 344) (F) 

Hepatic 11 53 M (increased relative liver 

weight) 

David et al. 1999 
K~Ytoa 

figure 

Species 

(Strain) 

Exposure/ 

duration/ 

frequency 

(Specific route) 

Table 3-2. Levels of Significant Exposure to Di-(2-ethylhexyl)phthalate - Oral (continued) 

LOAEL 

NOAEL Less serious Serious 

(mglkglday) (mg/kg/day) (mgWday) System 

Reference 

Chemical Form 

E! 

h 

r?,

in 

I

2 

-I 

I 

14 Rat 

(SpragueDawley) 

5d 

1 x/d 

(GO) 

Hepatic 10 100 (increased liver weight 

and activity of palmitoyl 

CoA oxidase and carnitine 

acetyl transferase) 

Dostal et al. 1987a v

711

I

2 

-I 

rn 

Renal 100 1000 (increased kidney 

weight) 

15 Rat 

(SpragueDawley) 

5d 

1 x/d 

(GO) 

Ld 6-10 

Hepatic 2000 

increased enzyme 

activity; decreased 

serum cholesterol) 

(increased liver weight; Dostal et al.1987b 

Bd Wt 2000 (1 8% decrease in body 

weight gain) 

rn

5

I 

16 Rat 

(SpragueDawley) 

5d 

1 x/d 

Ld 14-18 

(GO) 

Hepatic 2000 (increased liver weights 

and enzyme activities; 

decreased cholesterol 

and triglycerides) 

Dostal et al. 1987b rnn 

n 

rn 

Bd Wt 2000 (17% decrease in bd wt 

gain) 

Other 2000 (decreased food 

consumption) 

17 Rat 

(SpragueDawley) 

5d 

1 x/d 

Ld 2-6 

(GO) 

Hepatic 2000 (increased liver weight; 

increased enzyme 

activity; decreased 

plasma cholesterol and 

triglycerides) 

Dostal et al. 1987b 

Bd Wt 2000 (14% decrease in body 

weight gain) 

18 Rat 5d Bd Wt 500 1000 (1 5% decrease in body Dostal et al. 1988 

(SpragueDawley) 

1 x/d 

(GO) 

weight gain) w 

N 
Table 3-2. Levels of Significant Exposure to Di-(2-ethylhexyl)phthalate - Oral (continued) 

Exposure/ LOAEL duration/ 

K~Ytoa Species frequency NOAEL Less serious Serious Reference 

figure (Strain) (Specific route) System ~mglkglday) (mglkglday) (mg/kglday) Chemical Form 

19 Rat 

(Wistar) 

Bd Wt 2800 (1 1% decrease in final 

body weight) 

Gray and Butterworth 

1980 

20 Rat 

(Wistar) 

Bd Wt 2800 (21% reduction in final body weight) Gray and Butterworth 

1980 

21 Rat 

(Wistar) 

Bd Wt 2800 (22% reduction in final body 

weight) Gray and Butterworth 1980 

22 Rat 

(Wistar) 

Endocr 2000 (decreased serum T4 

ultrastructural changes 

consistent with thyroid 

hyperactivity) 

Hinton e! al. 1986 

23 

24 

Rat 

(SpragueDawley) 

Rat 

(Fischer-344) 1 dd 

(GO) 

Hepatic 

Hepatic 

Bd Wt 950 

2000 

950 

(35% increase in relative 

liver weight; induction of 

microsomal 

carboxylesterases) 

(26% increase in 

absolute liver weight; 

1300% increased DNA 

synthesis; 20% reduced 

apoptosis) 

Hosokawa et al. 1994 

James et al. 1998 

w 

w 
Table 3-2.Levels of Significant Exposure to Di-(2-ethylhexyl)phthalate - Oral (continued) 0 

N 

--

K~Ytofigure 

Exposure1 

duration1 

Species frequency 

(Strain) (Specific route) System 

NOAEL 

(mglkglday) 

Less serious 

(mglkglday) 

LOAEL 

Serious 

(mg/kg/day) 

Reference 

Chemical Form 

5 

25 Rat 

(SpragueDawley) 

Hepatic 1000 (72 Yoincreased relative 

liver weight; increased 

activity of peroxisomal 

and microsomal 

enzymes) 

Lake et al. 1986 i 

26 Rat 

(SpragueDawley) 

Bd Wt 1740 M (22% lower final body weight) Mehrotra et al. 1997 

27 Rat 

(Wistar) 

Hepatic 

Bd Wt 1500 

1000 (36% increased relative 

liver weight) 

Oishi 1989 

28 

29 

Rat 

(Wistar) 

Rat 

(albino) 

Hepatic 

Hepatic 

2000 

2000 

(52% increased relative 

liver weight) 

(increased liver weight, 

increased enzyme 

activity) 

Oishi 1994 

Parmar et al. 1988 

i 

rn 

n 

n 

rn 

f: 

v, 

Bd Wt 2000 (10% decrease in body 

weight gain) 

30 Rat 

(Wistar) 

Hepatic 2000 (40% increase in liver 

weight, peroxisome 

proliferation) 

Rhodes et al. 1986 

Renal 2000 

Bd Wt 2000 (40% decrease in body 

weight gain) 
Table 3-2. Levels of Significant Exposure to Di-(2-ethylhexyl)phthalate - Oral (continued) 0 

Exposure/ 

duration/ 

K~Ytoa Species frequency

figure (Strain) (Specific route) System 

NOAEL 

(Cmllday) 

Less serious 

(mglkglday) 

LOAEL 

Serious 

(mglkglday) 

Reference 

Chemical Form 

-I

I 

2 

31 Rat 

(SpragueDawley) 

14d 

(F) 

Hepatic 1905 (87% increased liver 

weight; peroxisome 

proliferation; increased 

synthesis of NAD' from 

tryptophan) 

Shin et al. 1999 v 

-0

I 

-i

E-I 

rn 

Bd Wt 1905 

32 Rat 

(SpragueDawley) 

14 d 

PP~25-38 

(F) 

Bd Wt 1000 (22% decreased body 

weight gain) 

Sjoberg et al. 1986a 

33 

34 

Rat 

(SpragueDawley) 

Rat 

(SpragueDawley) 

14 d 

PP~40-53 

(F) 

14 d 

PP~60-73 

(F) 

Bd Wt 

Bd Wt 

1700 

1000 

(22% decreased body 

weight gain) 

(26% decreased body 

weight gain) 

Sjoberg et al. 1986a 

Sjoberg et al. 1986a 

9J 

i

$ 

-n

rn

2 

35 Rat 

(SpragueDawley) 

14 d 

(F) 

Bd Wt 1000 (22% reduction in final body 

weight) 

Sjoberg et al. 1986b 

36 Rat 14 d 

(Fischer-344) (F) 

Hepatic 1200 (increasedliver weight, 

increasedoxidized 

deoxyguanosine in DNA) 

Takagi et al. 1990 

Renal 1200 (increased kidney 

weight) 

37 Rat 

(Wistar) 

14 d 

(F) 

Hepatic 1894 (38% increasedabsolute 

liver weight; peroxisomal 

proliferation) 

Van den Munckhof et 

al. 1998 

Bd Wt 1894 (17% reductionin final 

body weight) 

w 

cn 
Table 3-2. Levels of Significant Exposure to Di-(2-ethylhexyl)phthalate - Oral (continued) 

K~Ytoa Species 

figure (Strain) 

38 Mouse 

(B6C3F1) 

Exposure/ 

duration/

frequency 

(Specific route) 

7d 

(F) 

System 

Hepatic 188 

NOAEL 

(mglkg/day) 

LOAEL 

564 (increased relative liver 

Less serious 

(mglkg/day) 

weight) 

Serious 

(mglkglday) 

Reference 

Chemical Form 

David et al. 1999 

39 Mouse 

(C57BU6) 

7d 

(F) 

Hepatic 4000 (88% increase in relative 

liver weight; induction of 

microsomal 

carboxylesterases) 

Hosokawa et al. 1994 

40 Mouse 

(B6C3F1) 

2d 

1 x/d 

(GO) 

Hepatic 11 50 (9Y0increase in absolute 

liver weight; 248% 

increased DNA synthesis: 

90% decreased 

apoptosis) 

James et al. 1998 

Bd Wt 1150 

41 Mouse 

(C57BU6) 

7d 

(F) 

Hepatic 

Bd Wt 

385 (increased absolute and 

relative liver weight) 

3850 (17% decrease in final 

body weight) 

Muhlenkamp and Gill 

1998 

mn 

n 

m 

0

2 

42 Mouse 

(NS) 

7d 

1x/d 

(GO) 

Hepatic 

Bd Wt 2000 

2000 (increased liver weight, 

increased enzyme 

activity) 

Parmar et al. 1988 

43 GnPig 

(NS) 

7d 

1Xid 

(GO) 

Hepatic 

Bd Wt 

2000 (increased liver weight, 

increased enzyme 

activity) 

2000 (39% decrease in body 

weight gain) 

Parrnar et al. 1988 

44 Hamster 

(Golden

Syrian) 

7d 

(F) 

Hepatic 2686 (36% increase in relative 

liver weight) 

Hosokawa et al. 1994 

c3 

m 
Table 3-2. Levels of Significant Exposure to Di-(2-ethylhexyl)phthalate - Oral (continued) 

Exposure/ 

duration/ LOAEL 

K~Ytoa 

figure Species(Strain) frequency (Specific route) System 

NOAEL 

(mg/kg/day) 

Less serious 

(WWday) 

Serious 

(mglkglday) 

45 Hamster 14 d Hepatic 1000 (55% increased liver 

Chinese Ix/d 

(GO) 

weight, enzyme 

induction) 

46 Rabbit 

(NS) 

7d 

1x/d 

(GO) 

Hepatic 2000 (decreased liver weight, 

decreased enzyme 

activity) 

Bd Wt 2000 

Immunological/Lymphoreticular 

47 Rat once 5000 

(Fischer- 344) (GO) 

48 Rat 14 d 1500 

(Fischer- 344) 1 x/d 

(GO) 

Neurological 

49 Rat once 1500 5000 (signs of general 

(Fischer- 344) (GO) debilitation) 

50 Rat 14 d 1500 

(Fischer- 344) 1 x/d 

(GO) 

Reproductive 

51 Monkey 14d 500 M 

(Cynornolgus) 1 x/d 

(GI 

52 Monkey 14d 2000 

(Marmoset) 1dd 

(GO) 

Reference 

Chemical Form 

Lake et al. 1986 

Parmar et al. 1988 

Berman et al. 1995 

Berman et al. 1995 

Moser et al. 1995 

Moser et al. 1995 

Pugh et al. 2000 

Rhodes et at. 1986 

w 

F

5

I 

rn 

n 

n 

rn 

0

4 

cn 

-

0 

h 

ru

in

I

I

2

I 

v

TI

5 

I 

rn 
Table 3-2.Levels of Significant Exposure to Di-(2-ethylhexy1)phthalate - Oral (continued) -

B

K~Yto" 

figure 

Species

(Strain) 

Exposure1 

duration1 

frequency (Specific route) System NOAEL 

(m@kg/day) 

Less serious 

(mglkglday) 

LOAEL 

Serious 

(~sncsldaY) 

Reference 

Chemical Form 

i

I 

53 Rat 

(SpragueDawley) 

2000 F (suppressed ovulation with 

25% decrease in 

preovulatory follicle ' 

serum estradiol) 

Davis et al. 1994a 

granulosa cells and decresed 

v 

'D

I 

--I

I 

rn 

:

--I 

54 Rat 2000 (changes in milk Dostal et al. 1987b 

(Sprague- composition) 

Dawley) 

55 Rat 100 1000 (reduced absolute and Dostal et al. 1988 u 

(SpragueDawley) 

relative testes weight 

and number of Sertoli 

cells) 

rn

5

I 

56 Rat 

(SpragueDawley) 

100 1000 (loss of spermatids and 

spermatocytes; 

decreased testicular 

zinc) 

Dostal et al. 1988 

rn 

-n 

n 

rn 

cn 

2 

57 Rat 100 200 (reduced testicular Doslal et al. 1988 

(SpragueDawley) 

weight, delayed 

spermatid maturation 4 

weeks after dosing) 

58 Rat 

(SpragueDawley) 

200 500 (reduced relative testes 

weight and number of 

Sertoli cells) 

Dostal et al. 1988 

59 Rat 

(SpragueDawley) 

2800 Gray and Butterworth 

1980 

w 

a, 
Table 3-2. Levels of Significant Exposure to Di-(2-ethylhexyl)phthalate - Oral (continued) p 

Exposure1 

n duration/

Key to- Species frequency 

figure (Strain) (Specific route) 

60 Rat 

(SpragueDawley) 

System NOAEL 

(mglkglday) 

LOAEL 

Less serious 

(mg/kglday) 

2800 (moderate testicular 

damage; decrease in 

seminal vesicle prostate 

weight) 

Serious 

(mglkglday) 

Reference 

Chemical Form 

Gray and Butteworth 

1980 

m 

-I 

3

i

I 

rn

v 

2 

-0 

-I 

I 

61 Rat 

(Wistar) 

2800 (decreased weight of 

seminal vesicles and 

ventral prostate; tubular 

damage) 

Gray and Butteworth 

1980 

62 

63 

Rat 

(Wistar) 

Rat 

(SpragueDawley) 

2800 

2800 

(33% decreased relative 

testes weight; loss of 

germinal cells; decrease in 

seminal vesicle and ventral 

prostate weight) 

(47% decreased testes 

weight; severe testicular 

atrophy) 

Gray and Butteworth 

1980 

Gray and Butteworth 

1980 

w 

I 

rn 

$ 

-I

I 

rn2 

rn

2 0, 

64 Rat 

(SpragueDawley) 

20 M 100M (abnormal gonocytes 

and reduced Sertoli cell 

proliferation) 

Li et al. 2000 

65 Rat 

(SpragueDawley) 

1740M (25-50%changes in 

testicular xenobiotic 

enzyme activity) 

Mehrotra et al. 1997 

66 Rat 

(Wistar) 

2000 (aspermatogenesis with 

reduced testis, seminal 

vesicle, and ventral 

prostrate weights; 

decreased testicular 

zinc) 

Oishi 1986 
Exposure/ 

duration/ 

K~Ytoa Species frequency 

figure (Strain) (Specific route) 

67 

68 

69 

70 

71 

72 

73 

74 

Rat 

(Wistar) 

Rat 

(SpragueDawley) 

Rat 

(SpragueDawley) 

Rat 

(SpragueDawley) 

Rat 

(SpragueDawley) 

Rat 

(SpragueDawley) 

Rat 

(SpragueDawley) 

Rat 

(SpragueDawley) 

7d 

1 x/d 

(GO) 

Once 

(GO) 

14 d 

ppd 25-38 

1 x/d 

(GO) 

14 d 

ppd 60-73 

(F) 

14 d 

ppd 40-53 

(F) 

14 d 

PP~41-53 

lx/d 

(GO) 

14 d 

PP~60-73 

lx/d 

(GO) 

14 d 

PP~25-38 

(F) 

Table 3-2. Levels of Significant Exposure to Di-(2-ethylhexyl)phthalate - Oral (continued) 

LOAEL 

NOAEL Less serious Serious 

System (mg/kglday) (mg/kg/day) (mglkglday) 

2000 (38% reduced testis weight; 

shrunken seminiferous 

tubules with necrotic debris 

and aspermatogenesis) 

2800 (morphological changes 

in Sertoli cells) 

1000 (testicular damage) 

1700 

1000 1700 (43% decreased testicular 

weight and severe 

seminiferous tubule damage) 

1000 

1000 

1000 (21% decreased 1700 (79% decreased testicular 

testicular weight and weight and severe testicular 

tubular damage) damage) 

Reference 

Chemical Form 

Oishi 1994 

Saitoh et al. 1997 

Sjoberg et al. 1986a 

Sjoberg et al. 1986a 

Sjoberg et al. 1986a 

Sjoberg et al. 1986a 

Sjoberg et al. 1986a 

Sjoberg et a[. 1986~1 

w 

I

F 

rn2 

v) 

-

s

K 

-I

I 

$

I 

s 

rv 

-0

I 

-II 

t

-i 

rn 

P 

0 
Exposure1 

P duration/

Key to" Species frequency 

figure (Strain) (Specific route) 

75 Rat 4d 

(Sprague- Ix/d 

Dawley) (GO) 

Developmental 

Table 3-2. Levels of Significant Exposure to Di-(2-ethylhexyl)phthalate - Oral (continued) 

LOAEL 

NOAEL Less serious Serious 

System (mg/kg/day) (mglkglday) (mglkglday) 

2000 

Reference 

Chemical Form 

Zacharewski et al. 

1998 

-

0

w._

in 

3 

-1 

i

I 

rn

v

2 

W 

-1 

P 

I 

I 

3 

rn 

76 Rat 

(SpragueDawley) 

5d 

Ld 14-18 

Ix/d 

(GO) 

2000 (14% reduction in pup 

body weight; biochemical 

evidence of peroxisome 

proliferation in liver) 

Dostal et al. 1987b 

77 

78 

Rat 

(SpragueDawley) 

Rat 

(SpragueDawley) 

5d 

Ld 2-6 

Ix/d 

(GO) 

5d 

Ld 6-10 

Ix/d 

(GO) 

2000 

2000 

(26% reduction in pup 

body weight; biochemical 

evidence of peroxisome 

proliferation in liver) 

(20% reduction in pup 

body weight; biochemical 

evidence of peroxisome 

proliferation in liver) 

Dostal et al. 1987b 

Dostal et al. 1987b 

I*' 

I 

rn

5

I 

ci 

-TI 

rn2 01 

79 Rat 

(SpragueDawley) 

10 d 

Gd 14-21 

ppd 1-3 

1 x/d 

750 (significant delay in male Gray et al. 1999 

reproductive system 

maturation; reduced weight 

of sex organs in adult males) 

(GO) 

80 Rat 

(SpragueDawley) 

10 d 

Gd 14-21 

ppd 1-3 

1 x/d 

(GO) 

750 M (testicular degeneration and 

altered sexual differentiation 

in male offspring) 

Gray et al. 2000 
K~Ytoa 

figure 

Exposure1 

duration/ 

Species frequency 

(Strain) (Specific route) 

Table 3-2. Levels of Significant Exposure to Di-(2-ethylhexyl)phthalate - Oral (continued) 

(mg/kg/day) (mg/kg/day) (mglkglday) 

LOAEL 

System NOAEL Less serious Serious 

~~~~ ~ 

Chemical Form 

Reference 

-

II

x 

Y 

--I

I

<

r 

I

rn 

200 1000 (increased fetal death and 

incidenceof external, soft 

tissue, and skeletal 

malformations) 

Hellwig et al. 1997 

a2 Rat 

(SpragueDawley) 

10 d 

Gd 14-21 

ppd 1-3 

1 x/d 

(GO) 

750 M (decreased fetal testosterone Parks et al. 2000 

synthesis during male sexual 

differentiation) 

a3 

84 

(Wistar) Gd 12 

Rat Id 

1x/d 

(G) 

Rat 14d 

(Fischer- 344) ppd 1-21 

1 x/d 

(GO) 

4882 

1000 

(slight increase in dead, 

resorbed and malformed 

fetuses) 

(significant peroxisome 

proliferation in both liver 

and kidneys from pups) 

9756 (significant increase in dead, Ritter et al. 1987 

resorbed and malformed 

fetuses) 

Stefanini et al. 1995 

u 

I 

Fi=

-I

I 

n 

rn 

0

+ 

v, 

a5 Mouse 

(C57BU6N 

x Sv/l29) 

2d 

Gd 8-9 

1 x/d 

(GO) 

1000 (decreased fetal viability, 

increased resorptions and 

external malformations) 

Peters et al. 1997b 

86 Mouse 

(SIC-ICR) 

3d 

Gd 7-9 

1x/d 

250 1000 (decreased fetal viability, 

increased resorptions and 

external malformations) 

Shiota and Mirna 1985 

(GO) 

87 Mouse 

(ddY-SIC) 

Gd 6,7,8, 

99 Or 10 

1 x/d 

(GI 

50 100 (1 1.2 YOfetal lethality, 2.0% 

in controls) 

Tomita et al. 1982a 

P 

h) 
88 

Exposure/ 

duration/ 

K~Y toa Species frequency

figure (Strain) (Specific route) 

Mouse Gd 6,7, 8, 

(ddY-Slc) 9,or 10 

1 x/d 

(GI 

Table 3-2. Levels of Significant Exposure to Di-(2-ethylhexyl)phthalate - Oral (continued) 

LOAEL 

NOAEL Less serious Serious 

System (mg/kglday) (mg/kglday) (mg/kglday) 

1000 (60% fetal lethality) 

Reference 

Chemical Form 

Yagi et al. 1980 

u 

I 

rn

5

I 

rn 

n 

n 

rn 

cn 

2 

P 

W 
Table 3-2. Levels of Significant Exposure to Di-(2-ethylhexyl)phthalate - Oral (continued) -

o_ 

R 

Key tofigure Species

(Strain) 

Exposure/ 

duration/ 

frequency (Specific route) System NOAEL 

(mg/kg/day) 

Less serious 

(mgWday) 

LOAEL 

Serious 

(mdkglday) 

Reference 

Chemical Form 

P

in 

-I

I

< 

r

I 

v 

89 

INTERMEDIATEEXPOSURE 

Death 

Rat 15 d 

(Wistar) (GO) 

2000 (50% mortality after 3 weeks 

with subsequent 100% 

mortality) 

Parmar et al. 1987 

73

I 

-I

I 

22

m 

2 

90 Mouse 16 wk 2400 M (100% mortality between Ward et al. 1998 

SvIl29 (F) weeks 12 and 16) 

91 Gn Pig 15d 2000 (40% mortality) Parmar et al. 1988 

(NS) (GO) w

- 92 

(NS) 

Rabbit 

(GO) 

15 d 2000 (100% mortality) Parmar et al. 1988 -L 

rn 

F-I

I 

Systemic 

rn 

n 

n 

93 Monkey 

(Marmoset) 

13wk 

Idd 

Resp 2500 Kurataet al. 1998 

rn 

0 

4 

cn 

(GO) Cardio 2500 

Gastro 2500 

Hemato 2500 

Musclskel 2500 

Hepatic 2500 

Renal 2500 

Endocr 2500 

Dermal 2500 

Ocular 2500 

94 Monkey 25d Hepatic 500 Short et al. 1987 

(Cynomolgus)1x/d 

(GO) 

P 

P 
Table 3-2.Levels of Significant Exposure to Di-(2-ethylhexyl)phthalate - Oral (continued) 

K~Ytoa 

figure 

Exposure/

duration/ 

Species frequency 

(Strain) (Specific route) System 

NOAEL 

(mg/kg/day) 

Less serious 

(mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference 

Chemical Form 

95 Rat 21 d 

(Fischer-344) (F) 

Hepatic 12 643 (44% increase in relative 

liver weight; increased 

enzymatic activity 

indicative of peroxisome 

proliferation) 

Barber et al. 1987 

Bd Wt 1197 1892 (41% reduced final body 

weight) 

96 Rat 28 d 

(Fischer-344) (F) 

Hepatic 1200 (increased enzyme 

activities indicating 

peroxisome proliferation) 

Cattley et al. 1988 

w 

97 

98 

Rat 2-13 wk 

(Fischer-344) (F) 

Rat 4-1 6 wk 

(Fischer-344) (F) 

Hepatic 

Hepatic 

53 265 (increased relative liver 

weight) 

1054 (increased relative liver 

weight and biochemical 

evidence of cell 

proliferation) 

David et al. 1999 

Eagon et al. 1994 

I 

rn 

-4

I 

rn 

n 

n 

F 

rn 

(n 

2 

Endocr 1054 (altered metabolism of 

estradiol and estrogen 

receptor related 

functions) 

Bd Wt 1054 (1 9% reduction in final 

body weight relative to 

controls at 4 weeks) 

99 Rat 

(AlpWAP) 

28 d 

1dd 

(GO) 

Hepatic 1000 (increased 

palmitoyl-CoA oxidase 

activity; decreased 

superoxide dismutase 

and glutathione 

peroxidase activities) 

Elliot and Elcombe 

1987 

P

ul 
K~Ytoa 

figure Species(Strain) 

Exposure/ 

duration/ 

frequency (Specific route) 

LOAEL 

Table 3-2. Levels of Significant Exposure to Di-(2-ethylhexyl)phthalate - Oral (continued) 

NOAEL Less serious Serious 

System (mg/kglday) (mg/kg/day) (mg/kg/day) 

Reference 

Chemical Form 

z 

I 

h

K 

-I 

< 

r

I 

100 Rat 

(Wistar) 

21 d 

(F) 

Endocr 2000 (decreased serum T4 

ultrastructural changes 

consistent with thyroid 

hyperactivity) 

Hinton et al. 1986 v T) 

2 rn 

101 Rat 28 d 

(Fischer- 344) (F) 

Hepatic 705 (~53%increase in relative 

liver weights; 

morphological and 

biochemical evidence of 

peroxisome proliferation) 

Hodgson 1987 

102 Rat 

(albino) 

9 mo 

(F) 

Bd Wt 

Hepatic 

705 

50 (increased liver weight, 

morphological changes 

in bile ducts, lipid filled 

lysosornes, glycogen 

depletion, induction of 

peroxisomal enzymes 

and cytochrome P-450 

system) 

Mitchell et al. 1985b 

w 

I 

rnF 

I

I 

rn 

rn 

T 

T 

v) 

Bd Wt 50 200 (10-15% decreased body 

weight gain) 

103 Rat 

(Wistar) 

21 d 

(F) 

Hepatic 

Bd Wt 

1730 (41% increased absolute 

liver weight) 

1730 (28% reduction in final body 

weight) 

Mocchiutti and Bernal 

1997 

104 Rat 

(albino) 

15 d 

Idd 

(GO) 

Hepatic 

Bd Wt 

2000 (increased liver weight, 

changes in enzyme 

activity) 

2000 (24% decrease in body 

weight gain) 

Parrnar et al. 1988 
Table 3-2. Levels of Significant Exposure to Di-(2-ethylhexyl)phthalate - Oral (continued) h 

s 

K~Ytoa 

figure Species(Strain) 

Exposure/ 

duration/ 

frequency (Specific route) System NOAEL 

(mg/kg/day) 

Less serious 

(mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference 

Chemical Form 

h)

in 

I 

$ 

-I 

I 

105 Rat 

(SpragueDawley) 

Hemato 

Hepatic 

37.6 M 

37.6 M 

375 M (decreased RBCs and 

hemoglobin) 

375 M (increased absolute and 

relative liver weights; 

Poon et al. 1997 v -0

I 

-I

I

c--I 

rn 

peroxisome proliferation) 

Renal 37.6 M 375 M (increased kidney 

weight) 

Bd Wt 375 M 

Other 375 M u 

106 Rat Hemato 345 M (increased platelet count) Poon et al. 1997 -,-

L 

(SpragueDawley) 

Hepatic 345 M (increased absolute and 

relative liver weights; 

peroxisome proliferation) 

rn

Fi

I 

rn 

n 

n 

rn 

0 

Renal 345 M (increased kidney 

weight) 

Endocr 345 M (reduced follicle size and 

colloid density in the 

thyroid) 

107 Rat Endocr 1000 (ultrastructural changes Price et al. 1988a 

(Wistar) consistent with thyroid 

hyperactivity) 

108 Rat Cardio 1900 Shaffer et al. 1945 

(Wistar) 

Hemato 1900 

Hepatic 1900 

Renal 1900 

Bd Wt 200 400 (decreased weight gain) 
Exposure1 

duration1 

K~Ytoa Species frequency 

figure (Strain) (Specific route) 

109 Rat 21 d 

(Fischer- 344) (F) 

Table 3-2. Levels of Significant Exposure to Di-(2-ethylhexyl)phthalate - Oral (continued) 

LOAEL 

System 

Hepatic 11 105 (biochemical and 

of peroxisome 

NOAEL Less serious Serious 

(mg/kg/day) (mglkglday) (mgM.dday) 

morphological evidence 

proliferation) 

Bd Wt 2100 (no weight gain) 

Short et al. 1987 

Reference 

Chemical Form 

-

P

N 

in 

I

-I 

TI 

9

5 

2 

s II 

-I

I 

-

-I 

rn 

110 Rat 54 d 

(Fischer- 344)1dd 

(GO) 

Hepatic 2000 (89% increase in relative 

liver weight; peroxisome 

proliferation) 

Tomaszewski et al. 

1988 

111 Rat 20 d 

(Fischer- 344)Gd 0-20 

Hepatic 357 (increased relative liver 

weights) 

Tyl et al. 1988 

w 

(F) Bd Wt 357 666 (19% reduced maternal 

weight gain) 

856 (39% reduced maternal 

weight gain) 

112 

113 

Mouse 

(B6C3F1) 

Mouse 

(Cr1:CD-1) 

4-1 3 wk 

(F) 

126 d 

(F) 

Hepatic 

Hepatic 

188 F (increased relative liver 

weight) 

420 (increased liver weights) 

David et al. 1999 

Lamb et al. 1987 

rn 

T 

T

8

2 

Bd Wt 420 

114 Mouse 

(W 

4wk 

2d/wk 

Bd Wt 1171 Lee et al. 1997 

(GO) 

115 Mouse 

(NS) 

15 d 

1 dd 

(GO) 

Hepatic 2000 (increased liver weight, 

changes in enzyme 

activity) 

Parmar et al. 1988 

Bd Wt 2000 (1 1 % change in body 

weight gain) 
Table 3-2. Levels of Significant Exposure to Di-(2-ethylhexyl)phthalate - Oral (continued) c 

h 

N 

Exposure/ LOAEL 

duration/ 

K~Ytoa Species frequency NOAEL Less serious Serious Reference

figure (Strain) (Specific route) System (mglkglday) (mgkllday) (mglkglday) Chemical Form 

Other 44 91 (rough coat; lethargy) Tyl et al 1988 116 Mouse 17 d 

(CD-1) Gd0-17 

(F) Hepatic 91 191 (increased relative liver 

weight) 

Bd Wt 91 191 (30% reduced weight gain) 

117 Mouse 24 wk Hepatic 2400 M (degenerative liver lesions) Ward et at. 1998 

Sv/l29 (F) 

Renal 2400 M (degenerative renal lesions) 

Bd Wt 2400 M (50% lower final body weight) 

w 

I 1953 (significant increase in Weghorst et al. 1994 rn 118 Mouse 24 wk Hepatic 

(CH3/HeNCr) (F) relative liver weight) 5 

Bd Wt 1953 (final body weight reduced rn 

n over 50%) n 

m 

119 GnPig 15d Hepatic 2000 (increased liver weight, Parrnar et al. 1988 Yv) 

(NS) 1 x/d decreased enzyme 

activity) (GO) 

Bd Wt 2000 (1 9% decrease in body 

weight gain) 

120 Hamster 30wk Hepatic 1436 Maruyama et al. 1994 

(Golden (F)

Syrian) 

Renal 1436 (increase relative kidney 

weight) 

Bd Wt 1436 (16% reduction in final 

body weight) 

Immunological/Lymp horeticular 

121 Rat 90 d 1900 M Shaffer et al. 1945 

(Wistar) (F) P

ul 
Table 3-2.Levels of Significant Exposure to Di-(2-ethylhexyl)phthalate - Oral (continued) -

0 

K~Ytoa Species

figure (Strain) 

Exposure/ 

duration/ 

frequency

(Specific route) System 

NOAEL 

(mg/kg/day) 

Less serious 

(mgkllday) 

LOAEL 

Serious 

(mgWday) 

Reference 

Chemical Form 

h, in 

I

--I 

2 

Reproductive 

(Marmoset) 1dd 

122 Monkey 13 wk 

(GO) 

2500 M Kurata et al. 1998 

v 

73

I 

--I

I 

rn 

c--I 

123 Rat 

(Wistar) 

42 d 

(F) 

1200 (decreased testicular 

weight, seminal vesilce 

and ventral prostrate with 

gradual post-exposure 

recovery) 

Gray and Butterworth 

1980 

124 

125 

Rat 

(SpragueDawley) 

Rat 

(Wistar) 

40 d 

Gd 3-21 

ppd 1-21 

(GO) 

15 d 

(GO) 

375 M (altered sexual differentiation Moore et al. 2001 

and decreased testes and 

anterior prostate weights in 

male offspring) 

2000 (decreased testicular weight, Parrnar et al. 1987 

changes in tubules, 

damaged spermatogenic 

cells; reduced sperm count) 

w 

I 

rn

5

I 

rn 

-n 

n 

m 

v) 

126 Rat 

(Wistar) 

30 d 

Idd 

(GO) 

50 M (33% lower testicular 

weight) 

250 M (57% lower testicular weight, Parmar et al. 1995 

testicular germ cell damage) 

127 Rat 

(SpragueDawley) 

13 wk 

(F) 

3.7 M 37.6 M (mild vacuolation of 

Sertoli cells in 7110 rats) 

375.2 M (testicular atrophy with 

complete loss of 

spermatogenesis in 9/10 

rats) 

Poon et al. 1997 

128 Rat 13 wk 345 M (testicular atrophy) Poon et al. 1997 

(SpragueDawley) 1dd 

(F) 

Ln 

0 
Table 3-2. Levels of Significant Exposure to Di-(2-ethylhexyl)phthalate - Oral (continued) g 

h Exposure1 --I

duration/ LOAEL I

$ K~Ytoe Species frequency NOAEL Less serious Serious Reference I

figure (Strain) (Specific route) System (mg/kg/day) (mg/kg/day) (mdkglday) Chemical Form 

129 Rat 126 wk 339 M 1060 M (testicular lesions, reduced Schilling et al. 1999 i 

-0

I pre- and postnatal survival, -I (Wistar) (F) altered sexual differentiqtion 5 

in male offspring) 5-I

rn 

130 Rat 90 d 400 900 (tubular atrophy and Shaffer et al. 1945 

degeneration) (Wistar) (F) 

131 Mouse 126 d 14b 140 (decreased male fertility) Lamb et al. 1987 

(Cr1:CD-1) (F) 

132 Mouse 24 wk 2400 M (degenerative testicular Ward et al. 1998 

I*' 

I lesions) rn Svll29 (F) 5

Developmental I

rn 

133 Rat 21 d 500 (approximately 24% reduced Cimini et al. 1994 rn 

n 

n 

pup body weight on ppd 21) (Fischer- 344)ppd 1-21 2 

1 xfd (n

(GO) 

134 Rat 90d 340 1700 (10% decreased fetal Nikonorow et al. 1973 

(Wistar) preGd 90-Gdl weight and 8% decrease 

1x/d in placental weight) 

(GO) 

135 Rat 21d 164 313 (increased prenatal and Price et al. 1986 

perinatal mortality) (Fischer- 344)Gd 0-20 

(F) 

136 Rat 21 d 1000 (significant peroxisome Stefanini et al. 1995 

(Fischer- 344)PPd 1-21 proliferation in both liver 

1 xfd and kidneys from pups) 

(GO) 
Table 3-2. Levels of Significant Exposure to Di-(2-ethylhexyl)phthalate - Oral (continued) ~~ ~ 

Exposure1 LOAEL duration1 

Key to" Species frequency NOAEL Less serious Serious Reference 

figure (Strain) (Specific route) System (mglkglday) (mglkgldw) (mglkglday) Chemical Form 

137 Rat 20 d 357 666 (decreased fetal body 1055 (fetal resorptions) Tyl et al. 1988 

(Fischer-344) Gd 0-20 weight) 

1 x/d 

(F) 

138 Mouse 18d 48 95 (increased prenatal and Price et al. 1988c 

(CD-1) Gd 0-17 perinatal mortality) 

(F) 

139 Mouse Gd 1-18 83 1 70 (increased percent Shiota et al. 1980 

(ICR) (F) resorptions and dead 

fetuses) 

140 Mouse 17 d 44 91 (external, visceral and Tyl et al. 1988 

(CD-1) Gd 0-17 skeletal abnormalities) 

1x/d 

(F) 
Key tofigure 

Exposure/ 

duration/ 

Species frequency 

(Strain) (Specific route) 

Table 3-2. Levels of Significant Exposure to Di-(2-ethylhexyl)phthalate - Oral (continued) 

LOAEL 

NOAEL Less serious Serious 

System (mg/kglday) (mglkglday) (mg/kg/day) 

Reference 

Chemical Form 

h

P 

2

LLi

I 

I

=. 

sI--

141 

CHRONIC EXPOSURE 

Death 

Mouse 104 weeks 

(B6C3F1) (F) 

1266 M (45% reduced survival due to David et al. 1999, 

hepatocellular neoplasia) 2000b 

-0

I 

-I

I

D 

-1 

rn 

5 

Systemic 

142 Rat 

(Sherman) 

1 Yr 

(F) 

Resp 

Cardio 

200 

200 

Carpenter et al. 1953 

Gastro 200 

Hemato 200 

Hepatic 60 200 (increased liver weight at 

365 days) 

Renal 

Bd Wt 

60 

60 

200 

200 

(increased kidney weight 

at 365 days) 

(decreased body weight 

gain) 

-I 

v) 

143 Rat 

(Sherman) 

2 Yr 

(F) 

Resp 

Cardio 

190 

190 

Carpenter et al. 1953 

Gastro 190 

Hemato 190 

Hepatic 

Renal 190 

60 190 (increas~ d live weight) 

Bd Wt 60 190 (decreased body weight 

gain for males) 

144 Rat 2 Yr 

(Fischer-344) (F) 

Hepatic 92 (induced peroxisomal 

enzyme activities) 

Cattley et al. 1987 
K~Ytoa 

figure 

Species frequency 

Exposure/ 

duration/ 

(Strain) (Specific route) 

LOAEL 

Table 3-2. Levels of Significant Exposure to Di-(2-ethylhexyl)phthalate - Oral (continued) 

NOAEL Less serious Serious 

(WJ/kglday) (mg/kglday) (mglkglday) System 

Reference 

Chemical Form 

12 

I 

h

: 

I 

4 

< 

r 

145 Rat 104 weeks 

(Fischer- 344) (F) 

Gastro 

Hemato 

939 F 

939 F 

David et al. 1999, 

2000a 

Musckkel 939 F 

Hemato 939 F 

Hepatic 36 F 147M (28.2% increased liver 

weight and spongiosis 

hepatis) 

Renal 

Endocr 

Bd Wt 

36 F 

939 F 

147M 

789 M 

(9.8% increased relative 

kidney weight) 

(15% reduced body 

weight gain) 

w

-

1. 

m

F-I

I 

146 Rat 

(SpragueDawley) 

102wk 

(F) 

Hepatic 140 (morphological and 

enzymatic evidence of 

moderate peroxisome 

proliferation) 

Ganning et al. 1991 

m 

n 

Bd Wt 14 140 (approximately 10% 

lower final body weight 

than controls) 

1400 (approximately27% lower 

controls) 

final body weight than 

147 Rat 2 Yr 

(Fischer- 344) (F) 

Hepatic 322 (increased incidence of 

foci of clear cell changes 

in liver) 

Kluwe et al. 1982a 

Endocr 674 (anterior pituitary cell 

hypertrophy) 
Table 3-2.Levels of Significant Exposure to Di-(2-ethylhexyl)phthalate - Oral (continued) 

Exposure/ LOAEL 

duration/ 

K~Ytoa Species frequency NOAEL Less serious Serious Reference

figure (Strain) (Specific route) System (mg/kg/day) (mgWday) (mgWday) Chemical Form 

148 Rat 2 Yr Hepatic 1377 (increased relative liver Lake et al. 1987 

(Sprague- (F) weight; increases in 

Dawley) mitochondria, 

peroxisomes, lipofuscin 

deposits, conjugated 

dienes and peroxisomal 

enzymes) 

149 Rat 365 d Hepatic 947 (50% increase in relative Marsman et at. 1988 

(Fischer- 344) (F) liver weight and DNA 

synthesis; morphological 

and biochemical evidence w 

of peroxisome I 

rn proliferation) e

i

I Bd Wt 947 (final body weight rn reduced 17% relative to n 

n 

rn controls) 0 

4 

0) 

150 Rat 95 wk Hepatic 2444 (peroxisome Rao et al. 1987 

(Fischer-344) (F) proliferation, decreased 

catalase and increased 

fatty acid oxidase 

activity) 

151 Rat 108 wk Resp 2000 Rao et al. 1990 

(Fischer-344) (F) 

Gastro 2000 (pseudoductular lesions 

in the pancreas) 

Hepatic 2000 (100% increase in liver 

weight) 

Renal 2000 (lipofuscin pigments in 

tubular epithelium) 

Bd Wt 2000 (27% decrease in body 

weight gain) ul 

ul 
Table 3-2. Levels of Significant Exposure to Di-(2-ethylhexyl)phthalate - Oral (continued) -

0 

Y 

rn 

Exposure1 LOAEL a duration/ 

Key to- Species frequency NOAEL Less serious Serious Reference f 

figure (Strain) (Specific route) System rn (Wkg/day) (mglkdday) (mglkg/day) Chemical Form 

152 Rat 79 wk Hepatic 867 (changes in peroxisomal Tamura et al. 1990 

enzymes, increased liver (Wistar) (F) weight) 

Bd Wt 867 (21% decrease in body 

weight gain) 

David et al. 1999, 153 Mouse 104weeks Gastro 1458 F 

2000b (B6C3F1) (F) 

Hemato 1458 F 

M uscls kel 1458 F 

Hepatic 117 F 292 M (30.5% increase liver w 

weight with hepatocyte 

Renal 117 F 354 F (increased chronic 

progressive 

nephropathy, 12% rn 

decreased relative n 

n 

rn kidney weight) 0

-I

cn 

Endocr 1458 F 

Bd Wt 354 F 1266 M (9.8% reduced body 

weight gain) 

154 Mouse Renal 672 1325M (chronic inflammation of Kluwe et al. 1982a 

the kidney) (B6C3F1) 

155 Gn Pig Hepatic 19 64 (increase in liver weight) Carpenter et al. 1953 

(NS) 

Renal 64 

Bd Wt 64 

Hepatic 59 Carpenter et al. 1953 

Renal 59 

Bd Wt 59 
Table 3-2. Levels of Significant Exposure to Di-(2-ethylhexyl)phthalate - Oral (continued) 

Exposure/ LOAEL 

duration1 

Key to- Species frequency NOAEL Less serious Serious Reference 

figure (Strain) (Specific route) System (mg/kg/day) (mglkglday) (mg/kg/day) Chemical Form 

Immunological/Lyrnphoreticular 

157 Rat 2 Yr 190 i Carpenter et al. 1953 

(Sherman) (F) 

158 Gn Pig 1 yr 64 Carpenter et al. 1953 

(NS) (F) 

Reproductive 

328 Carpenter et al. 1953 

(Sherman) (F) 

159 Rat 1Yr 

w 

190 Carpenter et al. 1953 I 160 Rat 2 Yr 

(Sherman) (F) m

5 David et al. 2000a I 161 Rat 104 weeks 5.8' 29 (bilateral testicular rn

(Fischer- 344) (F) aspermatogenesis) n

n 

rn 

162 Rat 102 wk 14 (inhibition of Ganning et al. 1991 2 

spermatogenesis and v, 

(Sprague- (F) 

Dawley) general tubule atrophy) 

322 674 (severe seminiferous tubular Kluwe et al. 1982a 163 Rat 2 Yr 

degeneration and testicular (Fischer- 344) (F) atrophy) 

164 Rat 18 mo 2000 (testicular atrophy) Price et at. 1987 

(Wistar) (F) 

165 Mouse 104weeks 98.5 292 (reduced testes weights and David et al. 2000b 

hypospermia) (B6C3F1) (F) 

166 Mouse 2 yr 672 1325 (seminiferous tubular Kluwe et al. 1982a 

degeneration) (B6C3F1) (F) 
Table 3-2. Levels of Significant Exposureto Di-(2-ethylhexyl)phthalate - Oral (continued) -

0

Key Key to” to” Species figure (Strain)(Strain) 

Exposure1 

duration/ 

frequency (Specific (Specific route) System (mdkq/day) NOAEL NOAEL 

(mg/kg/day) I malkaldav) 

Less Less serious serious 

(mglkglday) 

LOAEL 

Imdkaldav) 

Serious Serious 

~mg/kg/day) 

Reference Reference 

ChemicalChemical Form 

in 

-I 

i

I 

rn 

i: 

s 

167 

168 

Cancer 

Rat 2 Yr 

(Fischer-344) (F) 

Rat 104 wk 

(Fischer-344) (F) 

1100 

147‘ M 

939 F 

CEL (hepatocellular , 

carcinoma) 

(CEL: 11/65 hepatocellular 

tumors) 

(CEL: 22/80 hepatocellular 

tumors) 

Cattley et al. 1987 

David et al. 1999, 

2000a 

v 

71

I

3

I

D

5

rri 

169 

170 

171 

Rat 78 wk 

(Fischer-344) (F) 

Rat 2 Yr 

Rat 2 Yr 

(Fischer-344) (F) 

(Sprague- (F) 

Dawley) 

1579 

322 

1377 

(CEL: 43% 

hepatocarcinomas, 0% in 

controls at week 78) 

CEL (hepatocellular 

carcinoma) 

CEL (hepatocellular 

carcinoma) 

Hayashiet al. 1994 

Kluwe et al. 1982a 

Lake et al. 1987 

w 

I 

rn? 

-I

I 

rn 

n 

n 

rn 

(I) 

172 Rat 95 wk 

(Fischer-344) (F) 

2444 CEL (hepatocellular 

carcinoma) 

Rao et al. 1987 

173 Mouse 

(B6C3F1) 

104 wk 

(F) 

292‘ M (CEL: 27/65 hepatocellular 

354 F (CEL: 19/65 hepatocellular 

tumors) 

tumors) 

David et al. 1999, 

2000b 
Table 3-2. Levels of Significant Exposure to Di-(2-ethylhexyl)phthalate - Oral (continued) 

Exposure1 LOAEL duration1 

Key to” Species frequency NOAEL Less serious Serious Reference figure (Strain) (Specific route) System (mg/kg/day) (mg/kg/day) (mglkglday) Chemical Form 

174 Mouse 2yr 672 CEL (hepatocellular Kluwe et al. 1982a 

(B6C3F1) (F) carcinoma) 

”The number corresponds to entries in Figure 3-2. 

to derive an intermediate-duration oral minimal risk level (MRL) of 0.1 mglkglday; The MRL was derived by dividing the NOAEL by an uncertainty factor of 100 (10 for 

animal to human extrapolation and 10 for human variability). 

‘Used to derive a chronic-duration oral minimal risk level (MRL) of 0.06 mglkglday. The MRL was derived by dividing the NOAEL by an uncertainty factor of 100 (10 for 

animal to human extrapolation and 10 for human variability). 

dDifferencesin levels of health effects and cancer effects between males and females are not indicated in Figure 3-2. Where such differences exist, only the levels of effect for the 

most sensitive gender are presented. 

Bd Wt = body weight; (C) =capsule; Cardio = cardiovascular; CEL = cancer effect level; d = day(s); DNA = deoxyribonucleic acid; (F) = feed; F = female; (G) = gavage; Gastro 

= gastrointestinal; Gd = gestation day; Gn pig = guinea pig; (GO) = gavage oil; Hemato = hematological; LOAEL = lowest-observed-effect level; Ld = lactation day; LD,, = lethal 

dose, 50% kill; mo = month@);M = male; NOAEL = no-observed=adverse=effectlevel; NS = not specified; ppd = postpartum day(s); Resp = respiratory; wk = week(s); x = 

time(s); yr = year(s) 

-

0 

h 

v

h 

-i

5

7

5 

si 

v 

71 

X 

-I

X

P

2 

rn 

w 

I 

rn 

I

5 

rn 

n

n 

rn 

0 

;1 
Figure 3-2. Levels of Significant Exposure to Di-(2-ethylhexyl)phthalate- Oral 

Acute (514 days) 

Systemic 

rnglkglday 

100000 

10000 

Ollr 

1000 

08k 08k @38m 

@41m 

@36r 

09k 030r 

@36r

@14r 

08k 

@22r 

012r 

I 

rn 

T 

n 

rn 

100 

A7 

A7 

038rn 

Q12r 

@1 3r 

@14r 014r 

1c 

c-Cat -Humans f-Ferret n-Mink +Cancer Effect Level-Animals Cancer Effect Level-Humans LD50/LC50

d-Dog k-Monkey j-Pigeon o-Other 0LOAEL, More Serious-Animals A LOAEL, More Serious-Humans I Minimal Risk Level 

r-Rat m-Mouse e-Gerbil @ LOAEL, Less Serious-Animals A LOAEL, Less Serious-Humans ;

A foreffects 

p-Pig h-Rabbit s-Hamster 0NOAEL -Animals A NOAEL- Humans other than 

a-Caw a-Sheeo a-Guinea Pia Cancer 
Figure 3-2. Levels of Significant Exposure to DL(2-ethylhexy1)phthalate- Oral (Continued) 

Acute (114days) 

Svstemic 

rnglkglda! 

100000 

10000 

0 

047r 849r I 

rn

5

I 

rn

049r 050r -n 

n 

rn 

1000 2 

v) 

08n 0 18r 

1oc 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans LD50lLC50 

d-Dog k-Monkey j-Pigeon o-Other 0LOAEL, More Serious-Animals A LOAEL, More Serious-Humans Minimal Risk Level 

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals A LOAEL, Less Serious-Humans : for effects 

p-Pig h-Rabbit s-Hamster . 0NOAEL -Animals aNOAEL - Humans other than 

_q-Cow__~~g-Gulnea-P!g-~ a-Sheep --~ ~- ~-- ~_ Cancer - __ 
Figure 3-2. Levels of Significant Exposure to Di-(2-ethylhexyl)phthalate- Oral (Continued) 

Acute (514 days) 0 

h

K 

-I

I

-<

c 

100000 

10000 .83r 

1oot 

05lk Q58r 

086rn 

857r 058r 081 r 

1O( 055r 056r 057r @64r .87m 

087m 

064r 

- IL 

ol 

N 
Figure 3-2. Levels of Significant Exposure to Di-(2-ethylhexyl)phthalate- Oral (Continued) 

Intermediate (15-364 days) 0 

ro 

in Systemic --I 

10000 

093k 093k 093k 093k 889; .89r .92h 0108r 0108r 

1000 

w 

I 

rn

? 

-I 100 I 

rn 

n 097r n 0105r 0105r rn 

0 

-I 

0) 

10 

1 

0.1 

LD50/LC50

d-Dog k-Monkey o-Other A LOAEL, More Serious-Humans : Minimalfor effects w 

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

j-Pigeon 0 LOAEL, More Serious-Animals Risk Level 0 

r-Rat m-Mouse e-Gerbil 0 LOAEL, Less Serious-Animals A LOAEL, Less Serious-Humans 

p-Pig h-Rabbit s-Hamster 0NOAEL-Animals NOAEL - Humans A other than 

q-Cow a-Sheep g-Guinea Pig __ Cancer 
rnglkglday 

10000 

1000 

100 

10 

1 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow 

Figure 3-2. Levels of Significant Exposure to Di-(2-ethylhexyl)phthalate- Oral (Continued) 

Intermediate(15-364 days) 

Svstemic 

0121 r 

81% 095r 

0113rn 0105r @Ioar Olllr 0105r

a102r 0108r .116rn 

0116rn a116rn 

0102r @I 26r 0116rn a1 27r 

Q131rn 

i 0127r 

w 

-Humans f-Ferret n-Mink Cancer Effect Level-Animals V Cancer Effect Level-Humans LD50/LC50

k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals A LOAEL, More Serious-Humans ; Minimal Risk Level 

m-Mouse e-Gerbil LOAEL, Less Serious-Animals A LOAEL, Less Serious-Humans I for effects 

h-Rabbit s-Hamster 0NOAEL - Animals A NOAEL - Humans A other than 

a-Sheep g-Guinea Pig Cancer 

u 

I 

rn

F

-I

I 

rn 

n 

n 

rn

2 cn 

-

0 

r?,

ril 

-I

I 

$

I 

sI--

73

I 

-I

I

t-I 

rn 

cn 

P 

0.1 
rnglkglday &* 

10000 

1000 

100 

10 

1 

0.1 

0.01 

0.001 

0.0001 

1E-5 

1 E-6 

c-Cat 

d-Dog r-Rat 

p-Pig

q-Cow 

-Humans f-Ferret n-Mink Cancer Effect Level-Animals V Cancer Effect Level-Humans LD50/LC50 

k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals A LOAEL, More Serious-Humans : Minimal Risk Level 

m-Mouse e-Gerbil 0 LOAEL, Less Serious-Animals A LOAEL, Less Serious-Humans : for effects 

h-Rabbit s-Hamster 0NOAEL -Animals NOAEL - Humans A other than 

a-Sheep g-Guinea pig__- Cancer 

Figure 3-2. Levels of Significant Exposure to Di-(2-ethylhexyl)phthalate - Oral (Continued) 

Chronic (2365days) 

Systemic 

0151r 8151r 

0153m0~45r O153m0145r 8182 

Q153rn 8147r 

8143r 8145 8146r 01 53rn 144r 0156d a1559 0142r 8143r 

0145r 

01559 

rn 

n 

n 

rn 

c)i 

v) 

E 

h 

x 

-I

I 

$

I 

rn

2 

t- v 

-0

I 

-I

I

E-I 

rn 
mglkglday 

10000 

1000 

100 

10 

1 

0.1 

0.01 

0.001 

0.0001 

1E-5 

1 E-E 

c-Cat 

Figure 3-2. Levels of Significant Exposure to Di-(2-ethylhexyl)phthalate - Oral (Continued) 

Chronic (2365 days) 

Systemic 

0 

h 

x 

-I

I

3

I 

I-sTI

I 

-I

5

5-I 

rn 

I 

rn

5

I 

rn 

n 

n 

rn

7 

cn 

m 

m 

a151r 0164r 

a154m 0166m 

0154m 0166m 0163 

a1 53m 

0165m 

01 589 

0161r 

0146r 0162r 

01 61 r 

w 

10-4 

10-5 

10-6 

*Doses represent the lowest dose tested per study that produced a tumorigenic 10-7-

response and do not imply the existence of a threshold for the cancer endpoint. 

-Humans f-Ferret n-Mink +Cancer Effect Level-Animals Cancer Effect Level-Humans 

A LOAEL, More Serious-Humans A LOAEL, Less Serious-Humans 

NOAEL - Humans 

e172r 

$I& r *171r

+174m 

*168r 

Estimated 

Upper-Bound 

Human Cancer 

Risk Levels 

LD501LC50 

;I Minimal for effects Risk Level 

A other than 

Cancer 
 

 

 

DI(2-ETHYLHEXYL)PHTHALATE 67 

3. HEALTH EFFECTS 

Respiratory Effects. No studies were located regarding respiratory effects in humans after oral 

exposure to DEHP. No adverse respiratory effects were reported in any of the animal studies reviewed. 

However, no study was located that evaluated pulmonary function. 

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

oral exposure to DEHP. No adverse cardiovascular effects were reported in any of the animals studies 

reviewed. However, no study was located that evaluated cardiovascular function in animals following 

oral exposure. 

A potential effect in human heart muscle contractility was identified in in vitro studies. 

Mono(2-ethylhexyl)phthalate (MEHP) (a product of DEHP hydrolysis) displayed a dose-dependent 

negative inotropic effect on human atrial trabecula (Barry et al. 1989, 1990). This suggests the possibility 

that high levels of serum MEHP could have a cardiotoxic effect in humans. However, rapid metabolism 

of MEHP would act to minimize the probability that MEHP concentrations would reach the concentration 

associated with the negative inotropic effect. The authors suggested that infants with multisystem failures 

would be the group at greatest risk to a cardiotoxic effect of MEHP. In contrast to the in vitro studies, 

there was no indication of cardiovascular effects in 18 infants who had increased plasma levels of DEHP 

(8.3±5.7 )g/mL, mean highest concentration) from exposure during extracorporeal membrane 

oxygenation (ECMO) therapy (DEHP had leached from plastic tubing) (Karle et al. 1997). Cardiac 

performance was evaluated by using echocardiograms to estimate output from heart rate, systolic blood 

pressure, left ventricular shortening fraction, and stroke volume measurements. 

Gastrointestinal Effects. Acute exposures to large oral doses of DEHP can cause gastrointestinal 

distress. When two humans were given a single oral dose of 5 or 10 g DEHP, the individual consuming 

the larger dose complained of mild abdominal pain and diarrhea (Shaffer et al. 1945). No other effects of 

exposure were noted. No adverse gastrointestinal effects were reported in any of the animal studies 

reviewed with the exception of pseudoductular lesions in the pancreas of rats administered 3,000 mg 

DEHP/kg/day in the diet for 108 weeks (Rao et al. 1990). The significance of this finding is unclear 

because pancreatic lesions were not observed in rats and mice that were similarly exposed to dietary 

DEHP at doses #939 and 1,458 mg/kg/day, respectively, for 104 weeks (David et al. 2000a, 2000b). 
 

 

 

DI(2-ETHYLHEXYL)PHTHALATE 68 

3. HEALTH EFFECTS 

Hematological Effects. No studies were located regarding hematological effects in humans after 

oral exposure to DEHP. There were no hematological changes in male Cynomolgus monkeys that were 

administered 500 mg DEHP/kg/day by gavage for 14 consecutive days (Pugh et al. 2000). Exposure of 

male albino rats to doses of 200–1,900 mg/kg/day DEHP in the diet for 90 days had no effect upon red 

blood cell counts, hemoglobin levels, or differential white cell counts (Shaffer et al. 1945). In contrast, a 

recent 13-week dietary study in Sprague-Dawley rats reported slight but significant decreases in red blood 

cell counts and serum hemoglobin in males that received approximately 375.2 mg DEHP/kg/day (Poon et 

al. 1997); a dose of 37.6 mg DEHP/kg/day was without effect. In a separate experimental series in the 

same study, it was reported that doses of 345 and 411 mg DEHP/kg/day (only levels tested) in male and 

female rats, respectively, significantly increased blood cell counts and decreased mean corpuscular 

hemoglobin in females, and significantly increased platelet counts in both males and females (Poon et al. 

1997). There is no apparent explanation for the inconsistent results between the Shaffer et al. (1945) and 

Poon et al. (1997) studies other than the fact that the Poon et al. (1997) values might still have been 

within the normal range for the rats; no statistical analysis was presented in the Shaffer et al. (1945) 

study. No adverse hematological effects were reported in an intermediate-duration gavage study in 

marmoset monkeys administered up to 2,500 mg DEHP/kg/day (Kurata et al. 1998). Exposures of rats to 

200 mg/kg/day for 1 year caused no changes in erythrocyte or total and differential leukocyte counts 

(Carpenter et al. 1953). Similarly, comprehensive hematological evaluations showed no toxicologically 

significant changes in F344 rats and B6C3F1 mice that were fed DEHP in the diet at doses #939 or 

1,458 mg DEHP/kg/day, respectively, for 104 weeks (David et al. 2000a, 2000b). 

Musculoskeletal Effects. No studies were located regarding musculoskeletal effects in humans and 

no reports of musculo/skeletal effects in animals were found in any of the studies reviewed. 

Hepatic Effects. No studies were located regarding hepatic effects in humans after oral exposure to 

DEHP. Limited information on hepatic effects in humans exposed to DEHP is available from studies of 

dialysis patients and cultured human hepatocytes. In one individual there was an increased number of 

liver peroxisomes after 1 year, but not after 1 month of treatment (Ganning et al. 1984, 1987). A serious 

limitation of this observation is that repeat biopsies were not obtained from the same patient, so that an 

appropriately controlled analysis is not possible. Additionally, analysis of liver biopsies from patients 

receiving other kinds of hypolipidemic drugs has not yielded any evidence for peroxisomal proliferation 

(Doull et al. 1999). Recognizing some limitations of using primary hepatocytes in vitro because of their 

tendency to lose some metabolic capabilities (Reid 1990), in cultured human hepatocytes there were no 

changes in the activities of peroxisomal palmitoyl-CoA oxidase and/or carnitine acetyltransferase when 
DI(2-ETHYLHEXYL)PHTHALATE 69 

3. HEALTH EFFECTS 

the cells were exposed to MEHP (Butterworth et al. 1989; Elcombe and Mitchell 1986; Hasmall et al. 

2000). 

There are abundant animal data detailing the effects of DEHP on liver structure and function. Rats and 

mice are most susceptible to the hepatic effects of DEHP, while dogs and monkeys are less likely to 

experience changes in the liver after exposure. In general, the data indicate that male rats are more 

susceptible to the hepatic effects of DEHP than are females. 

Hyperplasia/Hypertrophy. Oral exposures of rats and mice to DEHP characteristically result in a marked 

increase in liver mass (Barber et al. 1987; Berman et al. 1995; Carpenter et al. 1953; David et al. 1999, 

2000a, 2000b; DeAngelo et al. 1986; Dostal et al. 1987a, 1987b; James et al. 1998; Lake et al. 1986; 

Lamb et al. 1987; Marsman et al. 1988; Mitchell et al. 1985b; Oishi 1989a, 1994; Parmar et al. 1988; 

Poon et al. 1997; Rao et al. 1990; Rhodes et al. 1986; Shin et al. 1999; Takagi et al. 1990; Tamura et al. 

1990; Tomaszewski et al. 1988; Tyl et al. 1988). This is due to rapid cell division (hyperplasia), along 

with some enlargement of cells (hypertrophy). A 14-day exposure of rats to 1,200 mg/kg/day increased 

the relative liver weight by 52% after 1 week and 74% after 2 weeks (Takagi et al. 1990). Relative liver 

weight was significantly increased in F344 rats (28.2% higher than controls) and B6C3F1 mice (30.5% 

higher than controls) that were fed DEHP in the diet at doses of $147 and $292 mg/kg/day, respectively, 

for 104 weeks (David et al. 2000a, 2000b). 

Hepatic hyperplasia appears to be the initial physiological response to DEHP exposure in rats (Busser and 

Lutz 1987; Smith-Oliver and Butterworth 1987). When rats were exposed to single doses of $150 mg 

DEHP/kg, there was an increase in cell division within 24 hours (Berman et al. 1995; Busser and Lutz 

1987; Smith-Oliver and Butterworth 1987). Treatment for 2 days with approximately 1,000 mg DEHP/kg 

significantly increased relative liver weight and DNA synthesis in rats and to a lesser extent in mice 

(James et al. 1998). During the early stages of a chronic study, repeated oral doses of $50 mg/kg/day 

increased mitotic activity when given to rats for 3 consecutive days (Mitchell et al. 1985b). The increase 

in mitosis occurred only in the early stages of treatment and did not persist beyond the first week of 

exposure in studies with 3–12-month durations (Marsman et al. 1988; Mitchell et al. 1985b; Smith-Oliver 

and Butterworth 1987). The observation that DEHP causes an early transient increase in liver DNA 

synthesis above a certain dose level is similar to phenobarbital, a known rodent liver tumor promoter 

(Dalton et al. 2000), and strengthens the conclusion that DEHP is an epigenetic tumor promoting agent in 

rodents as discussed in Section 3.5.2 (Mechanisms of Toxicity). 
DI(2-ETHYLHEXYL)PHTHALATE 70 

3. HEALTH EFFECTS 

Morphology. Morphological changes which were observed in the livers of treated rats included fat 

deposits in the periportal area, a decline in centrilobular glycogen deposits, and structural changes in the 

bile ducts (Mitchell et al. 1985b; Price et al. 1987). Liver cells became enlarged and lipofuscin deposits 

accumulated, indicating that peroxidation of cellular lipids had occurred (Lake et al. 1987; Mitchell et al. 

1985b; Price et al. 1987). On a microscopic level, there was a definite increase in hepatic peroxisomes in 

the centrilobular and periportal areas of the liver and there was often an increase in the number of 

mitochondria (Hodgson 1987; Nair and Kurup 1987a). Lipid filled lysosomes were observed in some 

cases (Mitchell et al. 1985b). Each of these changes contributed to cellular hypertrophy. Many of the 

morphological changes described above were seen in the male rats at doses $50 mg/kg/day but did not 

appear in the females until doses of 200 mg/kg/day and above (Mitchell et al. 1985b), indicating that male 

rats are somewhat more susceptible than are females. Histopathological changes in the liver of rats that 

were exposed to DEHP in the diet for up to 104 weeks included spongiosis hepatis at doses 

$147 mg/kg/day, and diffuse hepatocellular enlargement, increased cytoplasmic eosinophilia, and 

increased Kupffer cell or hepatocyte pigmentation at $789 mg/kg/day (David et al. 2000a). Hepatic 

effects in mice that were similarly exposed to DEHP for 104 weeks included hepatocellular enlargement 

and increased hepatocyte pigmentation, cytoplasmic eosinophilia, and chronic inflammation at doses 

$1,266 mg/kg/day (David et al. 2000b). 

Peroxisome Proliferation. An increase in hepatic peroxisomes and induction of peroxisomal enzymes 

are markers of DEHP exposure in rodents. Acute exposures to doses of 1,000 mg/kg/day or greater were 

consistently associated with an increase in cellular peroxisomes (Ganning et al. 1989; Rhodes et al. 1986; 

Shin et al. 1999). Along with the increase in the number of peroxisomes, there is a simultaneous increase 

in the activities of many of the peroxisomal enzymes, especially those related to the catabolism of fatty 

acids. Peroxisomes are organelles that utilize molecular oxygen and produce hydrogen peroxide during 

substrate catabolism (Figure 3-3). They contain a variety of enzymes including oxidases, peroxidases, 

and catalase (McGilvery and Goldstein 1983). Peroxisomal fatty acid oxidation follows the same 

pathway utilized by mitochondria except that ATP is not generated and hydrogen peroxide is produced in 

place of water. Subsequently catalase and peroxidases reduce hydrogen peroxide to water. Peroxisomal 

fatty acid oxidation cannot completely degrade a fatty acid to acetyl-coenzyme A (CoA). Octanoyl CoA 

is exported to the mitochondria for the completion of oxidation by way of the citric acid cycle and 
Adapted from Stott 1988 

DI(2-ETHYLHEXYL)PHTHALATE 71 

3. HEALTH EFFECTS 

Figure 3-3. Peroxisomal Fatty Acid Metabolism 
DI(2-ETHYLHEXYL)PHTHALATE 72 

3. HEALTH EFFECTS 

electron transport chain (Figure 3-3). Accordingly, proliferation of peroxisomes and increased fatty acid 

catabolism by this organelle requires a simultaneous increase in mitochondrial fatty acid metabolism. 

There are multiple changes in peroxisomal enzymes that occur following exposures to DEHP. Some of 

the changes are due to peroxisomal proliferation, but induction of specific enzymes is also apparent. 

There is considerable agreement among studies that indicate that the activities of the enzymes responsible 

for fatty acid catabolism (palmitoyl-CoA oxidase, enoyl-CoA hydratase, carnitine acyltransferase, and 

α-glycerophosphate dehydrogenase) were increased in rodents after exposure to DEHP by factors as great 

as 1,500% (Cattley et al. 1988; David et al. 1999; Dostal et al. 1987a; Elliott and Elcombe 1987; Ganning 

et al. 1991; Lake et al. 1986; Poon et al. 1997; Rhodes et al. 1986; Ward et al. 1998). Some evidence of 

peroxisomal enzyme induction was apparent in rats within 3 weeks at a dose of 50 mg/kg/day (Barber et 

al. 1987; Mitchell et al. 1985b; Short et al. 1987) but not with doses as low as 5 and 11 mg/kg/day 

(Barber et al. 1987; Short et al. 1987). Chronic administration of 14 mg/kg/day DEHP to rats caused a 

gradual increase in the activities of selected enzymes (palmitoyl Co-A oxidase, carnitine 

acetyltransferase) over a period of 102 weeks. At the end of this time, enzyme activities were more than 

twice the values for the controls (Ganning et al. 1991). 

If fatty acid catabolism by peroxisomes is increased by DEHP exposure and excess hydrogen peroxide is 

produced, there is an increased requirement for detoxification by peroxisomal catalase and the cellular 

peroxidases. However, the data concerning the impact of DEHP on catalase in rats are inconsistent. 

There are reported dose and duration conditions where the activity of catalase decreased (Ganning et al. 

1989; Rao et al. 1987), where it remained constant (Elliott and Elcombe 1987; Perera et al. 1986), and 

where it increased (Perera et al. 1986; Tamura et al. 1990). Both increases and decreases in catalase were 

reported following various durations of exposure of rats to doses of 14, 140, or 1,400 mg/kg/day DEHP 

over a 102-week period (Ganning et al. 1991). In time course studies of 79 weeks at 867 mg/kg/day 

(Tamura et al. 1991) and 52 weeks at 6,000 mg/kg/day (Conway et al. 1989), increases in rat liver 

catalase were sustained. It should be noted that increases in catalase in these studies did not exceed 200% 

of control levels. 

In addition to catalase, the enzymes glutathione peroxidase and superoxide dismutase are important 

elements in the cellular defenses against free radical oxygen. Cytoplasmic activity of glutathione 

peroxidase was decreased in rats by 14 and 28 days of exposure to doses of 500–2,000 mg/kg/day DEHP 

(Elliott and Elcombe 1987; Perera et al. 1986) and superoxide dismutase activity was decreased by a 

28 day exposure of rats to 1,000 and 2,000 mg/kg/day (Elliott and Elcombe 1987). Glutathione 
DI(2-ETHYLHEXYL)PHTHALATE 73 

3. HEALTH EFFECTS 

peroxidase activity in rats was also found to be depressed to about 50% of control values throughout 

79 weeks of exposure to 867 mg/kg/day DEHP (Tamura et al. 1990) and throughout 52 weeks of 

exposure to 600 mg/kg/day (Conway et al. 1989). 

Peroxidases and catalase are present in hepatic cells and are able to detoxify the peroxide produced by the 

peroxisomes. Fluctuations in levels of glutathione peroxidase and catalase activity following DEHP 

treatment in rats might indicate that the capacity to oppose an increased production of hydrogen peroxide 

by the peroxisomes is limited. It can also be postulated that a variety of exogenous factors such as diet, 

and other metabolic demands on the liver might govern the capacity of the hepatic free radical defense 

system to respond to the increased peroxisomal production of hydrogen peroxide. In addition to the 

enzymes mentioned above, the lipid ubiquinone, which acts as an antioxidant protecting against lipid 

oxidation and also protein and DNA oxidation, was significantly increased after treatment with 

approximately 2,500 mg DEHP/kg/day for 21 days in rats of various ages (Turunen and Dallner 1998). 

The authors suggested that this increase might be a response to oxidative stress. DEHP 

(1,000 mg/kg/day) given in the diet of rats for 30 days also increased cellular ubiquinone, by 250% (Nair 

and Kurup 1987b). 

When peroxisomal catabolism of fatty acids is not accompanied by an increase in the ability of the liver 

to detoxify hydrogen peroxide, the excess hydrogen peroxide might react with cellular lipids, proteins, 

and nucleic acids (Reddy et al. 1986). Slight but significant increases in malondialdehyde and conjugated 

dienes (markers for the reaction of peroxides with fatty acids) were seen in rat hepatic cells following 

28 days of exposure to 2,000 mg/kg/day DEHP (Elliott and Elcombe 1987). The catalase activity was 

unchanged while glutathione peroxidase activity was decreased. In a separate study, there was no 

increase in oxidized lipids in exposed livers as indicated by malondialdehyde concentrations following 

79 weeks of dietary exposure to 867 mg/kg/day DEHP (Tamura et al. 1990). Catalase activity was 

increased and glutathione peroxidase activity decreased. Higher dose levels were not tested. Lipofuscin 

deposits, a long-term marker for lipid reactions with peroxides, were identified in the livers of rats 

exposed to between 500 and 2,000 mg/kg/day DEHP for their lifetime (Cattley et al. 1987; Price et al. 

1987). Thus, there are some data to support the hypothesis that at least a portion of the hepatic damage 

induced by DEHP is the result of the reaction of hydrogen peroxide with cellular lipids. 

Serum and Tissue Lipids. A decrease in circulating cholesterol and triglyceride levels is also associated 

with DEHP exposure in rats (Bell 1982; Dostal et al. 1987a; Eagon et al. 1994; Mocchiutti and Bernal 

1997; Oishi 1989a; Poon et al. 1997; Rhodes et al. 1986), but not in primates (Rhodes et al. 1986). 
DI(2-ETHYLHEXYL)PHTHALATE 74 

3. HEALTH EFFECTS 

Increased fatty acid catabolism decreases the concentration of free fatty acids available for export from 

the liver as circulating triglycerides. This provides a rationale for the lowered triglyceride values. The 

lowered serum cholesterol concentration apparently results from inhibition of cholesterol synthesis and 

stimulation of the conversion of cholesterol to bile acids in the liver (Nair and Kurup 1986). 

Studies by Bell and coworkers have shown that DEHP also can alter sterologenesis in rodents, which may 

have an impact on steroid-dependent functions, such as reproductive functions. For example, feeding 

female rats DEHP at an estimated dose of 500 mg/kg/day for 13 days significantly inhibited 

sterologenesis from 14C-mevalonate in liver and adrenal minces (Bell 1980). DEHP also inhibited 

cholesterol synthesis in the liver from male rats and rabbits as well as in rats’ testes (Bell 1982). In a 

subsequent study, Bell and Buthala (1983) demonstrated that the inhibition of cholesterol synthesis in the 

liver was due to a reduction in the activity of microsomal acylCoA:cholesterol acyltransferase, an enzyme 

responsible for the esterification of cholesterol. 

Mixed Function Oxidase Enzymes. The mixed function oxidase (MFO) system is a second hepatic 

enzyme system which appears to be affected by DEHP in rodents (Ganning et al. 1991; Hodgson 1987; 

James et al. 1998; Parmar et al. 1988; Rhodes et al. 1986; Short et al. 1987), but not in monkeys (Kurata 

et al. 1998; Rhodes et al. 1986). The MFO system consists of cytochrome P-450, a series of hydratases 

and hydroxylases. Peroxisome proliferators particularly induce P-450 isoenzymes of the CYP4A 

subfamily, which have fatty acid omega and omega-1 hydroxylase activity. Significant induction of fatty 

acid omega hydoxylase and P-450 4A1 mRNA were reported following DEHP administration to rats 

(Sharma et al. 1988, 1989). Changes in hepatic levels of cytochrome P-450, NADPH Cytochrome 

c reductase, lauryl-11- and 12-hydroxylase, ethoxycoumarin-O-deethylase, ethylmorphineN-demethylase, and aniline hydroxylase were increased by DEHP exposure in rats by doses as low as 

50 mg/kg/day (Ganning et al. 1991; Hodgson 1987; Mitchell et al. 1985b; Parmar et al. 1988; Rhodes et 

al. 1986; Short et al. 1987). A comparative study in rats, hamsters, and mice, using immunochemical 

techniques, showed that mice were the most responsive species for induction of hepatic microsomal 

carboxylesterases after 7 days of dosing with DEHP, whereas rats were less responsive and hamsters were 

poorly responsive or unresponsive, particularly in butinilicaine hydrolase activity (Hosokawa et al. 1994). 

Age-dependent effects on enzyme activities were examined in rats of three ages, 3, 6, and 10 weeks old 

(Parmar et al. 1994). Single administration of 2,000 mg DEHP/kg decreased the cytochrome P-450 

contents in the liver and activity of aryl hydrocarbon hydroxylase (AHH), aniline hydroxylase, and 

ethylmorphine N-demethylase in all age groups, while repeated exposure induced them with maximum 

increases occurring in 3-week-old rats. Administration of DEHP for 15 days decreased cytochrome 
DI(2-ETHYLHEXYL)PHTHALATE 75 

3. HEALTH EFFECTS 

P-450 and the activity of the three enzymes only in the 3-week-old rats. Six- and 10-week-old rats 

showed an inhibition of AHH and increased activity of aniline hydroxylase and ethylmorphine 

N-demethylase, which were lower than that seen after 7 days of exposure in their respective groups. The 

effect of the changes in the MFO enzymes on the liver is difficult to evaluate. Although the MFO system 

tends to process various foreign chemicals and thus be of benefit, some of the oxidized intermediary 

metabolites produced by the initial MFO reactions are more toxic than are the parent compounds. 

Carbohydrate Metabolism. Some impact of DEHP on carbohydrate metabolism in the liver of rats has 

also been observed. Glycogen deposits decline with DEHP exposure. This might be the result of a need 

to mobilize glucose for use in the liver. Since exposure to as little as 50 mg/kg/day DEHP for 28 days 

decreases the activity of hepatic glucose-6-phosphatase in rats (Mitchell et al. 1985b), the transport of 

glucose from the liver is limited. Therefore, the decline in hepatic glycogen might be the result of 

increased hepatic glucose utilization. Some of the glucose could be metabolized to produce the reducing 

equivalents necessary for the activity of glutathione peroxidase. This suggestion is supported by the 

finding that glucose-6-phosphate dehydrogenase activity is increased in both male and female rats 

exposed to 50–2,000 mg/kg/day DEHP (Gerbracht et al. 1990). The activities of glyceraldehyde3-phosphate dehydrogenase, malic enzyme (extramitochondrial), and lactic dehydrogenase were also 

increased (Gerbracht et al. 1990). These enzymes are used during hepatic catabolism of glucose and 

produce intermediary metabolites that are used, among other things, for the manufacturing of new cells 

during hepatic hyperplasia. 

Membrane Structure. The effect of DEHP on liver metabolism might be modulated through a change in 

the structure of the cell membranes. Both membrane proteins and lipids are altered with DEHP exposure 

(Bartles et al. 1990; Edlund et al. 1987; Ganning et al. 1987; Gupta et al. 1988). Following 15 days of 

dietary exposure to 1,000 mg/kg/day DEHP, the concentration of membrane protein CE-9 was increased 

in rats. This protein appears to be related to transport of the biochemical signal which stimulates 

peroxisome proliferation. Other membrane protein concentrations were decreased with DEHP exposure 

in rats including epidermal growth factor receptor, asialoglycoprotein receptor, dipeptidylpeptidase-IV, 

HA-312, and HA-4 (Bartles et al. 1990; Gupta et al. 1988). There was an increase in the concentrations 

of the membrane lipids dolichol and dolichol phosphate upon the introduction of DEHP into the diet of 

rats (Edlund et al. 1987; Ganning et al. 1987). Dolichol phosphate participates in the synthesis of 

membrane glycoproteins. Accordingly, glycoprotein membrane receptor sites could be affected by DEHP 

through this mechanism leading to altered movement of materials across membranes and signaling 

changes in cell metabolism. A recent study reported that administration of 1,200 mg DEHP/kg/day for 
DI(2-ETHYLHEXYL)PHTHALATE 76 

3. HEALTH EFFECTS 

3 days to rats resulted in significant increases in total liver lipid content and total phospholipid 

(Adinehzadeh and Reo 1998). Moreover, DEHP significantly increased the phosphatidylcholine, 

phosphatidylethanolamine, and cardiolipid in the liver. 

Other Species. The discussion of hepatic effects in the above subsections is based on effects in rats and 

mice. Not all animal species are equally susceptible to the hepatic effects of DEHP. Differences in 

responsiveness are particularly evident with respect to the increases in peroxisomal content of liver cells, 

induction of peroxisomal enzymes, and increased liver weight (hypertrophy and hyperplasia). Although 

these responses clearly occur in rats and mice, hamsters are only partially responsive and guinea pigs, and 

monkeys are refractory. 

Treatment of male rats for 14 days with 100 mg/kg/day of DEHP resulted in a 20% increase in relative 

liver weight, while in the same study, treatment of male hamsters with a 10-fold higher dose, 

1,000 mg/kg/day, also resulted in a 20% increase in relative liver weight, and 250 mg/kg/day DEHP had 

no effect (Lake et al. 1984a). In a study comparing male rats and guinea pigs, 950 mg/kg/day DEHP for 

4 days resulted in increased liver weight, peroxisomal fatty acyl CoA oxidase activity, peroxisome 

volume fraction, and hyperplasia in rats but not guinea pigs (Hasmall et al. 2000). In a study of male and 

female marmoset monkeys, 500 or 2,500 mg/kg/day DEHP for 13 weeks had no effect on relative liver 

weight, peroxisome volume density, or peroxisomal fatty acyl CoA oxidase activity (Kurata et al. 1998). 

In another marmoset study, 200 mg/kg/day DEHP for 14 days had no effect on relative liver weight, 

peroxisome area density, or peroxisomal fatty acyl CoA oxidase activity (Rhodes et al. 1986). Male 

cynomologus monkeys treated with 100 or 500 mg/kg/day DEHP by gavage for 25 days had no changes 

in relative liver weight or peroxisomal fatty acyl CoA oxidase activity (Short et al. 1987). Similarly, 

there were no effects on liver weight, liver histology, or hepatic markers for peroxisomal proliferation, 

including replicative DNA synthesis, peroxisomal beta-oxidation activity, and gap junctional intercellular 

communication, in male Cynomolgus monkeys that were administered 500 mg DEHP/kg/day by gavage 

for 14 consecutive days (Pugh et al. 2000). Since the reversible inhibition of gap junctional intercellular 

communication has been hypothesized to contribute to the mechanism of tumor promotion, and since 

most, if not all, tumor promoters, including DEHP (Malcolm and Mills 1983, 1989), have been shown to 

block gap junctional communication both in vitro and in vivo (Sai et al. 2000; Trosko 2001; Trosko and 

Chang 1988; Trosko et al. 1995), the lack of DEHP’s ability to inhibit gap junctional communication in 

the monkey where no tumor promotion occurs would be consistent with the results obtained. 
 

DI(2-ETHYLHEXYL)PHTHALATE 77 

3. HEALTH EFFECTS 

Dogs also appear to be resistant to hepatic effects from DEHP exposure. In dogs given doses of up to 

59 mg/kg/day DEHP for 1 year, there were no observed changes in liver weight or structure. Liver 

function as measured by sulfobromophthalein retention was not affected (Carpenter et al. 1953). Rabbits, 

on the other hand, experienced a significant decrease in relative liver weight following 7 days of exposure 

to 2,000 mg/kg/day DEHP (Parmar et al. 1988). There was a corresponding decrease in the activities of 

the MFO liver enzymes. Continued administration of this dose was lethal to the rabbits within 14 days. 

The role of peroxisome proliferation in DEHP-induced hepatocarcinogenesis in rodents and related issues 

are discussed in Section 3.5.2. 

Renal Effects. No studies were located regarding renal effects in humans after oral exposure to 

DEHP. A possible role of DEHP in polycystic kidney disease in long-term hemodialysis patients has 

been suggested (Bommer et al. 1985; Crocker et al. 1988; Krempien and Ritz 1980), but there is no 

conclusive evidence for such an association. No association can be inferred because significant 

confounding variables related to the compromised health status of dialysis patients usually preclude 

attributing a key role to DEHP. 

Studies in animals have provided an inconsistent picture. For example, acute (5–14-day) exposures of 

rats to doses of 1,000–1,200 mg/kg/day resulted in moderate increases in relative kidney weights (Dostal 

et al. 1987a; Takagi et al. 1990). In the Dostal et al. (1987a) study, the increase was observed in 21-, 42­

and 86-day-old rats, but not in younger rats. In other studies, gavage administration of 1,200 mg 

DEHP/kg/day for 3 days induced a 2–3-fold increase in kidney microsomal lauric acid omegahydroxylation activity in rats (Sharma et al. 1989), although gavage doses of 2,000 mg/kg/day 

administered to rats or marmoset monkeys for 14 days did not significantly alter kidney weights (Rhodes 

et al. 1986). There were no changes in kidney weight or histology in Cynomolgus monkeys that were 

exposed to 500 mg DEHP/kg/day by gavage for 14 consecutive days (Pugh et al. 2000). 

In intermediate-duration studies, doses of 1,900 mg/kg/day administered to rats for 90 days did not 

significantly alter kidney weights (Shaffer et al. 1945), but doses of approximately 375 mg/kg/day for 

13 weeks significantly increased relative kidney weight in a more recent rat study (Poon et al. 1997). A 

24-week feeding study of 2,400 mg/kg/day DEHP reported degenerative renal lesions in Sv/129 wild type 

(+/+) mice prior to death, but only minimal renal lesions in knockout (-/-) type mice for PPARα (Ward et 

al. 1998). Hamsters fed approximately 1,436 mg DEHP/kg/day for 30 weeks showed a significant 

increase in relative kidney weight, but no histopathological alterations (Maruyama et al. 1994). No 
DI(2-ETHYLHEXYL)PHTHALATE 78 

3. HEALTH EFFECTS 

adverse renal effects were reported in marmoset monkeys treated daily by gavage for 13 weeks with up to 

2,500 mg DEHP/kg/day (Kurata et al. 1998). 

In chronic-duration studies, effects observed in rats that were exposed to DEHP in the diet for 104 weeks 

included an increased incidence and severity of mineralization of the renal papilla in males at doses 

$5.8 mg/kg/day, increased relative kidney weight in both sexes at $147 mg/kg/day, and increased 

severity of normally occurring renal tubule pigmentation and chronic progressive nephropathy in both 

sexes at $789 mg/kg/day (David et al. 2000a). There were no significant changes in urine volume, urine 

creatinine concentration, creatinine clearance, or other urinalysis parameters in this study. Dietary 

administration of DEHP similarly caused increased kidney weights in rats that were exposed to 

200 mg/kg/day for 1 year, although no significant increase was observed after 2 years (Carpenter et al. 

1953), and lipofuscin pigments in the tubular epithelium of rats exposed to 3,000 mg DEHP/kg/day for 

108 weeks (Rao et al. 1990). Gavage administration of an average dosage of 0.92 mg DEHP/kg/day for 

1 year caused focal inflammatory changes accompanied by cystic dilation of the tubules in three of eight 

rats, as well as diminished mean creatine clearance in seven rats (Crocker et al. 1988). The lesions were 

consistent with spontaneous nephropathy commonly observed in old rats and suggested that treatment 

with DEHP might accelerate the onset of the lesion in younger rats. The significance of these findings is 

unclear due to the small number of animals, treatment of some animals with a leachate from an artificial 

kidney unit, unreported rat strain, and bolus method of exposure. Renal effects observed in mice that 

were exposed to DEHP in the diet for 104 weeks included increased severity of naturally occurring 

chronic progressive nephropathy at $354 mg/kg/day, but no toxicologically significant changes in 

urinalysis indices (David et al. 2000b). An increased incidence of chronic inflammation of the kidney 

was similarly observed in mice that ingested approximately 1,325 mg DEHP/kg/day in the diet for 2 years 

(Kluwe et al. 1982a). No adverse renal effects were seen in guinea pigs exposed to 64 mg DEHP/kg/day 

for 1 year, or in dogs exposed to 59 mg/kg/day for 2 years (Carpenter et al. 1953; Rhodes et al. 1986). 

The relevance of the kidney effects observed in the dietary studies in rats and mice is unclear because 

some of the findings (Crocker et al. 1988; David et al. 2000a, 2000b) indicate that they likely reflect 

exacerbation of age-, species-, and/or sex-related lesions by DEHP and are not accompanied by changes 

in kidney function. The mechanism of the effect induced by the lowest dietary dose of DEHP (i.e., 

mineralization of the renal papilla in rats exposed to 5.8 mg/kg/day) is unclear and might be consistent 

with male rat-specific precipitation of α2)-globulin (David et al. 2000a). Based on the available data, the 

kidneys do not demonstrate a consistent response to DEHP. 
 

 

 

DI(2-ETHYLHEXYL)PHTHALATE 79 

3. HEALTH EFFECTS 

Endocrine Effects. No information was located regarding endocrine effects in humans after oral 

exposure to DEHP. Three studies in rats found that DEHP can alter thyroid structure and activity, 

although the clinical significance of these changes is not clear. Male Wistar rats administered 2,000 mg 

DEHP/kg/day in the food for 3, 7, or 21 days showed significant reductions in serum thyroxine (T4) 

levels at all time points, but serum triiodothyronine (T3) levels were essentially unaffected (Hinton et al. 

1986). Electron microscopy revealed a considerable increase in the number and size of lysosomes. Also, 

the Golgi apparatus was enlarged and the mitochondria appeared damaged. These changes were 

considered indicative of thyroid hyperactivity. Similar changes in the thyroid were reported in a 3-month 

feeding study, also in male Wistar rats (Price et al. 1988a). In the latter study, the authors observed that 

in the DEHP-treated rats the colloid was retracted from the follicular cells and contained considerable 

numbers of basophilic deposits which stained positive for calcium. Although the changes were consistent 

with thyroid hyperactivity, the rats did not exhibit any clinical signs of hyperthyroidism. A more recent 

study in Sprague-Dawley rats reported reduced follicle size and colloid density in the thyroid following 

dietary administration of 345 mg DEHP/kg/day for 13 weeks (Poon et al. 1997). 

Other information on endocrine effects following oral exposure to DEHP includes that of no effects on 

adrenal weight in rats gavaged with up to 1,500 mg/kg/day for 14 days or once with up to 5,000 mg/kg 

(Berman et al. 1995), and of hypertrophy of anterior pituitary cells in rats administered approximately 

674 mg/kg/day for 2 years (Kluwe et al. 1982a). 

Further information regarding endocrine effects of DEHP can be found in the following Sections: 3.2.2.5 

Reproductive Effects, 3.2.2.6 Developmental Effects, 3.5.2 Mechanisms of Toxicity, and 3.6 Toxicities 

Mediated Through the Neuroendocrine Axis. 

Dermal Effects. No studies were located regarding dermal effects in humans or animals following 

oral exposure to DEHP 

Ocular Effects. No studies were located regarding ocular effects in humans or animals following oral 

exposure to DEHP 
 

DI(2-ETHYLHEXYL)PHTHALATE 80 

3. HEALTH EFFECTS 

Body Weight Effects. There have been no reports of body weight alterations in humans attributed to 

oral exposure to DEHP, but numerous studies have documented reductions in body weight gain in 

animals. Most of the information is on rodents and in general, doses $1,000 mg DEHP/kg administered 

for periods of 5 days or longer reduce weight gain. Differences between controls and treated animals of 

>10% in either body weight gain or final weight are considered to be biologically significant by ATSDR. 

This has been seen after acute-duration exposure in marmoset monkeys (Rhodes et al. 1986), rats (Dostal 

et al. 1987a, 1987b, 1988; Gray and Butterworth 1980; Mehrotra et al. 1997, 1999; Parmar et al. 1988; 

Sjoberg et al. 1986a, 1986b), mice (Muhlenkamp and Gill 1998), guinea pigs (Parmar et al. 1988), and 

rabbits (Parmar et al. 1988). Similar observations have been made in intermediate-duration studies in rats 

(Barber et al. 1987; Mitchell et al. 1985b; Moccchiutti and Bernal 1997; Parmar et al. 1988; Poon et al. 

1997; Shaffer et al. 1945; Short et al. 1987), mice (Ward et al. 1998; Weghorst et al. 1994), guinea pigs 

(Parmar et al. 1988), and hamsters (Maruyama et al. 1994). No treatment-related changes in body weight 

were observed in Cynomolgus monkeys that were administered 500 mg DEHP/kg/day by gavage for 

14 consecutive days (Pugh et al. 2000), and marmoset monkeys gavaged daily with up to 2,500 mg 

DEHP/kg for 13 weeks experienced only a 5% reduction in weight gain relative to controls (Kurata et al. 

1998). In a chronic study, decreases in weight gain (unquantified) were reported in rats with doses as low 

as 200 mg/kg/day, but not at 60 mg/kg/day (Carpenter et al. 1953). Other chronic studies in rats reported 

reductions in weight gain with DEHP doses ranging from 867 to 3,000 mg/kg/day (David et al. 2000a, 

2000b; Ganning et al. 1991; Marsman et al. 1988; Rao et al. 1990; Tamura et al. 1990). Dietary exposure 

to DEHP for 104 weeks caused weight gain reductions of 15% in rats and 9.8% in mice at doses of 

789 and 1,266 mg/kg/day, respectively (David et al. 2000a, 2000b). Neither guinea pigs nor dogs 

administered up to approximately 60 mg DEHP/kg/day for 1 year experienced significant changes in 

body weight (Carpenter et al. 1953). 

Not all studies monitored food consumption and among the ones that did, not all had pair-fed control 

groups. Therefore, it is unclear whether the reduced weight gain is due solely to reduced food intake or 

also to reduced food utilization. For example, in one study in rats in which a pair-fed control group was 

included, DEHP-treated rats had lower weights than the pair-fed controls, even though both groups 

consumed the same quantities of food (Dostal et al. 1987b). The relevance of these findings to human 

health is unknown. 
 

DI(2-ETHYLHEXYL)PHTHALATE 81 

3. HEALTH EFFECTS 

Other Systemic Effects. As mentioned above, food consumption has been monitored in a few 

animal studies during administration of DEHP either by gavage or in the feed. Decreases in food intake 

were reported in rats (Adinehzadeh and Reo 1998; Dostal et al. 1987b; Mitchell et al. 1985b; Sjoberg et 

al. 1986a, 1986b). However, it is unclear whether reduced food intake is a reflection of poor palatability 

of the diets containing DEHP, DEHP-induced decrease in appetite, or both. Thus, the body weight 

changes should be viewed in the context of a DEHP-induced decrease in food intake. 

3.2.2.3 Immunological and Lymphoreticular Effects 

No studies were located regarding immunological effects in humans after oral exposure to DEHP. There 

were no alterations in spleen and thymus weight or histopathological signs in these organs from rats 

treated once by gavage with up to 5,000 mg DEHP/kg (Berman et al. 1995). The same results were 

obtained after the rats were gavaged with up to 1,500 mg DEHP/kg/day for 14 days (Berman et al. 1995). 

No pathological changes were seen in the spleen during examination of the tissues from rats exposed to 

up to 1,900 mg DEHP/kg/day for 90 days (Shaffer et al. 1945) or up to 190 mg DEHP/kg/day for 2 years 

(Carpenter et al. 1953). Similarly, no histological alterations were observed in the spleen, lymph nodes, 

or bone marrow of F344 rats and B6C3F1 mice that were fed DEHP in the diet at doses #939 or 1,458 mg 

DEHP/kg/day, respectively, for 104 weeks (David et al. 2000a, 2000b). No study was located that 

evaluated immune function in animals following exposure to DEHP. 

3.2.2.4 Neurological Effects 

No studies were located regarding neurological effects in humans after oral exposure to DEHP. A 

functional observation battery and motor activity measurements were conducted in Fischer-344 rats 

before and after a single gavage dose of up to 5,000 mg DEHP/kg or daily gavage doses of up to 

1,500 mg/kg/day for 14 days (Moser et al. 1995). The tests assessed autonomic, sensorimotor, and 

neuromuscular functions as well as excitability and activity. DEHP showed no neurobehavioral toxicity; 

however, administration of the 5,000 mg/kg dose produced signs of general debilitation. In another 

study, DEHP had no significant effect on the brain weight in rats or monkeys exposed to 2,000 mg/kg/day 

for 14 days (Rhodes et al. 1986). No histological alterations were observed in the brain, peripheral and 

spinal nerves, or spinal cord of F344 rats and B6C3F1 mice that were fed DEHP in the diet at doses 

#939 or 1,458 mg DEHP/kg/day, respectively, for 104 weeks (David et al. 2000a, 2000b). An effect of 

DEHP on mammalian nervous tissue was shown in an in vitro study in which exposure to DEHP caused 

increased levels of intracellular Ca2+ in rat neurohypophysial nerve terminals and pheochromocytoma 
DI(2-ETHYLHEXYL)PHTHALATE 82 

3. HEALTH EFFECTS 

cells (Tully et al. 2000). Only the Moser et al. (1995) data are listed in Table 3-2 and plotted in 

Figure 3-2, since the end points in the other studies (David et al. 2000a, 2000b; Rhodes et al. 1986) are 

insufficient indicators of neurotoxicity due to the due to the lack of testing for neurobehavioral function. 

3.2.2.5 Reproductive Effects 

Testicular Effects. No studies were located regarding reproductive effects in humans after oral exposures 

to DEHP. Studies in rodents exposed to doses in excess of 100 mg/kg/day DEHP clearly indicate that the 

testes are a primary target tissue, resulting in decreased testicular weights and tubular atrophy (Dostal et 

al. 1988; Ganning et al. 1991; Gray and Butterworth 1980; Lamb et al. 1987; Oishi 1994; Parmar et al. 

1995; Poon et al. 1997; Saitoh et al. 1997; Shaffer et al. 1945; Sjoberg et al. 1986b). Weights of the 

seminal vesicles, epididymis, and prostate gland in rats and mice are also reduced by oral exposure DEHP 

(Gray and Butterworth 1980; Lamb et al. 1987). Within the testis, Sertoli cells appear to be the target of 

DEHP toxicity (Chapin et al. 1988; Gray and Beamand 1984; Gray and Gangolli 1986; Li et al. 2000; 

Saitoh et al. 1997; Sjoberg et al. 1986b; Ward et al. 1998). Alterations in Sertoli cells consisting of 

disruption of the ectoplasmic specializations, including the disappearance of actin bundles in the cells, 

were seen as early as 3 hours after a single gavage dose of 2,800 mg DEHP/kg in rats (Saitoh et al. 1997). 

Proliferation of Sertoli cells was reduced and morphology of germ cells was altered (gonocytes were 

enlarged and multinucleated) 24 hours after administration of a single gavage dose of $100 mg/kg to 

3-day-old rat pups (Li et al. 2000). Dietary exposure to DEHP for 90 days caused mild Sertoli cell 

vacuolation in rats at doses $37.6 mg/kg/day, but not at 3.7 mg/kg/day (Poon et al. 1987). Fertility was 

reduced in male mice that were exposed to DEHP over a period of 126 days in dietary doses of 

140 mg/kg/day, but not 14 mg/kg/day (Lamb et al. 1987), indicating that DEHP affected the process of 

spermatogenesis. Effects on spermatogenesis were also indicated by the appearance of damaged 

spermatogenic cells and abnormal sperm in rats exposed to 2,000 mg DEHP/kg/day in the diet for 15 days 

(Parmar et al. 1987). A study with 2-year-old (prepubertal) Cynomolgus monkeys showed no changes in 

testes/epididymides weight or testicular histology following treatment with 500 mg DEHP/kg/day by 

gavage for 14 consecutive days (Pugh et al. 2000). 

Biochemical changes in the testes were noted when 2,000 mg/kg/day DEHP was given to rats for 14 days. 

There was an increase in the activities of gamma-glutamyl transpeptidase (GGT), lactic dehydrogenase, 

and β-glucuronidase in the treated animals. Conversely, the activities of sorbitol dehydrogenase and acid 

phosphatase were decreased (Parmar et al. 1987). The significance of these biochemical effects is not 

clear. More recently, Mehrotra et al. (1997) observed significant reductions in activities of phase II 
DI(2-ETHYLHEXYL)PHTHALATE 83 

3. HEALTH EFFECTS 

metabolizing enzymes, in the testis from rats administered approximately 1,740 mg DEHP/kg/day in the 

diet for 10 days. The most pronounced reduction was that for NAD(P)H quinone oxidereductase, about 

50% reduction in activity relative to controls. Mehrotra et al. (1997) suggested that at least part of the 

testicular toxicity of DEHP might be due to reductions of protective factors against oxidative stress. 

There are not enough data to draw conclusions concerning the role that hormones play in the testicular 

toxicity of DEHP; however, they do appear to have an effect. The coadministration of testosterone with 

DEHP appeared to diminish but not abolish the testicular toxicity of DEHP in rats (Gray and Butterworth 

1980; Parmar et al. 1987). Luteinizing hormone aggravated the testicular toxicity of DEHP in rats (Oishi 

1989a). 

The age at first exposure to DEHP appears to have a clear influence on the degree and permanence of 

testicular damage (Dostal et al. 1988; Gray and Butterworth 1980; Gray and Gangolli 1986; Sjoberg et al. 

1986b). Tubular structure and spermatogenesis are more affected by prepubertal acute exposure than by 

postpubertal acute exposure. When newborn rats were exposed to DEHP for 5-day periods at different 

time intervals between postpartum days 6 and 86, the degree of testicular damage, as manifest in tubular 

structure, Sertoli cell nuclei, and spermatocytes, decreased as the age of first exposure increased (Dostal 

et al. 1988; Sjoberg et al. 1986b). When exposures cease prior to sexual maturity, there appears to be an 

absence of permanence of effect of DEHP on reproductive performance. Rats exposed to DEHP 1 week 

after birth for 5 days were later successfully mated with control female rats on weeks 8, 10, 11, 12, and 15 

(Dostal et al. 1988). There were no significant differences in fertility when the experimental animals 

were compared to controls. 

Testicular zinc levels were measured in all the experimental rats during the Dostal et al. (1988) study. 

There was no significant change in testicular zinc for any exposure group except the group first exposed 

when 86 days old. Testicular zinc levels decreased significantly with the 1,000 and 2,000 mg/kg/day 

doses in these animals. Since zinc is thought to be localized in the spermatids, and the testes from rats 

younger than 25 days old do not contain spermatids, Dostal et al. (1988) suggested that their results 

provided further evidence that loss of zinc is not involved in the testicular atrophy at these ages. The role 

of zinc on DEHP-induced testicular toxicity has been also examined in other studies (Agarwal et al. 1986; 

Gray and Butterworth 1980; Gray et al. 1982; Oishi and Hiraga 1983), and a more detailed discussion on 

this issue is presented in Section 3.5.2 Mechanisms of Toxicity. 
DI(2-ETHYLHEXYL)PHTHALATE 84 

3. HEALTH EFFECTS 

With chronic exposures to DEHP, the testicular damage persists, as was demonstrated by inhibition of 

spermatogenesis and atrophy seen in rats after lifetime exposure to 600–2,000 mg/kg/day (David et al. 

2000a; Kluwe et al. 1982a; Price et al. 1987). In the David et al. (2000a) study, 6-week-old male rats 

were fed diets that provided 0, 5.8, 29, 147, or 789 mg DEHP/kg body weight/day for 104 weeks. 

Testicular effects included significantly (p#0.05) increased incidences of bilateral aspermatogenesis at 

$29 mg/kg/day and reduced testes weight (63% absolute, 59% relative) at 789 mg/kg/day. Castration 

cells in the pituitary, apparently due to reduced testosterone secretion resulting from an effect of DEHP 

on the Sertoli cells, were also observed in the rats exposed to 789 mg/kg/day. Castration cells are 

vacuolated basophilic cells in the anterior pituitary gland usually observed after castration. The 

percentage of rats with aspermatogenesis was 58, 64, 78, 74, and 97% in the control to high dose groups, 

respectively. Because there is a clear dose-related increase in aspermatogenesis and the effect is 

consistent with the reduced testes weights observed at the highest dose, the NOAEL and LOAEL for 

testicular toxicity are 5.8 and 29 mg/kg/day, respectively (NTP 2000b). Using the 5.8 mg/kg/day 

testicular NOAEL, a chronic oral MRL of 0.06 mg/kg/day was derived for DEHP as discussed in 

Section 2.3 and detailed in Appendix A. Testicular effects (inhibition of spermatogenesis and general 

tubular atrophy) were also reported at dietary doses as low as 14 mg/kg/day in a 102-week rat study 

(Ganning et al. 1991), but assessment of the results is complicated by a lack of incidence data. 

In mice exposed to 140 and 420 mg/kg/day DEHP for 126 days in a continuous breeding experiment, 

there was a significant decrease in weights of the testes, epididymis, and prostate gland (Lamb et al. 

1987). The numbers of motile sperm and the sperm concentration were decreased significantly, and there 

was an increase in the number of abnormal sperm. The NOAEL for reduced fertility in this study, 

14 mg/kg/day, was used to derive an intermediate oral MRL of 0.1 mg/kg/day for DEHP as discussed in 

Chapter 2 and detailed in Appendix A. When the high dose (420 mg/kg/day) males were mated with 

unexposed females, significantly fewer litters were produced. The number of pups born alive and pup 

body weights were also significantly lower than the controls (Lamb et al. 1987). Although 

140 mg/kg/day is the lowest LOAEL for effects on reproductive function (Table 3-2), this dose might not 

represent a true LOAEL because development of the reproductive system and reproductive performance 

in the second generation were not evaluated, and testicular toxicity has occurred at lower doses 

($37.6 mg/kg/day) in other intermediate-duration studies in rats (Parmer et al. 1995; Poon et al. 1997). 

Testicular effects observed in mice exposed to DEHP in the diet for 2 years included decreased testes 

weights and increased incidence and severity of bilateral hypospermia and immature/abnormal sperm in 

the epididymis at $292 mg/kg/day (David et al. 2000b), and seminiferous tubular degeneration at 

1,325 mg/kg/day (Kluwe et al. 1982a). 
DI(2-ETHYLHEXYL)PHTHALATE 85 

3. HEALTH EFFECTS 

Development of the reproductive system was adversely affected in male offspring of rats that were 

exposed to DEHP at 1,060 mg/kg/day, but not #339 mg/kg/day, for 70 days prior to mating through 

gestation and lactation in a two-generation dietary study (Schilling et al. 1999). Effects observed in this 

study included reduced testes and epididymis weights, testicular lesions, and spermatocyte loss in F1 

males, reduced postnatal survival in F1 pups and reduced prenatal survival in F1 and F2 pups, and altered 

sexual differentiation in F1 males (increased nipple retention) and F2 males (reduced anogenital distance). 

Similar effects on the male reproductive system have been observed in developmental toxicity studies at 

lower doses (see Section 3.2.2.6 Developmental Effects). These studies provide evidence that abnormal 

development and formation of the male reproductive system are likely to be the most sensitive 

reproductive end points for DEHP. 

Female Fertility. Few studies of the reproductive effects of DEHP on females have been conducted. 

However, based on the existing data, long-term exposures of females also appear to have deleterious 

effects. When female mice were exposed to dietary doses of 140 mg/kg/day DEHP for 126 days and 

mated with control males, no litters were produced (Lamb et al. 1987). The combined weights of the 

ovaries, oviducts, and uterus were significantly lower than those for the controls. A more recent study in 

rats showed that DEHP short-term treatment with 2,000 mg DEHP/kg by gavage decreases serum 

estradiol levels resulting in increased serum FSH levels and absence of LH surges necessary for ovulation 

(Davis et al. 1994a). Thus, exposure to DEHP resulted in hypoestrogenic anovulatory cycles and 

polycystic ovaries in adult female rats. In a study that evaluated the estrogenic activity of DEHP and 

other phthalate esters, DEHP induced no reproducible significant increases in uterine wet weight in 

immature ovariectomized rats and did not affect the degree of vaginal epithelial cell cornification in 

mature ovariectomized rats (Zacharewski et al. 1998). Results from in vitro estrogenicity assays 

conducted in that study as well as in other studies are summarized in Section 3.5 Toxicities Mediated 

Through the Neuroendocrine Axis. 

Nonrodent Species. Few reproductive studies of DEHP have been conducted in nonrodent species. A 

dose of 2,000 mg/kg/day given to 12- to 18-month-old marmoset monkeys for a 14-day period had no 

effect on testicular weight (Rhodes et al. 1986). No changes in testes/epididymides weight or testicular 

histology occurred in 2-year-old Cynomolgus monkeys that were treated with 500 mg DEHP/kg/day by 

gavage for 14 consecutive days (Pugh et al. 2000). A 13-week gavage study in marmosets of unspecified 

age showed no significant treatment-related effects (up to 2,500 mg DEHP/kg/day) on gross or 

microscopical appearance of the testis or in testicular zinc content, or on gross or microscopical 
DI(2-ETHYLHEXYL)PHTHALATE 86 

3. HEALTH EFFECTS 

appearance of the uterus, vagina, or ovary (Kurata et al. 1998). These studies suggest that nonhuman 

primates are less sensitive than rodents to the effects of DEHP using these end points of toxicity. 

Responsible Metabolite. Since DEHP is metabolized to a variety of compounds following oral exposure, 

the question has been raised as to which of DEHP metabolites is responsible for the testicular effects of 

DEHP. Evidence suggests that mono(2-ethylhexyl) phthalate (MEHP) might be the toxic metabolite in 

the testes. In one study, 1,055 mg/kg/day of DEHP administered for 5 days to rats did not affect testicular 

weight or structure, but an equimolar dose of MEHP had a significant effect (Sjoberg et al. 1986a). 

Further information on the testicular toxicity of DEHP/MEHP is presented in Section 3.5.2 Mechanisms 

of Toxicity. 

The highest NOAEL values and all reliable LOAEL values for reproductive effects in each species and 

duration category are recorded in Table 3-2 and plotted in Figure 3-2. 

3.2.2.6 Developmental Effects 

No studies were located regarding developmental toxicity in humans after oral exposure to DEHP. DEHP 

has been demonstrated to cause developmental toxicity including teratogenic effects in both rats and 

mice. Effects observed included decreased fetal/pup body weight, increased rates of abortion and fetal 

resorptions, or malformations. Single very large doses of 4,882 and 9,756 mg/kg DEHP administered to 

pregnant Wistar rats on day 12 of gestation caused a dose-related increase in dead and resorbed fetuses 

and a number of malformations in the survivors (Ritter et al. 1987). The types of malformations observed 

in the newborn pups included hydronephrosis, cardiovascular malformations, and tail malformations. 

Repeated doses of 1,000 mg/kg on gestation days 6–15 increased the incidence of fetal deaths and of 

external, soft tissue, and skeletal malformations in offspring from Wistar rats (Hellwig et al. 1997); doses 

of 200 mg DEHP/kg had no significant effects. Administration of 1,700 mg DEHP/kg/day to Wistar rats 

for 90 days prior to confirmed pregnancy with no further dosing decreased fetal weight by 10% and 

placental weight by 8%, but it did not significantly increase the incidence of malformations relative to 

controls (Nikonorow et al. 1973). Dietary administration of DEHP to Fischer-344 rats throughout 

pregnancy caused increased percentages of resorptions and dead pups per litter at doses as low as 313 

mg/kg/day (Price et al. 1986; Tyl et al. 1988). There was no conclusive evidence of teratogenic 

malformations at doses #1,055 mg/kg/day (Tyl et al. 1988), and offspring of rats that were exposed to 

#573 mg/kg/day had no effects on growth and viability after postnatal day 4, age of acquisition for 
DI(2-ETHYLHEXYL)PHTHALATE 87 

3. HEALTH EFFECTS 

developmental landmarks (incisor eruption, wire grasping, eye opening, testes descent, or vaginal 

opening), spontaneous locomotor activity, or reproductive performance (Price et al. 1986). 

Mice appear to be more susceptible to the developmental effects of DEHP than rats, at least when DEHP 

is given in the diet and comparisons are limited to traditional teratogenicity studies (i.e., studies that are 

not specifically designed to detect male reproductive system abnormalities). Decreased fetal viability and 

increased resorptions and external malformations were observed in ICR mice gavaged with 1,000 mg 

DEHP/kg/day on gestation days 7–9 and examined on gestation day 18 (Shiota and Mima 1985); the 

NOAEL was 500 mg/kg/day. Defects of the anterior neural tube were the most commonly observed 

malformations. Experiments conducted by Yagi et al. (1980) and Tomita et al. (1982a), in which 

pregnant ddY-Slc mice were administered a single gavage dose of DEHP of gestation days 6, 7, 8, 9, or 

10 and killed on day 10, showed that the most severe effects occurred when the DEHP was given on 

gestation day 7. Dosing on day 7 with 100 mg DEHP/kg/day produced an 11% incidence of fetal 

lethality compared to 2.5% at 50 mg/kg and 0% in controls (Tomita et al. 1982a). The 11% rate was 

similar to that seen when dosing on day 9 with 7,500 mg/kg or on day 6 with 2,500 mg/kg. Doses of 

approximately 170 mg DEHP/kg administered to ICR mice in the food on gestation days 1–18 

significantly increased the percent of resorptions and dead fetuses (Shiota et al. 1980); all implanted ova 

died in utero at 683 mg/kg/day. The NOAEL was 83 mg/kg/day. A significant increase in malformations 

of the external viscera and skeleton was apparent in CD-1 mice at doses of 91, 191, and 292 mg/kg/day 

given throughout gestation (Tyl et al. 1988). Specific abnormalities observed included protrusion of the 

eyeball, exencephaly, blood vessel abnormalities, fused or branched ribs, misaligned and fused thoracic 

vertebrae, and tail malformations. Maternal and fetal toxicity were reflected in the body weight data. No 

adverse effects were seen at a dose of 44 mg/kg/day. Prenatal and perinatal mortality was increased in 

offspring of mice that were exposed to 95 mg/kg/day DEHP in the diet on gestation days 0–17, although 

there were no effects on growth and viability after postnatal day 4, age of acquisition for developmental 

landmarks, spontaneous locomotor activity, or reproductive performance (Price et al. 1988c). 

Since DEHP is a lipophilic substance, it has the potential to accumulate in maternal milk and be 

transferred to suckling offspring. Both DEHP (216 μg/mL) and MEHP (25 μg/mL) were detected in the 

milk collected from lactating Sprague-Dawley rats 6 hours after the last of three daily gavage doses of 

2,000 mg DEHP/kg (Dostal et al. 1987b). At this time, no DEHP could be detected in dams’ plasma, but 

substantial amounts of MEHP were detected. Pups’ plasma had no detectable DEHP or MEHP. No other 

dose levels were tested in this study. Dostal et al. (1987b) noted that exposure to DEHP was associated 

with an increase in milk solids and lipids. Addition of 14C-DEHP to milk in vitro resulted in 94% of the 
DI(2-ETHYLHEXYL)PHTHALATE 88 

3. HEALTH EFFECTS 

radioactivity associated with the fat globular layer, 4% was in the whey, and 1.6% was in the casein 

pellet. 

Developmental effects of DEHP in rats exposed via maternal milk have been studied. Treatment of 

Sprague-Dawley rats with 2,000 mg DEHP/kg/day on postpartum days 2–6, 6–10, or 14–18 reduced pup 

weight and induced palmitoyl-CoA and carnitine acetyltransferase in the pups liver (Dostal et al. 1987b). 

Administration of 500 mg DEHP/kg/day to Fischer-344 rats on postpartum days 1–21 caused 

approximately a 24% reduction in pup weight on postnatal day 21 (Cimini et al. 1994). All pups from 

groups administered 2,500 or 5,000 mg DEHP/kg/day died before postnatal day 12. The 

5,000 mg/kg/day dose caused 25% lethality in the dams. Results from peroxisome enzyme activities 

evaluation (only 1,000 mg/kg/day group) in 14-day-old pups liver, kidneys, and brain showed a doubling 

of catalase specific activity in the liver and kidneys, doubling of D-amino acid oxidase activity in the 

three organs, and of dihydroxyacetone phosphate acyltransferase in the liver. Palmitoyl-CoA oxidase was 

greatly induced in the liver, to a lesser extent in the kidneys, and only slightly in the brain. In general, 

changes in enzyme activity were reversible with time courses dependent on the enzyme and tissue. 

Electron microscopy showed peroxisome proliferation in both liver and kidneys, but no information was 

reported about the brain (Cimini et al. 1994). Peroxisome proliferation in the brain from pups exposed 

via breast milk from dams treated with 2,800 mg DEHP/kg/day had been reported earlier (Dabholkar 

1988). A significant observation of Cimini et al. (1994) was the fact that brain catalase activity doubled 

in adults dams treated with DEHP, but was not significantly changed in the pups. Results similar to those 

of Cimini et al. (1994) were reported by Stefanini et al. (1995). 

Gestational and lactational exposure to DEHP has been shown to profoundly alter reproductive system 

development in male rat offspring. Administration of 750 mg DEHP/kg/day by gavage from gestation 

day 14 to postnatal day 3 induced a variety of effects in androgen-dependent tissues in neonates and 

infant pups at 3–7 months of age, including reduced anogenital distance (female rats normally have a 

shorter anogenital distance than males), permanent female-like areolas and nipples, vaginal pouch 

formation, penile abnormalities (e.g., cleft phallus with hypospadias), hemorrhagic and undescended 

testes, testicular and epididymal atrophy or agenesis, and small to absent sex accessory glands (e.g., 

seminal vesicles and ventral prostate) (Gray et al. 1999, 2000; Parks et al. 2000). Dose levels other than 

750 mg/kg/day were not tested in these studies. Similar effects were observed in male offspring of rats 

that were exposed to 375, 750, and/or 1,500 mg DEHP/kg/day from gestation day 3 through postnatal 

day 21 as discussed below (Moore et al. 2001). Abnormalities that were dose-related included reduced 

anogenital distance, areola and nipple retention, undescended testes, permanently incomplete preputial 
DI(2-ETHYLHEXYL)PHTHALATE 89 

3. HEALTH EFFECTS 

separation, and greatly reduced anterior prostate weight. Most of the effects were observed at 

$750 mg/kg/day, although permanent areola/nipple retention and reduced anterior prostate weight also 

occurred at 375 mg/kg/day, indicating that this is the LOAEL for effects on male reproductive system 

development. The percentage of litters with major reproductive defects (defined as litters with at least 

one male with missing or severely malformed sex organs, one testis or epididymis that weighed <75% of 

the other, incomplete preputial separation, or an undescended testis in adulthood) were 0, 62.5, 87.5, and 

100% at 0, 375, 750, and 1,500 mg/kg/day, respectively. Behavioral observations indicated that many of 

the exposed males were sexually inactive in the presence of receptive control females, although sexual 

inactivity did not correlate with abnormal male reproductive organs. Evaluation of the behavioral data is 

limited by small numbers of animals; however, a total lack of sexual activity by three of seven males at 

375 mg/kg/day suggests the possibility that exposure to the LOAEL can also demasculinize sexual 

behavior. 

Developmental toxicity was observed in offspring of Long-Evans rats that were exposed to DEHP in the 

drinking water at reported estimated doses of 3.3 or 33 mg/kg/day throughout pregnancy and continuing 

during postnatal days 1–21 (Arcadi et al. 1998). Examinations of the pups on postnatal days 21–56 

showed effects that included severe testicular histopathological changes at both DEHP dose levels, 

particularly at 21 and 28 days of age. Alterations consisted of gross disorganization of the seminiferous 

tubules with detachment of the spermatogonial cells from basal membrane and absence of spermatocytes. 

These changes were still present in high-dose rats at 56 days of age; at this age, low-dose rats exhibited 

only a few elongated spermatides, whereas unexposed rats had fully developed tubular structure with 

complete spermatogenesis. The effect levels in this study are not considered to be reliable and are 

unsuitable for identifying a LOAEL and for use in MRL derivation because (1) the methods used to verify 

and characterize the administered doses were not clearly described or completely reported, and could not 

be resolved by the NTP Center for the Evaluation of Risks to Human Reproduction (NTP-CERHR) 

Expert Panel on DEHP, and (2) the authors did not put their blood DEHP concentration data into context 

with other studies (NTP 2000b). 

The morphological changes to the male reproductive system, as well as the male sexual behavioral 

observations, are consistent with an antiandrogenic action of DEHP. Other indications of antiandrogenic 

activity include a lack of significant effects on time to vaginal opening and first estrus in female offspring 

of the rats that were exposed to 375–1,500 mg DEHP/kg/day from gestation day 3 through postnatal 

day 21 (Moore et al. 2001). Additionally, exposure to 750 mg/kg/day from gestation day 14 to postnatal 

day 3 caused significantly reduced testicular testosterone production and testicular and whole-body 
DI(2-ETHYLHEXYL)PHTHALATE 90 

3. HEALTH EFFECTS 

testosterone levels in fetal and neonatal males (Parks et al. 2000). Differences in whole-body testosterone 

levels were greatest at gestation day 17 (71% lower than controls). As a consequence, anogenital distance 

on postnatal day 2 was reduced 36% in exposed male, but not female, offspring, and testis weight was 

significantly reduced at gestation day 20 and postnatal day 2 (18.6 and 49.4% lower than controls, 

respectively). Additional information on the antiandrogenic action of DEHP is discussed in Section 3.5.2 

(Mechanisms of Toxicity). 

Several studies have focused on identifying the active developmental toxicant. For example, in a gavage 

study in Wistar rats, on an equimolar basis, DEHP was less teratogenic than MEHP, which in turn was 

less teratogenic than 2-ethylhexanoic acid (Ritter et al. 1987). In ICR mice, gavage administration of 

DEHP caused more severe embryotoxicity and teratogenicity than MEHP (Shiota and Mima 1985). In 

Han:NMRI mice, the (R) enantiomer of 2-ethylhexanoic acid given intraperitoneally was highly 

teratogenic or embryotoxic, no such properties were seen for the (S) enantiomer (Hauck et al. 1990). In 

rabbits, 2-ethylhexanoic acid did not cause developmental effects even at oral doses (125 and 

250 mg/kg/day) that were maternally toxic (Tyl 1988b). 

The highest NOAEL values and all reliable LOAEL values for developmental effects in each species and 

duration category are recorded in Table 3-2 and plotted in Figure 3-2. 

3.2.2.7 Cancer 

No studies were located regarding cancer in humans after oral exposure to DEHP. However, several 

chronic feeding studies in rodents indicate that DEHP can cause liver tumors in rats and mice (David et 

al. 1999; Kluwe et al. 1982a; Rao et al. 1987, 1990). For example, a clear dose-dependent increase in the 

incidence of hepatocellular adenomas was noted in male/female mice fed 672/799 and 1,325/1,821 mg/ 

kg/day and male/female rats fed 322/394 and 674/774 mg/kg/day for 2 years (Kluwe et al. 1982a; NTP 

1982). With a dose of 3,000 mg/kg/day, 78.5% of the treated rats developed liver tumors and 29% 

pancreatic islet cell adenomas (Rao et al. 1990). These findings have been criticized on the basis that the 

doses given exceed the maximum tolerated dose and that liver tumors are common in control animals of 

these species (Northup et al. 1982). Hayashi et al. (1994) also observed a significant increase in the 

incidence of hepatocarcinomas in Fischer-344 rats fed a diet that provided approximately 1,580 mg 

DEHP/kg/day for up to 78 weeks. However, no hepatocarcinomas or nodules were seen at week 52. In 

DEHP-treated rats, peroxisomal β-oxidation activities increased 11–15-fold during the experimental 

period, but catalase activity increased only 2-fold after 10 weeks of treatment and by 30–78 weeks had 
DI(2-ETHYLHEXYL)PHTHALATE 91 

3. HEALTH EFFECTS 

gradually decreased. After 30 weeks, there was no indication of oxidative damage or of oxidative 

cytotoxicity. 

The relationship between hepatic peroxisome proliferation, cell proliferation, and carcinogenicity has 

been evaluated in chronic studies of DEHP in rats and mice (David et al. 1999, 2000a, 2000b). Animals 

were fed a diet containing DEHP for 104 weeks; additional groups treated for only 78 weeks were 

subsequently placed in a DEHP-free diet for 26 weeks to examine reversibility of the effects. In rats, 

relative liver weight was significantly increased at $147 mg/kg/day and this correlated with increased 

palmitoyl CoA oxidase activities. Treatment with DEHP resulted in hepatocellular adenomas and 

carcinomas at weeks 78 and 104; in general, the incidence of tumors at week 78 was low except for the 

high-dose group. Cessation of treatment resulted in a one-third to one-half decrease in the incidence of 

total neoplasia relative to the groups treated for 104 weeks and in a reduction in liver weight and 

palmitoyl Co-A oxidase activity. The increased incidence of hepatic tumors was significant at the 

147 mg/kg/day dose level and higher in rats. Similar findings were reported in B6C3F1 mice. Cessation 

of treatment in mice resulted in a 50% decrease in the incidence of total neoplasia in males relative to 

groups treated for 104 weeks, but the incidence in females decreased only slightly. The increased 

incidence in hepatocellular tumors achieved statistical significance at a dose levels of $292 mg 

DEHP/kg/day. 

DEHP did not induce forestomach tumors in ICR mice administered approximately 1,171 mg DEHP/kg/ 

day 2 days/week for 4 weeks and sacrificed after 22 weeks of treatment (Lee et al. 1997). Also in this 

study, DEHP had no significant effect on the number of forestomach tumors/mouse induced by treatment 

with benzo[a]pyrene once per week for 4 weeks. Initiation-promotion studies and the role of promotion 

in the carcinogenicity of DEHP are discussed in Section 3.5.2 Mechanisms of Toxicity. 

All Cancer Effect Level (CEL) values for rats and mice in the chronic-duration category are recorded in 

Table 3-2 and plotted in Figure 3-2. 

Based on the increased incidence of hepatocellular carcinoma and adenoma in male mice (NTP 1982), 

EPA calculated an oral slope factor of 1.4x10-2 (mg/kg/day)-1 (IRIS 2000). Based on this value, oral 

intakes of 7.1x10-3 to 7.1x10-6 mg/kg/day correspond to excess cancer risk levels of 10-4 to 10-7, 

respectively. Figure 3-2 shows this range of human upper bound risk values. 
 

 

DI(2-ETHYLHEXYL)PHTHALATE 92 

3. HEALTH EFFECTS 

3.2.3 Dermal Exposure 

3.2.3.1 Death 

No studies were located regarding lethality in humans after dermal exposure to DEHP. When rabbits 

were exposed to single doses of up to 19,800 mg/kg DEHP using a modification of the FDA cuff test, two 

of six rabbits in the highest dose group died. The dermal LD50 value calculated from these data was 

24,750 mg/kg (Shaffer et al. 1945). 

3.2.3.2 Systemic Effects 

No studies were located regarding respiratory, cardiovascular, gastrointestinal, hematological, 

musculoskeletal, hepatic, or renal effects in humans or animals after dermal exposure to DEHP. 

Dermal Effects. An unidentified quantity of DEHP was applied to the skin of 23 humans for a 7-day 

period without adverse effect. After 10 days without exposure, DEHP was applied to the same spot on 

each subjects' back. No adverse reactions were observed during either phase of the study indicating that 

DEHP is neither a dermal irritant, nor a sensitizer in humans (Shaffer et al. 1945). 

Single doses of up to 19,800 mg/kg DEHP were applied to rabbit skin using a modified FDA cuff test 

procedure. There was no evidence of dermal irritation caused by DEHP during the 14-day observation 

period. 

Ocular Effects. There was no necrosis of rabbit cornea after ocular exposure to a single dose of 

0.5 mL (495 mg) DEHP but a slight transient reddening of the eyelids was observed (Shaffer et al. 1945). 

These data indicate that neat DEHP does not act as a dermal or ocular irritant in rabbits. 

No studies were located regarding the following health effects in humans or animals after dermal 

exposure to DEHP: 
DI(2-ETHYLHEXYL)PHTHALATE 93 

3. HEALTH EFFECTS 

3.2.3.3 Immunological and Lymphoreticular Effects 

3.2.3.4 Neurological Effects 

3.2.3.5 Reproductive Effects 

3.2.3.6 Developmental Effects 

3.2.3.7 Cancer 

3.3 GENOTOXICITY 

No studies were located regarding genotoxic effects in humans after inhalation, oral, or dermal exposure 

to DEHP. As discussed below, DEHP has been extensively tested in a variety of short-term genotoxicity 

assays with predominantly negative or false-positive results. The weight of evidence from these assays, 

as well as the tumor initiating/promoting activity studies summarized in Section 3.5.2 (Mechanisms of 

Toxicity), indicate that DEHP does not induce lesions in nuclear DNA, is not mutagenic/genotoxic, and is 

not a tumor initiator, but rather that it is a rodent liver mitogen and tumor promoter, and is best 

characterized as an epigenetic toxicant. 

Mammalian in vivo genotoxicity studies are summarized in Table 3-3. Most of these assays found that 

DEHP is not genotoxic. Binding of DEHP to DNA in rat liver was reported by Albro et al. (1982a, 

1982b), but was not observed by other investigators (Gupta et al. 1985; Lutz 1986; Von Däniken et al. 

1984). 8-Hydroxydeoxyguanosine was detected in hepatic DNA from rats exposed to 1,200 mg/kg/day 

DEHP for 2 weeks (Takagi et al. 1990). Production of 8-hydroxydeoxyguanosine is a potential marker of 

genotoxicity; however, many chemicals that induced this lesion in total liver DNA have not been shown 

to be mutagenic, tumor initiators, or complete carcinogens (Trosko 2001; Trosko et al. 1998; Yakes and 

van Houten 1997). 

DEHP tested negative in mouse bone marrow micronucleus and rat liver DNA repair assays in vivo 

(Cattley et al. 1988; Putman et al. 1983). DNA synthesis increased in rats immediately following DEHP 

exposure due to increased cell division (Mitchell et al. 1985b; Smith-Oliver and Butterworth 1987), and 

rats that were exposed to 1,000 mg/kg/day DEHP for periods of 3 or 7 days alternating with 7-day 

withdrawal periods had increased liver cell division and numbers of tetraploid nuclei during the exposure 

periods (Ahmed et al. 1989). During the withdrawal periods in the latter study, the cell number declined 

and degenerated cells appeared to be those containing the tetraploid nuclei. Cells are more vulnerable to 

irreversible mutagenic alterations during a period of rapid cell division (Marx 1990), and it has been 

postulated that the carcinogenicity of DEHP might be a consequence of its induction of cell division in 
DI(2-ETHYLHEXYL)PHTHALATE 94 

3. HEALTH EFFECTS 

the liver in the presence of other mutagens (Smith-Oliver and Butterworth 1987). The evidence supports 

the interpretation that DEHP is mitogenic, not mutagenic, because mutagens, by inducing DNA lesions, 

would inhibit DNA synthesis and cell proliferation. 

Increased activity of liver poly (ADP-ribose) polymerase (pADPRP), an effect related to DNA repair, cell 

proliferation, and differentiation, was observed in rats treated orally with DEHP by gavage for 7 days or 

in the food for up to 97 weeks (Hayashi et al. 1998). Dominant lethal mutations were increased in mice 

that were exposed to DEHP by injection at dose levels that also resulted in decreased fertility, but not by 

oral administration (Autian 1982; Rushbrook et al. 1982; Singh et al. 1974). The results of these studies 

are not necessarily indicative of genotoxicity because DEHP has not been shown to induce DNA lesions 

in most studies and positive findings can be interpreted in different ways. For example, dominant lethal 

tests can be interpreted as indicating that the test chemical altered gene expression (i.e., by epigenetically 

shut off the marker gene) rather than by mutation. 
DI(2-ETHYLHEXYL)PHTHALATE 95 

3. HEALTH EFFECTS 

Table 3-3. Genotoxicity of DEHP In Vivo 

Species 

(tests system) End point Results Reference 

Mammalian cells: 

Human DNA damage + Anderson et al. 1999 

leucocytes 

Human Chromosomal aberrations – Thiess and Fleig 1978 

leucocytes 

Hamster embryo Chromosomal aberrations + Tomita et al. 1982b 

cells 

Hamster embryo Cell transformation + Tomita et al. 1982b 

cells 

Hamster embryo 8AG/6TG-resistant mutation + (?) Tomita et al. 1982b 

cells 

Rat bone Micronuclei – Putman et al. 1983 

marrow 

Rat bone Mitotic index – Putman et al. 1983 

marrow 

Mouse Dominant lethal test – Rushbrook et al. 1982 

Mouse Dominant lethal test + Autian 1982 

Mouse Dominant lethal test + Singh et al. 1974 

Mouse bone Micronuclei – Astill et al. 1986 

marrow 

Mouse bone Micronuclei – Douglas et al. 1986 

marrow 

Mouse bone Micronuclei – Putman et al. 1983 

marrow 

Rat liver DNA binding + Albro et al. 1982a 

Rat liver DNA binding – Gupta et al. 1985 

Rat liver DNA binding – Lutz 1986 

Rat liver DNA binding – Von Däniken et al. 1984 

Rat liver DNA repair – Butterworth et al. 1984 

Rat liver DNA repair – Cattley et al. 1988 

Rat liver DNA repair – Kornbrust et al. 1984 

Rat liver DNA repair + Hayashi et al. 1998 
DI(2-ETHYLHEXYL)PHTHALATE 96 

3. HEALTH EFFECTS 

Table 3-3. Genotoxicity of DEHP In Vivo (continued) 

Species (tests End point Results Reference 

system) 

Mouse liver DNA repair – Smith-Oliver and Butterworth 

1987 

Rat liver Strand breaks – Butterworth et al. 1984 

Rat liver Strand breaks – Elliott and Elcombe 1985 

Rat liver Strand breaks – Tamura et al. 1991 

Rat liver DNA base modification – Cattley and Glover 1993 

Rat liver DNA base modification + Takagi et al. 1990 

Rat liver Tetraploid nuclei + Ahmed et al. 1989 

Rat kidney Tumor promotion + Kurokawa et al. 1982 

Host-meditated 

assay: 

S. typhimurium Gene mutation – Kozumbo et al. 1982
 

(TA100)
 

Rat hostmeditated
 

Eukaryotic 

organisms: 

Drosophila Sex linked recessive lethal – Yoon et al. 1985
 

(injection)
 

– = negative result; + = positive result; ATPase = adenosine triphosphatase; GGTase = gamma glutamyl 

transferase 
DI(2-ETHYLHEXYL)PHTHALATE 97 

3. HEALTH EFFECTS 

Spot tests were conducted in which mouse embryos heterozygous for a number of recessive coat color 

mutations were exposed in utero with the direct monofunctional alkylating mutagen ethylnitrosourea 

(ENU), either alone or followed by intraperitoneal injection of the pregnant dam with DEHP (Fahrig and 

Steinkamp-Zucht 1996). DEHP, in combination with ENU, resulted in an increase in the number of spots 

indicative of reciprocal recombination compared to ENU treatment alone. Conversely, DEHP alone 

resulted in a reduction in the number of spots that arose from ENU-induced gene mutations. These 

findings are not necessarily indicative of interference with DNA repair processes because DEHP could 

have induced altered spots epigenetically rather than by mutagenic means. As discussed by Trosko 

(1997, 2001), mutation assays are often misinterpreted to give false positives results for epigenetic 

(nonmutagenic) agents. 

DEHP has been extensively tested in short-term in vitro genotoxicity assays, but does not appear to be 

mutagenic in most microbial and mammalian assay systems, as evident in the study results summarized in 

Table 3-4. The International Program on Chemical Safety (IPCS) investigated the in vitro genotoxicity of 

DEHP in a comprehensive study (IPCS 1985). They found no evidence for genotoxicity in standard 

bacterial tests. Likewise, there was no evidence for genotoxicity expressed as strand breaks, sister 

chromatid exchanges, chromosomal aberrations, micronuclei, or polyploidy in mammalian systems in 

vitro. Potential for mutagenicity in mammalian systems in vitro was suggested in only 1/10 assays, 

2/4 for DNA repair, 4/5 for cell transformation, 2/2 for aneuploidy, and 1/2 for metabolic cooperation. 

Genotoxicity tests using fungi yielded positive results in 1/7 assays for mutations, 3/7 (gene conversion), 

1/6 (crossing-over), and 2/4 (aneuploidy). The few positive test results from the IPCS (1985) study and 

the studies of other investigators (Table 3-4) were typically associated with limitations that included weak 

or nonreproducible positive responses, limited experimental conditions, positive responses only at 

restricted or cytotoxic dose levels, and lack of quantitative evaluation. Induction of cell transformation 

(Diwan et al. 1985; IPCS 1985; Mikalsen et al. 1990; Sanner and Rivedal 1985) and aneuploidy (IPCS 

1985; Stenchever et al. 1976) provided the clearest indications of genotoxic potential, but false positive 

interpretations are not precluded. 
DI(2-ETHYLHEXYL)PHTHALATE 98 

3. HEALTH EFFECTS 

Table 3-4. Genotoxicity of DEHP In Vitro 

Results 

With Without 

Species (test system) End point activation activation Reference 

Prokaryotic organisms: 

Salmonella Gene mutation – – Astill et al. 1986 

typhimurium 

S. typhimurium	 Gene mutation – – Barber et al.
 

1987
 

S. typhimurium Gene mutation – –	 Kirby et al. 1983 

S. typhimurium Gene mutation – + Kozumbo et al. 

(TA100) 1982 

S. typhimurium (TA98) Gene mutation – –	 Sato et al. 1994 

S. typhimurium Gene mutation – – Schmezer et al. 

(TA102) 1988 

S. typhimurium Gene mutation – – Seed 1982
 

(TA100)
 

S. typhimurium	 Gene mutation – – Tennant et al. 

1987 

S. typhimurium Gene mutation + Tomita et al.
 

(TA100) 1982b
 

S. typhimurium (TA98, Gene mutation – – Yoshikawa et al. 

TA100) 1983 

Escherichia coli PQ37 Gene mutation – –	 Sato et al. 1994 

E. coli WP2UVRA+ Gene mutation – – Yoshikawa et al. 

1983 

E. coli WP2UVRA Gene mutation – – Yoshikawa et al. 

1983 

Bacillus subtilis (rec DNA damage – – Tomita et al.
 

assay) 1982b
 

S. typhimurium	 Azaguanine – – Seed 1982
 

resistance
DI(2-ETHYLHEXYL)PHTHALATE 99 

3. HEALTH EFFECTS 

Table 3-4. Genotoxicity of DEHP In Vitro (continued) 

Results 

With Without 

Species (test system) End point activation activation Reference 

Eukaryotic organisms: 

Saccharomyces 

cerevisae Gene mutation – – Parry et al. 1985
 

(XV185-14C, D7, 

RM52, D6, D5, D6-1)
 

S. cerevisiae (JD1, D7- Gene conversion – – Parry et al. 1985 

144, D7) 

S. cerevisiae (D61M, Mitotic aneuploidy + + Parry et al. 1985 

D6) 

S. cerevisiae (D61M, Mitotic segregation – – Parry et al. 1985 

D6)
 

Schizosaccharomyces Gene mutation – – Parry et al. 1985
 

pombe (P1)
 

Aspergillus niger (P1) Mitotic segregation – NS Parry et al. 1985
 

Mammalian cells: 

Mouse lymphoma cells Mutagenicity – – Astill et al. 1986 

Mouse lymphoma cells Mutagenicity – – Kirby et al. 1983 

Mouse lymphoma cells Mutagenicity – – Tennant et al. 

1987 

Rat hepatocytes DNA damage – NA Schmezer et al. 

1988 

Hamster hepatocytes DNA damage – NA Schmezer et al. 

1988 

Human hepatocytes DNA repair – NA Butterworth et al. 

1984 

Mouse hepatocytes DNA repair – NA Smith-Oliver and 

Butterworth 1987 

Rat hepatocytes DNA repair – NA Astill et al. 1986 

Rat hepatocytes DNA repair – NA Butterworth 1984 

Rat hepatocytes DNA repair – NA Hodgson et al. 

1982 

Rat hepatocytes DNA repair – NA Kornbrust et al. 

1984 
DI(2-ETHYLHEXYL)PHTHALATE 100 

3. HEALTH EFFECTS 

Table 3-4. Genotoxicity of DEHP In Vitro (continued) 

Results 

With Without 

Species (test system) End point activation activation Reference 

Rat hepatocytes DNA repair – NA	 Probst and Hill 

1985 

V79 cells DNA repair – NA	 Kornbrust et al. 

1984 

CHO cells	 Sister chromatid – NA Abe and Sasaki 

exchange 1977 

CHO cells	 Sister chromatid – NA Phillips et al. 

exchange 1982 

CHO cells	 Sister chromatid + NA Tennant et al. 

exchange 1987 

Rat liver (RL4)	 Sister chromatid – NA Priston and Dean 

exchange 1985 

Human hepatocytes	 Chromosomal – NA Turner et al. 

aberrations 1974 

Human leucocytes	 Chromosomal – NA Stenchever et al. 

aberrations 1976 

CHO cells	 Chromosomal – NS Phillips et al. 

aberrations 1982 

CHO cells	 Sister chromatid – NA Tennant et al. 

exchange 1987 

Rat liver (RL4)	 Chromosomal – NA Priston and Dean 

aberrations 1985 

CH SV40-transformed Selective DNA – NA Schmezer et al. 

liver cells amplification 1988 

CHO cells Cell transformation + NS	 Sanner and 

Rivedal 1985 

SHE cells Cell transformation – NA	 Astill et al. 1986 

Mouse JB6 epidermal Cell transformation + NA Diwan et al. 1985 

cells 

SHE cells Cell transformation + NA	 Mikalsen et al. 

1990 

Mouse C3H/10T1/2 Cell transformation – NA Sanchez et al. 

fibroblasts 1987 
DI(2-ETHYLHEXYL)PHTHALATE 101 

3. HEALTH EFFECTS 

Table 3-4. Genotoxicity of DEHP In Vitro (continued) 

Results 

With Without 

Species (test system) End point activation activation Reference 

Chinese hamster 

fibroblasts 

Chinese hamster 

fibroblasts 

Rat hepatocytes 

Human fetal 

pulmonary cells 

Rat liver (RL4) 

Gap junction + 

intercellular 

communication

Gap junction – 

intercellular 

communication

DNA binding – 

Aneuploidy – 

Polyploidy – 

NS	 Malcolm and 

Mills 1989 

NS	 Kornbrust et al. 

1984 

NA	 Gupta et al. 1985 

NA	 Stenchever et al. 

1976 

NA	 Priston and Dean 

1985 

– = negative result; + = positive result; CHO = Chinese hamster ovary; NA = not applicable to mammalian cell 

cultures; NS = not specified; SHE = Syrian hamster embryo 
DI(2-ETHYLHEXYL)PHTHALATE 102 

3. HEALTH EFFECTS 

3.4 TOXICOKINETICS 

Human data indicate that gastrointestinal absorption of DEHP and its metabolites might amount to 

approximately 20–25% of an orally-administered dose. Trace amounts of DEHP might be absorbed 

through the skin. Parenteral routes of exposure are also a human concern since DEHP is found in plastic 

products that might be used in medical treatment devices or storage bags. No human data were available 

regarding the toxicokinetics of inhaled DEHP, although some degree of absorption from respiratory 

tissues would be expected. 

Animal data generally support the human findings. DEHP is hydrolyzed in the small intestines and 

absorbed as MEHP and 2-ethylhexanol. At high concentrations, a limited amount of unhydrolyzed DEHP 

might be absorbed. The degree of gastrointestinal absorption varies among animal species and is 

apparently greater in rodents than in monkeys. Animal studies indicate that DEHP might be absorbed 

through the skin in minute quantities. Absorption via the respiratory tract has also been indicated, 

although quantitative absorption studies have not been published. 

Limited human data from autopsies have indicated the presence of DEHP in adipose tissues and kidneys. 

Metabolic pathways for DEHP involve a number of reactions, as presented in Figure 3-4. Esteratic or 

hydrolytic cleavage of DEHP results in the formation of MEHP and 2-ethylhexanol. The esterases 

responsible for these hydrolytic steps are found in numerous body tissues, but highest levels occur in the 

pancreas (hydrolytic reactions occur more readily following oral exposure because of the high content of 

esteratic activity within the gastrointestinal tract). MEHP is further metabolized via numerous oxidative 

reactions, resulting in the formation of 30 or more metabolites, some of which can be conjugated with 

glucuronic acid for excretion. Oxidation of 2-ethylhexanol primarily yields 2-ethylhexanoic acid and 

several keto acid derivatives, which are excreted in the urine. 

In orally-exposed humans, approximately 65% of DEHP metabolites are excreted in the urine as 

glucuronide conjugates. The aglycone moiety of these conjugates as well as the nonconjugated DEHP 

metabolites excreted by humans are similar to those found in urine and feces of laboratory animals, 

although relative proportions might differ with species, dose, and time. No studies were located regarding 

fecal excretion of DEHP metabolites in humans. However, significant amounts of DEHP were noted in 

the feces of animals given DEHP by the oral route; it presumably represents unmetabolized 
Figure 3-4. DEHP Metabolitesa 

CH3CH2

COO C C (CH2)3 CH3 H2 H

COOH 

COO C C (CH2)3 CH3

R= DEHP H2

COOH CH2 COOH 

CH3 CH3 2-ethyl hexanol 

COOH CH2 

CH3 Phthalic acid 

H3C (CH2)3 C CH2OH H CH2

2-ethylhexanol 

COO C C (CH2)3 CH3 H2 H 

COOH 

MEHP 

CH2OH CH3 CH3 CH3 CH3 

R C 

H2 

(CH2)3 

CH2 C H 

CH3 

2-(2-hydroxyethyl)hexyl phthalate (VII) 

R C 

H2 

C H (CH2)3 CHOH 

CH3 

2(1-hydroxyethyl)hexyl phthalate (XVII) 

R C 

H2 

C H (CH2)3 CH2 

CH2OH 

2-ethyl-6-hydroxyhexyl phthalate (X) 

R C 

H2 

C H (CH2)2 CH2 

C H 

CH3 

OH 

2-ethyl-5-hydroxyhexyl phthalate (IX) 

R C 

H2 

C H 

C H 

CH2 

C H

OH 

2-ethyl-4-hydroxyhexyl 

COOH CH3 CH3 CH3 CH3 CH2 O CH2 CH2 CH2 

R C 

H2 

C H (CH2)3 CH3 R C H2 C H (CH2)3 CH3 R C H2 C H (CH2)3 COOH R C H2 C H (CH2)2 O CH3 R C H2 C H O C H

2-carboxymethylhexyl phthalate (IV) 2(1-oxyethyl)hexyl phthalate (XXVI) 2-ethyl-5-carboxypentyl phthalate (V) 2-ethyl-5-oxyhexyl phthalate (VI) 2-ethyl-4-oxyhexyl pht

CH3 CH3 COOH 

CH2 CH2 

R C C (CH2)3 CH3 H2 H R C C C COOH R C C (CH2)2 COOH H2 H H2 H2 H 2-carboxyhexyl phthalate (II) 

2-ethyl-3-carboxypropyl phthalate (I) 2-ethyl-4-carboxybutyl phthalate (III) 

metabolites illustrated in the metabolic pathway outlined above are oxidized at only one carbon site. Additional metabolites which are oxiare not shown in this figure. Adapted from Albro 1986 
DI(2-ETHYLHEXYL)PHTHALATE 104 

3. HEALTH EFFECTS 

DEHP. MEHP and other metabolites were frequently found in feces of DEHP-exposed animals, in some 

cases associated with biliary excretion products. 

3.4.1 Absorption 

3.4.1.1 Inhalation Exposure 

No quantitative data regarding absorption after inhalation exposures of humans or animals to DEHP were 

located. However, absorption can occur through the lungs of humans as evidenced by identification of 

DEHP in the urine or lung tissue of infants exposed to DEHP during respiration therapy (Roth et al. 

1988). 

In rats, inhalation of an aerosol containing 1,000 mg/m3

 of DEHP resulted in peroxisome proliferation 

(Merkle et al. 1988), indicating that absorption had occurred. However, no quantitative details were 

provided which could be used to estimate absorption in this study, or rule out inadvertent co-exposure by 

the oral route. 

3.4.1.2 Oral Exposure 

Measurement of DEHP excretory metabolites indicate that about 11–15% of a 30 mg oral dose is excreted 

in human urine and, therefore, was absorbed (Schmid and Schlatter 1985). However, the total absorption 

is probably higher (perhaps 20–25%), since animal studies indicate that biliary excretion accounts for 

15–20% of the absorbed dose (see Section 3.4.4.3). 

Analysis of animal data suggests that rodents absorb DEHP better than other animal species (Astill 1989; 

Rhodes et al. 1986). DEHP is absorbed primarily as MEHP and 2-ethylhexanol, along with small 

amounts of unhydrolyzed DEHP. At low concentrations, most of DEHP is hydrolyzed in the small 

intestines and absorbed as the MEHP and 2-ethylhexanol (Albro 1986; Albro et al. 1982b). At high 

concentrations, some unhydrolyzed DEHP is also absorbed. Based on urinary excretion of metabolites, 

rats can absorb at least 55% of a 2,000 mg/kg oral dose of DEHP (Rhodes et al. 1986). Actual absorption 

is probably greater than this since biliary excretion of previously absorbed and metabolized DEHP might 

account for a considerable portion of the fecal elimination. Larger percentages of smaller doses will be 

absorbed, since intestinal transport of MEHP and DEHP can be saturated at high doses (Short et al. 1987). 
DI(2-ETHYLHEXYL)PHTHALATE 105 

3. HEALTH EFFECTS 

A similar saturation phenomenon is seen in monkeys, although monkeys appear to absorb a smaller 

percentage of each oral dose than do rats (Astill 1989; Rhodes et al. 1986). 

3.4.1.3 Dermal Exposure 

DEHP does not appear to be readily absorbed through the human skin. Wester et al. (1998) estimated that 

dermal absorption amounts to approximately 1.8% of a 24-hour applied dose of DEHP solubilized in 

ethanol. They noted that 1.1% of the radioactivity from a 24-hour dermal application of 14C-labeled 

DEHP to the forearm of volunteers was excreted in the urine within 7 days postapplication. They used 

this finding and the observation that approximately 60.8% of an intravenously-injected dose of DEHP 

was excreted in the urine of Rhesus monkeys over the same posttreatment time period as the basis for 

their estimate. No other reports were located regarding dermal absorption of DEHP in humans. 

DEHP has been shown to be poorly absorbed through the skin of laboratory animals. Dermal absorption 

was reported to be approximately 5% in rats exposed for 7 days to an initial dose of 30 mg DEHP/kg 

(dissolved in ethanol); about 95% of the original radioactivity was recovered from the application site and 

5% in the urine and feces (Melnick et al. 1987). In more recent investigations concerning the migration 

of DEHP from PVC film and subsequent dermal absorption, Deisinger et al. (1998) subjected rats to 

24-hour dermal (rats were sacrificed after the 24-hour application period) applications of radiolabeled 

DEHP (approximate dose 1,739 mg DEHP/kg) contained in occluded PVC film patches, and estimated 

that approximately 0.0045% of the applied dose was dermally absorbed during the exposure period after 

accounting for radioactivity recovered in the PVC film, urine, feces, cage washes, and carcass. The mean 

calculated dermal absorption rate was 0.242 μg/cm2

/hour. Similarly exposed rats whose PVC was 

removed after the 24-hour exposure and were followed for 6 days postexposure exhibited a similar 

calculated absorption rate (0.239 μg/cm2

/hour), but had a slightly higher percent total absorption (0.01%). 

In vitro studies of DEHP absorption through human, rat, and porcine epidermal segments confirm the 

poor dermal absorption of DEHP (Scott et al. 1987; Wester et al. 1998). The steady state dermal 

absorption rate was only 1.06 μg/cm2

/hour in human skin segments and 2.24 μg/cm2/hour in rats; 

approximately 3.9% of an applied dose of DEHP penetrated perfused porcine skin flaps. In vivo 

absorption of DEHP from polyvinyl chloride film by shaved rats and in vitro data on rat and human 

dermal absorption rates were used to estimate an absorption rate from PVC film for humans of 

0.016 μg/cm2

/hour (Deisinger et al. 1991). 
DI(2-ETHYLHEXYL)PHTHALATE 106 

3. HEALTH EFFECTS 

3.4.2 Distribution 

Few studies were located regarding the distribution of DEHP in humans after exposure to DEHP. DEHP 

is lipophilic and tends to accumulate in adipose tissue. DEHP was present in human adipose tissues from 

accident victims at a concentration of 0.3–1.0 ppm (Mes et al. 1974) and in 48% of the adipose tissue 

specimens from cadavers autopsied in 1982 as part of the Human Adipose Tissue Survey from the 

National Human Monitoring Program (EPA 1989b). In addition, DEHP has been isolated in the kidneys 

of autopsied patients (Overturf et al. 1979). The presence of DEHP in tissues might be an artifact since 

DEHP can easily contaminate biological samples during laboratory processing operations. This can, at 

times, make DEHP appear to be more ubiquitous in tissues than it actually is. 

As detailed in Section 3.2.2.6 Developmental Effects, DEHP and/or metabolites administered during 

gestation can induce increased incidences of resorptions, fetal deaths and malformations in rats and mice 

(Hellwig et al. 1997; Ritter et al. 1987; Shiota and Mima 1985; Tomita et al. 1982a; Tyl et al. 1988; Yagi 

et al. 1980). While this might be interpreted as evidence of transplacental transfer of these substances, the 

possibility that the effects result from toxicity to the dams cannot be ruled out. 

3.4.2.1 Inhalation Exposure 

No studies were located regarding the distribution of DEHP in the tissues of humans or animals after 

inhalation exposure to DEHP. 

3.4.2.2 Oral Exposure 

No studies were located regarding the distribution of DEHP in humans after oral exposure to DEHP. 

However, since environmental exposures to DEHP occur primarily through foods, the data discussed in 

Section 3.4.2 concerning the presence of DEHP in human adipose deposits is a reflection of distribution 

following oral exposures, assuming that contamination was avoided. 

The liver, kidney, testes, and blood were identified as sites of DEHP metabolism or utilization after 

14-day oral exposure of rats to a 2,000 mg/kg/day dose containing 14C-DEHP labeled in the phenyl ring 

(Rhodes et al. 1986). At the end of the 14 days, the liver contained 205 μg/g, the kidney 105 μg/g, the 

blood 60 μg/g, and the testes 40 μg/g of DEHP equivalent. A very similar distribution pattern was seen in 

monkeys under the same exposure conditions (2,000 mg/kg/day), although the actual tissue 
DI(2-ETHYLHEXYL)PHTHALATE 107 

3. HEALTH EFFECTS 

concentrations were 10–15% of the amounts in the rat, reflecting the lower coefficient of absorption for 

DEHP in the monkey and possible differences in other aspects of pharmacokinetics (Rhodes et al. 1986). 

The tissue distribution in the monkeys, 7 days after administration of a single dose of 2,000 mg/kg DEHP, 

was similar to that observed after continuous exposures, except that the concentration of the label in the 

testes (3.75 μg/g) was greater than that in the liver and kidney (2.5 μg/g). The concentration of the label 

in the blood was <50% of that in the liver and kidney. 

The tissue distribution of a single radiolabeled dose of DEHP was investigated in rats, dogs, and 

miniature pigs given 50 mg/kg/day DEHP in the diet for 21–28 days before receiving the radiolabeled 

dose (5 μCi/kg in 50 mg/kg) by gavage or gelatin capsule (Ikeda et al. 1980). Tissue samples were 

evaluated in each species at 4 hours, 24 hours, and 4 days after administration of the radiolabeled sample. 

In all three species, the liver contained a substantial portion of the tissue label at 4 and 24 hours (Ikeda et 

al. 1980). Label was cleared from the dog liver less rapidly than from the liver of rats and pigs. Dogs 

also contained a relatively high percentage of label in muscle tissue, approximately twice that found in 

pigs. (The presence of label was not determined in rat muscle). In dogs, there was more of the label in the 

muscle at 4, 24, and 96 hours than in the fat tissue. In pigs, there was much more label in the fat than in 

the muscle. In all cases the amount of label in the tissues examined was <2% of the administered dose, 

except for a value of 2.24% in the rat liver. 

DEHP demonstrated a lower affinity for brain tissue than liver in mice following oral administration of 

0.7 mg DEHP/kg to 3-, 10-, and 20-day-old animals (Eriksson and Darnerud 1985). The retention of the 

label in the brain was minimal, but was greater in 3-day-old mice than in older mice. In 3-day-old mice, 

1.6% of the label was identified in the brain 24 hours after administration as opposed to approximately 

0.25% in 10-day-old mice and values below detection for the 20-day-old mice. This might indicate 

increased permeability of the blood-brain barrier to DEHP in neonates or developing organisms and help 

to explain the finding that there is an increase in neuronal peroxisomes in newborn mice exposed to 

DEHP (Dabholkar 1988). Alternatively, the higher level of DEHP in the brain might be a reflection of a 

slower rate of compound elimination in neonates. 

3.4.2.3 Dermal Exposure 

No studies were located regarding the distribution of DEHP in human tissues after dermal exposures to 

DEHP. In rats exposed to 30 mg/kg DEHP applied to the skin for 7 days, the liver contained 0.063% of 
DI(2-ETHYLHEXYL)PHTHALATE 108 

3. HEALTH EFFECTS 

the applied dose, the kidney 0.012%, the muscles 1.162%, and the fat 0.066% (Elsisi et al. 1989; Melnick 

et al. 1987). The small intestines were found to contain 0.161% of the dose, giving evidence for either 

intestinal uptake of DEHP from non-oral routes of exposure or the excretion of metabolites in the bile. 

3.4.2.4 Other Routes of Exposure 

Humans can be exposed to DEHP through medical practices such as dialysis, respiration therapy, blood 

transfusions, or total parenteral nutrition treatment (TPN) where the source of DEHP is the plastics 

utilized in medical treatment devices or storage bags. Thus, data on tissue distribution following alternate 

routes of exposure are important in evaluating the potential for DEHP to have an adverse effect on human 

health. Exposure can occur through the intravenous route as well as the oral, dermal, and respiratory 

routes. In addition, limited formation of MEHP occurs in storage bags, so that exposure includes DEHP 

plus MEHP (FDA 2001h). 

DEHP exposures through the parenteral route bypass the intestinal esterases so there will tend to be a 

greater proportion of the dose entering systemic circulation as DEHP rather than MEHP. This is evident 

in data from human studies following exchange transfusions and hemodialysis. Initially there is more 

DEHP than MEHP in the blood (Pollack et al. 1985a; Sjoberg et al. 1985d). However, DEHP levels 

decline rapidly with a half-life of 10 hours (Sjoberg et al. 1985d), and the MEHP levels increase until the 

time-averaged concentrations are roughly equal (Pollack et al. 1985a). It was not determined whether the 

differences in disappearance were due to volume of distribution or metabolism differences. Between 

exposures, both DEHP and MEHP disappear from the blood, and phthalic acid concentrations increase. 

Blood phthalic acid concentrations correlate better with the duration of dialysis than either DEHP or 

MEHP levels (Pollack et al. 1985a). Similar results were seen in animal studies. After arterial injection, 

DEHP was rapidly cleared from the blood of rats (Pollack et al. 1985b). 

The distribution of parenterally administered DEHP to soft tissues was studied in marmoset monkeys. 

Seven days after intravenous and intraperitoneal administration of 100 and 1,000 mg/kg doses in corn oil 

emulsion, respectively, the lungs were the major tissue retaining DEHP label (Rhodes et al. 1986). 

Following intravenous administration, the concentration of DEHP in the lungs was 4,257 μg/g; that in the 

liver, approximately 17 μg/g; the testes, 5 μg/g; and the kidney, 4 μg/g. The authors hypothesized that 

the DEHP in the lungs reflects entrapment of insoluble compound from the intravenous emulsion by 

alveolar capillaries. After intraperitoneal administration, the concentrations of label in the lung, liver, 

kidney, and testes were approximately 265, 80, 60, and 15 μg/g, respectively. Seven days after 
DI(2-ETHYLHEXYL)PHTHALATE 109 

3. HEALTH EFFECTS 

intraperitoneal administration, 85% of the dose remained in the peritoneal cavity. Although the results of 

the intravenous and intraperitoneal distribution experiments appear to indicate that DEHP can deposit in 

the lungs following parenteral exposures, there is insufficient basis to conclude this because only total 

radioactivity was measured, and DEHP might have been sequestered in the capillaries of the lungs due to 

a mechanical artifact of the solubilization rather than by being absorbed by the pulmonary parenchyma. 

Accumulation of DEHP in the lungs does not occur with oral or dermal exposures and is not expected to 

occur after inhalation exposure, although none of the studies conducted using this route have evaluated 

concentrations of DEHP in the tissues. 

3.4.3 Metabolism 

Based on data from both human and animal studies, the metabolism of DEHP involves a complex series 

of reactions with the production of 30 or more metabolites (Albro 1986; Albro et al. 1982a, 1982b, 1983, 

1987; Astill 1989; Schmid and Schlatter 1985). The first step in metabolism is the hydrolytic cleavage of 

DEHP resulting in the formation of MEHP and 2-ethylhexanol. This step occurs rapidly in the intestine, 

as evidenced by the disappearance of DEHP from rat gut homogenate (half-life 12.6 minutes), and the 

formation of approximately equal proportions of MEHP and 2-ethylhexanol (Barber et al. 1994). The 

formation of MEHP from the parent ester is acheived by lipases that have been identified in the pancreas 

and intestinal mucosa, as well as the liver, kidneys, lungs, skin, and plasma. The pancreatic tissue is the 

richest source of these esterases by several orders of magnitude (Albro 1986). The adipose tissue has the 

lowest concentration of esterase. Because of differences in tissue enzyme activities, DEHP exposure by 

the oral route results in a larger portion of the dose being converted to MEHP and 2-ethylhexanol than 

occurs with inhalation or dermal exposures. Hydrolysis of the second ester bond converts a small portion 

of the MEHP to phthalic acid but most of the MEHP undergoes ω- (omega) and ω-1-oxidation of the 

aliphatic side chain. The ω-oxidation step can be followed by α- or β-oxidation reducing the number of 

carbons in the 2-ethylhexyl side chain. A proposed metabolic pathway for oxidation of MEHP is 

presented in Figure 3-4. Each of the metabolites depicted in Figure 3-4 has been given a Roman numeral 

designation which is often used in place of its chemical name (Albro et al. 1983). After the primary 

metabolic conversions described above, the oxidized derivatives of MEHP can be conjugated with 

glucuronic acid for excretion (Albro 1986; Astill 1989). There is no evidence to suggest that the aromatic 

phthalic acid moiety is degraded during the metabolism of DEHP. 
DI(2-ETHYLHEXYL)PHTHALATE 110 

3. HEALTH EFFECTS 

2-Ethylhexanol is also metabolized through oxidative pathways. The primary urinary products from 

2-ethylhexanol are 2-ethylhexanoic acid and several keto acid derivatives which appear to be products of 

β-oxidation (Albro and Corbett 1978). 

No data were located regarding the metabolites produced in humans or animals after either inhalation or 

dermal exposures to DEHP. Metabolism following these routes of exposure is expected to be similar to 

that after oral exposures, since there are lipases present in the alveolar cells of the lungs and the 

epidermis. However, the activities of these lipases are about 20% of that for the pancreatic esterase 

secreted into the intestines (Albro et al. 1987), so it is possible that a larger portion of an absorbed dose 

from respiratory or dermal exposures to DEHP will initially be presented to the tissues as unhydrolyzed 

DEHP rather than MEHP. 

There have been studies of the metabolism of DEHP in humans after oral exposures as reflected by its 

urinary excretory products. In two volunteers exposed to 30 mg DEHP, metabolites I, II, III, IV, V, VI, 

VII, and VIII were identified in the urine by mass spectroscopy (Schmid and Schlatter 1985). MEHP 

accounted for 6–12% of the measured metabolites. Metabolite VI was approximately 20% of the excreted 

material, Metabolite IX approximately 30% and Metabolite V approximately 30%. The remaining 

metabolites were each less than 5% of the excreted material. Based on a comparison of the metabolites in 

the hydrolyzed urine as compared to the unhydrolyzed urine, approximately 65% of DEHP metabolites 

are excreted as glucuronide conjugates in humans. Each of these major metabolites is the product of 

oxidation of a different carbon in the 2-ethylhexyl substituent. 

The same DEHP metabolites are found in the urine and feces of monkeys, rats, mice, guinea pigs, and 

hamsters, although there are some differences in the proportion of the metabolites excreted as conjugates 

of glucuronic acid (Albro et al. 1982a; Astill 1989). Monkeys are similar to humans and excrete 60% of 

the urinary metabolites as conjugates (Albro et al. 1982a). Guinea pigs, hamsters, and mice appear to 

excrete a smaller and more variable portion of DEHP metabolites as conjugates, while none of the 

metabolites in rat urine are found as conjugates (Albro et al. 1982a). Based on examination of the urinary 

metabolites after hydrolysis with aryl sulfatase, acylase I, and carboxypeptidase A, there is no evidence 

that conjugation with glutathione, sulfates, or amino acids occurs in rats, mice, guinea pigs, or hamsters 

(Albro et al. 1982a). The quantities of free DEHP excreted are minimal in all species that have been 

examined. The amount of MEHP varies from species to species. A large fraction (72%) of MEHP was 

excreted in the urine of guinea pigs (Albro et al. 1982a). Monkeys and mice excreted 17–18% MEHP 

(Albro et al. 1982a; Rhodes et al. 1986); hamsters, 4.5% MEHP; and rats only traces of this compound 
DI(2-ETHYLHEXYL)PHTHALATE 111 

3. HEALTH EFFECTS 

(Albro 1986; Albro et al. 1982a; Astill 1989). Mice and hamsters excrete more phthalic acid than rats and 

guinea pigs (Albro 1986; Albro et al. 1982a). 

Metabolites I, IV, V, VI, VIII, and IX were the metabolites present in the highest concentrations in the 

animal species studied (Albro et al. 1982a, 1982b, 1987; Astill 1989; Rhodes et al. 1986; Short et al. 

1987). The relative proportions of metabolites differ with species, dose, and time (Lhuguenot et al. 1985, 

1988). The metabolites with multiple side chain oxidation sites are more water soluble than those with a 

single hydroxyl, carbonyl, or carboxyl functional group. The multiple oxidation site metabolites (XII 

through XXV) have, accordingly, been more difficult to isolate and quantify (Albro et al. 1983). 

3.4.4 Elimination and Excretion 

3.4.4.1 Inhalation Exposure 

No data were located concerning excretion in humans or animals after inhalation exposures to DEHP. 

3.4.4.2 Oral Exposure 

Humans exposed to a single dose of 30 mg DEHP excreted 11 to 15% of the dose as metabolites in the 

urine over 48 hours (Schmid and Schlatter 1985). When a smaller dose (10 mg) was given for each of 

4 sequential days, 15–25% of the dose was recovered in the urine. No measurements of fecal elimination 

of DEHP or its metabolites were made. 

The data from animal studies demonstrate that DEHP and it metabolites are excreted in both the urine and 

the feces. Rats exposed to 50–300 mg/kg DEHP excrete 32–70% of the dose in the urine as metabolites 

(Astill 1989; Ikeda et al. 1980; Short et al. 1987). An additional 20–25% of the absorbed dose was 

excreted with the bile in the fecal matter. The remainder of the fecal excretion was unabsorbed DEHP 

and MEHP. In monkeys, approximately 30% of a 100 mg/kg dose and 4% of a 2,000 mg/kg dose were 

excreted in the urine (Astill 1989; Rhodes et al. 1986; Short et al. 1987; Sjoberg et al. 1985b). The 

remainder was in the feces. A portion of the fecal metabolites was contributed by the bile. The biliary 

excretory products represent approximately 15% of the absorbed DEHP. In rats and mice administered 

radiolabeled DEHP, 85–90% of the label was excreted in the first 24 hours (Astill 1989; Ikeda et al. 

1980). In monkeys, a smaller portion of the label (50–80%) was excreted in the first 24 hours (Astill 

1989). Twenty-four hour excretion of label in urine and feces was also lower in dogs (67%) and 
DI(2-ETHYLHEXYL)PHTHALATE 112 

3. HEALTH EFFECTS 

miniature pigs (37%) than in rats and mice (Ikeda et al. 1980). Miniature pigs were unique in that very 

little label (26%) was found in the feces even with 4 day collected samples. This compares with values of 

53% in rats and 75% in dogs 4 days after administration of a 50 mg/kg dose containing 5 μCi/kg of 

radiolabel. It appears that biliary excretion of metabolites is very limited in miniature pigs. 

Because of their lipophilic nature, both DEHP and MEHP can accumulate in breast milk and subsequently 

be transferred to suckling offspring. For example, Dostal et al. (1987b) detected both DEHP (216 μg/mL) 

and MEHP (25 μg/mL) in the milk collected from lactating Sprague-Dawley rats 6 hours after the last of 

three daily gavage doses of 2,000 mg DEHP/kg (Dostal et al. 1987b). At this time, no DEHP could be 

detected in dams’ plasma, but substantial amounts of MEHP were detected. Pups’ plasma had no 

detectable DEHP or MEHP. Cimini et al. (1994) and Stefanini et al. (1995) also presented evidence of 

transfer of DEHP and/or metabolites to offspring via breast milk. In all of these studies, there was 

increased peroxisomal enzyme activities in pups’ livers. 

3.4.4.3 Dermal Exposure 

A mean of 1.1% of the radioactivity from 24-hour dermal application of radiolabeled DEHP was 

recovered in the urine of six volunteers 7 days postapplication sampling (Wester et al. 1998). 

DEHP derivatives were excreted in both the urine and feces following dermal exposures of rats to 

30 mg/kg for 7 days (Elsisi et al. 1989). Only 5% of the dose was excreted; 3% was in the urine and 2% 

in the feces. After 7 days, 95% of the dose was recovered from the skin surface. The finding of 

approximately 40% of the excreted label in the fecal matter is a reflection of the importance of the biliary 

excretion route. 

3.4.4.4 Other Routes of Exposure 

Twenty-four hours after a single intravenous injection of 14C-DEHP to rats, the radioactivity was mainly 

recovered in the urine and feces, suggesting that the major excretory pathways in rats are the urine and 

bile (Schulz and Rubin 1973). Excretion was dose-dependent as shown by the fact that 50–60% of the 

injected radioactivity from a low dose was recovered in urine and feces, whereas less than 50% was 

recovered when a high dose was injected (Schulz and Rubin 1973). In Rhesus monkeys, 60.8% of the 

radioactivity in an intravenously injected dose of radiolabeled DEHP was excreted in the urine during 

7 days postinjection, more than half of which was eliminated in the first day (Wester et al. 1998). 
DI(2-ETHYLHEXYL)PHTHALATE 113 

3. HEALTH EFFECTS 

Medical exposure to DEHP routinely occurs during intravenous infusion of blood and blood products 

(e.g., fluids and medication). Rapid elimination of DEHP that reaches the blood during transfusions and 

hemodialysis has been demonstrated in several studies (Barry et al. 1989; Lewis et al. 1978; Rubin and 

Schiffer et al. 1975; Sjorberg et al. 1985). For example, transfusion of platelets that were stored in vinyl 

plastic packs resulted in blood levels of DEHP (peak plasma concentrations ranging from 0.34 to 

0.83 mg/dL) that fell monoexponentially with a mean rate of 2.83% per minute and a half-life of 

28 minutes (Rubin and Schiffer 1975). Similarly, measurements on patients who had undergone 

>50 hemodialysis treatments indicated that most of the DEHP present in the serum at the completion of a 

dialysis session is likely to be gone in 5–7 hours (Lewis et al. 1978). 

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 et al. 

1987; Andersen and Krishnan 1994). These models are biologically and mechanistically based and can 

be used to extrapolate the pharmacokinetic behavior of chemical substances from high to low dose, from 

route to route, between species, and between subpopulations within a species. The biological basis of 

PBPK models results in more meaningful extrapolations than those generated with the more conventional 

use of uncertainty factors. 

The PBPK model for a chemical substance is developed in four interconnected steps: (1) model 

representation, (2) model parametrization, (3) model simulation, and (4) model validation (Krishnan and 

Andersen 1994). In the early 1990s, validated PBPK models were developed for a number of 

toxicologically important chemical substances, both volatile and nonvolatile (Krishnan and Andersen 
DI(2-ETHYLHEXYL)PHTHALATE 114 

3. HEALTH EFFECTS 

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) is 

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 3-5 shows a conceptualized representation of a PBPK model. 
Skin 

Kidney 

Richly 

perfused 

tissues 

Slowly 

perfused 

tissues 

Fat 

Liver 

Lungs 

V 

E 

N 

O 

U 

S 

B 

L 

O 

O 

D 

GI 

Tract 

Vmax Km 

Urine 

Chemicals in air 

contacting skin 

Feces 

Inhaled chemical Exhaled chemical 

Ingestion 

A
 

R
 

T
 

E
 

R
 

I
 

A
 

L
 

B 

L 

O 

O 

D 

DI(2-ETHYLHEXYL)PHTHALATE 115 

3. HEALTH EFFECTS 

Figure 3-5. Conceptual Representation of a Physiologically
 

Based Pharmacokinetic (PBPK) Model for a 

Hypothetical Chemical Substance
 

Source: adapted from Krishnan et al. 1994 

Note: This is a conceptual representation of a physiologically based pharmacokinetic (PBPK) model for a hypothetical 

chemical substance. The chemical substance is shown to be absorbed via the skin, by inhalation, or by ingestion, 

metabolized in the liver, and excreted in the urine or by exhalation. 
 

DI(2-ETHYLHEXYL)PHTHALATE 116 

3. HEALTH EFFECTS 

Keys et al. (1999) describe a PBPK model of DEHP in rats that simulates the pharmacokinetics of both 

DEHP and its major metabolite, MEHP. The model is intended for use in simulating doses of MEHP to 

the testes resulting from oral exposures to DEHP. 

Description of the Model. The Keys et al. (1999) model simulates six tissue compartments: small 

intestine, blood, liver, testis, slowly perfused tissues, and poorly perfused tissues. Conversion of DEHP 

to MEHP in the small intestine is simulated with km and Vmax terms, whereas conversion in liver and blood 

are simulated with separate first order rate constants, kl

 and kb, respectively. Elimination of DEHP and 

MEHP is assumed to be entirely by metabolism of DEHP to MEHP, and MEHP to unspecified 

metabolites; the latter transformation is represented in the model by km and Vmax terms. 

Keys et al. (1999) explored four approaches to modeling the pharmacokinetics of DEHP and MEHP. In a 

flow-limited version of the model, transfers between blood and tissues are simulated as functions of blood 

flow, tissue concentrations of DEHP or MEHP, and tissue:blood partition coefficients, assuming 

instantaneous partitioning of the compounds between tissue and blood (Ramsey and Anderson 1984). In 

a diffusion-limited version of the model, the tissue transfers include a first order rate term (referred to as 

the permeation constant) that relates the intracellular-to-extracellular concentration gradient to the rates of 

transfer. This model required estimates of extracellular tissue volume (ECV) and intracellular volume 

(ICV); ECV is assumed to be equal to tissue blood volume and ICV is assumed to be equal to the 

difference between tissue blood volume and total tissue volume. This approach would be expected to 

underestimate the true ECV of most tissues, which is approximately 45% of tissue mass (Edelman and 

Leibman 1959), and overestimate the true ICF; the significance of these potential differences are not 

discussed by Keys et al. (1999). In a pH-trapping version of the model, instantaneous partitioning (i.e., 

diffusion-limited) of only the nonionized species of MEHP between the intracellular and extracellular 

compartments of tissues is assumed, and the respective concentrations of the non-ionized and ionized 

species in each compartment are predicted by the pKa for the carboxylic acid moiety of MEHP (pKa is 

assumed to be 3.76, and intracellular pH is assumed to be approximately 7–7.05, depending on the tissue). 

A diffusion-limited version of the model is also described that includes a simulation of enterohepatic 

circulation of MEHP, in which the transfer of MEHP from the liver to the small intestine is represented 

with a first order rate constant (diffusion-limited) and a time delay constant for the subsequent 

reabsorption of MEHP from the small intestine. 

Tissue:blood partition coefficients for DEHP and nonionized MEHP were estimated from their 

n-octanol:water partition coefficients (Kow), using the approach reported by Poulin and Krishnan (1993). 
 

DI(2-ETHYLHEXYL)PHTHALATE 117 

3. HEALTH EFFECTS 

Tissue:blood partition coefficients for total MEHP (ionized and nonionized) were determined 

experimentally using a vial-equilibration method with correction for pH (Table 3-5). 

The models were developed to simulate the physiology (e.g., blood flows and body composition) of adult 

rats (Table 3-6). These parameter values were then extrapolated to juvenile rats to accommodate 

calibration and validation data in which juvenile rats were the test organisms. The extrapolation was 

achieved by scaling blood flows, metabolic constants, and adipose volumes to various functions of body 

weight (e.g., allometric scaling). 

Keys et al. (1999) note that certain model parameter values were estimated by applying a step-wise 

parameter optimization routine to data on blood or tissue levels following oral or intravenous exposure to 

DEHP and MEHP. The parameters estimated included the km and Vmax values for metabolism of DEHP 

and MEHP, and first order rate constants for the following parameters: metabolism of DEHP (e.g., liver), 

absorption of DEHP and MEHP in the small intestine, intracellular-to-extracellular transfer of nonionized 

MEHP, and biliary transfer of MEHP from liver to small intestine (these values are not provided in the 

profile because they are derived from optimization procedures and might not be directly useful for other 

models). Keys et al. (1999) do not explicitly cite or describe the data sets used to optimize model 

parameter values, or distinguish the data used in optimization from data used in validation exercises. 

Based on Table 5 of their report, it appears that at least some data from Pollack et al. (1985b) were used 

to optimize the model. 

Validation of the Model. Output from the various models were compared to observations of blood 

and testes concentrations reported from studies of oral gavage or intravenous exposures of rats to DEHP 

or MEHP (Oishi 1989a, 1990; Pollack et al. 1985b; Teirlynck and Belpaire 1985). Based on the 

comparisons of model outputs to observed time courses for blood MEHP concentrations from Pollack et 

al. (1985b), Keys et al. (1999) conclude that the pH-trapping model more closely represents the empirical 

data. However, it is difficult to interpret this finding if the same data were used in the model optimization 

(see Table 5 of Keys et al. 1999). The pH-trapping model simulated reasonably well the time courses for 

blood and testes concentrations of MEHP reported by Oishi (1989a, 1990) and Teirlynck and Belpaire 

(1985); however, comparisons to the output of other versions of the model are not presented. 
DI(2-ETHYLHEXYL)PHTHALATE 118 

3. HEALTH EFFECTS 

Table 3-5. Tissue:Blood Partition Coefficients Used in the
 

Keys et al. (1999) Model
 

Non-ionized 

DEHP MEHP Total MEHP Total MEHP 

Tissue (estimated) (estimated)a (experimental)b (estimated) 

Liver 21.8 21.6 1.70±32 3.0 

Fat 351.0 351.0 0.12±0.05 44.2 

Muscle 6.1 6.0 0.38±0.23 1.5 

Testes 6.5 6.5 1.02±0.07 1.6 

a

from Kow based on algorithms from Poulin and Krishnan (1993) b

vial equilibration study with pH correction 
DI(2-ETHYLHEXYL)PHTHALATE 119 

3. HEALTH EFFECTS 

Table 3-6. Physiological Parameter Values Used in the
 

Keys et al. (1999) Model
 

Description Value 

Body weight (kg) 0.89–0.38 

Cardiac output (L/hour-kg0.75) 15.33 

Blood flow as a fraction of cardiac output: 

Liver 0.183 

Fat 0.07 

Testes 0.013 

Slowly perfused tissues 0.157 

Rapidly perfused tissues 0.577 

Compartment volumes as fraction of body weight: 

Liver 0.0366 

Fat 0.034–0.08 

Testes 0.01 

Blood 0.07 

Small intestine 0.0139 

Slowly perfused tissues 0.73–0.78 

Rapidly perfused tissues 0.0534 

Compartment blood volume as fraction of tissue volumea

: 

Liver 0.21 

Fat 0.05 

Testes 0.03 

Slowly perfused tissues 0.04 

Rapidly perfused tissues 0.21 

a

This volume was assumed to represent tissue extracellular volume. 
 

 

 

 

DI(2-ETHYLHEXYL)PHTHALATE 120 

3. HEALTH EFFECTS 

Risk Assessment. The model provides an approach to estimating doses of MEHP to the testes of 

the rat following oral doses of DEHP and might be useful for internal dose-response assessment of rat 

bioassay data in which the toxicity end point of interest is testicular toxicity. However, such uses of the 

model, or other potential uses in risk assessment, have not been evaluated. 

Target Tissues. Output from the model, for which validation exercises were conducted, are 

predictions of blood and testes concentrations of MEHP. 

Species Extrapolation. The model is designed to predict the blood and testes concentrations of 

MEHP following oral doses of DEHP to rats. Extrapolation to other species would require modification 

of the model to account for different tissue masses, blood flows, and possibly other kinetic variables. 

Interroute Extrapolation. The model is designed to simulate the pharmacokinetics of DEHP and its 

metabolite, MEHP, when exposure is by the oral route. The pharmacokinetics of DEHP would be 

expected to be different for other routes of exposure; therefore, the output of the model cannot be 

extrapolated to other routes (e.g., dermal, inhalation) without modification of the model. Calibration and 

validation studies utilized gavage exposures for oral dosing, and therefore, the model might not be 

applicable to other oral exposure pathways (e.g., dietary, drinking water) without modification. 

3.5 MECHANISMS OF ACTION 

3.5.1 Pharmacokinetic Mechanisms 

DEHP is hydrolyzed to the monoester, MEHP, in the gastrointestinal tract by a pancreatic lipase. 

Hydrolytic activity varies considerably between species, the highest being in the mouse, followed by the 

rat, guinea pig, and hamster (Albro 1986; Lake et al. 1984a). In humans and primates, hydrolysis is 

considerably slower than in rats (Albro et al. 1982a; Rhodes et al. 1986). Of DEHP and MEHP, the 

former is considerably more lipophilic, and would be expected to be more readily absorbed in the 

gastrointestinal tract. However, using an everted gut-sac preparation from the rat small intestine, White et 

al. (1980) observed that all of the DEHP that entered the serosal buffer was in the monoester form. These 

findings suggested the presence of a hydrophilic barrier that limits the amount of DEHP that is absorbed 

in the intestines. This means that absorption is not only species-dependent but also dose-dependent, as 

shown in several in vivo studies (Albro et al. 1982a; Astill 1989; Rhodes et al. 1986). Furthermore, there 

also appears to be age-related differences in absorption as shown by Sjoberg et al. (1986a, 1986b) in rats 
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administered DEHP by gavage; absorption was greater in young animals. Sjoberg et al. (1985b) 

suggested that the relatively higher proportion of intestinal tissue in relation to body weight and the 

relatively higher blood flow through the gastrointestinal tract might be factors causing increased 

absorption in young animals. The mechanism of dermal absorption of DEHP is not known. 

Experiments have been conducted to simulate leaching of phthalates from blood bags by allowing human 

plasma to extract added phthalates from coated Celite (Albro and Corbett 1978). It was found that more 

than 80% of the DEHP was associated with lipoproteins, in the order LDL > VLDL > HDL > 

chilomicrons. The remaining DEHP was adsorbed weakly and nonspecifically to other proteins including 

albumin. MEHP was in equilibrium between free in solution and adsorbed to albumin, no MEHP was 

bound to lipoproteins. Rock et al. (1986) reported that in human plasma, the lipase that hydrolyzes DEHP 

copurified with the albumin, and once in the plasma, the MEHP bound to albumin. An earlier study by 

Jaeger and Rubin (1972) reported that in human blood stored in PVC bags, the bulk of DEHP was 

associated with lipoproteins, but a substantial amount was in a fraction likely to represent DEHP soluble 

in plasma water as well as bound to plasma proteins and cell membranes. 

Oral administration of DEHP to rats always results in higher levels of MEHP than DEHP in blood, but 

after intravenous dosing, DEHP predominates because first pass conversion to MEHP (i.e., the putative 

toxicant) is avoided. Intravenous exposure from medical procedures therefore might have a lower 

potential for toxicity compared to oral exposure, even though high level human exposure is not expected 

to occur from oral exposure, but rather from intravenous exposure. Studies by Sjoberg and coworkers 

showed that after gavage dosing, DEHP levels in blood were 40–50% of the MEHP levels and 35–70% 

after intravenous injection (Sjoberg et al. 1985a, 1986a, 1986b). In general, after oral dosing, there is 

only a weak correlation between the dose applied and the resulting blood level (Huber et al. 1996). This 

might be due to different dosing regimes, time of blood sampling after dosing, and failure to consider the 

capacity of erythrocytes to store DEHP (Huber et al. 1996). 

3.5.2 Mechanisms of Toxicity 

Mechanisms for the major effects of DEHP are discussed in this section. In animals, these effects include 

hepatotoxicity and alterations of the male reproductive system. In rodents, particularly rats and mice, 

hepatotoxicity leads to liver cancer if exposure is sustained; therefore, the mechanisms of liver effects and 

cancer are discussed together. An exhaustive discussion on mechanisms of action is beyond the scope of 

this document. Rather, the information below is intended only as a summary of the most important 
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issues. Although information is available on the underlying biological mechanisms of DEHP in animals, 

demonstration of these mechanisms does not necessarily mean that exposure will cause health effects in 

humans. 

Numerous comprehensive reviews on the role of peroxisome proliferation in liver cancer have been 

published in recent years and much of the information in summarized in this section has been gleaned 

from them (Cattley and Roberts 2000; Cattley et al. 1998; Doull et al. 1999; Green 1995; Huber et al. 

1996; Lake 1995; Melnick 2001; Rao and Reddy 1996; Tugwood et al. 1996). As discussed below and in 

Section 3.5.3, humans are nonresponsive to peroxisomal proliferation and are probably less susceptible to 

liver cancer than rodents due to the species specificity of the mechanism. DEHP is best classified as a 

nongenotoxic epigenetic chemical that can reversibly inhibit gap junctional intercellular communication 

and thereby alter homeostatic control of cell proliferation, cell differentiation, and programmed cell death 

(Trosko et al. 1998). Epigenetic characteristics of DEHP (as well as other epigenetic toxicants such as 

phenobarbital) include enhance mitogenesis, no-effect/threshold levels of action, and multiple and 

reversible toxic end points. 

Hepatotoxicity and Liver Cancer. A characteristic effect of exposure to DEHP in rodents, particularly 

rats and mice, is an increase in liver weight, associated with both morphological and biochemical 

changes. Liver enlargement is due to both hepatocyte hyperplasia and hypertrophy. Morphological 

examination reveals an increase in both the number and the size of peroxisomes in the liver. Peroxisomes 

are single membrane-limited cytoplasmic organelles found in the cells from animals, plants, fungi, and 

protozoa. Peroxisomes contain catalase, which destroys hydrogen peroxide, and a number of fatty-acid 

oxidizing enzymes, one of which, acyl CoA oxidase, generates hydrogen peroxide (Lazarow and deDuve 

1976). The main biochemical alterations consist of induction of both peroxisomal and microsomal fatty 

acid-oxidizing enzyme activities. The activity of the peroxisomal fatty acid β-oxidation cycle is normally 

determined either by measuring the overall activity (e.g., as cyanide-insensitive palmitoyl CoA oxidation) 

or by determining the first rate-limiting enzyme of the cycle, acyl-CoA oxidase. An important 

observation is that while the β-oxidation cycle enzymes can be greatly induced by peroxisome 

proliferators, other peroxisome enzymes, such as D-amino acid oxidase and catalase, are increased to a 

much lesser extent. As discussed below, this induction imbalance has been postulated to play a major 

role in phthalate-induced liver carcinogenicity. The increase of microsomal fatty acid-oxidizing enzyme 

activity, usually measured as lauric acid 12-hydroxylase, is due to induction of cytochrome P-450 

isozymes in the CYP4A subfamily. In general, there is good correlation between enzyme activity and 
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changes in peroxisome morphometry (Lake 1995), allowing palmitoyl-CoA oxidation to be used as a 

specific biochemical marker of peroxisome proliferation. 

Induction of peroxisome proliferation following treatment with DEHP is not due to the parent compound, 

but to DEHP metabolites. Studies with MEHP in vitro have demonstrated that the proximate peroxisome 

proliferators are mono(2-ethyl-5-oxohexyl) phthalate (metabolite VI) and mono(2-ethyl-5-hydroxyhexyl) 

phthalate, (metabolite IX) and that for 2-ethylhexanol, the proximate proliferator is 2-ethylhexanoic acid 

(Elcombe and Mitchell 1986; Mitchell et al. 1985a). Similar findings were observed by Maloney and 

Waxman (1999), who showed that MEHP (but not DEHP) activated mouse and human PPARα and 

PPARγ, while 2-ethylhexanoic acid activated mouse and human PPARα only, and at much higher 

concentrations. Based on its potency to induce enzyme activities, such as the peroxisomal fatty acid 

β-oxidation cycle and carnitine acetyltransferase, DEHP might be considered a relatively weak 

proliferator. 

The increase in peroxisomal β-oxidation enzymes and microsomal CYP4A-associated enzymes seen 

shortly after administration of peroxisome proliferators is paralleled by an increase in their respective 

mRNAs, which is due to an increase in the transcription of their respective genes (Hardwick et al. 1987; 

Reddy et al. 1986). This suggested a common mechanism of induction, and raised the possibility that 

peroxisome proliferators act like steroid hormones by activating transcription factors (nuclear receptors) 

that regulate peroxisome proliferator inducible genes. Screening for nuclear receptor cDNAs in mouse 

liver, Issemann and Green (1990, 1991) identified a clone encoding a previously unidentified molecule, 

which could be activated by a variety of peroxisome proliferators, and termed it PPARα, for Peroxisome 

Proliferator Activated Receptor. Testing PPARα for its ability to activate gene transcription using various 

peroxisome proliferators revealed that there was a good correlation between the proliferators’ ability to 

activate the receptor and their potency either as peroxisome proliferators or as rat liver carcinogens 

(Issemann and Green 1990; Issemann et al. 1993). Thus far, four different PPAR subtypes (α, β, γ, and δ) 

have been identified in various species, although only α, γ, and δ have been isolated from both rodents 

and humans (Cattley et al. 1998). Peroxisome proliferators regulate gene transcription through a 

heterodimer receptor complex composed of the PPARα and the retinoid receptor (RXR). These receptors 

can be activated by both peroxisome proliferators and certain fatty acids. Recently, Fan et al. (1998) 

showed that in acyl-CoA oxidase-deficient mice, unmetabolized long-chain acyl-CoA can function as a 

biological ligand of PPARα. The activated receptor complex regulates transcription by binding to DNA 

regulatory sequences, PP response elements (PPRE). The consensus PPRE is a direct repeat of the 

sequence TGACCT, located in the promoters of peroxisome proliferator responsive genes, including 
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those involved in peroxisomal β-oxidation of fatty acids and cytochrome P-4504A (Cattley et al. 1998; 

Tugwood et al. 1996). In situ hybridization studies in the rat have shown that PPARδ subtypes are 

ubiquitously expressed, whereas PPARγ is largely restricted to adipose tissue. The highest levels of 

expression of PPARα are observed in the liver, but there is also expression in brown adipose tissue, 

kidney, heart, and weakly in skeletal muscle, small intestine, testis, and thymus (Issemann and Green 

1990). Human PPARα cDNA has been isolated, and encodes a functional PPARα when tested in 

heterologous expression studies (Mukherjee et al. 1994; Sher et al. 1993). Further information regarding 

the human PPAR is presented in Section 3.5.3 Animal-to-Human Extrapolations. 

The role of PPAR in peroxisome proliferators-induced toxicity has been examined in several studies. For 

example, Lee et al. (1995) observed that PPARα-deficient mice (knockout mice) orally administered the 

peroxisome proliferators clofibrate or Wy-14,643 for 2 weeks did not exhibit hepatomegaly or 

peroxisome proliferation, and no transcriptional activation of target genes was detected. More recently, 

Peters et al. (1997a) fed Wy-14,643 to knockout mice lacking a functional PPARα and to normal mice. 

After 11 months of treatment, normal mice showed a 100% incidence of livers with multiple tumors. In 

contrast, in PPARα knockout mice, all livers were completely devoid of tumors. Furthermore, the same 

group of investigators showed that the DEHP-induced fetotoxicity and teratogenicity are not mediated 

through PPARα-dependent mechanisms (Peters et al. 1997b). In a study by Ward et al. (1998), treatment 

of PPARα wild-type mice with DEHP for up to 24 weeks resulted in typical upregulation of mRNA for 

peroxisomal and CYP4A enzymes in the liver and kidney, while treated null mice were no different from 

control wild-type or null mice. Whereas treated wild-mice had liver, kidney, and testicular toxicity, 

treated PPARα-deficient mice did not exhibit liver toxicity, but showed delayed moderate kidney and 

testicular toxicity. This suggested that while DEHP-induced liver toxicity is mediated solely by PPARα

activation, both renal and testicular toxicities have both a receptor- and nonreceptor-mediated response. 

A study using human hepatoma cells expressing PPARα, β/δ, or γ showed that the DEHP metabolite, 

MEHP, activated all three isoforms of PPAR in a dose-related fashion, but DEHP did not (Lapinskas and 

Corton 1997). In addition, the metabolite 2-ethylhexanoic acid was isoform-specific since it activated 

PPARα but not β/δ or γ. Similar findings were observed by Maloney and Waxman (1999) who showed 

that MEHP (but not DEHP) activated mouse and human PPARα and PPARδ, while EHA activated mouse 

and human PPARα only, and at much higher concentrations. These data are consistent with observations 

in vivo and in vitro indicating that the toxicity of DEHP is due mainly to MEHP. 

The exact mechanism(s) by which peroxisomal proliferating agents such as DEHP induce hepatic cancer 

in rodents are not precisely known, but might be related to the modulation of peroxisomal β oxidation, the 
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PPAR α receptor, gap junctional intercellular communication, and replicative DNA synthesis (Isenberg et 

al. 2000, 2001; Smith et al. 2000). Two major mechanisms have been proposed to account for 

peroxisome proliferator-induced hepatocarcinogenicity in rodents: induction of sustained oxidative stress 

and enhanced cell proliferation and promotion. Suppression of hepatocellular apoptosis has also been 

suggested to play a role. 

Oxidative Stress. Several investigators have hypothesized that liver tumor formation arises from an 

imbalance between hydrogen peroxide generation and degradation within the peroxisome (Rao and 

Reddy 1987; Reddy and Lalwani 1983; Reddy and Rao 1989). This imbalance is the result of a much 

greater induction by peroxisome proliferators of hydrogen peroxide-generating enzymes than induction of 

catalase. This might be compounded by a reduction in enzyme activities that detoxify active forms of 

oxygen and organic hydroperoxides. Hydrogen peroxide that escapes the peroxisome might damage 

intracellular membranes and/or DNA (Reddy and Rao 1989). Lipid peroxidation and lipofuscin 

deposition have been observed in hepatocytes from rats treated with DEHP and other peroxisome 

proliferators (Cattley et al. 1987; Conway et al. 1989; Lake et al. 1987). Tagaki and coworkers have 

examined the possibility of DNA damage by DEHP by measuring the induction of 8-hydroxydeoxyguanosine (8-OH-dG), a marker of DNA oxidation, in the liver and kidney from male rats 

administered DEHP for various periods of time (see Sai-Kato et al. [1995] for review). Increased levels 

of 8-OH-dG were seen in the liver after 1 or 2 weeks or 12 months of treatment, but no increases were 

seen in the kidney. In general, the increases were small (2-fold) and in some cases, were not sustained 

with prolonged DEHP treatment (Cattley and Glover 1993). Moreover, the increased levels of 8-OH-dG 

do not correlate with carcinogenic potency, as similar levels of induction have been associated with 

divergent carcinogenic activities (Marsman et al. 1988, 1992). Furthermore, DEHP and other peroxisome 

proliferators have consistently lacked initiation activity unlike other DNA-damaging agents. The overall 

evidence suggests that increased production of hydrogen peroxide and DNA oxidation are not solely 

responsible for peroxisome proliferator-induced liver tumor formation. 

Cell Proliferation. Increased liver weight is a typical response in rodents exposed to DEHP and other 

peroxisome proliferators. This response is largely due to a transient increase in replicative DNA synthesis 

and cell division. Although considered a weak inducer of cell proliferation, DEHP causes an almost 

immediate increase in cell division in rats and mice (Busser and Lutz 1987; Smith-Oliver and Butterworth 

1987). A single dose of 664 mg/kg DEHP produced a significant increase in DNA synthesis in the rat 

liver, as indicated by the incorporation of radioactive thymidine into polynucleotides during the first 

24 hours (Busser and Lutz 1987). In mice, a dose of 500 mg/kg stimulated mitosis within 24 hours of 
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administration (Smith-Oliver and Butterworth 1987). Repeated oral doses of as little as 50 mg/kg/day 

increased mitotic activity when administered to rats for 3 consecutive days (Mitchell et al. 1985b). 

Similar findings were reported in rats and mice in a more recent study (James et al. 1998). The increase 

in mitosis only occurred in the early stages of treatment and did not persist beyond the first week in 

several exposure studies with 3–12 month durations (Marsman et al. 1988; Mitchell et al. 1985b; 

Smith-Oliver and Butterworth 1987). During periods of mitotic activity, there was no evidence for DNA 

repair according to standard repair assays (Smith-Oliver and Butterworth 1987). Increased cell division is 

an important factor in the tumorigenicity of both genotoxic and nongenotoxic substances because it can 

increase the frequency of spontaneous mutations and the probability of converting DNA adducts from 

both endogenous and exogenous sources into mutations before DNA can be repaired. As shown by 

Marsman et al. (1988), the carcinogenicity of DEHP and Wy-14,643 correlates better with sustained DNA 

replication than peroxisome proliferation suggesting that peroxisome proliferators induce tumors by 

influencing the growth of initiated lesions and therefore, act as tumor promoters. Moreover, the cell 

proliferation caused by peroxisome proliferators is mediated by PPARα, since treatment of wild type mice 

with Wy-14,643 increased S-phase, while no effect was observed in receptor knockout mice (Peters et al. 

1997a). 

DEHP has been examined for initiation/promotion activities in several studies. DEHP was not an initiator 

in the liver from mice given a single gavage dose of DEHP at 4 weeks of age, followed by treatment with 

phenobarbital (PB) continuously for 6 weeks; the mice were killed at 6 and 18 months (Ward et al. 1986). 

Similar results were reported by Williams et al. (1987), who found no evidence of induction of 

hepatocellular altered foci or hepatic neoplasms after treatment of rats with DEHP for 7 weeks followed 

by PB. Garvey et al. (1987) also found no initiating activity in the liver after single or subchronic dosing 

of rats with DEHP followed by PB. In promotion studies, the results have been mixed in rats, but 

generally positive in mice. Positive promotion activity has been reported in rat liver (Gerbracht et al. 

1990; Oesterle and Deml 1988; Sano et al. 1999), rat kidney (Kurokawa et al. 1988), and mouse liver 

(Ward et al. 1984, 1986, 1990; Weghorst et al. 1994). Negative promotion activity was reported in rat 

liver (Popp et al. 1985; Ward et al. 1986; Williams et al. 1987), rat kidney (Hagiwara et al. 1990), mouse 

skin (Ward et al. 1986), and hamster liver and pancreas (Maruyama et al. 1994; Schmezer et al. 1988). 

There is some evidence that nongenotoxic carcinogens alter apoptosis, a process that maintains the correct 

cell number and removes damaged cells, and that this plays a role in their carcinogenicity. As mentioned 

above, damaged or initiated cells (induced or spontaneous) might represent preferential targets for 

promotion. James et al. (1998) showed that in rat and mouse hepatocytes in vitro, MEHP induced DNA 
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synthesis and suppressed both spontaneous and TGFβ1-induced apoptosis. When tested in vivo in both 

species, DEHP significantly increased the expression of P-4504A1 and induced liver DNA synthesis and 

suppressed apoptosis. James et al. (1998) suggested that the carcinogenicity of nongenotoxic liver 

carcinogens is strongly associated with the ability to perturb hepatocyte growth regulation. Because 

similar results were obtained with 1,4-diclorobenzene, a chemical that is not a hepatocarcinogen in rats, 

James et al. (1998) suggested that the growth perturbation might need to exceed a threshold for 

carcinogenesis. Other in vitro studies with rat hepatocytes support the hypothesis that, although 

disruption of the mitogenic/apoptotic balance contributes to the development of DEHP-induced 

hepatocarcinogeneisis in rodents, a direct link between the level of oxidative stress via peroxisome 

proliferation and the heptocarcinogenic potential of DEHP might exist (Goll et al. 1999). Additionally, 

an absence of effects of DEHP on both peroxisome proliferation-associated parameters and mitogenic/ 

apoptotic balance supports the hypothesis that human liver cells are refractory to DEHP-induced 

hepatocarcinogenesis. 

In summary, there is strong evidence that hepatocarcinogenesis of DEHP and other peroxisome 

proliferators is due to their increased production of hydrogen peroxide by peroxisomes and enhanced cell 

proliferation; alteration of mitogenic/apoptotic balance might also contribute. These events are triggered 

by the activation of gene expression via a nuclear receptor, PPARα. It should be noted that if liver cancer 

in humans can be promoted by DEHP via a mechanism not involving peroxisome proliferation (i.e., 

inhibition of gap junctional intercellular communication), the fact that this was not measured in human 

liver and that promotion must occur on initiated liver cells for long periods of time at a concentration that 

exceeds a potential threshold level (a characteristic of chemical tumor promoters) might still implicate 

DEHP as a potential human liver tumor promoter. However, because the model chemical, phenobarbital, 

is also a rodent tumor promoter and has not been shown to be a human liver tumor promoter, it is 

reasonable to conclude that normal exposures to DEHP will not be a significant risk factor for human 

liver cancers. 

Reproductive Effects. DEHP induces testicular toxicity characterized by structural as well as 

biochemical alterations in the testis. Structural alterations consist of gross disorganization of the 

seminiferous tubules, with detachment of the spermatogonial cells from the basal membrane and absence 

of spermatocytes. Alterations in structure have been shown to be more severe in young rats than in 

mature animals (Dostal et al. 1988; Gray and Butterworth 1980; Sjoberg et al. 1985b, 1986a, 1986b). 

Structural alterations have been seen after acute- (Dostal et al. 1988; Gray and Butterworth 1980; Gray 

and Gangolli 1986; Oishi 1994), intermediate- (Gray and Butterworth 1980; Parmar et al. 1987; Poon et 
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al. 1997), and chronic-duration exposures (Ganning et al. 1991; Kluwe et al. 1982a; Price et al. 1987). 

Biochemical effects consisting of changes in specific activities of testicular enzymes associated with postand premeiotic spermatogenic cells, Sertoli cells, or interstitial cells have been reported (Oishi 1986, 

1994; Parmar et al. 1987, 1995). 

The role of zinc in DEHP-induced testicular atrophy has been examined in several studies since a 

reduction in testicular zinc is a primary event following administration of DEHP. A decrease in testicular 

zinc, but not in serum or liver zinc, was reported in rats given DEHP (Oishi 1985; Oishi and Hiraga 

1980b). After a 45-day recovery period, when there was morphological evidence of seminiferous tubule 

regeneration, testicular zinc was still lower than in controls (Oishi 1985). Simultaneous oral 

administration of DEHP and oral or intraperitoneal administration of zinc did not prevent testicular 

atrophy in rats, and zinc supplementation did not increase the concentration of zinc in the testis despite 

increases in liver and serum (Oishi and Hiraga 1983). This suggested that DEHP-induced testicular 

effects do not result from interference with gastrointestinal absorption of zinc, but that atrophy might be 

related to endogenous testicular zinc, and thus, cannot be prevented by zinc supplementation (Oishi 

1985). Agarwal et al. (1986) observed a reduction in the weight of the testis, seminal vesicle, prostate, 

and epididymes in rats treated with DEHP and maintained in a low zinc diet, but no such effects were 

apparent in rats maintained in a normal or high zinc diet. Since DEHP induced effects on the liver and on 

serum lipids independently of the zinc concentration in the diet, Agarwal et al. (1986) concluded that the 

enhancement of DEHP-induced testicular toxicity in rats in a low zinc diet is limited to the testis, and 

confirmed that testicular atrophy is not related to zinc absorption. Zinc is thought to be localized in the 

spermatids; therefore, loss of zinc could be just a reflection of loss of spermatids induced by DEHP. This 

hypothesis was tested by Dostal et al. (1988) who treated suckling rats (<25 days of age), whose testes do 

not contain spermatids, with DEHP. Morphological alterations were indeed seen in the testis from the 

rats, suggesting that loss of zinc is not involved in the testicular atrophy at the early ages. In contrast to 

findings in rats, no testicular atrophy was seen in mice treated with DEHP doses that significantly reduced 

the zinc concentration in the testis (Oishi and Hiraga 1980a). In hamsters, DEHP did not decrease 

testicular zinc concentration or increase urinary excretion of zinc, as seen in rats, and caused only minor 

testicular alterations (Gray et al. 1982). In this case, however, the apparent lack of sensitivity of the 

hamster seemed to be related to a reduced rate of hydrolysis of DEHP to MEHP in the intestine, since 

administration of MEHP (see below for discussion regarding the active metabolite) did cause focal 

seminiferous tubular atrophy in hamsters (Gray et al. 1982). 
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The effects of DEHP on hormones that influence testicular maturation and function have also been 

explored. As was the case with zinc, DEHP administered to mice significantly reduced the concentration 

of testosterone in the testis, but no testicular atrophy was observed (Oishi and Hiraga 1980a). DEHP 

administered intraperitoneally to mature rats decreased the concentration of testosterone in the testis 

(Oishi and Hiraga 1979), but oral administration to 5-week-old rats increased the concentration of 

testosterone in the testis and reduced that in serum (Oishi and Hiraga 1980b). Increases in testicular 

concentration of testosterone along with decreases in testicular content of testosterone seen after DEHP 

treatment suggested that testosterone-producing Leydig cells are normal, but that the total number of cells 

is less than in controls or that the cells are less active in testosterone production (Oishi 1985). 

Simultaneous administration of DEHP and testosterone or follicle stimulating hormone (FSH) did not 

prevent the DEHP-induced testicular atrophy in 4-week-old rats, but did prevent the depression in 

accessory gland weight (Gray and Butterworth 1980). Parmar et al. (1987) reported that DEHP plus 

testosterone protected against DEHP-induced testicular atrophy in 10-week-old rats; however, Parmar et 

al. (1987) also administered a dose of testosterone 5 times higher than that used by Gray and Butterworth 

(1980). In a later study, Oishi (1989b) reported that co-administration of DEHP and testosterone 

apparently aggravated the testicular damage caused by DEHP, an effect that seemed to be due to 

testosterone prolonging the biological life and the mean residence time of MEHP in the testis. A 

mechanism for such an effect was not discussed. In a similar study, luteinizing hormone-releasing 

hormone significantly enhanced the testicular toxicity of DEHP when given together with DEHP (Oishi 

1989a). 

Mehrotra et al. (1997, 1999) presented preliminary evidence for the involvement of the thyroid and the 

hypophysis in DEHP-induced testicular toxicity in rats. They reported that hypothyroidism or 

hypophysectomy prevented, to some extent, DEHP-induced alterations in several xenobiotic-metabolizing 

enzymes in the testis. The significance of these findings is unclear due to a lack of DEHP-induced 

decreased testicular weight in sham-operated controls, which complicates comparison to the 

hypophysectomized animals. 

Results from both in vivo and in vitro studies have indicated that the Sertoli cell is the main target for 

DEHP-induced testicular toxicity and that MEHP is the ultimately active testicular toxicant (Chapin et al. 

1988; Creasy et al. 1986; Gray and Beamand 1984; Gray and Gangolli 1986; Sjoberg et al. 1986b). 

However, effects on Leydig cells have also been reported (Jones et al. 1993). The Sertoli cell is a somatic 

cell type whose integrity and functionality is required for the growth and maintenance of the germ cells as 

they divide and differentiate from spermatogonia to spermatocytes and ultimately to spermatids. The 
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latter are released by the Sertoli cell into the lumen as sperm. Gray and Butterworth (1980) had suggested 

that the Sertoli cell and not the germ cell was the direct target of DEHP toxicity since the germinal cells 

affected were those inside the Sertoli cell barrier. Studies by Foster et al. (1982) and Creasy et al. (1983) 

showed that the earliest changes after treatment with phthalates were vacuolation of the Sertoli cell 

followed by degenerative changes in ultrastructure in Sertoli cells, spermatocytes, and spermatids. 

Addition of MEHP to a mixed culture of Sertoli cells and germ cells from rat testes (4 weeks old) 

significantly increased the rate of germ cell detachment from Sertoli cells; no effect was seen after adding 

DEHP or 2-ethylhexanol (Gray and Beamand 1984). There was little effect on viability of either the 

germ cells or Sertoli cells with a concentration that caused germ cell detachment, although there were 

alterations of the Sertoli cell morphology. Also, germ cell detachment was less marked in hamsters than 

in rat testicular cell cultures. Testing cultures from rats of different ages showed that the enhancement of 

germ cell detachment produced by MEHP decreased progressively with increasing age (Gray and 

Beamand 1984). This indicates that, at least in vitro, there are factors other than pharmacokinetics that 

might play a role in age-related differences in susceptibility. In mixed cultures of Sertoli and germ cells, 

addition of MEHP caused the plasma membrane of Sertoli cells to show altered configuration (Creasy et 

al. 1986). Membrane disruption and mitochondrial hypertrophy were frequently observed. In primary 

testicular cell cultures (78–84% Sertoli cells), addition of MEHP decreased cellular ATP and the 

production of carbon dioxide from acetate (<60 minutes) and decreased media pyruvate, increased media 

lactate and intracellular lipid, and decreased mitochondrial succinate dehydrogenase (Chapin et al. 1988). 

All of these changes suggested that the Krebs cycle is at least one of the biochemical targets for MEHP in 

Sertoli cells (Chapin et al. 1988). As early as 1 hour after administration of a single oral dose of MEHP 

to immature rats, there were changes in Sertoli cell function as reflected by a reduction in secretion of 

seminiferous tubule fluid and of androgen binding protein, both specific markers of Sertoli cell function 

(Gray and Gangolli 1986). 

Several studies have examined the role of FSH in phthalates-induced Sertoli cell toxicity. This was 

prompted by the fact that the initial testicular lesion in adult rats treated with dipentyl phthalate is 

restricted to tubules in stages with the highest FSH responsiveness (Parvinen 1982). Primary testicular 

cell cultures pretreated with MEHP showed a concentration-related reduction in FSH-stimulated cAMP 

accumulation in Sertoli cells (Lloyd and Foster 1988). This suggested a MEHP-induced perturbation at 

the level of the FSH membrane receptor. Further studies showed that inhibition of FSH-stimulated 

elevation of cAMP levels in primary rat Sertoli cell cultures required a lag period of 6 hours and did not 

affect the dose of FSH that gave half-maximal stimulation, suggesting that MEHP does not compete with 

FSH for binding to its receptor (Heindel and Chapin 1989). Later findings by Grasso et al. (1993) 
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revealed that in cultured rat Sertoli cells (from 18–45-day-old rats) preincubated with MEHP, there was a 

reduced binding of 125I-hFSH to purified membrane preparations; preincubation with DEHP had no effect. 

The decrease in binding occurred only when MEHP was incubated with intact Sertoli cells, but not when 

MEHP was incubated with purified Sertoli cell membranes. Using cocultures of Sertoli cells and 

gonocytes from 2-day-old pups, Li et al. (1998) showed that MEHP induces germ cell detachment from 

Sertoli cells regardless of the presence or absence of FSH and that MEHP inhibits Sertoli cell 

proliferation regardless of the presence of either FSH or cAMP. No effects were seen with DEHP. Based 

on their results, Li et al. (1998) proposed that MEHP acts in neonatal testis either at a post-cAMP site in 

the FSH pathway and/or via a mechanism independent of FSH. In the study, Li et al. (1998) observed 

germ cell detachment with MEHP concentrations much lower than those used in other studies (Chapin et 

al. 1988; Gray and Beamand 1984) which confirmed that, at least in vitro, there is an age-related 

differential sensitive of Sertoli cells to MEHP. Overall, there is insufficient evidence to conclude that the 

mechanism of Sertoli cell toxicity involves interference of FSH signaling function by MEHP (NTP 

2000b). 

Alterations in Sertoli cell cytoskeleton after exposure to phthalates also have been reported. Sertoli cells 

form a blood-testis barrier that divides the epithelium of the seminiferous tubules into two compartments 

by specialized occluding tight junctions. These tight junctions are associated with actin fibers contained 

in the ectoplasmic specialization. Ectoplasmic specializations are plasma membranes associated with a 

cellular structure consisting of cells incorporating actin filament bundles, endoplasmic reticulum, and 

microtubules. Actin filaments in Sertoli cells play a crucial role in maintaining Sertoli cell to Sertoli cell 

and germ cell to germ cell interactions. A single oral dose of DEHP given to 4-week-old rats induced 

disruption of the ectoplasmic specialization of Sertoli cell as early as 3 hours after dosing (Saitoh et al. 

1997). The lesion was characterized by marked dilation of the endoplasmic reticulum facing the tight 

junction and by disappearance of the actin filament bundles associated with the ectoplasmic 

specialization. Richburg and Boekelheide (1996) treated 4-week-old rats with a single MEHP oral dose 

and observed a collapse in vimentin filaments 3 hours after dosing without accompanying changes in the 

pattern of Sertoli cell tubulin or actin. Vimentin filaments (a type of intermediate filament) surround the 

Sertoli cell nucleus and extend long apical filaments which radiate toward the periphery of the cell where 

they associate with the plasma membrane in the region of the Sertoli-germ cell attachments (Richburg and 

Boekelheide 1996). These changes were correlated with an initial decrease, followed by a later increase 

in the normal incidence of germ cell apoptosis (programmed cell death) seen in young rats. Based on 

these findings, the investigators (Richburg and Boekelheide 1996) hypothesized that the Sertoli cell is 

responsible for directing germ cell apoptosis and that the signaling mechanism between these two cells 
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requires that they maintain close physical contact. Thus, MEHP-induced detachment of germ cells would 

uncouple the signal transduction mechanism responsible for normal cell apoptosis. Subsequent studies by 

the same group of investigators showed that expression of the cell surface protein Fas, an apoptosisrelated system that modulates germ cell death in the testis, was highly increased in 4-week-old rats after 

oral exposure to MEHP (Boekelheide et al. 1998; Lee et al. 1999). Target cells undergo apoptosis when 

Fas ligand, a cell surface molecule belonging to the tumor necrosis factor family, binds to Fas (its 

receptor) (Nagata and Golstein 1995). 

Exposure to DEHP during gestation and lactation has altered development of the reproductive system in 

male rat offspring. Oral administration of $375 mg DEHP/kg/day from gestation day 3 to postnatal 

day 21, or 750 mg DEHP/kg/day from gestation day 14 to postnatal day 3, has induced a variety of effects 

in androgen-sensitive tissues of male neonates and infants, including female-like anogenital distance and 

permanent nipples, vaginal pouch, penile morphological abnormalities, hemorrhagic and undescended 

testes, testicular and epididymal atrophy or agenesis, and small to absent sex accessory glands (Gray et al. 

1999, 2000; Moore et al. 2001; Parks et al. 2000). Behavioral observations indicated that many of the 

exposed males were sexually inactive in the presence of receptive control females (Moore et al. 2001). 

The morphological effects and sexual behavioral changes are consistent with an antiandrogenic action of 

DEHP. Other indications of antiandrogenic activity include the lack of significant effects on time to 

vaginal opening and first estrus in female offspring of rats that were exposed to $375 mg DEHP/kg/day 

from gestation day 3 to postnatal day 21 (Moore et al. 2001). Additionally, exposure to 750 mg/kg/day 

from gestation day 14 to postnatal day 3 caused significantly reduced testicular testosterone production 

and reduced testicular and whole-body testosterone levels in fetal and neonatal male rats (Parks et al. 

2000). Histological examinations of the testes in these rats showed that DEHP induced increased 

numbers of multifocal areas of Leydig cell hyperplasia, as well as multinucleated gonocytes, at gestation 

day 20 and postnatal day 3. In vitro assays showed that neither DEHP nor its metabolite MEHP 

displayed affinity for the human androgen receptor at concentrations up to 10 )M (Paganetto et al. 2000; 

Parks et al. 2000). The available evidence indicates that DEHP is not an androgen receptor antagonist, 

but acts as an antiandrogen during a critical stage of reproductive tract differentiation by reducing 

testosterone to female levels in the fetal male rat. Parks et al. (2000) hypothesized that DEHP, or a 

metabolite, reduces testosterone production either by directly acting on the Leydig cells to reduce 

testosterone synthesis, or by interfering with Sertoli cell paracrine factors that regulate Leydig cell 

differentiation and function. Regardless of the mechanism, if the Leydig cells in exposed males continue 

to divide rather than differentiate for only a brief period of sexual differentiation, this could delay the 
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onset of Leydig cell testosterone production and lead to malformations of the reproductive tract, externial 

genitalia, and other androgen-dependent tissues (e.g., nipples) (Parks et al. 2000). 

The role of gene transcription, via the PPARα, in the testicular toxicity of DEHP was examined by Ward 

et al. (1998). Male Sv/129 mice (6 weeks old), F4 homozygous wild type (+/+) or knockout (-/-) for 

PPARα were used. Knockout (-/-) mice for PPARα lack expression of PPARα protein and are refractive 

to peroxisomal proliferators (Lee et al. 1995). Both strains of mice were administered DEHP in the diet at 

an approximate dose level of 2,400 mg DEHP/kg/day for up to 24 weeks. DEHP caused high lethality in 

(+/+) mice but not in (-/-) mice. All (+/+) mice showed focal tubular degenerative lesions in the testis, 

with diminished spermatogenesis by 8–16 weeks of treatment. In contrast, (-/-) mice had primarily 

normal testis after 4–8 weeks of treatment except for a few tubules in the outer portion of the testis that 

showed abnormal spermatogenesis. However, after 24 weeks, most (-/-) mice had severe tubular lesions. 

The delayed testicular toxicity of DEHP in (-/-) mice resembled the early toxicity observed in (+/+) mice 

and suggested that this early toxicity was mediated by PPARα. These findings indicate that PPARα is not 

required for DEHP-induced testicular lesions. Ward et al. (1998) speculated that other receptor subtypes 

(PPARδ or γ) might play a role in the delayed toxicity or that the high dose of DEHP might modify the 

pharmacokinetics of DEHP in the (-/-) mice. Interestingly, Peters et al. (1997b) showed that the fetotoxic 

and teratogenic properties of DEHP are not mediated by PPARα since effects were observed in both wildtype and PPARα-null mice treated with DEHP during gestation. Maloney and Waxman (1999) reported 

that PPARγ was stimulated by MEHP and not DEHP, and speculated that PPARγ could be responsible for 

some of the testicular effects associated with DEHP exposure. Further studies are needed to support the 

suggestion that activation of PPARγ is a possible mechanism for testicular effects. 

Other research sought to determine whether the fetotoxic/teratogenic effects of DEHP are mediated by the 

PPARα (Peters et al. 1997b). Pregnancy outcome was assessed in female F4C57BL/6N x Sv/129, wild 

type (+/+), and PPARα-null (-/-) mice on gestation days 10 and 18 after administration of DEHP by 

gavage on Gd 8 and 9. PPARα-null mice lack expression of PPARα protein and are refractive to 

peroxisomal proliferators (Lee et al. 1995). Relative to controls, DEHP significantly decreased the 

percentage of live fetuses, increased the percentage of resorptions, decreased fetal weight, and increased 

the percentage of fetuses with external malformations in both mice strains. On gestation day 10, maternal 

liver CYP4A1 mRNA was significantly elevated in DEHP-treated (+/+) mice but not in (-/-) mice, 

consistent with their respective phenotype. Mean maternal liver metallothionein and zinc levels were 

significantly higher in DEHP-treated mice (both strains) compared to controls. Maternal plasma zinc was 

not significantly altered as a result of treatment with DEHP. Embryonic zinc was significantly reduced in 
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conceptus from both mice strains. These findings indicated that DEHP-induced fetotoxicity and 

teratogenicity, and altered zinc metabolism are not mediated through PPARα-dependent mechanisms, and 

that alterations in zinc metabolism might contribute to the mechanism underlying DEHP-induced 

fetotoxicity and teratogenicity. 

It has been hypothesized that nongenotoxic chemicals such as DEHP affect reproduction and 

development via the modulation (inhibition) of gap junctional intercellular communication, as proposed 

for liver tumor promotion (Rosenkranz et al. 2000; Trosko and Chang 1988; Trosko et al. 1998) 

Gavage administration of a very high dose of 2,000 mg DEHP/kg/day to adult virgin female rats for 

1–10 days resulted in prolonged estrous cycle (Davis et al. 1994a). DEHP significantly suppressed 

preovulatory follicle granulosa cell estradiol production, subsequently resulting in lack of luteinizing 

hormone (LH) surge necessary for ovulation and increases in FSH; the end result was anovulation. No 

other dose levels were tested in this study. The mechanism of DEHP-altered granulosa cell estradiol 

production was examined in cultures of rat granulosa cells exposed to the active metabolite MEHP (Davis 

et al. 1994b). MEHP suppressed estradiol in a concentration-related manner whether granulosa cells were 

stimulated with FSH or 8-bromo cyclic AMP. These findings suggested that MEHP suppressed 

aromatase conversion of testosterone to estradiol. 

3.5.3 Animal-to-Human Extrapolations 

There is ample evidence suggesting that there are species differences in both the pharmacokinetics and 

toxicity of DEHP; strain differences have also been described. In some cases, the differences in toxicity 

can be explained by differences in pharmacokinetics. The issue of greatest importance to be considered is 

whether DEHP can induce liver cancer and reproductive toxicity in humans, as seen in rodents. As 

previously mentioned, the hepatocarcinogenic response to DEHP in rats and mice is associated with 

peroxisome proliferation and increased hepatocyte replication. Studies in animals have shown that after 

exposure to peroxisome proliferators, rats and mice exhibit the greatest response, hamsters exhibit an 

intermediate response, whereas primates, guinea pigs, and dogs are either unresponsive or refractory 

(Cattley and Roberts 2000; Cattley et al. 1998; Huber et al. 1996). Studies conducted in patients treated 

with several hypolipidemic agents have provided no evidence for peroxisome proliferation or increased 

hepatocyte division (Ashby et al. 1994; Bentley et al. 1993; Cattley et al. 1998). Studies of peroxisome 

proliferation with primary hepatocytes in vitro have supported the results in vivo, thus validating the in 

vitro model for comparative studies. For example, Elcombe and Mitchell (1986) found that in vitro 
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exposure of rat hepatocytes to MEHP resulted in marked peroxisome proliferation and peroxisomal 

β-oxidation, but no such responses were observed in cultured guinea pig, marmoset monkey, or human 

hepatocytes, appropriately controlled for viability. In order to rule out the possibility that the species 

differences were due to differences in the biotransformation of MEHP, Elcombe and Mitchell (1986) 

isolated MEHP metabolites from rat urine and tested them in cultures from rat, guinea pig, marmoset, and 

human liver. Metabolite VI, biochemically and morphologically identified as the proximate proliferator 

in the rat, had little or no effect in marmoset, guinea pig, or human hepatocytes. These findings suggested 

the existence of intrinsic species differences of liver cells to peroxisome proliferators. 

If peroxisome proliferation and liver carcinogenicity is mediated by PPARα, the species differences could 

reflect either variation in PPARα itself or in the gene networks regulated by PPARα (Green 1995). As 

previously mentioned, human PPARα cDNA have been isolated that encode a functional PPARα when 

tested in heterologous expression studies (Mukherjee et al. 1994; Sher et al. 1993). Marked species 

differences in the expression of PPARα mRNA have been identified. Mukherjee et al. (1994) showed 

that the peroxisome proliferator Wy-14,643 was a much more potent activator of the rat PPARα than the 

human PPARα when analyzed in CV-1 cells. However, the hypolipidemic drug clofibric acid activated 

equally the human and rat receptor in CV-1 cells and HepG2 cells. Palmer et al. (1998) using a sensitive 

immuno/DNA binding assay showed that human liver contains 10-fold lower levels of PPARα mRNA 

than mouse liver and that a fraction of this RNA lacks exon 6 and does not encode a functional receptor. 

Palmer et al. (1998) suggested that the low expression in human liver might permit PPARα to mediate 

some therapeutic responses to fibrates but limit the pathological changes, including peroxisome 

proliferation, which lead to liver cancer in rats and mice. Recently Maloney and Waxman (1999) showed 

that in COS-1 cells transfected with human or mouse PPARα expression plasmids and a PPRE-luciferase 

reporter DEHP did not activate PPARα. However, MEHP activated both human and mouse PPARα and 

both preparations were equally sensitive. This suggested that differential sensitivity of human PPARα

cannot alone account for the lack of peroxisome proliferation response seen in humans, but other factors, 

such as the much lower level, as found by Palmer et al. (1998), are also likely to be important. Another 

important factor might be species differences in responsiveness of genes to PPARα-mediated 

transcription. The promoter region of the human acyl CoA oxidase gene is unresponsive to PPARα due 

to sequence differences from the mouse gene (Varanasi et al. 1996; Woodyatt et al. 1999) 

As for testicular toxicity, which does not seem to be related to peroxisomal proliferation to the extent that 

liver cancer is, differential sensitivity among animal species has been found. Studies in vivo have shown 

that rats and guinea pigs are highly sensitive while mice are fairly sensitive, and hamsters and monkeys 
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3. HEALTH EFFECTS 

are highly resistant (Gray et al. 1982; Kurata et al. 1998). A lack of information precludes ranking 

humans relative to other species. Differences in pharmacokinetics might play a role in the differential 

sensitivity between species, but differences in tissue sensitivity might play a role as well. Mixed cultures 

of Sertoli cells and germ cells from rat testes were more sensitive to MEHP toxicity than cultures from 

hamster testes (Gray and Beamand 1984). Also, cultures from older rats were less sensitive than cultures 

from young animals, suggesting that intrinsic cell factors might account for different susceptibility. 

Studies with the knockout mice for PPARα have suggested that other receptor subtypes (PPARδ or γ) 

might play a role in the delayed testicular toxicity observed in these mice or that the high dose of DEHP 

might modify the pharmacokinetics of DEHP in the (-/-) mice (Ward et al. 1998). Maloney and Waxman 

(1999) recently reported that PPARγ was stimulated by MEHP and not DEHP, and speculated that 

PPARγ could be responsible for some of the testicular effects associated with DEHP exposure. Further 

studies are needed to support the suggestion that activation of PPARγ is a possible mechanism for 

testicular effects. Clearly, much additional information will be necessary to determine whether the 

DEHP-induced testicular effects in animals are likely to occur in exposed humans. 

There is information suggesting that primates may be less sensitive to DEHP than rodents and that oral 

absorption of DEHP is less in primates than in rodents. For example, no histopathological effects on the 

testes or other tissues, or other signs of toxicity, were observed in marmoset monkeys exposed to doses as 

high as 2,500 mg/kg/day daily for 13 weeks (Kurata et al. 1998) or in cynomolgus monkeys exposed to 

500 mg/kg/day daily for 2 weeks (Pugh et al. 2000). Several studies indicate that oral absorption of 

DEHP is reduced in monkeys compared to rats (Albro et al. 1982a, 1982b; Astill 1989; Rhodes et al. 

1986). For example, 24 hours following the last of 14 consecutive gavage doses of 2,000 mg/kg/day, 

tissue levels of DEHP or its metabolites were between 5 and 10 times lower in marmoset monkeys than in 

rats (Rhodes et al. 1986). 

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 was 

used by the Environmental Protection Agency (EPA) in 1996 when Congress mandated EPA to develop a 

screening program for “...certain substances [which] may have an effect produced by a naturally 

occurring estrogen, or other such endocrine effect[s]...”. To meet this mandate, EPA convened a panel 
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called the Endocrine Disruptors Screening and Testing Advisory Committee (EDSTAC), which in 1998 

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. Some 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). 

In recent years, concern has been raised that many industrial chemicals, DEHP among them, are 

endocrine-active compounds capable of having widespread effects on humans and wildlife (Crisp et al. 

1998; Daston et al. 1997; Safe et al. 1997). Particular attention has been paid to the possibility of these 

compounds mimicking or antagonizing the action of estrogen, and more recently, their potential 

antiandrogenic properties. Estrogen influences the growth, differentiation, and functioning of many target 

tissues, including female and male reproductive systems, such as mammary gland, uterus, vagina, ovary, 

testes, epididymis, and prostate. Thus far, there is no evidence that DEHP is an endocrine disruptor in 

humans at the levels found in the environment. 

The wealth of information in animals administered DEHP for periods ranging from a few days to lifetime 

studies indicate that DEHP is a developmental and reproductive toxicant by mechanisms not yet 

completely understood. As discussed below, the mechanisms do not appear to involve binding of DEHP 

to the estrogen or androgen receptors. DEHP administered perinatally to females is embryotoxic and 

teratogenic (reduced fetal body weight, increased rates of abortion and fetal resorptions, skeletal 
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3. HEALTH EFFECTS 

malformations) (Section 3.2.2.6 Developmental Effects) and in males, it causes testicular toxicity 

(Section 3.2.2.5 Reproductive Effects). Whether these effects are caused by DEHP-induced hormonal 

disruption is not clear. As previously mentioned, a study by Davis et al. (1994a) showed that 

administration of 2,000 mg DEHP/kg/day to adult virgin female rats for 1–10 days resulted in prolonged 

estrous cycle and anovulation. Further studies in cultures of rat granulosa cells exposed to the active 

metabolite MEHP showed that MEHP suppressed estradiol in a concentration-related manner whether 

granulosa cells were stimulated with FSH or 8-bromo cyclic AMP and suggested that MEHP suppressed 

aromatase conversion of testosterone to estradiol. In males, the role of hormones in DEHP-induced 

testicular effects has also been examined, but no clear picture has emerged. DEHP administration 

reduced the serum level of testosterone in rats (Oishi and Hiraga 1980b) and mice (Gray and Butterworth 

1980), although in mice, there was no testicular atrophy. Coadministration of DEHP and testosterone 

appeared to diminish, but not abolish the testicular toxicity of DEHP (Gray and Butterworth 1980). Also 

in rats, LH releasing hormone (LRH) significantly decreased testis weight when administered 

simultaneously with DEHP, while LRH and DEHP alone had no effects (Oishi 1989a). A more detailed 

discussion on the DEHP mechanisms of testicular toxicity is presented in Section 3.5.2, Mechanisms of 

Toxicity. 

Early studies in experimental animals, mostly studies on pesticides, administered the chemicals orally or 

by parenteral routes, whereas in recent years, most of the research has focused on elucidating the 

mechanisms of action involved using tests systems in vitro which, although not without limitations, are 

easier to manipulate and can be developed into biomarker assays for (anti)estrogenic or (anti)androgenic 

activity. In general, results from in vivo and in vitro studies indicate that DEHP has negligible estrogenic 

potency relative to the endogenous hormone, 17β-estradiol. For example, the ability of DEHP to induce 

uterine wet weight and vaginal cell cornification was assessed in ovariectomized Sprague-Dawley rats 

(Zacharewski et al. 1998). With gavage doses of up to 2,000 mg/kg/day for 4 days, DEHP showed no 

consistent effects on uterine weight in duplicate experiments and did not induce vaginal cell cornification. 

In the same study, in an in vitro competitive ligand-binding assay, DEHP did not compete with 

17β-estradiol for binding to the rat uterine estrogen receptor. The IC50 (the concentration that causes 50% 

response inhibition) for 17β-estradiol was 1.3 nM; an IC50 could not be calculated for DEHP. In assays to 

evaluate the effect of DEHP on estrogen receptor-mediated gene expression in transfected human breast 

cancer MCF-7 cells and HeLa cells, the EC50 for 17β-estradiol for this response was about 0.2 nM for 

both MCF-7 and HeLa cells; DEHP had no significant activity at the concentrations tested (0.1–10 μM). 

Furthermore, DEHP exhibited no estrogen receptor-mediated growth in S. cerevisiae at a concentration of 

10 μM; 1 nM 17β-estradiol was used as positive response. The findings of Zacharewski et al. (1998) are 
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3. HEALTH EFFECTS 

in good agreement with those of others (Blom et al. 1998; Harris et al. 1997; Jobling et al. 1995; 

Paganetto et al. 2000) in similar in vitro assays indicating no estrogenic activity for DEHP under the 

conditions of the assays. 

The potential antiandrogenic properties of DEHP have been investigated in several studies. Exposure to 

DEHP during gestation and lactation altered development of the reproductive system in male rat 

offspring. Oral administration of $375 mg DEHP/kg/day from gestation day 3 to postnatal day 21, or 

750 mg DEHP/kg/day from gestation day 14 to postnatal day 3, has induced a variety of effects in 

androgen-sensitive tissues of male neonates and infants, including female-like anogenital distance and 

permanent nipples, vaginal pouch, penile morphological abnormalities, hemorrhagic and undescended 

testes, testicular and epididymal atrophy or agenesis, and small to absent sex accessory glands (Gray et al. 

1999, 2000; Moore et al. 2001; Parks et al. 2000). Behavioral observations indicated that many of the 

exposed males were sexually inactive in the presence of receptive control females (Moore et al. 2001). 

The morphological effects and sexual behavioral changes are consistent with an antiandrogenic action of 

DEHP. Other indications of antiandrogenic activity include lack of significant effects on time to vaginal 

opening and first estrus in female offspring of rats that were exposed to $375 mg DEHP/kg/day from 

gestation day 3 to postnatal day 21 (Moore et al. 2001). Additionally, exposure to 750 mg/kg/day from 

gestation day 14 to postnatal day 3 caused significantly reduced testicular testosterone production and 

reduced testicular and whole-body testosterone levels in fetal and neonatal male rats (Parks et al. 2000). 

In vitro assays showed that neither DEHP nor its metabolite MEHP displayed affinity for the human 

androgen receptor at concentrations up to 10 )M (Paganetto et al. 2000; Parks et al. 2000). The findings 

suggest that long-term alterations in the male reproductive system might be a consequence of perinatal 

exposure to DEHP. Available evidence also indicates that DEHP is not an androgen receptor antagonist, 

but acts as an antiandrogen during a critical stage of reproductive tract differentiation by reducing 

testosterone to female levels in the fetal male rat. 

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. 
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Children 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). 

Children are mainly exposed to DEHP orally from mouthing toys and other soft PVC products and 

possibly food, and dermally from handling materials containing DEHP. As discussed in Chapter 6 

(Section 6.6, Exposures of Children), the most likely source of DEHP exposure for young children by the 

oral route might be toys. Other potential sources of oral exposure for young children as well as dermal 

exposure to all children include general household items made from PVC (e.g., dolls, plastic baby pants, 

furniture upholstery, floor tiles, shower curtains, tablecloths, rainwear, and shoes), which are available for 

mouthing by children. Oral exposure might also occur when children handle the PVC items containing 

DEHP and mouth their hands. Indoor exposure is possible from inhalation of both vapor and particle 

bound DEHP as well ingestion following inhalation of large particles containing DEHP and deposition in 

the upper airways and swallowing. Children’s exposures to DEHP from inhalation of outdoor air is likely 

to be small because of the relatively low ambient concentrations. Considerable exposure to DEHP can 

occur from a multitude of plastic medical devices constructed from PVC, but the number of children 

exposed from such devices is very small compared to the population at large. 

As discussed below, there is no evidence that would support the contention that children are more 

susceptible or predisposed to toxicity from DEHP exposure based on inherent biological differences from 

adults. Although they might be more highly exposed to DEHP in certain situations (e.g., during clinical 

procedures), for the vast general public, children are not expected to be more susceptible than adults. 

No studies were located that specifically addressed effects of exposure to DEHP in children. Thus far, 

there is no convincing evidence of adverse health effects in humans exposed to DEHP with the exception 

of an early report by Shaffer et al. (1945) of mild gastric disturbances and moderate diarrhea in an adult 

who swallowed 10 g of DEHP. It is reasonable to expect a similar response in children exposed in a 

similar manner. 

In animals, age might influence the susceptibility to the acute lethal effect of high doses of DEHP. Two 

oral doses of 2,000 mg/kg DEHP caused a high incidence of mortality in #21-day-old rats, but no 

mortality occurred in $42-day-old rats (Dostal et al. 1987a). 

In animals, particularly rats and mice, exposure to DEHP results in liver and testicular toxicity; long-term 

exposures induced liver cancer (David et al. 1999; Kluwe et al. 1982a). DEHP is also embryotoxic and 
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3. HEALTH EFFECTS 

has teratogenic properties (Arcadi et al. 1998; Dostal et al. 1987b; Hellwig et al. 1997; Ritter et al. 1987; 

Tyl et al. 1988). These effects are dose-related and have only been observed at very high doses in 

comparison to known or expected human exposures. Among the effects observed after perinatal 

administration are reduced fetal body weight, increased rates of abortion and fetal resorptions, and 

skeletal malformations. With regard to testicular toxicity, both in vivo and in vitro studies indicate that 

the Sertoli cell is the target for DEHP toxicity (Dostal et al. 1988; Grasso et al. 1993; Gray and Beamand 

1984; Gray and Gangolli 1986; Poon et al. 1997; Sjoberg et al. 1986a, 1986b) and the metabolite MEHP 

is thought to be the active testicular toxicant. Sertoli cell alterations include vacuolization, inhibition of 

seminiferous tubule fluid formation, and altered testicular enzyme activities. In addition, experiments in 

vitro have shown disruption of the Sertoli-germ cell physical interaction (Li et al. 1998). There is some 

evidence that younger animals are more susceptible than older ones to the lethal effects of high DEHP 

doses (Parmar et al. 1994) and to the adverse testicular effects (Gray and Butterworth 1980; Gray and 

Gangolli 1986; Dostal et al. 1987a, 1988; Sjoberg et al. 1986a, 1986b). For example, testicular toxicity 

has been produced following oral exposure of prepubertal rats to DEHP at doses lower than those 

required to cause testicular effects in sexually mature rats. Some of these differences appear to be due to 

differences in pharmacokinetics of absorption and distribution, but there is also evidence for intrinsic 

differences in tissue sensitivity (Gray and Beamand 1984; Li et al. 1998). An increased permeability of 

the blood-testis barrier in children as compared to adults could result in increased testicular exposure to 

DEHP or MEHP (FDA 2001h). The blood-testis barrier forms just before puberty in humans (Furaya 

1978). 

DEHP altered development of the reproductive system in male rat offspring that were exposed to 

$375 mg/kg/day during gestation and lactation. A variety of effects were observed in androgen-sensitive 

tissues of young male rats, including reduced (female-like) anogenital distance and permanent nipples, 

vaginal pouch, penile morphological abnormalities, hemorrhagic and undescended testes, testicular and 

epididymal atrophy or agenesis, and small to absent sex accessory glands (Arcadi et al. 1998; Gray et al. 

1999, 2000; Moore et al. 2001; Parks et al. 2000). These morphological effects, as well as reduced fetal 

and neonatal testosterone levels and adult sexual behavioral changes in male rats following gestational 

and lactational exposure, are consistent with an antiandrogenic action of DEHP. The changes in the 

development, structure, and function of the male reproductive tract indicate that effects of DEHP on 

reproduction and development are interrelated, and that long-term alterations in the male reproductive 

system might be a consequence of perinatal exposure to DEHP. Other evidence indicates that DEHP is 

not an androgen receptor antagonist, but acts as an antiandrogen during a critical stage of reproductive 
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tract differentiation by reducing testosterone to female levels in the fetal male rat (Paganetto et al. 2000; 

Parks et al. 2000). 

A neurobehavioral alteration was observed in 30-day-old offspring of rats that were exposed to DEHP in 

the drinking water at a reported estimated dose of 33 mg/kg/day throughout pregnancy and lactation 

(Arcadi et al. 1998). The pups therefore were exposed both in utero and via breast milk. Exposure 

caused impaired performance in a test designed to assess locomotor activity by employing a learned 

avoidance task (i.e., ability to walk on a beam in order to avoid a negative stimuli). The relevance of this 

finding is unclear because concerns regarding the conduct of the study have been documented 

(particularly with respect to reliability of the dose levels) (NTP 2000b), other neurotoxicity tests were not 

performed (a battery of tests is needed for adequate assessment), and no effects were found in another 

study of DEHP that evaluated several neurodevelopmental measures. In particular, offspring of rats that 

were exposed to DEHP by inhalation in concentrations as high as 300 mg/m3

 for 6 hours/day on 

days 6–15 of gestation showed no postnatal alterations in tests of righting ability on day 6, gripping reflex 

on day 13, pupillar reflex on day 20, and hearing on day 21 (Merkle et al. 1988). 

There is no information regarding possible transgenerational effects of DEHP in humans. A dominant 

lethal test in mice reported no significant effects (pregnancy rate, live fetuses, early and late fetal deaths) 

after treating male mice with DEHP (up to 9,860 mg/kg/day), MEHP (up to 200 mg/kg/day), or 

2-ethylhexanol (up to 1,000 mg/kg/day) and then mating them with virgin females (Rushbrook et al. 

1982). 

No specific information was located regarding the pharmacokinetics of DEHP in children. Analysis of 

urine samples from humans exposed to DEHP suggests the involvement of both phase I and phase II 

metabolic enzymes in the biotransformation and elimination of DEHP. The specific P-450 isozymes 

involved in phase I metabolism are not known with certainty so no conclusions can be drawn based on 

general differences in isozyme activities between adults and children. Phase II reactions involve 

conjugation with glucuronic acid, but the specific isoform of glucuronosyltransferase is not known. 

Compared to adults, children generally have a reduced capacity to metabolize compounds via 

glucuronidation (FDA 2001h). Since approximately 60% of an administered dose of DEHP is excreted as 

the glucuronide conjugate in humans (Albro et al. 1982a, 1982b), a reduced glucuronidation capacity 

could result in delayed excretion of DEHP or its metabolites. FDA (2001h) has speculated that reduced 

glucuronidation capacity could contribute to hepatic effects (e.g., cholestasis) observed in children 

undergoing ECMO therapy who were likely exposed to DEHP leached from plastic tubing used in heart­
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lung bypass circuits. ECMO refers to the use of cardiopulmonary bypass to supplement blood 

oxygenation. The MEHP metabolite of DEHP also undergoes glucuronidation and has been shown to 

interfere with bilirubin conjugation (Sjoberg et al. 1991), possibly as a competitive inhibitor of 

glucuronidation (FDA 2001h). 

DEHP has been detected in human breast milk (FDA 2001h) and therefore can be lactationally transferred 

from nursing mothers to children. Data are unavailable for DEHP in milk from mothers who have 

undergone or are undergoing medical procedures such as hemodialysis, which could result in higher 

levels than healthy mothers (FDA 2001h). It is well established in animals that DEHP (or metabolites) 

can cross the placenta and be transferred via breast milk to the offspring (Arcadi et al. 1998; Dostal et al. 

1988; Hellwig et al. 1997; Peters et al. 1997b; Ritter et al. 1987; Tyl et al. 1988). 

The metabolism of DEHP to the presumed toxic metabolite, MEHP, is achieved by lipases that are mainly 

in the gastrointestinal tract. Gastric lipase activity is high in infants to aid in the digestion of fats in milk, 

peaking in children at 28–33 weeks of age (FDA 2001h; Lee et al. 1993). Consequently, young children 

might be able to convert DEHP to MEHP more efficiently than older children or adults (FDA 2001h). 

No specific information was located regarding nutritional factors that might influence the absorption or 

toxicity of DEHP. Because DEHP might exert toxic effects on the testes through depletion of zinc or 

vitamin E, and both zinc and vitamin E deficiencies are not uncommon in preterm infants due to side 

effects of parenteral nutrition, depletion of these substances could increase the potential for DEHPinduced testicular toxicity (Chan et al. 1999; Obladen et al. 1998; Roth et al. 1988). DEHP could also 

exacerbate zinc and vitamin E deficiencies that occur in preterm infants from other causes (FDA 2001h). 

Unusual lung disorders were observed during the fourth week of life in children that were mechanically 

ventilated as preterm infants (Roth et al. 1988). The effects clinically and radiologically resembled 

hyaline membrane disease, a disorder caused by insufficient surfactant production in the lungs of 

newborn infants. Although interpretation of these findings is complicated by the preexisting 

compromised health status of the preterm infants, the information indicates that the lung disorders were 

related to DEHP released from the walls of PVC respiratory tubes. Due to its lipophilicity, it was 

speculated that DEHP could either inhibit the formation or promote the degradation of lung surfactant in 

immature lungs (Roth et al. 1988), and that this effect is less likely to be seen in adult lungs because of 

the increased ability of adults to produce surfactant (FDA 2001h). 
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There are no biomarkers of exposure or effects for DEHP that have been validated in children or in adults 

exposed as children. No relevant studies were located regarding interactions of DEHP with other 

chemicals in children or adults. No information was located regarding pediatric-specific methods for 

reducing peak absorption following exposure to DEHP, reducing body burden, or interfering with the 

mechanism of action for toxic effects. As for adults, there are no data on methods for reducing toxic 

effects that might be either indicated or contraindicated in children. 

3.8 BIOMARKERS OF EXPOSURE AND EFFECT 

Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as markers of exposure, markers of effect, and markers of susceptibility (NAS/NRC 1989). 

Due to a nascent understanding of the use and interpretation of biomarkers, implementation of biomarkers 

as tools of exposure in the general population is very limited. A biomarker of exposure is a xenobiotic 

substance or its metabolite(s) or the product of an interaction between a xenobiotic agent and some target 

molecule(s) or cell(s) that is measured within a compartment of an organism (NAS/NRC 1989). The 

preferred biomarkers of exposure are generally the substance itself or substance-specific metabolites in 

readily obtainable body fluid(s), or excreta. However, several factors can confound the use and 

interpretation of biomarkers of exposure. The body burden of a substance may be the result of exposures 

from more than one source. The substance being measured may be a metabolite of another xenobiotic 

substance (e.g., high urinary levels of phenol can result from exposure to several different aromatic 

compounds). Depending on the properties of the substance (e.g., biologic half-life) and environmental 

conditions (e.g., duration and route of exposure), the substance and all of its metabolites may have left the 

body by the time samples can be taken. It may be difficult to identify individuals exposed to hazardous 

substances that are commonly found in body tissues and fluids (e.g., essential mineral nutrients such as 

copper, zinc, and selenium). Biomarkers of exposure to DEHP are discussed in Section 3.8.1. 

Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an 

organism that, depending on magnitude, can be recognized as an established or potential health 

impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of 

tissue dysfunction (e.g., inhibited gap junctional intercellular communication, 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 
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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 DEHP 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 DEHP 

As discussed in Section 3.4.1, DEHP and its hydrolyzed derivatives, MEHP and 2-ethylhexanol, are 

absorbed from the intestinal tract, skin, and lungs into the blood (Albro 1986). Once absorbed, they are 

widely distributed in the body, with the liver being the major repository organ. The half-life in humans 

has been estimated as 12 hours (Schmid and Schlatter 1985). DEHP, MEHP, and 2-ethylhexanol are 

rapidly metabolized to a variety of oxidized derivatives, which are excreted in the urine and bile; some 

phthalic acid is also produced. 

DEHP and its metabolites can be measured in the blood and urine to confirm recent exposures. Since 

urine samples will provide equivalent data to blood samples and can be collected using noninvasive 

techniques, urine samples are preferred for monitoring purposes. Analysis of the urine for DEHP is not 

suggested since little DEHP is excreted and measurement of DEHP in biological samples is highly subject 

to false positives from laboratory and sample contamination. Monitoring for MEHP, 2-ethyl5-carboxypentyl phthalic acid, 2-ethyl-5-oxyhexyl phthalic acid, or 2-ethyl-5-hydroxyhexyl phthalic acid 

is more valuable since these are major urinary metabolites in humans (Schmid and Schlatter 1985). 

Particularly useful is a sensitive and highly selective analytical technique that enables exposure to DEHP 

to be specifically monitored by measuring urinary levels of MEHP (Blount et al. 2000b), and thereby 

avoids the ubiquitous contamination problem that limits the biomarker usefulness of direct measurements 

of DEHP. This analytical approach also allows specific biomonitoring of other phthalates by direct 

measurement of their monoester metabolites. Urinary measurements of phthalic acid can be performed, 

either directly or after hydrolysis to convert all phthalate derivatives to phthalic acid, but this is a 

nonspecific biomarker of exposure since other phthalate ester plasticizers, such as butyl benzyl phthalate, 

dibutyl phthalate, and diethyl phthalate, will also produce free phthalic acid after hydrolysis. Additional 

information on analytical methods can be found in Chapter 7. 
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The feasibility of using the monoester metabolites as specific biomarkers of exposure to DEHP and six 

other commonly used phthalates was shown in a study of urine samples collected from 289 adults during 

1988–1994 as part of the Third National Health and Nutrition Examination Survey (NHANES III) 

(Blount et al. 2000a). The monoesters with the highest urinary levels were MEHP (95th percentile, 

3,750 ppb), monobutyl phthalate (294 ppb), and monobenzyl phthalate (137 ppb), reflecting exposure to 

DEHP, dibutyl phthalate, and benzyl butyl phthalate, respectively. Although these measurements 

established a good basis for exposure biomonitoring, further calculations are needed to relate them to 

dose. Estimates based on the urinary MEHP measurements obtained by Blount et al. (2000a) suggest that 

the average total daily ambient exposure of individuals in the United States to DEHP is likely to be 

<3.6 μg/kg/day (David 2000; Kohn et al. 2000). Study populations larger than the 289 individuals 

studied by Blount et al. (2000a) are needed to gain a representative sampling of the exposure of the U.S. 

population to DEHP, including possible demographic variations in exposure and/or metabolism. 

DEHP exposure of humans might result from intravenous administration of blood that has been stored in 

plastic containers, or through hemodialysis. Under situations such as these, in which DEHP is introduced 

directly into the blood, it is possible to evaluate exposure by measuring blood DEHP concentrations. 

DEHP metabolites, MEHP and phthalic acid, are also measured in the blood to determine exposure from 

medical products or devices (Barry et al. 1989; Sjoberg and Bondesson 1985). If the total amount of 

phthalate is to be monitored, the phthalate esters are first de-esterified (Liss et al. 1985). Techniques that 

measure total phthalic acid are not specific for DEHP exposure since other alkyl phthalic acid esters that 

are used as plasticizers will also produce phthalic acid after de-esterification. 

DEHP is lipophilic and tends to migrate into adipose deposits. Since it is cleared from these deposits 

slowly, analysis of fat tissues probably provides the best test for previous exposure to this plasticizer. 

Analysis of human abdominal adipose tissues from accident victims indicated that DEHP was present in 

these tissues at a concentration of 0.3–1.0 ppm (Mes et al. 1974). DEHP was also identified in 48% of 

the adipose tissue specimens from cadavers autopsied in 1982 as part of the Human Adipose Tissue 

Survey from the National Human Monitoring Program (EPA 1989b). Neither study contained data on 

DEHP exposure history of the subjects, however, and there is no information regarding correlation of 

adipose tissue concentrations with DEHP exposure concentration and duration. 
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3.8.2 Biomarkers Used to Characterize Effects Caused by DEHP 

Based on the animal data, the most consistent effect of exposure to DEHP is the increase in the 

concentration of liver peroxisomes. This effect occurs to varying degrees in all species that have been 

evaluated. However, evidence for an effect of DEHP exposure on human liver peroxisomes is weak. 

Limited data regarding biopsies from human livers, under circumstances in which DEHP was present in 

the hemodialysis equipment, did not lead to meaningful conclusions (Ganning et al. 1984, 1987). 

Therefore, a liver biopsy with subsequent histopathological examination of the cells would seldom if ever 

be justified as a test for the long-term effects of DEHP exposure due to the difficulties associated with this 

procedure. 

Lipofuscin deposits in the liver might also be used as an indication of prolonged DEHP exposure based 

on the results of animal studies (Mitchell et al. 1985b). However, there are no data that indicate that this 

marker of DEHP toxicity in animal studies occurs in the human liver. In addition, lipofuscin production 

is not specific to DEHP; therefore a highly invasive liver biopsy to obtain a tissue sample for lipofuscin 

identification cannot be recommended. 

3.9 INTERACTIONS WITH OTHER CHEMICALS 

Limited information was located regarding possible interactions of DEHP with other chemicals in 

humans. Urinary measurements of the monoester metabolites of seven common phthalates in 289 adults 

from the U.S. population, determined using the selective and sensitive analytical approach discussed in 

Section 3.8.1 (Biomarkers Used to Identify or Quantify Exposure to DEHP), showed detectable levels of 

monoethyl phthalate (95th percentile concentration, 3,750 ppb), monobutyl phthalate (294 ppb), 

monobenzyl phthalate (137 ppb), 2-ethylhexyl phthalate (21.5 ppb), cyclohexyl phthalate (8.6 ppb), 

isononyl phthalate (7.3 ppb), and octyl phthalate (2.3 ppb), reflecting exposure to DEHP, dibutyl 

phthalate, benzyl butyl phthalate, di-(2-ethylhexyl) phthalate, dicyclohexyl phthalate, di-isononyl 

phthalate, and dioctyl phthalate, respectively (Blount et al. 2000a). Considering evidence such as this 

which indicates that co-exposure to multiple phthalates can occur, as well as the likelihood that many of 

these compounds exert effects via a common mechanism of action, there is a potential for interactions 

between DEHP and other phthalate esters. 

Human mononuclear leukocytes were isolated from healthy young adults and incubated with 

0.1–10,000 nM DEHP (Sager and Little 1989). There was no change in cell viability after 1 hour of 
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exposure to even the highest DEHP concentration, and no change in the binding of propyl2,3-dihydroalprenol (DHA), a β-adrenergic blocker drug, to the α-1 glycoprotein β-adrenergic membrane 

binding site. DEHP did, however, displace DHA from its low affinity sites on the mononuclear 

leukocytes. This suggests that DEHP could potentially affect the pharmacology of the β-adrenergic class 

of pharmaceuticals, but further study is needed in animals before a conclusive statement can be made. 

Additional information on interactions of DEHP with other chemicals was identified in animal studies. In 

most instances both the levels of DEHP and the interactant were high relative to potential environmental 

exposures. 

DEHP effects on the peroxisomal system of the liver appeared to be increased in rats kept on a choline 

deficient diet (Perera et al. 1986). This conclusion was based on an increase in the conjugated dienes in 

the microsomes of choline-deficient animals exposed to 500 mg/kg DEHP for 4 weeks. Conjugated 

dienes are indicators of free radical oxygen modification of cellular lipids. 

In studies of the effects of DEHP ingestion on the metabolism of ethanol, there was a distinct difference 

between the action of single doses of 1,500–7,500 mg/kg DEHP and the same doses given over a 7-day 

period (Agarwal et al. 1982b). The single dose appeared to decrease the metabolism of intraperitoneal 

ethanol, given 18 hours after DEHP, as reflected by an increase in the ethanol-induced sleeping time of 

the exposed rats and inhibition of hepatic alcohol dehydrogenase activity. On the other hand, when 

DEHP was given for 7 days before the ethanol, the ethanol-induced sleeping time was decreased and the 

activities of both alcohol and aldehyde dehydrogenase were increased. This indicates the changes in 

sleeping time were the result of more rapid metabolic removal of the alcohol from the system in the rats 

treated with repeated doses of DEHP and slower metabolism in the rats given one dose. 

Companion in vitro studies of the effects of DEHP, MEHP and 2-ethylhexanol on the activities of alcohol 

and aldehyde dehydrogenase indicate that it is the metabolites of DEHP that affect the enzymes rather 

than unmetabolized DEHP (Agarwal et al. 1982b). The authors suggest that 2-ethylhexanol acts as a 

competitive inhibitor of alcohol dehydrogenase when a single dose of DEHP is administered. When 

DEHP exposure has occurred for several days prior to ethanol exposure, the liver has adjusted to the 

metabolic demands of the 2-ethylhexanol. Thus, at the time of ethanol ingestion, most of the 

2-ethylhexanol has been metabolized and the capacity of the liver to metabolize the ethanol has been 

expanded due to the induction of the alcohol metabolizing enzymes. 
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Data are available suggesting that DEHP might act as an antagonist for the hepatic damage caused by 

other chemicals. DEHP was combined with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to determine if 

the hypolipidemic effects of DEHP could counteract the hyperlipidemic effects of the TCDD 

(Tomaszewski et al. 1988). Pretreatment with DEHP mitigated many of the toxic effects of TCDD. 

There was a 50% decrease in TCDD-related mortality when the rats received DEHP pretreatment. DEHP 

administered after TCDD administration had considerably less of an effect on TCDD toxicity, but did 

alleviate the TCDD toxic effects to a slight extent. The authors postulated that the antagonist properties 

of DEHP could have resulted from either or both of two mechanisms. One possible mechanism is a 

reduction in TCDD-induced hyperlipidemia by DEHP stimulation of peroxisomal lipid metabolism. A 

second explanation is that DEHP altered the hepatic distribution of the TCDD. 

Intermediate-duration oral studies in rats have shown that high doses of DEHP can affect thyroid cell 

structure (e.g., hypertrophy of Golgi apparatus, increases in lysosomes, dilation of the endoplasmic 

reticula, and increase in colloid droplets) and function (e.g., decrease levels of circulating T4) (Hinton et 

al. 1986; Poon et al. 1997; Price et al. 1987, 1988a). When large oral doses of 500 and 2,500 mg/kg/day 

DEHP were combined with dietary exposure to a compound which has similar effects on the thyroid 

(Aroclor 1254, a polychlorinated biphenyl mixture), there was an apparent additive effect of the two 

compounds on changes in thyroid cell structure and decreases in serum T3 and T4. At lower doses of 

DEHP (50 and 100 mg/kg/day) and Aroclor 1254 there were no additive effects apparent with the 

changes in cell structure or the levels of T3 and T4. 

A combination of 150 mg/kg caffeine administered by injection to pregnant rats in conjunction with a 

single dose of 9,756 mg/kg DEHP on day 12 of gestation caused a 5-fold increase in the number of dead 

and resorbed fetuses and nearly a 4-fold increase in the malformed survivors as compared to the effects of 

DEHP alone (Ritter et al. 1987). The mean fetal weight was also depressed. The addition of the caffeine 

to the treatment using equimolar quantities of 2-ethylhexanol and 2-ethylhexanoic acid at doses half of 

the molar quantity used for DEHP resulted in 2–30-fold increases in the dead and malformed fetuses and 

malformed survivors, but only minor decreases in the fetal weights. 

Interactions between DEHP, trichloroethylene, and heptachlor on developmental toxicity have been 

investigated (Narotsky et al. 1995). The compounds were administered to rats by gavage on days 6–15 of 

gestation singly and in combination using five dose levels of each in a 5x5x5 factorial design. The dose 

levels were 0, 24.7, 78, 247, and 780 mg/kg/day for DEHP; 0, 10.1, 32, 101, and 320 mg/kg/day for 

trichloroethylene; and 0, 0.25, 0.8, 2.5, and 8 mg/kg/day for heptachlor. End points that were analyzed 
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for possible interactions of the three chemicals included maternal death, maternal body weight gain on 

gestation days 6–8 and 6–20, full-litter resorption, prenatal loss, postnatal loss, pup body weight on 

postnatal days 1 and 6, and pups/litter with eye defects. Statistical analysis of the three maternal and six 

developmental end points yielded several significant two-way interactions. DEHP and heptachlor showed 

synergism for maternal death on gestation days 6–8 and antagonism for maternal weight gain on gestation 

days 6–8, full-litter resorption, and pup weight on postnatal days 1 and 6. DEHP and trichloroethylene 

were synergistic for maternal weight gain on gestation days 6–8, prenatal loss, and pup weight on 

postnatal day 6. No significant three-way interactions were observed. 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 

A susceptible population will exhibit a different or enhanced response to DEHP than will most persons 

exposed to the same level of DEHP 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 may result in reduced detoxification or excretion of DEHP, or compromised function of 

organs affected by DEHP. Populations who are at greater risk due to their unusually high exposure to 

DEHP are discussed in Section 6.7, Populations With Potentially High Exposures. 

Although certain subpopulations (e.g., dialysis patients and ECMO infants) are likely to be more highly 

exposed to DEHP than the general population, there are few indications of people with intrinsic, 

biological polymorphisms or conditions that preferentially make them unusually susceptible to DEHP 

toxicity. 

No data were located that suggest there are populations genetically at risk to DEHP toxicity, but the issue 

of PPAR polymorphism is beginning to be explored (Tugwood et al. 1996). However, there is strong 

evidence that humans, like other nonrodent species, are less susceptible than rodents to peroxisome 

proliferation after exposure to DEHP. 

Data discussed in the sections on metabolism and reproductive effects suggest that the very young and the 

elderly might also bear an increased risk to DEHP toxicity if the response of humans is similar to that of 

rats and mice. The suggestion has been made that newborn infants with hyalin membrane disease due to 

immature lungs might be at risk from exposure to DEHP if they are exposed through respiration 

equipment during the postnatal period, due to interference with formation or turnover of alveolar 

surfactant (Roth et al. 1988). This possibility is not strongly supported because it is based on a limited 
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data base consisting of one study. Based on rodent data, testicular damage and brain damage are more 

likely to occur with exposures during the prenatal or early postnatal period (Arcadi et al. 1998; Cimini et 

al. 1994; Dabholkar 1988; Dostal et al. 1988; Tyl et al. 1988). 

Physiological and pharmacodynamic changes that occur in critically ill or injured patients might place 

them at increased risk for developing adverse health effects following exposure to DEHP released from 

PVC plastic medical devices used in various procedures including blood transfusion, cardiopulmonary 

bypass, and ECMO (FDA 2001h). As discussed in Children’s Susceptibility (Section 3.7), factors that 

increase the lipase-mediated metabolism of DEHP to MEHP, or the metabolism of MEHP via 

glucuronidation, will increase the potential for DEHP to induce adverse effects in exposed patients. 

Additional factors that can place patients at increased risk include increased reduced renal elimination 

capacity, uremia, protein malnutrition, reduced levels of antioxidants, and impaired cardiovascular status 

(FDA 2001h). 

Limited evidence from animal studies suggests that aged rats excrete lower quantities and different 

proportions of DEHP metabolites than young rats (Albro et al. 1983). However, it is not clear whether 

age-related shifts in DEHP metabolism, or impaired liver function could exacerbate the harmful effects of 

DEHP on this organ. 

3.11 METHODS FOR REDUCING TOXIC EFFECTS 

This section will describe clinical practice and research concerning methods for reducing toxic effects of 

exposure to DEHP. 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 DEHP. When specific 

exposures have occurred, poison control centers and medical toxicologists should be consulted for 

medical advice. 

No texts were located that provided specific information about treatment following exposure to DEHP. 

Most of the strategies discussed in this section will apply to high dose exposures and are consistent with 

guidelines generally recommended for reducing exposure to a variety of toxicants. The balance between 

the benefits and detriments of mitigation for low dose chronic exposures might differ from those for high 

dose exposures. Methods to reduce toxic effects should not be applied indiscriminately to individuals 

exposed to all doses of DEHP; good clinical judgement should be used. 
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3.11.1 Reducing Peak Absorption Following Exposure 

After acute dermal or ocular exposure due to DEHP spills or other accidents, contaminated clothing 

should be removed and exposed skin thoroughly washed with soap and water (HSDB 2000). Exposed 

eyes should be flushed with a clean neutral solution such as water or saline. 

A number of strategies have been suggested to minimize absorption from the gastrointestinal tract 

following acute, high dose ingestion. Introducing emesis is generally discouraged because DEHP can 

irritate the esophagus (HSDB 2000). Gastric lavage can remove DEHP from the stomach if the ingestion 

was recent (within 60 minutes) (HSDB 2000). Ingestion of activated charcoal is one method for reducing 

the intestinal absorption of DEHP since DEHP will adsorb to the carbon surface and be excreted with the 

fecal matter (HSDB 2000). Another method for reducing absorption is the use of a cathartic. In practice, 

activated charcoal is frequently given as a slurry in saline or sorbitol cathartics (HSDB 2000). Specific 

DEHP-binding or DEHP-reactive agents which might prevent absorption are currently not available. 

3.11.2 Reducing Body Burden 

In most species, including humans, DEHP is hydrolyzed in the gut to MEHP and 2-EH. Orally absorbed 

MEHP is probably distributed first to the liver where it is partially metabolized and then distributed to the 

rest of the body. Identification of the rate limiting step in metabolism and excretion of MEHP, and 

methods to accelerate it, might be helpful in designing future mitigation strategies. Most of the oxidized 

DEHP metabolites are conjugated with glucuronic acid in humans; excretion is in the bile and urine 

(Albro et al. 1982a). Fecal metabolites have been measured, but not quantitatively compared with 

metabolites secreted from the bile duct; thus it is unclear whether enterohepatic recirculation occurs. If 

significant enterohepatic recirculation were to be demonstrated, methods to interfere with re-uptake of 

DEHP metabolites into circulation might be effective in accelerating their excretion. Potential strategies 

for reducing intestinal resorption of bile excretions include repeated doses of activated charcoal (Levy 

1982) and oral administration of the anion exchange resin, cholestyramine (Boylan et al. 1978). Neither 

of these approaches to promoting DEHP excretion has been studied in humans or animals, and they would 

only be useful for higher doses. 
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3.11.3 Interfering with the Mechanism of Action for Toxic Effects 

Significant advances have been made in recent years in the understanding of the mechanisms of liver 

carcinogenicity of DEHP in rats and mice. However, there is increasing mechanistic evidence suggesting 

that rats and mice are not an appropriate model for extrapolating to humans (Cattley et al. 1998; Doull et 

al. 1999; Huber et al. 1996). Therefore, speculation on how to prevent liver cancer in humans based on 

information in rodents seems without scientific basis. 

Experiments in rats have shown that simultaneous treatment with DEHP and vitamins C and E prevents 

the testicular atrophy observed when rats are treated with DEHP alone (Ishihara et al. 2000). However, 

none of these theoretical interventions have been studied in DEHP-poisoned patients, and they are not 

currently recommended in human clinical medicine. The effect of a low protein diet on toxicity of DEHP 

in rats was addressed in a study by Tandon et al. (1992). Animals maintained on a low protein diet were 

more susceptible to DEHP-induced testicular damage than animals receiving a normal protein diet. 

However, the effects of a high protein diet were not examined and potential interactions of diet and DEHP 

toxicity have not been studied in humans. 

Albro et al. (1989) suggests that testicular toxicity is due partially to depletion of zinc in the tissue, 

although it is unknown whether whole body stores are depleted by DEHP. If it were to be shown that 

body stores of zinc are generally depleted, then oral zinc supplementation could conceivably reduce the 

testicular toxicity. The success of this strategy would depend on whether the amount of oral zinc needed 

to increase testicular zinc levels is substantially less than that which causes zinc toxicity. Studies of zinc 

supplementation in rats (Agarwal et al. 1986; Oishi and Hiraga 1983) have produced conflicting data. 

Oishi and Hiraga (1983) found that concurrent treatment of rats with DEHP and zinc did not prevent 

testicular atrophy and did not increase the concentration of zinc in the testes, although the concentration 

of zinc in the liver and serum was increased by supplementation. In contrast Agarwal et al. (1986) found 

that pretreatment with a diet containing higher than normal concentrations of zinc prevented DEHPinduced reductions in body weight gain and testicular damage, but did not reduce liver damage due to 

DEHP. However, the relevance of the protective effects of zinc on testicular atrophy in rats is unclear 

because induction of testicular toxicity by DEHP in humans has not been demonstrated. Oishi (1994) 

found that simultaneous administration of DEHP (2,000 mg/kg/day) and the vitamin B12 derivative 

adenosyl cobalamine for 7 days protected against the DEHP-induced testicular toxicity in rats, but not 

against the liver toxicity. Also, a different vitamin B12 derivative, methyl cobalamine, was ineffective in 

protecting against either testicular or liver DEHP-induced toxicity. 
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It is not known with certainty whether any of DEHP phase I metabolites are less toxic than the others, so 

shifting the metabolism toward phthalic acid or a particular oxidized phthalate derivative might not 

change the toxicity. 

Mitigation strategies developed for other peroxisome proliferators such as the fibric acid drugs should be 

investigated for their applicability to DEHP. Consideration should be given to the fact that other 

peroxisome proliferators, such as trichloroethylene, might be commonly found at the same NPL sites and 

toxic interactions could occur. 

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 DEHP 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 DEHP. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

3.12.1 Existing Information on Health Effects of DEHP 

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to 

DEHP are summarized in Figure 3-6. The purpose of this figure is to illustrate the existing information 

concerning the health effects of DEHP. 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 
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3. HEALTH EFFECTS 

Figure 3-6. Existing Information on Health Effects of DEHP 
DI(2-ETHYLHEXYL)PHTHALATE 157 

3. HEALTH EFFECTS 

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. 

Few health effects have been associated with exposure to DEHP in humans as indicated in Figure 3-6. 

The data that exist relating to the inhalation and chronic systemic effects in humans originate from 

medical case studies following exposure to DEHP through respiration and hemodialysis equipment. The 

data are insufficient to allow for any correlation of dose and response, and there are many confounding 

variables that preclude reaching any conclusions concerning cause-and-effect relationships. The existing 

acute systemic exposure data originate from voluntary exposures of a small number of humans to daily 

doses of 0.01–10 g DEHP for periods of 1 or 4 days. The only parameters measured were urinary 

excretion and clinical signs. 

The animal database on the health effects of DEHP is more complete, especially for studies using the oral 

route (Figure 3-6). Most studies have been conducted in rodent species, particularly rats and mice, using 

acute, intermediate, and chronic exposure durations. However, results are available from monkey studies 

as well. Systemic investigations have focused on the liver. There are limited data for the kidney, thyroid, 

and pancreas. There are limited data from in vivo studies of immune function or neurotoxicity. On the 

other hand, there are a number of studies that have evaluated the developmental and reproductive effects 

of DEHP. There is also adequate information to demonstrate that DEHP is not genotoxic in any 

conventional in vivo or in vitro studies of genotoxicity. The hepatic carcinogenic potential of DEHP has 

been clearly demonstrated in rodents. 

As is apparent from Figure 3-6, there are minimal data on health effects following dermal absorption. In 

addition, there were only two studies on toxicokinetics that used the dermal exposure route. Although 

there are several animal studies that evaluated the health effects of DEHP through the respiratory route, 

these studies are also limited in scope. In each case, exposures were at very low levels and without effect. 

Although the exposure concentrations were relevant to human exposures through inhalation, the lack of 

observed effects makes it difficult to evaluate whether there are specific risks that apply to respiratory 

exposures. 
 

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As indicated above and discussed below, the health effects of DEHP are generally well characterized by 

the oral route in laboratory animal models. While additional information is always desirable, from a 

health assessment perspective, there appear to be few overriding needs for additional toxicological 

information for the principal route of human exposure to DEHP. Of particular importance are additional 

data that could enable derivation of an acute-duration oral MRL, which is currently precluded by 

insufficient information on male reproductive system development in offspring acutely exposed during 

gestation and/or lactation. 

3.12.2 Identification of Data Needs 

Acute-Duration Exposure. No human data are available for acute exposures following any route 

except through incidental, iatrogenic exposures from medicinal practices and a limited oral study. 

Additional efforts to quantify these exposures and measure their effects on target tissues such as the liver 

and kidney would be useful when such research efforts are consistent with standard medical practices. 

No data are available in animals from standard studies of acute toxicity using the inhalation or dermal 

routes of exposure. Therefore, an MRL value for acute inhalation exposures cannot be derived. DEHP 

concentrations in the atmosphere are limited by the low vapor pressure of this compound. Dermal 

absorption of neat DEHP is demonstrated as minimal (Deisinger et al. 1991; Melnick et al. 1987). 

Specific acute toxicity studies of exposures by the inhalation and dermal routes are probably not justified 

since exposure by these routes is thought to contribute minimally to body burden. 

The liver and testes are primary targets for acute oral exposure to DEHP in adult and developing animals. 

When rodents are exposed to DEHP through the oral route, there is an almost immediate increase in 

mitotic cell division in the liver and a corresponding increase in liver weight (Barber et al. 1987; Berman 

et al. 1995; David et al. 1999; DeAngelo et al. 1986; Dostal et al. 1987a, 1987b; Lake et al. 1986; Lamb 

et al. 1987; Marsman et al. 1988; Mitchell et al. 1985b; Oishi 1989a, 1994; Parmar et al. 1988; Rao et al. 

1990; Rhodes et al. 1986; Takagi et al. 1990; Tamura et al. 1990; Tomaszewski et al. 1988; Tyl et al. 

1988). The number of liver peroxisomes increases and there is induction of the peroxisomal enzyme 

activities (David et al. 1999; Ganning et al. 1989; Rhodes et al. 1986). The activity of the MFO system is 

also increased (Ganning et al. 1989; Hodgson 1987; Hosokawa et al. 1994; James et al. 1998; Parmar et 

al. 1988; Rhodes et al. 1986; Short et al. 1987). An increase in cell division is apparent within 24 hours 

of administration. Further efforts to define dose-response relationships and to identify cell division and 

enzyme induction thresholds would be valuable. Since the pharmacokinetics and metabolism of DEHP 
 

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appear to differ between rodents and primates, it would be informative to study these phenomena in the 

primate. In addition to the liver, the testes (Dostal et al. 1988; Gray and Butterworth 1980; Gray and 

Gangolli 1986; Oishi 1986, 1994; Saitoh et al. 1997; Sjoberg et al. 1986a, 1986b) is a target tissue in 

rodents following DEHP exposures. Continued research to elucidate the mechanism of Sertoli cell 

toxicity and the role of PPARs in the reproductive toxicity of DEHP is necessary. 

Acute exposure to DEHP also induces fetotoxicity and teratogenicity in rats and mice (Dostal et al. 

1987b; Hellwig et al. 1997; Shiota and Mima 1985; Tomita et al. 1982a; Yagi et al. 1980). No 

mechanism to explain these effects has yet been proposed; thus, further studies to explore this issue are 

warranted. An acute oral MRL was not derived because of concern that the highest NOAEL identified 

(50 mg/kg/day) below all LOAELs might not be protective for testicular effects that might occur in rat 

pups exposed to DEHP in utero for acute-duration exposures. Pharmacokinetics data are available in 

various animal species. 

Intermediate-Duration Exposure. No human data were located concerning intermediate-duration 

exposures of humans to DEHP by any route. No data were located from animal studies after inhalation or 

dermal exposures. Therefore, MRL values cannot be determined for intermediate-duration exposures by 

the inhalation route. Due to the low vapor pressure of DEHP and its poor dermal absorption, and the fact 

that the contribution of the inhalation and dermal routes of exposure to body burden is considered 

minimal, specific studies of intermediate-duration exposures and dose-response pattern by the inhalation 

and dermal routes do not appear justified. 

Animal data from oral exposure studies indicate that the liver (Barber et al. 1987; David et al. 1999; Lamb 

et al. 1987; Mitchell et al. 1985b; Poon et al. 1997) and testes (Gray and Butterworth 1980; Lamb et al. 

1987; Parmar et al. 1995; Poon et al. 1997) are main systemic targets for DEHP toxicity following 

intermediate-duration exposure, although some studies also reported kidney effects (Maruyama et al. 

1994; Poon et al. 1997; Ward et al. 1998). Perinatal exposure to DEHP for intermediate-duration periods 

also caused fetotoxicity and teratogenicity in rats and mice (Arcadi et al. 1998; Cimini et al. 1994; 

Nikonorow et al. 1973; Shiota et al. 1980; Tyl et al. 1988). The Arcadi et al. (1998) study reported liver, 

kidney, and testicular alterations in neonatal rats whose mothers were exposed to DEHP during gestation 

and for 21 additional days postnatally. The LOAEL for this effect was much lower than those for other 

end points; however, this study has been judged to be inadequate for MRL derivation because the NTPCERHR Expert Panel on DEHP (NTP 2000b) concluded that the effect levels are unreliable. In 

particular, NTP (2000b) found that (1) the methods used to verify and characterize the administered doses 
 

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were not clearly described or completely reported, and could not be resolved, and (2) the study authors 

did not reconcile their blood DEHP concentration data with other studies. Therefore, it appears that some 

additional dose-response studies on liver, kidney, testis, and behavioral end points would be useful, 

particularly to verify that the basis for the intermediate-duration oral MRL, reproductive toxicity in mice 

(Lamb et al. 1987), is the most sensitive end point for repeated oral exposures. Research efforts should 

concentrate on examining the relationship between exposure during various developmental periods and 

the reversibility of the effects seen in the young and trying to elucidate the mechanism(s) of fetotoxity and 

teratogenicity. Pharmacokinetics data are available in various animal species; however, there is lack of 

information regarding the pharmacokinetics of placental transfer as well as transfer of DEHP or 

metabolites via breast milk to offspring, although DEHP has been detected in human milk (FDA 2001h). 

Chronic-Duration Exposure and Cancer. Data concerning chronic exposures of humans to 

DEHP were not identified in the available literature. A chronic inhalation MRL was not derived from the 

data from the one existing chronic animal inhalation study due to the limited number of end points that 

were evaluated (longevity and cancer incidence). Due to the fact that the vapor pressure of DEHP is very 

low and the impact on body burden of DEHP following inhalation and dermal exposure is expected to be 

minimal relative to oral exposure, specific studies of chronic inhalation exposures to DEHP are not 

recommended at this time. 

There are many studies of oral chronic exposure durations in animals that indicate that the liver 

(Carpenter et al. 1953; David et al. 1999, 2000a, 2000b; Ganning et al. 1991; Lake et al. 1987; Marsman 

et al. 1988; Rao et al. 1987) and testes (David et al. 2000a, 2000b; Ganning et al. 1991; Kluwe et al. 

1982a; Price et al. 1987) are main targets for DEHP. Sporadic effects in the kidneys (Crocker et al. 

1988), pancreas (Rao et al. 1990), and pituitary (Kluwe et al. 1982a) also have been reported. The lowest 

LOAEL identified following chronic exposures is from a study where an increase in inflammation and 

cystic tubules were seen in the rat kidney and there was a statistically significant decrease in creatinine 

clearance with a gavage dose of 0.92 mg/kg/day over a 12-month period (Crocker et al. 1988). The 

significance of these findings is unclear due to a small number of animals, treatment of some rats with a 

leachate from an artificial kidney unit, limited information on kidney evaluation procedure, unreported 

strain and sex, and bolus method of exposure. There also was no accompanying measurement of hepatic 

toxicity in the exposed animals. The doses were also given for 3 of every 7 days rather than daily. No 

other chronic-duration study observed renal effects in rats even at much higher doses ($600 mg/kg/day). 

Therefore, a more systematic evaluation of renal effects following long-term oral administration of DEHP 

would be useful. Perhaps of greater concern is the report of testicular toxicity in rats in a 2-year feeding 
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study by Ganning et al. (1991) since the testis is a known target for DEHP. Little detail was provided by 

Ganning et al. (1991) other than stating that the lowest dose (approximately 14 mg/kg/day) “exerted a 

pronounced effect on the function of the testis after prolonged treatment, consisting of inhibition of 

spermatogenesis and general tubular atrophy.” This effect was considered a serious LOAEL, and 

therefore, it was not considered suitable for chronic oral MRL derivation. A chronic MRL was based on 

a NOAEL of 5.8 mg/kg/day for testicular pathology in male rats from a comprehensive 104-week toxicity 

study (David et al. 2000a). 

There is no evidence that exposure to DEHP causes cancer in humans. Long-term oral administration of 

DEHP caused liver cancer in rats and mice (David et al. 1999; Hayashi et al. 1994; Kluwe et al. 1982a; 

NTP 1982). Great advances have been made in recent years with regard to the mechanism of liver 

carcinogenicity in rodents, particularly rats and mice, induced by peroxisome proliferators. As discussed 

in Section 3.5.2, Mechanisms of Toxicity, and Section 3.5.3, Animal-to-Human Extrapolations, the 

existing information suggests that rats and mice represent an inappropriate model for evaluating the risk 

of developing liver cancer by humans. The central element to developing liver cancer in rats and mice is 

the activation of a nuclear receptor, PPARα, which regulates the pleiotropic effects of peroxisome 

proliferators including the regulation of gene expression. Activation of PPARα leads to increased activity 

of peroxisomal enzymes of β-oxidation and of microsomal enzyme cytochrome P-4504A1. This is 

accompanied by increased cell replication which, along with increased production of hydrogen peroxide, 

are proposed to be the main mechanisms of peroxisome proliferator-induced hepatocarcinogenesis 

(Cattley et al. 1998; Doull et al. 1999; Green 1995; Lake 1995). Humans have low liver expression of 

PPARα and are refractory to peroxisome proliferators, and so are primates. Future research should focus 

on (1) further characterization of the human PPARα and its tissue distribution, (2) studies of mechanisms 

by which the low receptor expression could be altered (increased) resulting in human responses to 

peroxisome proliferators similar to rodents, (3) better understanding on how peroxisome proliferators and 

fatty acids activate PPRAα, (4) examination of possible polymorphism of PPARs in populations of 

different ethnic backgrounds, (5) characterization of the interaction between hypolipidemic drugs and 

PPARα resulting in reduced serum triglycerides, but no stimulation of peroxisome proliferation, and (6) 

characterization of other PPAR subtypes, such as PPAR γ, and their tissue distribution and role in other 

DEHP-induced toxicities, such as reproductive toxicity. 

Populations occupationally exposed to DEHP as well as subjects exposed through medical devices should 

continue to be monitored for liver effects. 
 

 

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Additional bioassays in animals do not seem necessary. Further research on dose-response relationships 

for the many biochemical effects of peroxisome proliferators leading to liver cancer in rodents, 

identification of specific thresholds, and potential reversibility, would be informative only if an 

extrapolation model for cancer was deemed appropriate in spite of profound differences between human 

and rodent responses. 

Genotoxicity. The genotoxicity of DEHP and its primary metabolites, MEHP and 2-ethylhexanol, has 

been extensively evaluated in most standard short-term tests of genetic toxicity. The data are consistent 

and indicate that DEHP, MEHP, and 2-ethylhexanol are not genotoxic. 

The role of oxidative DNA damage, as measured by induction of 8-hydroxydeoxyguanosine (8-OH-dG), 

in the liver of rats following DEHP exposure has been examined by Takagi and coworkers (Sai-Kato et 

al. 1995). While increased induction of 8-OH-dG was demonstrated, the increased was small (2–3-fold) 

and, in some cases, was not sustained during prolonged treatment (Cattley and Glover 1993). Additional 

studies might be valuable to clarify whether nuclear DNA is, in fact, oxidized following treatment with 

DEHP by analyzing repair enzyme activity and/or excised base levels in the urine, along with oxidative 

DNA products other than 8-OH-dG. Studies to compare 8-OH-dG levels in purified nuclear DNA from 

DNA of mitochondria from hepatocytes and nonparenchymal liver cells from control and DEHP-treated 

rats would resolve the issue of whether the 8-OH-dG issue is relevant to DEHP genotoxicity or 

mitogenesis. These data would provide additional information on whether or not free radical oxidation 

resulting from peroxisome proliferation plays a role in the carcinogenesis of DEHP in rodents. 

Reproductive Toxicity. There are no reported reproductive effects of DEHP in humans, but there is 

ample evidence that DEHP has adverse effects on reproductive effects in rats and mice. In males, 

exposure to DEHP affects the weight of the male reproductive organs and the process of spermatogenesis 

(Dostal et al. 1988; Ganning et al. 1991; Gray and Butterworth 1980; Gray and Gangolli 1986; Lamb et 

al. 1987; Oishi 1986; Parmar et al. 1995; Poon et al. 1997; Saitoh et al. 1997; Shaffer et al. 1945; Sjoberg 

et al. 1986a, 1986b; Ward et al. 1998). Effects are seen after acute-, intermediate-, and chronic-duration 

exposure, and NOAELs for testicular and reproductive toxicity were used as the basis of the intermediate 

and chronic oral MRLs as discussed in Chapter 2 and detailed in Appendix A. The effects of DEHP are 

most severe when they occur during the process of male sexual organ development or maturation, and 

thus are age related (Arcadi et al. 1998; Dostal et al. 1988; Gray and Butterworth 1980; Gray et al. 1999, 

2000; Moore et al. 2001; Parks et al. 2000; Sjoberg et al. 1985b, 1986a, 1986b). However, the testicular 

changes appear to be reversible if DEHP exposure ceases before puberty (Dostal et al. 1988). The data on 
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the testicular toxicity of DEHP indicate that the Sertoli cell is the main target and that MEHP is the 

ultimate active testicular toxicant (Chapin et al. 1988; Creasy et al. 1986; Gray and Beamand 1984; Gray 

and Gangolli 1986; Sjoberg et al. 1986b). Since pharmacokinetic data indicate that DEHP is converted to 

MEHP primarily in the gastrointestinal tract, oral studies seem most relevant. Additional research on the 

mechanism of Sertoli cell toxicity and on the characterization of PPARγ and its role in DEHP-induced 

reproductive toxicity is necessary (Maloney and Waxman 1999; Peters et al. 1997b). Further studies that 

directly examine the susceptibility of PPARγ target genes in various tissues and species to MEHP would 

be valuable. A physiologically based pharmacokinetic (PBPK) model of DEHP in rats that simulates the 

pharmacokinetics of both DEHP and its major metabolite, MEHP was recently described (Keys et al. 

1999). The model provides an approach to estimating doses of MEHP in the testes of the rat following 

oral doses of DEHP and might be useful for internal dose-response assessment of rat bioassay data in 

which the toxicity end point of interest is testicular toxicity. However, such uses of the model, or other 

potential uses in risk assessment, have not been evaluated. 

DEHP altered development of the reproductive system in male rat offspring that were exposed during 

gestation and lactation. A variety of effects were observed in androgen-sensitive tissues of young male 

rats, including reduced (female-like) anogenital distance and permanent nipples, vaginal pouch, penile 

morphological abnormalities, hemorrhagic and undescended testes, testicular and epididymal atrophy or 

agenesis, and small to absent sex accessory glands (Arcadi et al. 1998; Gray et al. 1999, 2000; Moore et 

al. 2001; Parks et al. 2000). These morphological effects, as well as reduced fetal and neonatal 

testosterone levels and adult sexual behavioral changes in male rats following gestational and lactational 

exposure, are consistent with an antiandrogenic action of DEHP. The changes in the development, 

structure, and function of the male reproductive tract indicate that effects of DEHP on reproduction and 

development are interrelated, and that long-term alterations in the male reproductive system might be a 

consequence of perinatal exposure to DEHP. Other evidence indicates that DEHP is not an androgen 

receptor antagonist, but acts as an antiandrogen during a critical stage of reproductive tract differentiation 

by reducing testosterone to female levels in the fetal male rat (Paganetto et al. 2000; Parks et al. 2000). 

Because the dose-response relationships for reproductive effects following exposures in gestational versus 

postnatal ages are unknown, low-dose studies examining sensitive end points following late gestational 

exposure are a critical data need. 

The mechanism of the effect of DEHP on the female reproductive processes has not been studied as 

extensively as that of the male. Female mice orally exposed to high doses of DEHP (420 mg/kg/day) 

failed to produce any litters when mated with control males (Lamb et al. 1987). DEHP affected female 
 

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fertility and pup survival in cases where pregnancy was achieved. A reproductive toxicity NOAEL of 

14 mg/kg/day from this study was used as the basis of the intermediate oral MRL. Information on the 

dose-response relationship for these effects as reflected in DEHP's impact on ovulation, implantation, and 

the early stages of gestation would be useful. It would also be useful to know if the metabolite 

responsible for the female reproductive effects is 2-ethylhexanoic acid, the metabolite responsible for the 

developmental effects, or a different DEHP degradate. Davis et al. (1994a) showed that DEHP induced 

anovulation in virgin adult rats by altering granulosa cell estradiol production. Further studies with 

cultures of granulosa cells in vitro suggested that MEHP suppressed aromatase conversion of testosterone 

to estradiol (Davis et al. 1994b). The possible role of these findings in fertility changes in females needs 

to be explored. In marmoset monkeys, 2,500 mg/kg/day DEHP by oral administration for 13 weeks did 

not cause any gross or microscopic effects in ovary, uterus, or vagina (Kurata et al. 1998). 

Developmental Toxicity. There are no data concerning developmental effects in humans following 

DEHP exposures. There are animal data for exposures by the inhalation (Merkle et al. 1988) and oral 

routes (Arcadi et al. 1998; Cimini et al. 1994; Dostal et al. 1987b; Hellwig et al. 1997; Peters et al. 1997b; 

Price et al. 1986, 1988c; Ritter et al. 1987; Shiota and Mima 1985; Shiota et al. 1980; Tomita et al. 1982a; 

Tyl et al. 1988; Yagi et al. 1980). There are no dermal data in animals. DEHP is a teratogen in rats and 

mice when given orally during the gestation period. Mice appear to be more vulnerable to the teratogenic 

effects of DEHP than rats (Tomita et al. 1982a; Tyl et al. 1988). Studies in mice using single dosing 

during one of several gestation days identified day 7 of gestation as the most sensitive (Tomita et al. 

1982a). Malformations of the skeleton and neuronal tube were commonly observed. The DEHP 

metabolite responsible for the teratogenic effects appears to be 2-ethylhexanoic acid (Hauck et al. 1990; 

Ritter et al. 1987). Furthermore, it has been suggested that only the (R) enantiomer of this compound acts 

as a teratogen (Hauck et al. 1990). The mechanism of fetotoxicity/teratogenicity of DEHP (or 

metabolites) has not been elucidated. Results from a study by Peters et al. (1997b) in mice suggested 

teratogenicity and fetotoxicity of DEHP was not mediated by the nuclear receptor PPARα. Further 

research into the possible role of other receptor subtypes could provide valuable information on the 

mechanisms underlying the developmental toxicity of DEHP. Studies in primates would be particularly 

relevant to humans. Data needs related to effects of DEHP on the development of the male reproductive 

system are discussed in the previous section. Since the developmental effects of DEHP in animals might 

be caused by a metabolite(s) resulting from chemical reactions that follow oral exposure, inhalation or 

dermal studies do not seem necessary at this time. 
 

 

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There is lack of information regarding the pharmacokinetics of placental transfer as well as transfer of 

DEHP or metabolites via breast milk to the offspring, although DEHP has been detected in human milk 

(FDA 2001h). 

Immunotoxicity. There are currently no in vivo studies in humans or animals that examined 

immunocompetence following exposure to DEHP by any route of exposure. No histopathological 

alterations to organs of the lymphoreticular system due to treatment with DEHP were reported by any 

animal study. DEHP does bind to mononuclear leukocytes in vitro (Sager and Little 1989) but this is not 

an inherently toxic phenomenon. The overall evidence suggests that the immune system is not a target for 

DEHP toxicity. Specific studies addressing this issue do not seem necessary at this time. 

Neurotoxicity. There are no data concerning neurotoxic effects in humans following DEHP exposure 

by any route; data in animals are very limited. Moser et al. (1995) found no evidence of neurotoxicity in 

rats following administration of a single dose of up to 5,000 mg DEHP/kg of daily dose of up to 1,500 mg 

DEHP/kg for 14 days. Signs of general debilitation seen at 5,000 mg/kg cannot be categorized as specific 

signs of neurotoxicity. Tests conducted by Moser et al. (1995) assessed autonomic, sensorimotor, and 

neuromuscular functions, as well as excitability and activity. No neurological effects were reported in 

any long-term study. Data from developmental studies in animals indicate that DEHP interferes with 

normal development of the nervous system in rodents (Hellwig et al. 1997; Shiota and Mima 1985; Shiota 

et al. 1980; Tyl et al. 1988; Yagi et al. 1980). Exencephaly and neural tube defects have been seen in 

several studies that have evaluated the effects of DEHP administered during gestation. Also, in a study in 

female rats given DEHP in the drinking water from gestation day 1 to day 21 after delivery, female pups 

showed neurobehavioral impairment when tested at 30 days of age (Arcadi et al. 1998). This finding is 

unique to this study and replication of the results would greatly increase the confidence in the study. 

Studies should be designed to elucidate the mechanism(s) for this effect. In addition, DEHP exposure 

through maternal milk was associated with an increase in brain peroxisomes in newborn rats (Cimini et al. 

1994; Dabholkar 1988). A significant observation of Cimini et al. (1994) was the fact that brain catalase 

activity doubled in adult dams treated with DEHP, but was not significantly changed in the pups. This 

led them to suggest that immature neural cells are not yet able to modulate this activity and are therefore 

more susceptible to oxidative stress than mature ones. Thus, research concerning the role of the 

peroxisomes in the developing brain and the effect of DEHP induced changes in the activity of the brain 

peroxisomes would be beneficial. Of particular interest would be knowledge as to whether or not DEHP 

causes a modification of the brain lipids, particularly those of the myelin sheath, through oxidative 

processes. Changes in membrane proteins in the brain could also be studied since receptor site 
 

 

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interactions are so important in brain development and function. Additional studies in adult animals do 

not seem necessary at this time based on the lack of effects in long-term studies. Also, structurally, 

DEHP does not appear to be a neurotoxicant. 

Epidemiological and Human Dosimetry Studies. Information on health effects of DEHP in 

humans is essentially limited to observations of gastrointestinal distress in two individuals who ingested a 

single large dose of the compound (Shaffer et al. 1945). Repeated dose oral studies in rats and mice have 

established that the main targets of DEHP toxicity are the liver and testes. In contrast to the findings in 

rats and mice, monkeys appear to be relatively insensitive to the hepatic and testicular effects of DEHP 

(Kurata et al. 1998; Rhodes et al. 1986; Short et al. 1987). Sustained long-term oral exposure to DEHP is 

hepatocarcinogenic in rats and mice, but the mechanism by which liver cancer (and liver toxicity) is 

induced in these species does not appear to be operative in humans (David et al. 1999; Kluwe et al. 

1982a; Rao et al. 1987, 1990). The available data indicate that DEHP is unlikely to cause adverse health 

effects in environmentally exposed humans and therefore do not establish a clear need for 

epidemiological and human dosimetry studies. Identification and follow-up studies of children who were 

heavily exposed to DEHP, particularly the evaluation of reproductive system development and function in 

premature infants with still developing testicles exposed via plastic devices during medical procedures, 

could address the issue of whether there are functional effects in the most heavily exposed and vulnerable 

human population; however, such studies are not relevant to general population exposure due to the 

intensive and unnatural nature of the intravenously or and/or intratracheal procedures. 

Biomarkers of Exposure and Effect. There may be no particular benefit in better characterizing 

biomarkers for DEHP because (1) given its ubiquity (albeit at low environmental levels), there appears to 

be no great need to ascertain whether humans have been exposed (unless in known, high-exposure 

situations), and (2) there is no confirmed or compelling evidence that ambient exposure to DEHP can 

harm human health. 

Exposure. Because DEHP is rapidly metabolized and excreted, it is difficult to monitor anything but 

recent human exposures through the body fluids. MEHP and several oxidized MEHP metabolites can be 

measured in blood and urine and are biomarkers of exposure, and DEHP has been detected in human 

milk. Since DEHP is a lipophilic substance, it has the potential to deposit in adipose tissues. More 

chronic exposures can be detected with a fat biopsy, but there are no validated approaches for assessment 

of chronic exposure by fat biopsy analysis. Additional studies of methods for monitoring DEHP exposure 

would be of value. 
 

 

DI(2-ETHYLHEXYL)PHTHALATE 167 

3. HEALTH EFFECTS 

Effect. Currently there are no simple methods of measuring the effects of DEHP exposure. An increase 

in liver peroxisomes and peroxisomal enzyme activities appears to be the best marker of effect in rodents. 

This is not of great value in human studies since there is extensive evidence that humans, as well as 

primates, are refractory to peroxisome proliferators. Accordingly, research to identify reliable biomarkers 

for DEHP effects in humans would be useful in order to evaluate the prevalence and magnitude of 

exposure in an at-risk population. 

Absorption, Distribution, Metabolism, and Excretion. There are no data on the absorption, 

distribution, and excretion of DEHP following inhalation exposure of humans. The only human data 

apply to the urinary excretion of DEHP metabolites following oral exposures. In animals, there are data 

pertaining to the dermal and oral routes. Dermal data were provided in studies by Melnick et al. (1987) 

and Deisinger et al. (1998) in rats and suggested that dermal absorption is limited. DEHP is hydrolyzed 

by esterases found in a variety of tissues, although pancreatic lipase is the most effective enzyme 

hydrolyzing DEHP. Therefore, DEHP is absorbed primarily as MEHP and 2-ethylhexanol (Albro 1986). 

With high exposure concentrations, some DEHP might also be absorbed. DEHP metabolites are 

distributed to tissues via the blood. MEHP and 2-ethylhexanol are metabolized to a variety of more 

oxidized compounds. The liver is the main target tissue for DEHP metabolites (Ikeda et al. 1980; Rhodes 

et al. 1986). In species other than the rat, some of the oxidized intermediates are conjugated with 

glucuronic acid for excretion (Albro et al. 1982a). These metabolites are excreted in the urine and bile. 

Unabsorbed DEHP and MEHP are excreted in the feces. Additional data on the identity of the 

metabolites excreted in the bile and the portion that is excreted as conjugates would be useful in 

interpreting the absorption and metabolic data. Studies of dermal absorption from various vehicles are 

also justified since this has never been examined and the vehicle might have a profound effect on 

absorption. 

Comparative Toxicokinetics. The toxicity of DEHP differs among species. This is due both to 

differences in pharmacokinetics and species-specific differences in target tissue susceptibilities. For 

example, there are species differences in the rate of hydrolysis of DEHP to MEHP in the intestine. 

Hydrolytic activity is highest in the mouse, followed by the rat, guinea pig and hamster (Albro 1986; 

Lake et al. 1984a). Hydrolysis in primates and in humans is considerably slower than in rats (Albro et al. 

1982a; Rhodes et al. 1986). This of great importance because MEHP is the active peroxisome 

proliferator. The proportions of the different metabolites excreted and the proportions of metabolites that 

are excreted as conjugates vary (Albro et al. 1982a, 1982b, 1987; Astill 1989; Rhodes et al. 1986; Short et 

al. 1987). Primates glucuronidate the oxidative metabolites of MEHP more completely, while oxidizing 
 

 

DI(2-ETHYLHEXYL)PHTHALATE 168 

3. HEALTH EFFECTS 

metabolites less effectively, and rats do not glucuronidate DEHP metabolites. There are only a few 

studies on primate and canine species and none of these were rigorous. Primate studies are especially 

important in light of the fact that rodents have been, and will continue to be, the subject of much research 

due to their suitability as a model for the peroxisome proliferation phenomenon. Additional data on 

DEHP metabolites which occur in humans would also be useful in evaluating the potential for health 

effects to occur following DEHP exposures. 

Methods for Reducing Toxic Effects. There are no established methods for reducing absorption 

of DEHP or metabolites because the mechanism of absorption is not known. There have been no studies 

of compound-specific techniques for reducing DEHP body burden. External contact with DEHP can be 

treated by thoroughly washing the affected area. Activated carbon, possibly combined with a cathartic, 

will diminish absorption of ingested DEHP from the gastrointestinal tract (HSDB 2000). 

There are no tested methods for preventing or minimizing the toxic effects of DEHP. Currently, there are 

no records of cases of high-dosage human exposure to DEHP, aside from an early toxicology experiment 

(Shaffer et al. 1945). If situations leading to high-dose exposures are identified, research on minimizing 

acute toxic effects would be important. A study of the impact of dietary modifications (increased intake 

of antioxidants, zinc and glutathione precursors, and decreased dietary fat) on the effects of chronic 

exposure to DEHP might be useful. Given that an in vivo rodent study has shown that antioxidant green 

tea components could reduce the inhibitory effects on gap junctional intercellular communication by 

pentachlorophenol, a nongenotoxic liver tumor promoter, and because DEHP also has been shown to 

inhibit gap junctional intercellular communication (Malcolm and Mills 1983, 1989), a study designed to 

see if green tea or its antioxidant components could reduce the liver tumor promoting activity of DEHP 

would be warranted. 

Children’s Susceptibility. There is virtually no information on the health effects of DEHP in 

humans. Most studies in animals have been conducted in rodents, particularly rats and mice. In these 

species, DEHP causes testicular toxicity (Dostal et al. 1988; Gray and Butterworth 1980; Gray and 

Gangolli 1986; Poon et al. 1997; Saitoh et al. 1997; Sjoberg et al. 1986a, 1986b), is fetotoxic and 

teratogenic (Arcadi et al. 1998; Dostal et al. 1987b; Hellwig et al. 1997; Ritter et al. 1987; Tomita et al. 

1982a; Tyl et al. 1988), and induces liver cancer (David et al. 1999; Kluwe et al. 1982a). The rats and 

mice in which DEHP has induced liver cancer do not appear to represent an accurate model for human 

carcinogenicity (IARC 2001) and there is no information on whether the developmental process is altered 

in humans exposed to DEHP. There is no evidence that DEHP has hormone-like effects, but limited 
DI(2-ETHYLHEXYL)PHTHALATE 169 

3. HEALTH EFFECTS 

information from one study using one high dose (750 mg/kg/day) indicates that DEHP might have 

antiandrogenic properties in male pups from rats given DEHP during gestation and for few days during 

nursing (Gray et al. 1999). Further studies are necessary to characterize the dose-response and examine 

potential interactions of DEHP (or metabolites) with the androgen receptor. 

There are no adequate data to evaluate whether pharmacokinetics of DEHP in children are different from 

adults. It is not known whether DEHP (or metabolites) can cross the placenta in humans, although it has 

been detected in breast milk (FDA 2001h). Studies in animals have shown that DEHP (or metabolites) 

crosses the placenta and can be transferred to offspring via mother’s milk; however, quantitative data are 

lacking. There is no information to evaluate whether metabolism of DEHP is different in children than in 

adults since the specific phase I enzymes involved in DEHP metabolism have not been identified. It is 

known that phase II metabolism involves conjugation with glucuronic acid, but the specific isoform of 

glucuronosyltransferase is not known. 

There is no information about whether children differ in their susceptibility to the health effects of DEHP. 

However, studies in animals indicate that the younger the animal, the more severe the testicular effects 

induced by DEHP (Gray and Butterworth 1980; Sjoberg et al. 1986a, 1986b) This differential 

susceptibility is partly related to differences in pharmacokinetics (Sjoberg et al. 1985b), but other, yet 

undetermined factors, also might play a role (Gray and Beamand 1984). One study in which rats were 

exposed during gestation and lactation reported altered neurological responses in female offspring tested 

at 30 days of age (Arcadi et al. 1998). These findings need to be replicated by others, and if so, research 

efforts should focus on the possible underlying mechanism(s) that are responsible for such alterations. 

Continued research into the development of sensitive and specific early biomarkers of exposure and effect 

for DEHP would be valuable for both adults and children. There are no pediatric-specific methods to 

reduce peak absorption for DEHP following exposure, to reduce body burdens, or to interfere with the 

mechanism of action. Based on the information available, it is reasonable to assume that methods 

recommended for treating 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. 
DI(2-ETHYLHEXYL)PHTHALATE 170 

3. HEALTH EFFECTS 

3.12.3 Ongoing Studies 

Several ongoing studies concerning health effects associated with DEHP have been identified in the 

Federal Research in Progress (FEDRIP 2001) and are listed in Table 3-7. 
DI(2-ETHYLHEXYL)PHTHALATE 171 

3. HEALTH EFFECTS 

Table 3-7. Ongoing Studies on the Health Effects of DEHP 

Investigator Affiliation Research description Sponsor 

Jirtle RL Duke University Medical Ctr. 

Durham, North Carolina 

Tumor suppressor function of 

the M6P/IGF2 receptor 

NIEHS 

Lied M Oregon State University 

Corvallis, Oregon 

Molecular determinants of 

peroxisomal proliferator action 

NIEHS 

Orth JM Temple University 

School of Medicine 

Philadelphia, Pennsylvania 

Mechanism of toxicant induced 

injury in neonatal testes 

NIEHS 

Richburg JH University of Texas 

Division of Pharmacology 

and Toxicology, Austin, 

Texas 

Environmental testicular toxicity 

and germ cell apoptosis 

NIEHS 

Swenberg JA, 

Thurman RG 

University of North Carolina 

Chapel Hill, North Carolina 

Lipid metabolism and phthalate 

toxicity interactions 

NIEHS 

Source: FEDRIP 2001 

NIEHS = National Institute of Environmental Health Sciences 
DI(2-ETHYLHEXYL)PHTHALATE 172 

4. CHEMICAL AND PHYSICAL INFORMATION 

4.1 CHEMICAL IDENTITY 

Information regarding the chemical identity of DEHP is located in Table 4-1. 

4.2 PHYSICAL AND CHEMICAL PROPERTIES 

Information regarding the physical and chemical properties of DEHP is located in Table 4-2. 
DI(2-ETHYLHEXYL)PHTHALATE 

4. CHEMICAL AND PHYSICAL INFORMATION 

173 

Table 4-1. Chemical Identity of DEHP 

Characteristic Information Reference 

Chemical name 

Synonym(s) 

Registered trade name(s) 

Chemical formula 

Chemical structure 

Identification numbers: 

CAS registry 

NIOSH RTECS 

EPA hazardous waste 

OHM/TADS 

DOT/UN/NA/IMCO shipping 

HSDB 

NCI 

Di(2-ethylhexyl) phthalate 

DEHP; dioctylphthalate; bis(2-ethylhexyl) 

phathalate 

Bisoflex 81; Eviplast 80; Octoil; Plantinol 

DOP; Staflex DOP 

C24H38O4 

COOCH2CH(C2H5)(CH2)

3CH3 

COOCH2CH(C2H5)(CH2)3CH3 

117-81-7 

TI0350000 

U028 

7216693 

No data 

334 

C52733 

RTECS 2000 

RTECS 2000 

RTECS 2000 

RTECS 2000 

Howard and 

Meylan 1997 

Cadogan and 

Howick 1996 

RTECS 2000 

HSDB 1990 

HSDB 1990 

HSDB 1990 

Montgomery and 

Welkom 1990 

CAS = Chemical Abstracts Services; DOT/UN/NA/IMCO = Department of Transportation/United Nations/North 

America/International Maritime Dangerous Goods Code; EPA = Environmental Protection Agency; 

HSDB = Hazardous Substances Data Bank; NCI = National Cancer Institute; NIOSH = National Institute for 

Occupational Safety and Health; NFPA = National Fire Protection Association; OHM/TADS = Oil and Hazardous 

Materials/Technical Assistance Data System; RTECS = Registry of Toxic Effects of Chemical Substances 
DI(2-ETHYLHEXYL)PHTHALATE 174 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of DEHP 

Property Information Reference 

Molecular weight 390.57 Howard and Meylan 1997 

Color Colorless Montgomery and Welkom 

1990 

Physical state Liquid Staples et al. 1997 

Melting point -47 EC Staples et al. 1997 

Boiling point 384 EC Howard and Meylan 1997 

Density 0.984 g/mL at 20 EC Cadogan and Howick 1996 

Odor Slight odor HSDB 1990 

Odor threshold: 

Water No data 

Air No data 

Solubility: 

Water 

Organic solvent(s) 

41 μg/L at 25 ECa 

Miscible in mineral oil and hexane 

Leyder and Boulanger 1983 

HSDB 1990 

Partition coefficients: 

Log Kow 

Log Koc 

7.50 

4.9–6 

Staples et al. 1997 

Staples et al. 1997 

Vapor pressure 1.0x10-7 mmHg at 25 EC Staples et al. 1997 

Henry's law constant: 1.71x10-5 atm-m3/mole at 25 EC Staples et al. 1997 

Autoignition temperature 735 EF (390 EC) HSDB 1990 

Flashpoint 384.8 EF (196 EC) (open cup) Montgomery and Welkom 

1990 

Flammability limits No data 

Conversion factors 1 ppm=15.94 mg/m3 Clayton and Clayton 1981 

Explosive limits 0.3% (lower limit) 

No data (upper limit) 

Montgomery and Welkom 

1990 

a

The solubilities of DEHP in distilled water that have been determined both experimentally and theoretically vary 

between 1.1 and 1,200 μg/L (Staples et al. 1997). The value of 41 μg/L was the lowest experimentally derived 

value for the solubility of DEHP in distilled water. A value of 3 μg/L for the water solubility of DEHP has been 

recommended by Staples et al. that is “based on available evidence”, rather than any one specific experimentally 

derived value. Unfortunately, the authors do not indicate how they derived their recommended value of 3 μg/L. 

Yet, the “true” solubility may be at or below the value of 3 μg/L value, based on estimated solubilities obtained from 

the SPARC (2.6 μg/L) and EPIWIN (1.1 μg/L) estimation models (Staples et al. 1997). Indeed, in a recent report 

(Ellington 1996) describing the results obtained from a slow-stir method for determining the water solubility of 

phthalate esters, the water solubility of a chemical analogue of DEHP, dioctylphthalate (DOP), was found to be 

0.51 μg/L. It is likely that the solubility of DEHP in distilled water will be similar to that obtained for DOP using the 

same experimental method. However, the solubility of DEHP in distilled water has yet to be determined 

experimentally using the slow-stir method. Thus, it is clear that more experimental data are required before the 

“true” solubility of DEHP in distilled water can be determined. 

DI(2-ETHYLHEXYL)PHTHALATE 176 

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

5.1 PRODUCTION 

DEHP is a member of a group of compounds commonly referred to as the phthalate esters, a group of 

related compounds whose predominant use is as plasticizers in flexible products made from polyvinyl 

chloride (Mannsville Chemical Products Corporation 1999). DEHP is produced by the esterification of 

phthalic anhydride with 2-ethylhexyl alcohol in the presence of an acid catalyst (Mannsville Chemical 

Products Corporation 1999; NTP 1989). Production volumes for DEHP alone are not available, but 

estimated production information is available for a group of phthalate esters referred to as the dioctyl 

phthalates (DOP) by Mannsville Chemical Products Corporation (1999). Dioctyl phthalates include diethylhexyl phthalate, diisooctyl phthalate, and di-n-octyl phthalate. According to Mannsville Chemical 

Products Corporation (1999), 1998 domestic production of DOP was 285 million pounds. Previous years 

showed domestic production volumes of 309, 258, 280, 280, and 287 million pounds for the years 1990, 

1994, 1995, 1996, and 1997, respectively. Based on the demand for 830 million pounds of 2-ethylhexanol, and its use in the manufacture of plasticizers (48% of 2-ethylhexanol is used in the manufacture 

of plasticizers, of which 60% are dioctyl phthalates), it is projected that 241 million pounds of dioctyl 

phthalates were produced in the United States in 1999 (ChemExpo 1999). 

Four companies operating five facilities appear to be the primary U.S. producers of DEHP. These are 

Aristech Chemical Company in Neville Island, Pennsylvania; Hatco Chemical Company in Fords, New 

Jersey; Teknor Apex Company in Brownsville, Tennessee and Hebronville, Massachusetts; and 

Tennessee Eastman Company in Kingsport, Tennessee (Mannsville Chemical Products Corporation 

1999). SRI (1998a), however, lists only Tennessee Eastman and Aristech Chemical Company, as above, 

but also adds Velsicol Chemical Corporation in Chestertown, Maryland, which was not included in the 

above list. Table 5-1 summarizes the information on U.S. companies that reported the use and production 

of DEHP in 1999 (TRI99 2001). The TRI data should be used with caution since only certain types of 

facilities are required to report. This is not an exhaustive list.

 According to Mannsville Chemical Products Corporation (1999), production of DEHP is expected to 

grow at a rate less than the gross domestic product over the next few years due to limited growth in 

polyvinyl chloride (PVC) markets which have been the primary consumers of DEHP. In addition, 
DI(2-ETHYLHEXYL)PHTHALATE 177 

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

Table 5-1. Facilities that Produce, Process, or Use DEHP 

Number of Minimum amount Maximum amount 

Statea facilities on site in poundsb on site in poundsb Activities and usesc 

AL 1 0 99 13 

AR 4 1,000 999,999 8, 9, 13 

CA 16 1,000 999,999 2, 3, 8, 9, 10, 13 

CO 1 10,000 99,999 8 

CT 3 1,000 99,999 8, 9 

FL 3 1,000 999,999 8, 9 

GA 6 1,000 999,999 8, 9, 10, 12 

IA 3 10,000 99,999 8, 9, 10 

IL 17 1,000 999,999 7, 8, 9, 10, 11, 13 

IN 7 100 999,999 2, 3, 7, 8, 9, 13 

KS 6 100 99,999 2, 3, 8, 9, 10, 13 

KY 3 1,000 99,999 8, 13 

LA 2 1,000 99,999 7, 8 

MA 15 1,000 999,999 1, 6, 8, 9, 10, 11 

MD 3 10,000 999,999 1, 4, 8 

MI 5 100 9,999,999 2, 3, 8, 9, 12, 13 

MN 6 1,000 99,999 7, 8, 9, 13 

MO 12 1,000 99,999 7, 8, 9, 10, 13 

MS 4 10,000 999,999 8, 9 

NC 14 100 9,999,999 8, 9, 10, 11, 12 

NE 3 1,000 99,999 1, 5, 7, 8, 9 

NH 2 1,000 9,999 9, 13 

NJ 11 1,000 9,999,999 2, 3, 8, 9, 10, 11 

NV 2 100,000 999,999 8 

NY 6 1,000 999,999 8, 9 

OH 24 1,000 999,999 2, 3, 7, 8, 9, 10, 11, 13 

OK 3 10,000 999,999 2, 3, 8, 9, 12 

PA 15 100 9,999,999 1, 4, 8, 9, 13 

PR 6 10,000 999,999 8, 9 

RI 3 1,000 999,999 8, 9 

SC 7 1,000 999,999 8, 9, 12, 13 

SD 1 1,000 9,999 9 

TN 11 1,000 9,999,999 1, 3, 4, 5, 6, 7, 8, 9, 11 

TX 15 1,000 999,999 2, 3, 7, 8, 9, 10, 12, 13 

UT 2 1,000 9,999 2, 5, 8, 9, 12 

VA 3 1,000 999,999 8, 13 

VT 1 10,000 99,999 8 
178 

8 

DI(2-ETHYLHEXYL)PHTHALATE 

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

Table 5-1. Facilities that Produce, Process, or Use DEHP (continued) 

Number of Minimum amount Maximum amount 

Statea facilities on site in poundsb on site in poundsb Activities and usesc 

WA 4 1,000 9,999,999 2, 4, 8, 9, 10, 13 

WI 6 1,000 99,999 8, 9 

WV 1 1,000 9,999 

Source: TRI99 2001 

a

Post office state abbreviations used 

b

Amounts on site reported by facilities in each state c

Activities/Uses: 

1. Produce 6. Impurity 10. Repackaging 

2. Import 7. Reactant 11. Chemical Processing Aid 

3. Onsite use/processing 8. Formulation Component 12. Manufacturing Aid 

4. Sale/Distribution 9. Article Component 13. Ancillary/Other Uses 

5. Byproduct 
DI(2-ETHYLHEXYL)PHTHALATE 179 

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

decreasing demand for DEHP due to continued concern over health effects might further impact 

production volume (Mannsville Chemical Products Corporation 1999). 

5.2 IMPORT/EXPORT 

Import quantities of dioctyl phthalates were about 4 million pounds in 1998. No data were located 

regarding past import volumes of DEHP or the dioctyl phthalates. Exports of dioctyl phthalates have 

been about 14–27 million pounds per year from 1994 to 1998 (Mannsville Chemical Products 

Corporation 1999). Import/export statistics specific for DEHP were not located. 

5.3 USE 

DEHP is principally used as a plasticizer in the production of flexible PVC products. According to 

Mannsville Chemical Products Corporation (1999), at least 95% of DEHP produced is used as a 

plasticizer for PVC. PVC is made flexible by addition of plasticizers and is used in many common items 

such as wall coverings, tablecloths, floor tiles, furniture upholstery, shower curtains, garden hoses, 

swimming pool liners, rainwear, baby pants, dolls, toys, shoes, automobile upholstery and tops, 

packaging film and sheet, sheathing for wire and cable, medical tubing, and blood storage bags. 

Polyvinyl chloride is also used to produce disposable medical examination and surgical gloves, the 

flexible tubing used to administer parenteral solutions, and the tubing used in hemodialysis treatment 

(Mannsville Chemical Products Corporation 1999; NTP 1989). DOP is also used as a plasticizer in 

products such as polyvinyl butyral, natural and synthetic rubber, chlorinated rubber, ethyl cellulose, and 

nitrocellulose (Mannsville Chemical Products Corporation 1999). 

Numerous nonplasticizer uses of DEHP have been reported. However, it is not clear to what extent these 

uses are, or have ever been, important. These include the use of DEHP as a solvent in erasable ink, as an 

acaracide in orchards, as an inert ingredient in pesticide products, in cosmetics, in vacuum pump oil, as a 

component of dielectric fluids in electrical capacitors, to detect leaks in respirators, and for use in testing 

of air filtration systems (HSDB 1990; Mannsville Chemical Products Corporation 1990; NTP 1989). 

Because of concerns regarding health effects from exposure to DEHP, many toy manufacturers have 

discontinued use of all phthalates in their products (Mannsville Chemical Products Corporation 1999; 

Wilkinson and Lamb 1999). The use of DEHP in domestically produced teethers and rattles has been 

discontinued (Consumer Product Safety Commission 1999d). DEHP is also no longer used as a 
DI(2-ETHYLHEXYL)PHTHALATE 180 

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

plasticizer in plastic food wrap products (Mannsville Chemical Products Corporation 1999). In addition, 

some applications, like automobile upholstery, might switch from DEHP to linear phthalates because of 

their superior performance and low toxicity, which will put further downward pressure on DEHP use 

(Mannsville Chemical Products Corporation 1999). Finally, in the future, polyolefin metallocene 

plastomers might replace flexible applications for PVC altogether because they provide flexibility without 

the need for plasticizers. 

5.4 DISPOSAL 

When DEHP (as a commercial chemical product or chemical intermediate) becomes a waste, its disposal 

is regulated by law (see Chapter 8). DEHP disposal is regulated under the Resource Conservation and 

Recovery Act (RCRA). Regulations promulgated under this Act control the treatment, storage, and 

disposal of waste DEHP. Land disposal restrictions are the responsibility of the EPA Office of Solid 

Waste. In 1998, it was estimated that about 0.96 million pounds of waste DEHP were transported from 

production facilities or points of usage for disposal, including publically owned treatment works (TRI98 

2000). No data were located regarding the quantity of waste DEHP which was disposed of by any 

specific means. No data were located regarding trends in DEHP disposal. 

DI(2-ETHYLHEXYL)PHTHALATE 182 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.1 OVERVIEW 

DEHP has been identified in at least 737 of the 1,613 hazardous waste sites that have been proposed for 

inclusion on the EPA National Priorities List (NPL) (HazDat 2002). However, the number of sites 

evaluated for DEHP is not known. The frequency of these sites can be seen in Figure 6-1. Of these sites, 

730 are located within the United States, 5 are located in the Commonwealth of Puerto Rico, and 1 is 

located in the Virgin Islands, and 1 is located in Territory of Guam (the Commonwealth of Puerto Rico, 

the Virgin Islands, and Territory of Guam are not shown in Figure 6-1). 

DEHP is a widely used chemical that enters the environment both through disposal of industrial and 

municipal wastes in landfills and by leaching into consumer products stored in plastics. It tends to sorb 

strongly to soils and sediments and to bioconcentrate in aquatic organisms. Biodegradation is expected to 

occur under aerobic conditions. Sorption, bioaccumulation, and biodegradation are likely to be 

competing processes, with the dominant fate being determined by local environmental conditions. 

The principal route of human exposure to DEHP is oral. Much of the monitoring database is old and 

might not represent current exposures, especially since the uses of DEHP in certain applications has been 

changing (Mannsville Chemical Products Corporation 1999; Wilkinson and Lamb 1999). Some recent 

estimates of the average total daily individual ambient exposures to DEHP of 0.210–2.1 mg/day (in a 

70-kg adult) have been proposed (Doull et al. 1999; Huber et al. 1996; NTP 2000b; Tickner et al. 2001). 

Populations residing near hazardous waste disposal sites or municipal landfills might be subject to higher 

than average levels of DEHP in ambient air and drinking water. Even so, the concentrations of DEHP in 

these media will be greatly limited by the low volatility and low water solubility of DEHP. Occupational 

exposures might be significant, but the highest exposures to DEHP result from medical procedures such 

as blood transfusions (e.g., estimated upper bound limit of 8.5 mg/kg/day) or hemodialysis (e.g., 

estimated upper bound limit of 0.36 mg/kg/day), during which DEHP might leach from plastic equipment 

into biological fluids (FDA 2001h). Exposures of neonates to DEHP can be especially high as a result of 

some medical procedures; total parenteral nutrition (TPN) administration (e.g., estimated upper bound 

limit of 2.5 mg/kg/day), and extracorporeal membrane oxygenation (ECMO) (e.g., estimated upper bound 

limit of 14 mg/kg/day) (FDA 2001h). 
Figure 6-1. Frequency of NPL Sites with DEHP Contamination 

1-7-17264879 

Frequency of

NPL Sites 

Derived from HazDat 2002 
DI(2-ETHYLHEXYL)PHTHALATE 184 

6. POTENTIAL FOR HUMAN EXPOSURE 

When DEHP is present in the environment it is usually at very low levels. It should be noted that it is 

very difficult to determine these low levels accurately since DEHP is a ubiquitous laboratory 

contaminant. Laboratory contamination might cause false positives to be reported in the literature. 

Laboratory contamination often undermines the credibility of the data and, therefore, reported 

concentrations of DEHP in environmental samples must be carefully reviewed. 

6.2 RELEASES TO THE ENVIRONMENT 

Industrial manufacturers, processors, and users of DEHP are required to report the quantities of this 

substance released to environmental media annually (EPA 1988d). The data compiled in the Toxics 

Release Inventory (TRI99 2001), are for releases in 1999 to air, water, soil, and transfers for offsite 

disposal. These data are summarized in Table 6-1. Total releases (rounded to three-place accuracy) of 

DEHP to the environment in 1999 were approximately 264,000 pounds (approximately 120 metric tons) 

(TRI99 2001), of which approximately 229,000 pounds (104 metric tons), or about 87% of the total, were 

released to the air. Another 32,000 pounds (14.5 metric tons) or approximately 12% of the total were 

released to the land, while less than 1.1% (2,880 pounds, 1.3 metric tons) were released to water. The 

TRI data should be used with caution because only certain types of facilities are required to report. This 

is not an exhaustive list. 

Industrial releases are only a fraction of the total environmental releases of DEHP. Release of DEHP into 

the environment is thought to originate from diffuse sources, mainly from end-uses of DEHP (e.g., as an 

additive to plastics). Disposal of plastic products containing DEHP (see Section 5.3) is also a possible 

source of environmental release (Bauer and Herrmann 1997; EPA 1981). Quantitative information on 

releases of DEHP to specific environmental media are discussed below. 

6.2.1 Air 

As presented in Chapter 4, DEHP has a relatively low vapor pressure and Henry’s law constant, as well as 

a relatively high octanol/water partition coefficient and soil sorption coefficient. This combination of 

properties is consistent with a chemical that is found to only a limited extent in air (see Staples et al. 

1997). Nonetheless, DEHP appears to be a common air contaminant that is present globally in the low 

ng/m3

 concentrations (see Section 6.4), although specific information that quantifies emissions of DEHP 

to air appears to be insufficient to account for this apparent widespread presence. For example, while 
Table 6-1. Releases to the Environment from Facilities that Produce, Process, or Us

Reported amounts released in pounds per yeara 

Number 

Stateb 

of facilities Airc Water 

Underground injection Land 

Total on-site released 

Total off-sreleasee 

AL 1 10 No data No data 19,880 19,890 500 

AR 4 7,005 0 No data No data 7,005 7,544 CA 16 7,086 5 No data No data 7,091 27,249 

CO 1 5 No data No data No data 5 250 

CT 3 26,858 3 No data No data 26,861 2,272 

FL 3 605 No data No data No data 605 No data 

GA 6 1,370 No data No data 250 1,620 20,316 

IA 3 7 No data No data No data 7 1,639 

IL 17 2,773 5 No data 0 2,778 16,774 

IN 7 762 0 No data No data 762 11,978 

KS 6 290 5 No data No data 295 28,915 

KY 3 10 No data No data 0 10 250 

LA 2 4 0 No data No data 4 45 MA 15 4,269 No data No data No data 4,269 24,103 

MD 3 3,044 0 No data 0 3,044 10,000 

MI 5 1,186 No data No data 7,764 8,950 12,928 

MN 6 174 0 No data No data 174 4,572 

MO 12 2,797 0 No data 1,685 4,482 139,505 MS 4 511 5 No data No data 516 30,417 NC 14 44,189 250 No data No data 44,439 114,938 

NE 3 1,653 No data No data No data 1,653 41,515 

NH 2 No data No data No data No data No data No data 

NJ 11 10,418 0 No data 750 11,168 3,630 

NV 2 2,696 No data No data No data 2,696 1,500 

NY 6 3,294 No data No data No data 3,294 73,613 
Table 6-1. Releases to the Environment from Facilities that Produce, Process, or Use DEH

Reported amounts released in pounds per yeara 

Number 

Stateb 

of facilities Airc Water 

Underground injection Land 

Total on-site released 

Total off-sreleasee 

OH 24 8,725 9 No data 0 8,734 39,446 

OK 3 60,669 No data No data No data 60,669 17,740 

PA 15 7,124 3 0 0 7,127 30,354 

PR 6 572 No data No data No data 572 93,992 

RI 3 229 No data No data No data 229 6,646 

SC 7 4,186 No data No data No data 4,186 24,580 SD 1 No data No data No data No data No data 250 

TN 11 5,863 2,342 No data No data 8,205 50,933 TX 15 12,921 3 No data 2,000 14,924 45,513 

UT 2 5 No data No data No data 5 No data 

VA 3 6,427 No data No data No data 6,427 No data 

VT 1 No data No data No data No data No data No data 

WA 4 257 250 No data 5 512 3,150 

WI 6 454 No data No data No data 454 56,960 

WV 1 500 No data No data No data 500 No data 

Total 257 228,948 2,880 0 32,334 264,162 944,017 

Source: TRI99 2001 aData in TRI are maximum amounts released by each facility.bPost office state abbreviations are used.cThe sum of fugitive and stack releases are included in releases to air by a given facility.dThe sum of all releases of the chemical to air, land, water, and underground injection wells.eTotal amount of chemical transferred off-site, including to publicly owned treatment works (POTW).
DI(2-ETHYLHEXYL)PHTHALATE 187 

6. POTENTIAL FOR HUMAN EXPOSURE 

monitoring data show that elevated fallout concentrations of DEHP are associated with industrial activity 

(Thurén and Larsson 1990), elevated fallout concentrations were only seen near a stack, and no elevated 

concentrations could be seen 2 km away from the stack. In addition, these authors could not correlate 

DEHP fallout rates with specific sources or transport routes on a nationwide basis in Sweden. They 

found no “distributional patterns or gradient”, which possibly suggests that any local patterns were 

obscured by DEHP contribution from other sources or that emission sources of roughly equal magnitude 

are diffuse. By contrast, a pattern associating distance from sources and concentration was seen with 

DEHP by Ritsema et al. (1989) in Lake Yssel in the Netherlands, while for other lower-molecular-weight 

phthalate esters, no pattern was evident. The authors suggested that an upstream source is the dominant 

mechanism by which DEHP enters the lake. The possibility of many diffuse sources of DEHP is 

potentially supported by some of the uses. For example, some of the products that use DEHP include thin 

sheets and coatings, such as floor tiles, shower curtains, tablecloths, and furniture upholstery (see 

Chapter 5). These products characteristically have large surface area-to-volume ratios, which might allow 

DEHP to volatilize more readily relative to other products with smaller surface area-to-volume ratios. 

Cadogan et al. (1994) and Cadogan and Howick (1996) reported that an indoor emission rate of 

2.3x10-4 mg/second-m2

 at 25 EC has been calculated for all phthalate plasticizers in products such as wall 

coverings, flooring, upholstery, and wire insulation. These authors used this emission estimate to 

calculate overall releases of phthalate esters to air. Cadogan and Howick (1996) also noted that 

approximately 47% of the phthalate ester used is DEHP. Applying this DEHP use percentage to their 

emission estimates, total end-use emissions of DEHP to the air from indoor household uses in Western 

Europe in 1990 is approximately 300 tons per year. Emissions from exterior end uses were estimated to 

be 2,600 tons per year for DEHP (the authors noted that this estimate was not well defined). These 

estimates support the conclusion that the major sources of DEHP are from end-uses and that these 

represent a geographically diffuse source. Finally, Jones et al. (1996) estimated that between 0.001 and 

3.6 metric tons of DEHP are emitted per year (depending on assumptions about vapor equilibria and mass 

transfer used in model calculations) from sewer manholes in a large U.S. city having an average DEHP 

sewage concentration of 26 μg/L. 

Industrial atmospheric emissions (rounded to three-place accuracy) of DEHP reported to the TRI for 1999 

totaled about 229,000 pounds (104 metric tons) (TRI99 2001) and comprise about 87% of the total 

releases. It has been estimated that less than 3% of the total U.S. domestic supply of DEHP is released to 

air (EPA 1981). Based on an estimated current U.S. supply in 1998 of about 285 million pounds 

(241 million pounds in 1999) (see Section 5.1), the estimated annual atmospheric emission of DEHP from 

all sources in the United States is about 6.6 million pounds in 1998 (5.6 million in 1999). 
DI(2-ETHYLHEXYL)PHTHALATE 188 

6. POTENTIAL FOR HUMAN EXPOSURE 

DEHP has been identified in air samples collected from 7 of the 737 NPL hazardous waste sites where it 

was detected in some environmental media (HazDat 2002). 

6.2.2 Water 

Total releases of DEHP to water are also estimated to be about 3% of domestic supplies (EPA 1981). 

Some of these releases are expected to be in industrial effluents from the manufacture and processing of 

DEHP (EPA 1981). Industrial releases (rounded to three-place accuracy) to surface water reported to the 

TRI for 1998 were about 2,880 (1.3 metric tons) (TRI99 2001). 

DEHP was detected in 13% of 86 samples of urban storm water runoff evaluated for the National Urban 

Runoff Program, at concentrations ranging from 7 to 39 ppb (Cole et al. 1984). In some locations, storm 

and sanitary sewers are separated so that storm water runoff in these locations directly enters surface 

water. Even in locations with combined storm and sanitary sewers, DEHP is still expected to enter the 

environment, but probably to a lesser extent. For example, Stubin et al. (1996) reported that DEHP was 

present in 48% of the influent and 12% of the effluent samples taken from New York City sewage 

treatment plants during 1989–1993. Thus, storm water runoff, even when it goes through a sewage 

treatment plant, might enter the environment. In addition, DEHP also appears to be present in the 

treatment plant influent whether or not it receives storm water. DEHP has also been reported in waste 

water from a petrochemical plant (Castillo et al. 1998), leachate from industrial and municipal landfills 

(Brown and Donnelly 1988; Castillo et al. 1998; Ghassemi et al. 1984; Roy 1994), and sewage sludge 

(O’Connor 1996). It is anticipated that water from all these sources enters the environment and might 

contain DEHP. 

DEHP has been identified in ground water samples collected from 650 sites and surface water samples at 

215 of the 737 NPL hazardous waste sites where it was detected in some environmental media (HazDat 

2002). 

6.2.3 Soil 

The principal source of DEHP release to land is likely the disposal of industrial and municipal waste to 

landfills (EPA 1981). Industrial releases (rounded to three-place accuracy) of DEHP to land reported to 

the TRI for 1998 total about 32,000 pounds (TRI99 2001). In addition, another 944,000 pounds is 

transferred off-site for treatment (including publically owned treatment works) or disposal and some of 
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6. POTENTIAL FOR HUMAN EXPOSURE 

this material might be discharged to soils. Municipal wastes might contain substantial quantities of 

DEHP-containing plastics, which might significantly increase the total quantity of DEHP released to land. 

Based on an estimate that 92% of U.S. domestic supplies of DEHP are released to landfills (EPA 1981) 

and current U.S. domestic supplies in 1998 of approximately 285 million pounds (241 million pounds in 

1999) (Section 5.1), about 262 million pounds (222 million pounds in 1999) of DEHP are deposited in 

landfills annually. Bauer and Herrmann (1997) reported the concentration of DEHP in various fractions 

of household wastes from the regions of Bayreuth and Straubling in Germany. The wastes included food 

waste, paper for recycling, unusable paper, cardboard, plastic films, other plastics, textiles, 8–40 mm 

screened fraction, <8 mm screened fraction, compound packing waste, compound materials, and 

disposable diapers. DEHP was found in all of the fractions. It is anticipated that household waste from 

continental Europe is similar to the United States, so that the same profile would be expected in both 

places. Further information on this study is presented in Section 6.4.4. 

Land application of sewage sludge might also release DEHP to soil. The National Sewage Sludge Survey 

estimated that mean DEHP concentrations in sludge range from 55 to 300 ppm, with a national mean of 

75 ppm (EPA 1990d). It is also estimated that about 42% of sewage sludge generated in the United States 

annually, or 5.1 billion pounds, is applied to land. Another 20% (2.4 billion pounds) is deposited in 

landfills, and 14% (1.7 billion pounds) are incinerated (EPA 1990d). Using the national mean 

concentration and a total of 7.5 billion pounds of sludge deposited in soils, sludge accounts for 

approximately 7,500 pounds of DEHP released to soils annually. 

This compound has also been reported in ocean sediments at levels up to 25 ppm at points of urban 

sewage outfall (Swartz et al. 1985), and in 100% of the sediments in rivers near combined sewer 

overflows in New Jersey (Ianuzzi et al. 1997). Concentrations of phthalates, including DEHP, are 

approximately 10 times higher in stream sediments that are influenced by urban activity than in areas 

under other land-use activities (Lopes and Furlong 2001). 

DEHP has been identified in soil samples collected from 582 sites and sediment samples at 248 of 

737 NPL hazardous waste sites where it was detected in some environmental media (HazDat 2002). 
DI(2-ETHYLHEXYL)PHTHALATE 190 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.3 ENVIRONMENTAL FATE 

6.3.1 Transport and Partitioning 

DEHP is ubiquitous in air at low concentrations (e.g., 0.06–5.0 ng/m3

) (Eisenreich et al. 1981; Ligocki et 

al. 1985a), is in both the vapor phase and associated with particulates, and is subject to both wet (rain and 

snow) and dry (wind and settling) deposition on the Earth's surfaces. Eisenreich et al. (1981) calculated 

that wet and dry deposition of DEHP into the five Great Lakes amounted to approximately 47.7 metric 

tons per year, which corresponds to an average fallout rate of 16.2 μg/m2

 per month. A similar average 

fallout rate of 23.8 μg/m2

 per month (the range was 5.96–195.5 μg/m2 per month) was reported by Thurén 

and Larsson (1990) for DEHP in Sweden. Thurén and Larsson (1990) also estimated the median fallout 

concentration to be 48 ng/L. The authors noted that the fallout rate for DEHP decreased with increasing 

distance (but only up to 2 km away) from a stack at a facility that used DEHP (see Section 6.2), but noted 

that no specific overall concentration or fallout patterns were observed. This is consistent with diffuse 

sources of DEHP. In addition, DEHP has been found in Antarctic surface and sub-surface snow (up to 

3 m deep), and in pack ice (Desideri et al. 1994, 1998), as well as in the atmosphere over the Gulf of 

Mexico (Giam et al. 1980), suggesting that DEHP can be transported for long distances. Thus, the DEHP 

measured in one part of the world might have originated elsewhere. This transport is likely particle 

sorbed DEHP (Atlas and Giam 1981) because vapor phase DEHP reacts rapidly with hydroxyl radicals in 

the atmosphere (see Section 6.3.2.1), while particle-sorbed DEHP does not react rapidly with hydroxyl 

radicals. Nearly half the DEHP detected in the atmosphere over the Gulf of Mexico was in the particulate 

phase (Giam et al. 1980). Atmospheric fallout is negatively correlated with temperature so that less 

DEHP is subject to fallout in the summer than in the winter (Staples et al. 1997; Thurén and Larsson 

1990). This is in keeping with a higher proportion of the atmospheric DEHP in the vapor state in the 

warm summer and less in the cold winter, and further indicates that the partitioning between particles and 

vapor are controlled by vapor pressure. DEHP is removed from the atmosphere by both wet (rain and 

snow) and dry (wind and settling) deposition (Atlas and Giam 1981; Eisenreich et al. 1981; Ligocki et al. 

1985a, 1985b). 

In water, DEHP is predominantly sorbed to suspended particulates and sediments, but some remains 

dissolved in the aqueous phase. Volatilization is not a dominant transport process. Volatilization from 

water and soil is not expected to be important, based on the low Henry's law constant (estimated value 

1.71x10-5 atm-m3

/mol; Staples et al. 1997). It has been estimated that the evaporative half-life of DEHP 
DI(2-ETHYLHEXYL)PHTHALATE 191 

6. POTENTIAL FOR HUMAN EXPOSURE 

from water would be about 15 years (EPA 1979), and that only about 2% of DEHP loading of lakes and 

ponds would be volatilized (Wolfe et al. 1980a). 

Adsorption onto soils and sediments is a significant sink for DEHP. DEHP released to water adsorbs 

strongly to suspended particulates and sediments (Al-Omran and Preston 1987; Staples et al. 1997; 

Sullivan et al. 1982; Wolfe et al. 1980a). Distribution of DEHP between the water column and the 

sediments was modeled for several types of freshwater aquatic environments (Wolfe et al. 1980a). 

Between 69 and 99% of DEHP was estimated to partition to the sediments. Adsorption of DEHP to 

marine sediments might be greater than adsorption to freshwater sediments, due to reduced solubility of 

DEHP in saltwater (Al-Omran and Preston 1987; Sullivan et al. 1982; Zhou and Liu 2000). Levels of 

DEHP in a marine environment ranged from 0.1 to 0.7 ppb in the water and from 280 to 640 ppb in the 

suspended particulates (Preston and Al-Omran 1989). DEHP shows greater adsorption to the smaller size 

particle fractions of suspended particulates or colloids (Al-Omran and Preston 1987; Zhou and Liu 2000). 

Complexation of DEHP with fulvic acid, a compound associated with humic substances in water and soil, 

might increase solubilization and thus increase the mobility of DEHP in aquatic systems (Johnson et al. 

1977). Ritsema et al. (1989) noted that DEHP in the River Rhine was mainly associated with suspended 

particulates, but on some sampling days, dissolved DEHP was at a higher concentration than the sorbed 

material. By contrast, in Lake Yssel, DEHP concentrations in the suspended material were approximately 

100 times higher than the dissolved material. In addition, the authors reported that a distinct 

concentration gradient was noted across the lake suggesting that DEHP entered the lake from the River 

Yssel rather than nonpoint sources as was the case with some other phthalates. 

Percolation of DEHP through the soil to groundwater might occur during times of rapid infiltration. 

DEHP concentrations were generally reduced by infiltration through a soil column, but all column 

effluents contained measurable levels (Hutchins et al. 1983). In hazardous waste sites, the presence of 

common organic solvents such as alcohols and ketones might increase the solubility of relatively 

insoluble compounds such as DEHP, thereby increasing the amounts that might leach from the waste site 

into subsoil and groundwater (Nyssen et al. 1987). This is consistent with the measurement of DEHP in 

leachate of some landfills at levels in excess of its usual water solubility (see Section 6.2.2). 

Bioconcentration of DEHP has been observed in invertebrates, fish, and terrestrial organisms. Mean 

bioconcentration factors (BCFs) have been reported for algae (3,173±3,149, two species), molluscs 

(1,469±949, five species), crustacea (1,164±1,182, four species), insects (1,058±772, three species), 

polychaetes (422, one species), fish (280±230, five species), and amphibians (605, one species) have been 
DI(2-ETHYLHEXYL)PHTHALATE 192 

6. POTENTIAL FOR HUMAN EXPOSURE 

compiled by Staples et al. (1997). Residues of DEHP have been found in the organs of terrestrial animals 

such as rats, rabbits, dogs, cows, and humans (EPA 1979). However, accumulation of DEHP will be 

minimized by metabolism, and biomagnification of DEHP in the food chain is not expected to occur 

(EPA 1979; Johnson et al. 1977; Staples et al. 1997; Wofford et al. 1981). Several metabolites of DEHP 

might be detected in animal tissues (Johnson et al. 1977). Uptake of DEHP from soil by plants has also 

been reported (EPA 1986; O’Connor 1996). 

6.3.2 Transformation and Degradation 

6.3.2.1 Air 

Reaction of DEHP vapor with hydroxyl radicals in the atmosphere has been predicted, with an estimated 

half-life of about 6 hours using the Atmospheric Oxidation Program (Meylan and Howard 1993). The 

atmospheric half-life, however, is expected to be longer for DEHP adsorbed to atmospheric particulates. 

Based on the estimated half-life alone, extensive transport of DEHP would not be expected and 

concentrations in Antarctic snow would not be predicted. Nonetheless, DEHP appears to be present in 

urban and rural atmospheres (see Section 6.4), and its transport might be mainly in the sorbed state. Data 

confirming this degradation pathway have not been located. Direct photolysis and photooxidation are not 

likely to be important (Wams 1987). 

6.3.2.2 Water 

Biodegradation might be an important fate process for DEHP in water under aerobic, but not anaerobic, 

conditions (O'Connor et al. 1989; O'Grady et al. 1985; Sugatt et al. 1984; Tabak et al. 1981; Thomas et al. 

1986). DEHP was significantly biodegraded (>95%) after gradual acclimation of the microbial 

population over a period of about 3 weeks under conditions of the static-flask and shake-flask screening 

tests (Sugatt et al. 1984; Tabak et al. 1981). In the shake flask study using an acclimated inoculum, initial 

biodegradation was low on days 2 and 3 but increased 5–10-fold by days 6 and 7; degradation to carbon 

dioxide was 87% at 28 days (Sugatt et al. 1984). The reported half-life of DEHP due to microbial activity 

in river water is about 1 month (Wams 1987). In freshwater, degradation has been reported to range from 

0 to >99%, and is dependent on many variables including temperature (Staples et al. 1997). Reported 

removal of DEHP from aqueous systems by activated sludge biodegradation under aerobic conditions 

ranged from 70 to >99%, and from 0 to 90% in waste water depending on the microbial strains present 

and other variables (Kurane 1986; Nasu et al. 2001; O'Grady et al. 1985; Staples et al. 1997). In spite of 
DI(2-ETHYLHEXYL)PHTHALATE 193 

6. POTENTIAL FOR HUMAN EXPOSURE 

the many reported rapid degradation rates, DEHP has been found in sewage sludge (O’Connor 1996) and 

in sewage treatment plant effluents (Stubin et al. 1996) indicating that under actual sewage treatment 

plant conditions (which are more rigorous than environmental waters), DEHP is not always completely 

degraded, but rather becomes sorbed to sludge solids. Nonetheless, DEHP does not appear to be 

accumulating in the environment so that biodegradation is removing the apparent constant influx of 

DEHP. Under anaerobic conditions, biodegradation of DEHP is slower (O'Connor et al. 1989; Staples et 

al. 1997; Wams 1987). 

Chemical hydrolysis of DEHP occurs too slowly to be important (Howard 1989; Staples et al. 1997). The 

estimated half-life for DEHP hydrolysis in water is 100 years (Wams 1987). 

6.3.2.3 Sediment and Soil 

Biodegradation of DEHP also occurs in soil, but at a slower rate than in water, since adsorption onto the 

soil organic matter reduces the availability of DEHP for degradation (Cartwright et al. 2000; Cheng et al. 

2000; Wams 1987). According to Cartwright et al. (2000), DEHP is reported to be recalcitrant in soil 

and, as such, is predicted to account for the majority of phthalate contamination in the environment. 

Many other environmental factors, in addition to soil organic content, influence the rate of DEHP 

biodegradation (Cartwright et al. 2000; Gejlsberg et al. 2001). In sediments, optimum degradation of 

DEHP occurred at high concentration, warm temperatures, and in a nutrient-rich system (Johnson et al. 

1984). Anaerobic biodegradation of DEHP in sediments was reported to occur, but more slowly than 

under aerobic conditions (Johnson et al. 1984). 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 

One problem that is encountered when reviewing the concentrations of DEHP in environmental water 

samples is evaluating the accuracy of the reported values of DEHP dissolved in water. Many of the 

concentrations of DEHP that have been reported for environmental water samples often exceed the 

solubility of DEHP in distilled or deionized water (Staples et al. 1997). Evaluating the values is 

complicated by the fact that a true solubility of DEHP in water has been difficult to determine 

experimentally, with values ranging between 0.0006 and 0.40 mg/L depending on the method of analysis 

(Staples et al. 1997). In addition, the solubility of DEHP in aqueous environmental media can be greatly 

affected by the types and concentration of dissolved organics in the sampled water; for example, humic 

substrates in landfill leachates (Staples et al. 1997). Another complication to determining the 
DI(2-ETHYLHEXYL)PHTHALATE 194 

6. POTENTIAL FOR HUMAN EXPOSURE 

concentration of DEHP in environmental water samples is the possible introduction of DEHP from other 

sources (Howard et al. 1985). For example, the measurement of DEHP in water can be confounded by a 

number of sampling problems. Samples can be contaminated by additional amounts of DEHP contained 

in sampling devices and laboratory containers. Since DEHP is a common laboratory contaminant, many 

times laboratory and field blanks show concentrations similar to those in the media under study. 

Sampling of water through the air-water interface can be contaminated by DEHP that is contained in 

surface films, due to the limited solubility of DEHP in water and a density that is slightly lower than 

water. Consequently, the reliability of the values that have been reported to represent the concentration of 

DEHP dissolved in water will have to be judged upon the quality of the sampling and analytical 

techniques used to measure DEHP in aqueous environmental media. 

6.4.1 Air 

As presented in Chapter 4, DEHP has a relatively low vapor pressure and Henry’s law constant, as well as 

a relatively high octanol/water partition coefficient and soil sorption coefficient. This combination of 

properties is consistent with a chemical that is found to only a limited extent in air. Nonetheless, DEHP 

appears to be ubiquitous in air with urban air having somewhat higher concentrations than air in rural or 

uninhabited areas. The monitoring studies reported here appear to have taken reasonable efforts to 

eliminate contamination from their analyses. DEHP has been reported over the Pacific and Atlantic 

Oceans at mean levels of approximately 1.4x10-6 mg/m3

 (3.2x10-7–2.6x10-6 mg/m3, 0.32–2.68 ng/m3) 

(Atlas and Giam 1981; Giam et al. 1980), in outdoor air in Sweden at a median concentration of 

2.0x10-6 mg/m3

 (2.8x10-7–77.0x10-6) mg/m3, 0.28–77.0 ng/m3) (Thurén and Larsson 1990), over Portland, 

Oregon at a mean level of 3.9x10-7 mg/m3 (6.0x10-8–9.4x10-7 mg/m3

, 0.06–0.94 ng/m3) (Ligocki et al. 

1985a), and over the Great Lakes at a mean concentration of 2.0x10-6 mg/m3

 (5.0x10-7–5.0x10-6 mg/m3, 

0.50–5.0 ng/m3

) (Eisenreich et al. 1981). DEHP was not among the four phthalate esters detected in 

industrialized areas along the Niagara River (Hoff and Chan 1987). DEHP was detected but not 

quantified in a forest atmosphere in Germany (Helmig et al. 1990). Average atmospheric concentrations 

reported in the literature appear to be within a relatively narrow range regardless of whether monitored 

over oceans or in industrial areas. This might suggest that DEHP is mainly emitted from many small 

sources that are geographically diffuse and that it sorbs to atmospheric particulates that provide a 

reservoir of DEHP that is not degraded by hydroxyl radicals. 

DEHP levels in indoor air might be higher due to slow volatilization from plastic products (EPA 1981; 

Wams 1987). As noted in Section 6.2.1, Cadogan et al. (1994) reported that an indoor overall emission 
DI(2-ETHYLHEXYL)PHTHALATE 195 

6. POTENTIAL FOR HUMAN EXPOSURE 

rate of 2.3x10-4 mg/second-m2 at 25 EC has been calculated for all phthalate plasticizers in products such 

as wall coverings, flooring, upholstery, and wire insulation. The air from rooms recently covered with 

polyvinyl chloride (PVC) tiles contained 0.15–0.26 mg/m3

 (150,000–260,000 ng/m3) phthalate esters 

(EPA 1981). Indoor air levels in rooms with new flooring could be about 0.2–0.3 mg/m3

 (Wams 1987). 

DEHP was detected in samples (one from a commercial site and five from residential sites) of both dust 

and air obtained from all sites (Rudel et al. 2001). In dust, the concentration of DEHP ranged from 

69.4 to 524 μg/g dust, with a mean concentration of 315 μg/g dust. In air, 4/6 sites had DEHP at 

concentrations above the minimum detection limit (MDL), ranging from 0.02 to 0.114 μg/m3

, with a 

mean concentration of 0.061 μg/m3

. In another study, indoor measurements of DEHP taken in six homes 

in the spring of 2000 ranged from 0.04 to 0.23 μg/m3 (Otake et al. 2001). In one workplace (plastic 

melting facility), a value of 11.5 μg/m3

 was measured in air (Rudel et al. 2001). 

Emission of DEHP from PVC wall coverings (containing 30% phthalic esters) was measured in a test 

chamber at room temperature, maximum concentration of 0.94 μg/m3

 for DEHP in air over 14-day test 

period (Udhe et al. 2001). Other citations within this reference noted that DEHP in test chambers was not 

detectable at room temperature, but maximum concentrations of 5.2 and 2 μg/m3

 were measured at 60 and 

40 EC, respectively. Increases in DEHP emissions with increasing ambient temperature are especially 

important within car interiors, where DEHP concentrations in air have been shown to range from 1 μg/m3 

at room temperature to 34 μg/m3 at 65 EC (Udhe et al. 2001). 

6.4.2 Water 

DEHP has been detected frequently in surface water, rainwater, and groundwater in the United States at 

concentrations generally in the low ppb range. It also has been detected in finished drinking water, but no 

literature was located reporting positive detections within the past 15 years. Roy (1994) reported a range 

of 34–7,900 μg/L in U.S. landfill leachate. Concentrations of DEHP have been measured at 

0.6–2,400 ppb in surface waters, and at 0.04–420 ppb in groundwater obtained from private wells, offsite 

from landfills and facilities that use DEHP in manufacturing processes (HazDat 2002). Canter and 

Sabatini (1994) reported that the Biscayne aquifer in Florida had a maximum DEHP concentration of 

8,600 μg/L, but no DEHP was detected in the municipal well fields that draw water from that aquifer. 

Eckel et al. (1993) also reported the presence of DEHP in the groundwater in Florida. DEHP was 

detected in petrochemical plant waste waters and industrial landfill leachate at <0.1–30 μg/L (Castillo et 

al. 1998) and in New York City municipal treatment plant effluents up to 50 μg/L (Stubin et al. 1996). 
DI(2-ETHYLHEXYL)PHTHALATE 196 

6. POTENTIAL FOR HUMAN EXPOSURE 

DEHP was detected in 24% of 901 surface water samples recorded in the STORET database at a median 

concentration of 10 ppb (Staples et al. 1985) and in water samples from four of the five Great Lakes (IJC 

1983). DEHP was also found in water samples from several U.S. rivers (DeLeon et al. 1986; Hites 1973; 

Sheldon and Hites 1979). Reported concentrations ranged from 0.5 to 1 ppb. Average concentrations of 

DEHP in seawater ranging from 0.005 to 0.7 ppb have also been reported (Giam et al. 1978a; McFall et 

al. 1985b). DEHP was detected in drinking water concentrates from several U.S. cities (EPA 1984). 

Bauer and Herrmann (1997) reported that DEHP was present in the leachate from various fractions of 

household wastes from the regions of Bayreuth and Straubling in Germany. The wastes included food 

waste, paper for recycling, unusable paper, cardboard, plastic films, other plastics, textiles, 8–40 mm 

screened fraction, <8 mm screened fraction, compound packing waste, compound materials, and 

disposable diapers. Approximately 50 kg of these wastes were cut into 5–10 cm pieces and placed in 

laboratory fermenters then flooded with water. Stable methanogenic conditions were obtained in 

3 months. Leachate from a mixture of all waste categories except food waste contained a maximum of 

147 μg/L of DEHP, while leachate from a mixture of waste categories limited to plastic films, other 

plastics, textiles, 8–40 mm screened fraction, <8 mm screened fraction, compound materials contained a 

maximum of 56 μg/kg DEHP. The authors were careful to exclude inadvertent sources of phthalate 

esters. This report demonstrates that DEHP is present in European household waste and that it leaches 

from that waste to percolating water. The extent to which this occurs in a landfill is unclear as is whether 

or not the dissolved DEHP leaches to groundwater after leaving landfills. 

6.4.3 Sediment and Soil 

Monitoring data for DEHP in soil were not located. DEHP was detected in both marine and freshwater 

sediments at average levels ranging from 6.6 to 1,500 ppb. Maximum values are usually observed near 

industrial effluent discharge points (Fallon and Horvath 1985; Murray et al. 1981; Ray et al. 1983). The 

highest value reported in the United States was 7,800 ppb in a marine sediment from Portland, Maine 

(Ray et al. 1983), and a value of 1,480 ppm was reported in a sediment sample from a river in Sweden 

(Thuren 1986). In the New York Bight (a sector of the Middle Atlantic Ridge adjoining the New York 

and New Jersey shorelines), which is an area containing disposal sites for dredging mud, sewage sludge, 

and industrial acid waste, DEHP has been measured in sediments at concentrations ranging from 0.1 to 

10.1 ppm (Friedman et al. 2000). Iannuzzi et al. (1997) reported that DEHP was present in every 

sediment sample taken adjacent to combined sewer overflows to the Passaic River in New Jersey at 

concentrations between 960 and 27,000 μg/kg (a total of 40 samples). Of the 431 stream bed sediments 
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6. POTENTIAL FOR HUMAN EXPOSURE 

collected from throughout the United States, 39.2% showed DEHP concentrations, with a median 

concentration of 180 μg/kg (the high concentration was 17,000 μg/kg) (Lopes et al. 1997). DEHP was 

reported in 40% of 367 sediment samples recorded on the STORET database at a median concentration of 

1,000 ppb (Staples et al. 1985) and in sediments near a hazardous waste site (Hauser and Bromberg 

1982). 

6.4.4 Other Environmental Media 

DEHP has been found in several kinds of food. Fish and other seafood have been reported to be 

contaminated with concentrations ranging from 2 to 32,000 ppb (DeVault 1985; Giam and Wong 1987; 

Giam et al. 1975; McFall et al. 1985a; Ray et al. 1983; Stalling et al. 1973; Williams 1973). DEHP was 

detected in 33% of 139 biota samples (not necessarily edible) recorded on the STORET database at a 

median concentration of 3,000 ppb (Staples et al. 1985). DEHP has also been reported in processed 

canned and frozen fish in Canada at concentrations up to 160 ppb (Williams 1973). 

DEHP can become an indirect additive in packaged foods due to its use in plastic wraps, heat seal 

coatings for metal foils, closure seals for containers, and printing inks for food wrappers and containers 

(Ministry of Agriculture Fisheries and Foods 1990); however, DEHP has not been used in food film wrap 

products for over 20 years (Mannsville Chemical Products Corporation 1999). Monitoring data indicate 

that DEHP residues are generally low in U.S. foods, but the available data are in excess of 10 years old 

and might not be representative of current conditions. DEHP has been detected in such foods as milk, 

cheese, meat, margarine, eggs, cereal products, baby food, infant formula, in addition to fish (Cerbulis 

and Byler 1986; EPA 1981; Petersen and Breindahl 2000). Most samples contained less than 1 ppm 

DEHP, but fatty foods had higher levels. Chocolate bars contained DEHP at levels up to 2.4 ppm (Castle 

et al. 1989). Although one study found that levels of DEHP in fatty foods such as milk, cheese, and meat 

did not differ significantly from background levels (CMA 1986), high levels of DEHP in "blank" samples 

and other analytical problems indicate that laboratory contamination might have confounded the results. 

DEHP has been detected in indoor dust samples. Øie et al. (1997) reported that sedimented dust samples 

from 38 dwellings in Oslo, Norway contained an average of 640 μg/mg sedimented dust 

(100–1,610 μg/g), while suspended particulate matter from six dwellings contained an average of 

600 μg/g (24–94 μg/g). 
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6. POTENTIAL FOR HUMAN EXPOSURE 

Blood products available for transfusions might be contaminated with DEHP due to leaching from the 

plastic equipment used to collect and store the blood. Reported concentrations of DEHP in blood 

products stored in PVC bags are: whole blood (2–620 ppm); platelet concentrates (23.4–267 ppm); red 

cell concentrates (4.3–152 ppm); and plasma (4.3–1,230 ppm) (Ching et al. 1981b; Cole et al. 1981; 

Contreras et al. 1991; Dine et al. 1991; FDA 2001h; Jaeger and Rubin 1972; Loff et al. 2000; NTP 2000b; 

Rock et al.1978; Shintani 2000; Sjoberg et al. 1985c; Vessman and Rietz 1974). DEHP was also detected 

in intravenous fluids, such as saline and glucose, used for parenteral therapy of hospitalized patients, at 

levels ranging from 9 to 13 ppb (Ching et al. 1981b). Karle et al. (1997) reported that DEHP 

concentrations at the end of the blood prime in extracorporeal membrane oxygenation circuits in an in 

vitro study had mean values of 18.3, 21.8, and 19.3 μg/mL for different circuits and was dependent on the 

surface area of each circuit. After 3 days, DEHP concentrations in infants averaged 4.9±4.0 μg/mL. 

Shneider et al. (1991) reported that serum DEHP concentrations varied depending on the nature of the 

treatment. They reported that for an infant cardiopulmonary bypass, pediatric hemodialysis, exchange 

transfusion, and extracorporeal membrane oxygenation, serum DEHP concentrations ranges were 1.1–5.1, 

0.4–4.2, 5.4–21.5, and 18–98 μg/mL, respectively. 

Soft plastic products available for use by infants might contain low levels of DEHP. DEHP was detected 

in four commercial pacifiers at concentrations of 31–42% by weight (Lay and Miller 1987). However, 

current levels of DEHP in these products have been greatly reduced, since manufacturers of toys and 

pacifiers voluntarily agreed to reduce the use of DEHP in their products (Wilkinson and Lamb 1999), 

although some PVC toys manufactured in a small number of foreign countries have been reported to 

contain up to 11–19% DEHP (Stringer et al. 2000). DEHP was the most common plasticizer in soft PVC 

products intended for children until the early 1980s. Manufacturers of PVC pacifiers and teethers set a 

limit of 3% by weight DEHP as a voluntary standard (Wilkinson and Lamb 1999). This limit should 

effectively eliminate the intentional addition of DEHP as a plasticizer in those products manufactured 

under the voluntary guidelines for DEHP content. In fact, the U.S. Consumer Product Safety 

Commission has reported that DEHP could not be found in pacifiers or bottle nipples currently on the 

market (Consumer Product Safety Commission 1998, 1999d). Except for one manufacture whose pacifier 

and bottle nipple products were found to contain diisooctylphthalate, all other known manufacturers of 

pacifiers and bottle nipples used latex or silicone instead of PVC in their products. 

As presented in Section 6.4.2 above, Bauer and Herrmann (1997) reported that mixed household waste 

contained DEHP. Table 6-2 summarizes the concentration of DEHP detected in various categories of 

waste. The authors also calculated that 177.5–1,469.5 mg/kg DEHP was present in the waste on a dry­
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6. POTENTIAL FOR HUMAN EXPOSURE 

weight basis and constituted the most commonly found phthalate ester, constituting 91.9–93.3% of the 

total phthalates found in the waste. 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 

The general population is exposed to DEHP via oral, dermal, and inhalation routes of exposure. DEHP is 

present in environmental media and in numerous consumer articles that are used world-wide (see 

Chapter 4). Estimates of the average total daily individual ambient exposure to DEHP in the United 

States have ranged from 0.21 to 2.1 mg/day (David 2000; Doull et al. 1999; Huber et al. 1996; Kohn et al. 

2000; Tickner et al. 2001). These estimates do not include workplace air exposures or exposures to 

DEHP offgassing from building materials. DEHP exposures in the Canadian population were estimated 

in 1994 to be 8.9–9.1, 19, 14, 8.2, and 5.8 μg/kg body weight/day for age groups 0–0.5, 0.5–4, 5–11, 

12–19, and 20–70 years, respectively (NTP 2000b). Some of the information presented is based on old 

data and might not represent current exposures, especially since there have been recent changes in the use 

patterns for DEHP (see Section 6.6 for specific examples). However, there are current estimates, based 

on the measurement of the DEHP metabolite, MEHP, in human urine obtained by Blount et al. (2000a), 

which suggest that the average total daily ambient exposure of individuals in the United States to DEHP 

is likely to be <3.6 μg/kg body weight/day (David 2000; Kohn et al. 2000). Larger study populations will 

be required beyond the 289 individuals examined in the Blount et al. (2000a) work to 
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6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-2. Concentration of DEHP in Categories of Household Waste 

Concentration of DEHP (mg/kg)a,b 

Waste fraction Minimum Maximum Mean 

Food waste 64.3 4.8 334.7 

8–40 mm Fraction 1,259.1 584.9 2,253.5 

<8 mm Fraction 95.5 76.1 132.5 

Paper for recycling 29.7 10.0 60.3 

Unusable paper 71.1 41.4 106.4 

Cardboard 47.4 10.1 70.5 

Plastic films 444.9 169.0 907.9 

Other plastics 1,027.6 373.8 2,035.3 

Textiles 205.7 14.9 686.1 

Compound packing waste 151.9 57.7 393.7 

Compound materials 16,820.6 7,862.4 26,352.0 

Disposable diapersc 74.1 14.2 322.2 

Source: Bauer and Herrmann (1997) 

a

Results are from six extractions except “compound material” for which the results are for nine extractions. b

The precision of the values presented in this table is the same as the original paper.
 c

Described as “nappies” in the original paper
 
DI(2-ETHYLHEXYL)PHTHALATE 201 

6. POTENTIAL FOR HUMAN EXPOSURE 

gain a representative sampling of the exposure of the U.S. population to DEHP, including possible 

demographic variations in exposure and/or metabolism that was noted by Blount and coworkers. 

It is difficult to determine the dominant source of DEHP exposure by the oral route. While in the past, it 

is likely that food represented the major source of DEHP for at least the general population and possibly 

many children (Doull et al. 1999; Huber et al. 1996; NTP 2000b), much of the literature supporting this is 

10–25 years old (see Huber et al. 1996). Some attempts have been made to estimate exposures of DEHP 

to the general population (3–30 μg/kg body weight/day) through ingestion that is based on current use 

patterns for DEHP (NTP 2000b), but more information is still needed. The National Health and Nutrition 

Examination Survey (NHANES) has obtained measurements of DEHP metabolites (mono-2-ethylhexyl 

phthalate) in urine as a method to assess exposures of the general population (6 years of age and older) to 

DEHP (Blount et al. 2000b; CDC 2001); however, no correlation of these measurements with actual 

DEHP intake has yet been determined. In addition, much of the current literature on DEHP 

contamination of foodstuffs is foreign or not typically associated with consumer exposures, and it is 

uncertain how applicable this information is to U.S. exposures (e.g., Fayad et al. 1997, migration of 

DEHP into bottled water, Saudi Arabia; Gramiccioni et al. 1990, migration of DEHP from caps into 

foods, Italy; Cohen et al. 1991, migration of DEHP from a plastic bag containing contaminated corn in a 

laboratory [the corn was not intended for consumer use], Canada/France; Tsumura et al. 2001, migration 

of DEHP from PVC gloves to prepared food, Japan; Bluthgen 2000, post-secretory migration of DEHP 

during milk processing and storage, Germany; and Morelli-Cardoso et al. 1999, migration of DEHP into 

food simulants, Brazil). Finally, while the Food and Drug Administration (FDA) allows the use of DEHP 

in food contact applications (e.g., can coatings FDA 1999g; adhesives FDA 1999a; defoaming agent in 

paper manufacture FDA 1999e; as a flow promoter at no more than 3% in acrylic and modified acrylic 

single and repeated use containers FDA 1999c; in cellophane used for food packaging at a concentration 

not to exceed 5% FDA 1999b; and as a surface lubricant in the processing of metal foil at a concentration 

not to exceed 0.015 mg/in2

 of metal surface FDA 1999d), it is not clear if industry currently uses DEHP 

in these applications (e.g., Mannsville Chemical Products Corporation [1999] reported that DEHP has not 

been used in food film wrap for over 20 years; they also included no food applications in their list of uses, 

see Chapter 5). Thus, the uncertainty associated with current concentrations in food as outlined above, 

makes quantifying intakes speculative. This might be especially true given the recent activity (as noted in 

Section 6.6) in eliminating phthalates from some consumer products. 

Oral exposure from drinking water is not expected to be a significant route of exposure (Doull et al. 1999; 

Huber et al. 1996; NTP 2000b) based on estimates of <30 ppb for DEHP in water (Huber et al. 1996). 
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6. POTENTIAL FOR HUMAN EXPOSURE 

Stubin et al. (1996) noted that DEHP was commonly present (48% of the samples) in municipal sewage 

treatment plant influent, suggesting that DEHP is present in domestic waste water. DEHP in domestic 

waste water can come from either the source tap water or from activities within the household such as 

washing floors that contain DEHP, showering using a shower curtain containing DEHP, or washing other 

DEHP-containing materials. 

Dermal exposure to DEHP can occur when items containing DEHP as a plasticizer are handled. Schwope 

and Reid (1988) noted that DEHP migrated into dry materials in contact with PVC containing DEHP. 

From the data available in this study, however, it is not clear how much DEHP will be transferred. A 

study of the migration of DEHP from PVC film to rat skin found that the mean dermal uptake of DEHP 

was small, only 0.24 μg/cm2

-hour (Deisinger et al. 1998), a rate that is likely to be 2–4 times faster than is 

expected for human skin (Barber et al. 1992; Scott et al. 1987). A report to the Consumer Product Safety 

Commission (2001) provided a range of time-weighted average daily dermal exposure estimates for 

another phthalate diester, diisononyl phthalate (DINP), of between 0.45 and 11 μg/kg/day in adults 

(Consumer Product Safety Commission 2001). However, it is noted in the same report that these current 

estimates of potential dermal exposure remain speculative. Because many common household products 

contain DEHP, including furniture upholstery, shower curtains, tablecloths, wall coverings, floor tiles, 

garden hoses, swimming pool liners, rainwear, baby pants, toys, shoes, and automobile upholstery (see 

Chapter 5), there are opportunities for exposure, but how much DEHP is transferred to, and absorbed by, 

an individual is still indeterminate. 

Inhalation exposure can occur from breathing ambient air and indoor air, and is not considered to be a 

primary or significant route of exposure to DEHP. Huber et al. (1996) and Doull et al. (1999) have 

suggested, based on monitoring studies from the 1970s and 1980s, that inhalation exposures from 

breathing ambient air are low. No recent ambient air studies were found in the available literature; 

however, available studies report concentrations that span a relatively narrow range, even in industrialized 

areas (see Section 6.4.1); although industrial areas appear to have higher concentrations in some cases. 

Thurén and Larsson (1990) reported that higher concentrations of DEHP were seen adjacent to a facility 

using DEHP, but these concentrations fell off rapidly. Thus, it is anticipated that people living near 

DEHP use and disposal areas might be exposed to elevated levels, but it is unclear how much higher these 

concentrations might be. It is further anticipated that use facilities where DEHP is actively used, such as 

DEHP production or PVC manufacturing facilities, will emit more DEHP to the offsite environment (e.g., 

through air-borne particulates or water) than storage or disposal facilities because of the tendency of 

DEHP to sorb to organic matter in the soil or sediment (see Section 6.3.1). 
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6. POTENTIAL FOR HUMAN EXPOSURE 

Occupational exposure to DEHP might be important during the manufacture and processing of this 

compound. Workers might be exposed to relatively high concentrations of DEHP during the 

compounding of this plasticizer with resins and the manufacture of PVC plastic products. The National 

Institute for Occupational Safety and Health (NIOSH) estimated that about 340,000 workers (of which 

approximately 106,900 were female) were potentially exposed to DEHP in the early 1980s (NOES 1990). 

Workplace air levels of DEHP ranging from 0.02 to 4.1 mg/m3

 were reported at facilities using or 

manufacturing the compound (Hill et al. 2001; IARC 1982; Liss et al. 1985). These levels are below the 

current OSHA Permissible Exposure Limit (PEL) for DEHP for an 8-hour work-day of 5 mg/m3

 (OSHA 

1989). Exposures of phthalate and PVC production workers to DEHP are estimated to be typically less 

than 143 and 286 μg/kg body weight/workday, respectively (NTP 2000b). The types of industries using 

DEHP-containing products (see Table 6-3) can be inferred from the types of industries that reported 

DEHP emissions to the TRI (TRI99 2001). 

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). 
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6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-3. Types of Industries Using DEHP-containing Products 

abrasive products 

adhesives and sealants 

agricultural chemicals 

asbestos products 

boat building and repairing 

cement 

chemical preparations 

chemicals and allied products 

coated fabrics (not rubberized) 

crowns and closures 

current-carrying wiring devices 

custom compound purchased resins 

electrical industrial apparatus 

electromedical equipment 

electronic capacitors 

electronic components 

fabric dress and work gloves 

fabricated metal products 

fabricated rubber products 

gaskets 

gray and ductile iron foundries 

hand and edge tools 

hard surface floor coverings 

household laundry equipment 

hydraulic 

industrial inorganic chemicals 

industrial organic chemicals 

manufacturing industries 

mattresses and bedsprings 

meat packing plants 

Source: TRI (TRI99 2001) 

mechanical rubber goods 

medicinals and botanicals 

minerals (ground or treated) 

motor vehicle parts and accessories 

motor vehicles and car bodies 

noncurrent-carrying wiring devices 

nonferrous wire drawing and insulating 

nonmetallic mineral products 

packing and sealing devices 

paints and allied products 

paper (coated and laminated) 

pharmaceutical preparations 

photographic equipment and supplies 

plastics foam products 

plastics materials and resins 

plastics pipe 

plastics products 

plating and polishing 

refuse systems 

rubber and plastic footwear 

rubber and plastic hose and belting 

sporting and athletic goods 

surface active agents 

surgical and medical instruments 

tires and inner tubes 

unsupported plastics film and sheet 

unsupported plastics profile shapes 

wood household furniture 

wood products 
DI(2-ETHYLHEXYL)PHTHALATE 205 

6. POTENTIAL FOR HUMAN EXPOSURE 

Children are exposed to DEHP orally from mouthing toys and other soft PVC products and possibly food, 

by inhalation from ambient and indoor air, and dermally from handling materials containing DEHP. In 

addition, children are potentially exposed from medical devices via the inhalation, dermal, oral, and 

intravenous routes. Exposures from medical devices will be treated separately in this section. It should 

be noted that assessing exposures to DEHP, and especially children’s exposures, is difficult because the 

uses of DEHP, while constant for many years, have changed over the last 20 years (Consumer Product 

Safety Commission 1999d; Wilkinson and Lamb 1999). For example, manufacturers including Chicco, 

Little Tikes, Disney, Mattel (Fisher-Price ARCOTOYS, Tyco Preschool), Evenflo, Safety 1st, The First 

Years, Sassy, Gerber, Shelcore Toys, and Hasbro (including Playskool) stopped using phthalates in 

teethers and rattles in early 1999 (Consumer Product Safety Commission 1999d). In addition, a number 

of retail stores, including Toys-R-Us, Walmart, Sears, Target, K-Mart, ShopKo Stores, Inc., and Warner 

Brothers Studio Stores, have removed phthalate-containing teethers, rattles, pacifiers, and bottle nipples 

from their product lines. This change, and others that might be made in the near future, makes an 

assessment of a child’s exposure to DEHP more difficult than would otherwise be the case. 

It is difficult to determine the dominant source of DEHP exposure by the oral route for children, just as is 

the case with the general population. While in the past, food represented the dominant source of oral 

exposure to DEHP, as noted above in Section 6.5, the literature base supporting this is old and might not 

represent current exposures. A recent Danish study published by Petersen and Breindahl (2000) 

estimated the dietary intake of DEHP in infants (based on measurements of DEHP in baby food and 

formula) to be between 0.005 and 0.010 mg/kg body weight. However, without more recent information, 

quantifying either the amount or the extent of food exposures would be speculative. Drinking water is not 

anticipated to be a significant source of DEHP exposure; however, the database supporting this is old (see 

Section 6.5). DEHP concentrations in human breast milk of 70–160 μg/kg milk (mean concentration of 

93±37.5 μg/kg milk) and 0–110 μg/kg milk (mean concentration of 0.034±0.043 μg/kg milk) have been 

reported (FDA 2001h). However, no information is available relating the concentration of DEHP in 

human breast milk obtained from women with high occupational exposures to DEHP or exposures that 

result from medical treatments (e.g., hemodialysis). 

A source of DEHP exposure for young children by the oral route might be plastic toys. The exposure will 

be dependent on the time that a child spends mouthing a toy and the DEHP content of the toy. 

Information on children’s mouthing behavior is available and indicates that the behavior is dependent on 

the age of the child and the items mouthed (Consumer Product Safety Commission 2001; Juberg et al. 

2001). Juberg et al. (2001) found that children spend an average of 23 minutes/day (children between the 
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6. POTENTIAL FOR HUMAN EXPOSURE 

ages of 0 and 18 months), and 5 minutes/day (children between the ages of 19 and 36 months) mouthing 

toys and teethers; these times are shorter than the estimated mouthing times (e.g., 1–3 hours) found 

elsewhere (Health Canada 1998). These average mouthing times provided by Juberg et al. included 

children who did not exhibit mouthing behavior. If the averages included only children exhibiting 

mouthing behavior, then the time spent by these children mouthing teethers and toys increases to 

48 minutes/day (children between the ages of 0 and 18 months), and 41 minutes/day (children between 

the ages of 19 and 36 months). Juberg et al. (2001) also reported pacifier use to average 

108±187 (mean±1 standard deviation) minutes/day for children ages 0–18 months, and 

126±246 minutes/day for children ages 19–36 months. However, manufacturers for some children’s toys 

have discontinued the use of DEHP and other phthalates in pacifiers, teethers, rattles, and toys designed 

for very young children (see above). Therefore, the mouthing of pacifiers, teethers, and toys is not 

expected to be a significant route of exposure of young children to DEHP. Yet, there is no information 

about a similar action with other toys or toys for older children (toys, and specifically dolls, were 

identified by Mannsville Chemical Products Corporation (1999) as products that used DEHP as a 

plasticizer). In addition, families might hand down toys containing phthalates from older children rather 

than buy new toys that contain no phthalates. While some of these toys might have less than 3% DEHP 

(Wilkinson and Lamb 1999), this percentage likely cannot be applied to all toys that young children 

might play with. At the present time, however, sufficient information is not available to quantify these 

exposures. 

Some research has been conducted to examine the migration of DEHP and other plasticizers from PVC 

into saliva. Steiner et al. (1998) reported that migration of DEHP from PVC into a saliva simulant was 

dependent on the contact time and agitation of the test matrix. In vivo studies of the migration of DEHP 

into human saliva from four adult volunteers chewing PVC balls (185 mg DEHP/g) showed a migration 

rate of 44.4 μg/10 cm2

/hour (Niino et al. 2001). However, no other studies, especially in children, are 

available evaluating DEHP migration rates in toys. 

Other potential sources of oral exposure for young children as well as dermal exposure to all children 

include general household items made from PVC including dolls, plastic baby pants, furniture upholstery, 

floor tiles, shower curtains, and tablecloths (all of which are available for mouthing by children in 

addition to touching) (see also Chapter 5). In addition, young children might be exposed to DEHP when 

wearing such items as rainwear and shoes made from PVC. Dermal uptake of DEHP from PVC film to 

rat skin was found to be low, only 0.24 μg/cm2

-hour (Deisinger et al. 1998), but is expected to be 

2–4 times lower for human skin (Barber et al. 1992; Scott et al.1987). A report to the Comsumer Product 
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6. POTENTIAL FOR HUMAN EXPOSURE 

Safety Commission (2001) provided a range of time-weighted average daily dermal exposure estimates 

for another phthalate diester, diisononyl phthalate (DINP), of between 3.2 and 79 μg/kg/day in children 

ages 19–36 months (Consumer Product Safety Commission 2001). However, it is noted in the same 

report that these current estimates of potential dermal exposure remain speculative. Oral exposure also 

might occur when children handle PVC items containing DEHP, and then the children’s hands are 

mouthed. However, no specific reference to DEHP transfer from items to skin was found in the available 

literature. Therefore, sufficient information is not available to assess this route of exposure to DEHP. 

All children might have inhalation exposures from both vapor and particle bound DEHP as well as oral 

exposure to DEHP from inhalation of large particles containing DEHP followed by deposition in the 

upper airways and swallowing (Hill et al. 2001). Øie et al. (1997) reported that sedimented dust samples 

from 38 dwellings in Oslo, Norway (including samples taken from sheets in a child’s bed and floor in a 

child’s bedroom) contained an average of 640 μg/g sedimented dust (100–1,610 μg/g), while suspended 

particulate matter from six dwellings contained an average of 600 μg/g (24–94 μg/g). The authors noted 

that exposure to particle bound DEHP is 0.4–1.2 μg/day for adults, but suggested that children, and 

especially small children, are “subject to the highest exposure risk” because they usually have small 

rooms that have higher surface to volume ratios and few doors or windows. Children’s exposures to 

DEHP from inhalation of outdoor air is likely small because of the relatively low ambient concentrations 

(Doull et al. 1999; Huber et al. 1996). While the database of outdoor concentrations is dated (1970s 

through the 1980s), the concentrations appear to be very consistent both spatially and temporally. 

A possible exception to the anticipated low exposure from inhalation to outdoor air might be in the 

vicinity of hazardous waste sites containing large concentrations of DEHP or use facilities. DEHP has a 

low volatility and is not expected to enter the air extensively; nonetheless, Thurén and Larsson (1990) 

noted higher concentrations of DEHP near a facility that used it, indicating that somewhat higher 

concentrations might be anticipated near use or storage facilities. Those industries that emitted more than 

10,000 pounds into the air in 1998 were crowns and closures, fabricated rubber products, motor vehicle 

parts and accessories, plastics foam products, unsupported plastics film and sheet (TRI99 2001). Children 

living near the vicinity of one of these facilities might be exposed to somewhat elevated concentrations of 

DEHP, although exact concentrations are not known. 

Children’s exposures to DEHP during medical procedures have been reported (Hill et al. 2001; Karle et 

al. 1997; Latini and Avery 1999; NTP 2000b; Plonait et al. 1993; Shneider et al. 1991). Shneider et al. 

(1991) reported that serum DEHP concentrations varied depending on the nature of the treatment. They 
DI(2-ETHYLHEXYL)PHTHALATE 208 

6. POTENTIAL FOR HUMAN EXPOSURE 

reported that for an infant cardiopulmonary bypass, pediatric hemodialysis, exchange transfusion, and 

extracorporeal membrane oxygenation (ECMO), serum DEHP concentrations ranges were 1.1–5.1, 

0.4–4.2, 5.4–21.5, and 18–98 μg/mL, respectively. Karle et al. (1997) confirmed this study, but reported 

lower concentrations. The authors reported that blood DEHP concentrations at the end of the blood prime 

during in vitro studies in extracorporeal membrane oxygenation circuits had mean values of 18.3, 21.8, 

and 19.3 μg/mL for different circuits and was dependent on the surface area of each circuit. The authors 

noted that the extraction rates were 0.32±0.12 and 0.57±0.14 μg/mL-hour for circuits A and B, 

respectively, but the extraction rates were identical when corrected for surface area. In contrast to the 

other two, the concentration of DEHP in circuit C decreased at a rate of 0.2±0.04 μg/mL-hour. The 

authors suggested that this was due to the heparin coating on the surfaces and noted that heparin might 

offer protection from DEHP leaching. After 3 days, DEHP concentrations in 18 infants averaged 

4.9 μg/mL; the highest level seen was 8.3±5.7 μg/mL. Karle et al. (1997) calculated DEHP exposures 

during ECMO therapy averaged 1.2 mg/kg (2.0 mg/kg maximum) for a 3-day exposure, based on an 

average patient weight of 3.3 kg and an average blood volume of 800 mL for the 18 infants studied. 

These authors also reported that DEHP concentrations were below the detection limit in all patients after 

decannulation. They also noted that patients treated for longer periods did not have higher DEHP 

concentrations. 

Latini and Avery (1999) reported that 60–120 mg of DEHP/g of tube was removed from endotracheal 

tubes during use (range of 44 samples). The authors also noted that zinc was lost from the tubes as well. 

Plonait et al. (1993) studied 16 newborn infants receiving blood exchange transfusions. The authors 

calculated exposures of 1.2–22.6 mg/kg-body weight, based on the volume of blood transfused and the 

mean DEHP concentration in the plasma of the blood units. They also noted that for three infants, 12.5, 

22.9, and 26.5% of the DEHP introduced into the infants was eliminated in the waste (exchanged) blood. 

The authors reported that no correlation was found between the volume of blood transfused and the serum 

DEHP concentration immediately after the transfusion. There was also no correlation between the 

concentration of DEHP in the plasma and the storage time of the red cell bag. The authors reported that 

serum DEHP concentrations decreased rapidly after the transfusion was complete. Plonait et al. (1993) 

also reported that ethylhexanoic acid concentrations in the urine of infants undergoing transfusion therapy 

was below the detection limit (45 ng/mL) before or during the transfusion, but ranged from 50 to 

416 ng/mL (median 130 ng/mL) in six infants 6 hours after the transfusion. Peak levels occurred within 

the first 18 hours, and then declined to close to the detection limit where they remained for 96 hours. 

Finally, these authors noted that for two infants, DEHP concentrations appeared to accumulate resulting 
DI(2-ETHYLHEXYL)PHTHALATE 209 

6. POTENTIAL FOR HUMAN EXPOSURE 

in higher concentrations in the post exchange serum than the average DEHP concentration in the blood 

received by the patients. 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 

Several population subgroups might have above average exposure to DEHP. These include hemophiliacs 

and others who require frequent blood transfusions, dialysis patients who might be exposed to DEHP 

leached from the dialysis tubing (see Section 6.4.4), and preterm infants (Doull et al. 1999; FDA 2001h; 

Huber et al. 1996; Latini 2000; NTP 2000b; Tickner et al. 2001). Estimates of exposure levels indicate 

that hemophiliacs might be exposed up to 1–2 mg/day and dialysis patients might receive average doses 

of 40 mg/day (Pollack et al. 1985a; Wams 1987). Faouzi et al. (1999) estimated that dialysis patients 

received an average of 75 mg of DEHP per treatment and an average of almost 12 g of DEHP over a 

1-year period (assuming dialysis treatments 3 times a week). Adult exposures to DEHP from 

hemodialysis have been estimated at <5–155 mg/day or <0.1–3.1 mg/kg/day and can vary considerably 

between patients (Dine et al. 2000; FDA 2001h; Huber et al. 1996; NTP 2000b). Infants receiving 

exchange transfusions might be exposed to >4 mg/kg/day (FDA 2001h; Sjoberg et al. 1985c), based on a 

worst-case scenerio. Plonait et al. (1993) reported higher plasma concentrations than those in the Sjoberg 

et al. (1985c) study, but the blood units used had a lower initial DEHP concentration. Plonait et al. 

(1993) suggest that this can be explained by pauses during the exchange transfusion during the Sjoberg et 

al. (1985c) study, which resulted in a lowering of the DEHP concentration. Faouzi et al. (1994) reported 

that administration of teniposide is sometimes associated with a nonionic surfactant polyoxyethylated 

castor oil. The presence of this surfactant increases the concentration of DEHP that is leached from the 

PVC bags into the administered solution. The authors reported that 52 mg was extracted at 48-hour room 

temperature storage. Preterm infants can be exposed to DEHP at levels estimated to be as high as 

10–20 mg/day during the course of their care (Loff et al. 2000). Measured concentrations of DEHP in 

total parental nutrition (TPN) solutions (423±47 μg/mL), blood products (platelet-rich plasma, 

13.9±2.5 μg/mL; fresh frozen plasma, 24.9±17 μg/mL) and selected drugs (propofol, 655±96 μg/mL) 

have been obtained in these solutions/products as a consequence of contact with PVC bags and tubing. 

Exposures to DEHP can be especially high for infants receiving TPN solutions (contains approximately 

20% lipid emulsions), where a 24-hour infusion can deliver up to an estimated 10 mg of DEHP (Loff et 

al. 2000). 

Workers in industries manufacturing or using DEHP plasticizer might be frequently exposed to above 

average levels of this compound (see Section 6.5). Those living near industrial facilities or hazardous 
 

 

DI(2-ETHYLHEXYL)PHTHALATE 210 

6. POTENTIAL FOR HUMAN EXPOSURE 

waste sites with higher than average levels of DEHP in water might also have potential above average 

exposure (see Section 6.4). 

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 DEHP 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 DEHP. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

6.8.1 Identification of Data Needs 

Physical and Chemical Properties. The physical and chemical properties of DEHP are 

sufficiently well characterized to allow estimation of its environmental fate and transport profile. On this 

basis, it does not appear that further research in this area is required. 

Production, Import/Export, Use, Release, and Disposal. Data on the production and uses of 

DEHP in the United States are available (ChemExpo 1999; HSDB 1990; Mannsville Chemical Products 

Corporation 1999; TRI99 2001). Production has been fairly constant over the past 5 years and is 

expected to remain so during the next few years due to limited growth in PVC markets. Disposal of 

DEHP is mainly to landfills and the recently promulgated land disposal restrictions should ensure 

reduction of the disposal of untreated DEHP wastes. Available information appears to be sufficient for 

assessing the potential for release of, and exposure to, DEHP. 
 

 

DI(2-ETHYLHEXYL)PHTHALATE 211 

6. POTENTIAL FOR HUMAN EXPOSURE 

According to the Emergency Planning and Community Right-to-Know Act of 1986, 42 U.S.C.
 

Section 11023, industries are required to submit chemical release and off-site transfer information to the
 

EPA. The Toxics Release Inventory (TRI) contains this information from 1988 to 1999.
 

While information on uses is available (Mannsville Chemical Products Corporation 1999), specific
 

information on uses in certain potentially high exposure applications is either changing or lacking. 

Specifically, information on the use of DEHP in food contact applications such as coatings used in cans,
 

bottle caps, and films would allow a better estimation of potential exposures from food. Currently, the
 

only information available is that these applications are allowed by FDA rules, but it is unclear if DEHP
 

is used.
 

Environmental Fate. The environmental fate of DEHP has been fairly well characterized. Its
 

transport in the atmosphere, sorption to sediments, bioconcentration in aquatic organisms, and
 

biodegradation by water and soil microorganisms seem to be well understood (Al-Omran and Preston
 

1987; Atlas and Giam 1981; Barrows et al. 1980; Eisenreich et al. 1981; EPA 1980a; Kenaga 1980;
 

Ligocki et al. 1985a, 1985b; Suggatt et al. 1984; Sullivan et al. 1982; Thurén and Larsson 1990; Wams
 

1987; Wolfe et al. 1980a). Sorption and biodegradation are competing processes for DEHP removal from
 

water (Ritsema et al. 1989; Wams 1987). Reaction of atmospheric DEHP is rapid (Meylan and Howard
 

1993), but sorption might play an important role in slowing the oxidation process. Additional data on the
 

rates of these reactions under various environmental conditions would be useful for more accurately
 

predicting the fate of DEHP in all environmental media. Of particular interest would be additional
 

information on the fate of DEHP leached into groundwater in order to document further that it is of minor
 

concern in subsurface environments. Additionally, information on the atmospheric oxidation rate of
 

DEHP sorbed to particulates would be of great interest. In designing such studies, it is critical to address
 

the issue of laboratory contamination by DEHP.
 

Bioavailability from Environmental Media. On the basis of data from available toxicokinetics
 

studies, DEHP will be absorbed following ingestion of contaminated drinking water and foodstuffs and
 

inhalation of contaminated ambient air. Absorption following dermal exposure to soils is expected to be
 

limited because of the strong sorption of DEHP to soils and because, in the absence of solvents, DEHP
 

does not penetrate skin well. However, additional information would be useful to determine whether
 

DEHP would be absorbed following dermal exposure to contaminated water and soils and ingestion of
 

contaminated soils. This information will be helpful in assessing the relative importance of these
 

pathways for exposed humans.
 
 

 

 

 

DI(2-ETHYLHEXYL)PHTHALATE 212 

6. POTENTIAL FOR HUMAN EXPOSURE 

Food Chain Bioaccumulation. Bioconcentration of DEHP in aquatic organisms has been 

documented for several aquatic species (Barrows et al. 1980; EPA 1980a; Kenaga 1980; Staples et al. 

1997). Based on the relatively high Kow, it appears that accumulation can occur. However, rapid 

metabolism of DEHP in higher organisms seems to prevent biomagnification in the food chain (EPA 

1979; Johnson et al. 1977; Staples et al. 1997; Wofford et al. 1981). 

Exposure Levels in Environmental Media. Several studies are available documenting levels of 

DEHP in air, water, sediments, and biota in rural and urban areas. DEHP has been detected in surface 

water, groundwater, and soil samples taken in the environs of hazardous waste sites during recent 

monitoring surveys (Canter and Sabatini 1994; Eckel et al. 1993; Hauser and Bromberg 1982; Plumb 

1987). Concentrations in ambient air at hazardous waste sites are available at only four sites. Ambient 

levels of DEHP are generally low in all environmental media. Since DEHP is a ubiquitous laboratory 

contaminant (see Chapter 7), it is very difficult to accurately determine these low levels. Often, 

laboratory contamination has undermined the credibility of the data generated. Additional monitoring 

data for DEHP in all environmental media, using recently suggested techniques for reducing laboratory 

contamination (see Section 7.2), would be useful to better assess the potential for human exposure to this 

compound. 

Exposure Levels in Humans. Detection of DEHP in blood, urine, and adipose tissue might be 

indicators of human exposure. However, since DEHP is rapidly metabolized in vivo, levels in these 

biological materials have not been directly associated with environmental levels. Additional data 

correlating levels in environmental media with human tissue levels of DEHP or its metabolites, 

particularly for populations living in the vicinity of hazardous waste sites containing DEHP, would be 

helpful in establishing levels of DEHP to which humans have been exposed. 

Exposures of Children. Little is known about exposures of children for DEHP. DEHP is widely 

used in many applications that can result in exposures. Toys were once considered an important route of 

exposure for children, especially in children under 36 months of age. However, toy manufactures have 

voluntarily reduced DEHP content below 3% by weight since 1986 and, more recently, have been 

phasing out the use of DEHP in most toys or using non-PVC materials, especially in pacifiers and 

teethers. However, there is only limited information on exposure of children to DEHP in items 

commonly encountered within the household and elsewhere (e.g., automobile interiors, daycare centers, 

etc.). The need for this information is highlighted by the fact that children below the age of 36 months 

were found to mouth many household items, in addition to those items currently under investigation, such 
 

DI(2-ETHYLHEXYL)PHTHALATE 213 

6. POTENTIAL FOR HUMAN EXPOSURE 

as pacifiers, teethers, and toys that are manufactured for use by young children (Juberg et al. 2001). In 

addition, while information is available on dust exposure in Norway, no information is available for the 

United States. This type of information along with indoor vapor measurements would allow a more 

precise estimation of indoor exposures where children, and especially young children, spend significant 

amounts of time. 

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 DEHP were located. This compound is not 

currently one of the compounds for which a subregistry has been established in the National Exposure 

Registry. The compound 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 might be related to 

the exposure to this compound. 

6.8.2 Ongoing Studies 

The Federal Research in Progress (FEDRIP 2001) database provides additional information obtainable 

from ongoing studies that might fill in some of the data needs identified in Section 6.8.1. No ongoing 

projects were identified in FEDRIP (2001). 

The Consumer Product Safety Commission (1999c) has proposed a study to examine the mouthing 

behavior of children between 36 and 72 months old. The results of this study will help to refine the 

understanding of children’s exposures. However, the status of this research could not be determined. 

Recent work from Juberg et al. (2001) has provided data that will aide in understanding the mouthing 

behavior children between the ages of 0 and 36 months. 

Remedial investigations and feasibility studies at NPL sites that contain DEHP will provide further 

information on environmental concentrations and human exposure levels near waste sites. 

DI(2-ETHYLHEXYL)PHTHALATE 215 

7. ANALYTICAL METHODS 

The purpose of this chapter is to describe the analytical methods that are available for detecting, 

measuring, and/or monitoring DEHP, its metabolites, and other biomarkers of exposure and effect to 

DEHP. 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. 

Detection and quantification of very low levels of DEHP are seriously limited by the presence of this 

compound as a contaminant in almost all laboratory equipment and reagents. Plastics, glassware, 

aluminum foil, cork, rubber, glass wool, Teflon sheets, and solvents have all been found to be 

contaminated (EPA 1988a; Giam et al. 1975; Williams 1973). While efforts have been made to reduce 

laboratory contamination (Giam et al. 1975; Thuren 1986), DEHP is still reported in laboratory blanks, 

even with thorough cleaning methods (EPA 1988a; Giam et al. 1975). Therefore, practical sample 

detection limits are often more than an order of magnitude higher than instrument or method detection 

limits. The EPA (1988a) reports that DEHP, along with other common phthalate and adipate esters, 

cannot generally be accurately or precisely measured at concentrations below about 2 ppb, due to blank 

contamination. 

7.1 BIOLOGICAL MATERIALS 

Laboratory contamination is a significant issue when measuring DEHP in biological materials and care 

must be taken to address this concern, as discussed in the introduction to Chapter 7. 

Gas chromatography (GC) is the most common analytical method for detecting and measuring DEHP in 

biological materials (Ching et al. 1981a; EPA 1986f; Hillman et al. 1975; Jaeger and Rubin 1972; Sjoberg 

and Bondesson 1985). High performance liquid chromatography (HPLC) might also be employed 

(Kambia et al. 2001; Pollack et al. 1985a; Shintani 2000). The chromatography separates complex 

mixtures of organic compounds and allows individual compounds to be identified and quantified by a 
DI(2-ETHYLHEXYL)PHTHALATE 216 

7. ANALYTICAL METHODS 

detector. Detectors used to identify DEHP include the electron capture detector (ECD) (Mes et al. 1974; 

Vessman and Rietz 1974) and the flame ionization detector (FID) (Albro et al. 1984). When unequivocal 

identification is required, a mass spectrometer (MS) coupled to the GC column might be employed 

(Ching et al. 1981a; EPA 1986f; Hillman et al. 1975; Sjoberg and Bondesson 1985). Analytical methods 

for the determination of DEHP in various biological fluids and tissues are summarized in Table 7-1. 

Prior to analysis, DEHP must be separated from the biological sample matrix and prepared for 

introduction into the analytical instrument. DEHP might be separated from the matrix by several methods 

including: extraction with an organic solvent such as chloroform, hexane, heptane, or acetonitrile (Ching 

et al. 1981a; Jaeger and Rubin 1972; Kambia et al. 2001; Sjoberg and Bondesson 1985); gel permeation 

chromatography (EPA 1986f); precipitation (Mes et al. 1974); solid phase extraction (Shintani 2000); and 

cleanup with Florisil® (EPA 1986f). Often, more than one of these procedures is required to separate the 

analyte from fats and other lipophilic materials. 

Biological materials (blood fractions, urine, tissue) are often monitored for a chemical substance in order 

to evaluate the extent of human exposure to that substance. It appears that monitoring biological tissues 

for DEHP might underestimate exposure, because this compound is metabolized in vivo quickly and 

extensively (Albro et al. 1984; Liss et al. 1985; Sjoberg et al. 1985c). Therefore, in order to better 

estimate exposure levels, it is important to test for the metabolites of DEHP as well. The primary 

metabolite appears to be mono(2-ethylhexyl) phthalate (Niino et al. 2001; Sjoberg et al. 1985c); although 

other metabolites (2-ethylhexanoic acid, 2-ethyl-3-hydroxyhexanoic acid, and 3-ethyl-3-oxohexanoic 

acid) have been identified and can be measured in urine (Gunther et al. 2001; Wahl et al. 2001). 

However, since numerous metabolites have been identified (see Section 3.3.3), monitoring biological 

materials for total phthalates might often be appropriate (Albro et al. 1984). Monitoring total phthalates 

would not, of course, be specific for DEHP exposure. 

Methods for analysis of individual phthalates in saliva, blood, urine, and/or feces involve separation of 

metabolites by HPLC combined with GC/MS (Niino et al. 2001; Sjoberg et al. 1985c) or GC/FID (Albro 

et al. 1984). Analysis for metabolites differs from analysis for DEHP mainly in sample preparation 

procedures (Albro et al. 1984; Sjoberg and Bondesson 1985). Metabolites from urine and/or feces are 

often treated with β-glucuronidase to remove conjugated glucuronic acid moieties. When GC methods 
DI(2-ETHYLHEXYL)PHTHALATE 217 

7. ANALYTICAL METHODS 

Table 7-1. Analytical Methods for Determining DEHP in Biological Materials 

Sample 

Sample Analytical detection Percent 

matrix Preparation method method limit recovery Reference 

Blood	 Extract with propanol/ GC/MS 3 μg/mLa No data Ching et al. 

serum	 heptane/ sulfuric acid 1981a 

dissolve in benzene 

methylate fatty acids, 

redissolve in acetone 

Blood Extract with acetonitrile GC/MS 0.15 μg/mL 93 Sjoberg and 

plasma and hexane Bondesson 

1985 

Blood	 Mix 1:1 with 1 M NaOH, HPLC/UV 20 ng/mL >97 Kambia et al. 

plasma	 extract with hexane, 2001 

reduce to dryness, 

resuspend in acetonitrile 

Blood Extract with ethyl acetate HPLC/UV	 0.345 No data Pollack et al. 

μg/mL 1985a 

Blood	 Mix blood 1:1 with 10 mM HPLC/UV No data 98–102 Shintani 2000 

acetate buffer (pH 3), 

extract with SPE (elute 

with acetonitrile/acetic 

acid) 

Urine	 Samples deconjugated HPLC-APCI- 1.2 ng/mL 78–91% Blount et al. 

with β-glucoronidase, MS/MS (MEHP) 2000b 

purified using two-step 

solid phase extraction 

Tissue	 Extract with GC/MS 0.02 μg/g No data Hillman et al. 

chloroform/methanol 1975 

Tissue	 Extract with GC 5 μg/g 60–90 Jaeger and 

chloroform/methanol Rubin 1972 

Adipose 

tissue 

Extract with methylene 

chloride, remove bulk lipid 

by gel permeation 

chromatography, 

fractionate on Florisil 

HRGC/MS 9 ng/g No data EPA 1986f 

(elute with diethyl ether/ 

hexane) 

a

Lowest concentration reported. 

GC = gas chromatography; HPLC = high performance liquid chromatography; HPLC-APCI-MS/MS = high
 

performance liquid chromatography - atmospheric pressure chemical ionization - tandem mass spectrometry;
 

HRGC = high resolution gas chromatography; MS = mass spectrometry; SPE = solid phase extraction;
 

UV = ultraviolet
 
DI(2-ETHYLHEXYL)PHTHALATE 218 

7. ANALYTICAL METHODS 

are employed for metabolite identification, carboxyl groups are first converted to methyl esters using 

diazomethane (Albro et al. 1983, 1984). Another method involves the oximation of the DEHP 

metabolites with O-(2,3,4,5,6-pentafluorobenzyl)-hydroxyamine hydrochloride before sample 

purification, followed by the conversion of the metabolites to their tert-butyldimethylsilyl derivatives for 

GC/MS analysis (Wahl et al. 2001). 

Application of LC-MS/MS techniques to the analysis of phthalate ester metabolites in urine have also 

been developed. For example, Blount et al. (2000b) have developed an assay to quantify the monoester 

metabolites (including MEHP) of eight phthalate diesters in urine, utilizing HPLC coupled with 

atmospheric pressure chemical ionization and tandem mass spectrometric (APCI-MS/MS) detection 

techniques. Urine samples were treated with β-glucuronidase to release the free phthalate monoesters 

followed by a two-step solid phase extraction procedure. After evaporative concentration of the eluant, 

the analytes in the purified samples are further separated on a phenyl reverse phase HPLC column and 

quantified by APCI-MS/MS, following careful optizimation of the APCI-MS/MS instrument. The limits 

of detection for MEHP were determined to be 1.2 ng/ml urine with recovery efficiencies of between 

78 and 91%. 

7.2 ENVIRONMENTAL SAMPLES 

Laboratory contamination is a significant issue when measuring DEHP in environmental samples and care 

must be taken to address this concern, as discussed in the introduction to Chapter 7. 

Determination of DEHP in air, water, soil/sediments, and food is usually by GC analysis (Cartwright et 

al. 2000; EPA 1982a, 1982b, 1986c, 1986d, 1988a; Ishida et al. 1981; NIOSH 1985b; Otake et al. 2001; 

Rudel et al. 2001; van Lierop and van Veen 1988; Williams 1973). An HPLC method for food has also 

been developed (Giust et al. 1990). Several representative methods appropriate for quantifying DEHP in 

each of these media are summarized in Table 7-2. The EPA has developed methods for analysis of 

drinking water (EPA 1988a), waste water (EPA 1982a, 1982b), and soil/sediment (EPA 1986c, 1986d) 

samples. Many of the APHA (1989) methods for water are equivalent to the EPA methods. 

Determination of DEHP in polyvinyl chloride (PVC) plastics might also be of interest and can be 

accomplished by GC analysis as described in the American Society for Testing and Materials (ASTM) 

Method D 3421-75 (Stringer et al. 2000). 
DI(2-ETHYLHEXYL)PHTHALATE 219 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining DEHP in Environmental Samples 

Sample 

Sample	 Analytical detection limit Percent 

matrix	 Preparation method method recovery Reference 

Air	 Collect on cellulose 

membrane filter, 

desorb with carbon 

disulfide 

Air	 Collect on charcoal, 

ultrasonic solvent 

extraction of charcoal 

with toluene 

Air	 Collected on XAD-2 

resin sandwiched 

between polyurethane 

foam plugs, Soxhlet 

extracted with 6% 

ether/hexane 

Water	 Extract in LSE 

cartridge, elute with 

methylene chloride 

Waste Extract with methylene 

water chloride, exchange to 

hexane 

Waste	 Extract with methylene 

water	 chloride at pH>11 and 

again at pH<2 

Waste	 Continuous liquid-liquid 

water	 extraction (methylene 

chloride as extraction 

solvent) 

Soil	 Extract with methylene 

chloride, clean-up, 

exchange to hexane 

Soil	 Extract from sample, 

clean-up 

Soil	 Ultrasonic solvent 

extraction with ethyl 

acetate and 

unltracentrifuged 

Sediment	 Extraction from sample 

using SFE, purification 

on silica gel column, 

exchanged into hexane 

GC/FID	 0.01 mg/ 

sample 

GC/MS	 0.17 μg/ 

sample 

GC/MS	 1.0691 μg/ 

extract 

HRGC/MS	 2 μg/La 

GC/ECD	 2 μg/L 

GC/MS	 2.5 μg/L 

GC/MS	 0.05–0.20 μg/L 

GC/ECD	 1.3 mg/kg 

HRGC/MS	 660 μg/kg 

GC/FID	 0.1 μg/mL 

GC/MS	 0.81 μg/g 

107	 NIOSH 1985a 

98	 Otake et al. 

2001 

114	 Rudel et al. 

2001 

95–100	 EPA 1988a 

85±4	 EPA 1982b 

82 EPA 1982a 

No data	 Brown et al. 

1999 

Db

–158 EPA 1986d 

8–158	 EPA 1986d 

73.3	 Cartwright et 

al. 2000 

70-85	 McDowell and 

Metcalfe 2001 
DI(2-ETHYLHEXYL)PHTHALATE 220 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining DEHP in Environmental Samples 

(continued) 

Sample 

matrix Preparation method 

Analytical 

method 

Sample 

detection limit Percent 

recovery Reference 

Sewage 

sludge 

Ultrasonic solvent 

extraction into 

methanol/dichloromethane, cleanup with 

reverse phase 

extraction cartridge, 

dissolved in methanol 

LC-APCI-MS 50 ng/g 78 Petroviƒ and 

Barceló 2000 

Food Extract with 

chloroform/methanol, 

dry with sodium sulfate, 

dissolve in ethyl ether 

GC/FID 0.01–1.0 ppm 58–90 Ishida et al. 

1981 

Food Extract with hexane 

acetonitrile, petroleum 

ether, dry with sodium 

sulfate, elute with ethyl 

ether/petroleum ether 

GC/FID 15 ppba 65–70 Williams 1973 

PVC 

plastic 

toys 

Cooled in liquid 

nitrogen, grated, 

sonicated in hexane 

GC/MS No data 87.9 Stringer et al. 

2000 

Food Extract with 

acetonitrile, methylene 

chloride/petroleum 

ether, dry with sodium 

sulfate, clean-up on 

Florisil 

GC/ECD 1 ppb 70–100 Giam et al. 

1975 

Food Extract with acetonitrile 

and petroleum ether, 

dry with sodium sulfate 

clean-up with Florisil 

GC/ECD 0.1 μga 91 Thuren 1986 

a

Limited by laboratory contamination; see text. b

Detected, result greater than zero. 

ECD = electron capture detector; FID = flame ionization detector; GC = gas chromatography; HRGC = high 

resolution gas chromatography; LC-APCI-MS = liquid chromatography-atmospheric pressure chemical ionizationmass spectrometry; LSE = liquid-solid extraction; MS = mass spectrometry; PVC = polyvinyl chloride; 

SFE = supercritical fluid extraction 
 

DI(2-ETHYLHEXYL)PHTHALATE 221 

7. ANALYTICAL METHODS 

Separation of DEHP from environmental samples is usually by extraction with an organic solvent such as 

acetonitrile, chloroform, ethyl acetate, hexane, or methylene chloride. Air samples are drawn through a 

solid sorbent material (e.g., charcoal or XAD-2 resin) and desorbed with carbon disulfide (NIOSH 1985b) 

or ether/hexane (Rudel et al. 2001). A purge and trap method might be used for separation of DEHP from 

the fat in foods (van Lierop and van Veen 1988). Detector options are identical to those mentioned above 

(Section 7.1). Detection limits for these methods are generally in the ppb range. 

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 DEHP 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 DEHP. 

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 to DEHP might be 

evaluated by measuring the levels of this compound or its metabolites in blood, adipose tissue, and urine. 

Sensitive analytical methods, including GC/MS and HPLC, are available for these determinations (Ching 

et al. 1981a; EPA 1986f; Hillman et al. 1975; Jaeger and Rubin 1972; Kambia et al. 2001; Pollack et al. 

1985a; Shintani et al. 2000; Sjoberg and Bondesson 1985). However, development of improved methods 

for sample extraction and of better ways to reduce laboratory contamination levels of DEHP would be 

valuable in reducing practical detection limits or degradation of DEHP during sample isolation and 

workup. 
 

DI(2-ETHYLHEXYL)PHTHALATE 222 

7. ANALYTICAL METHODS 

Methods for Determining Parent Compounds and Degradation Products in Environmental 

Media. Food and water are the media of most concern for human exposure to DEHP. Existing 

analytical methods can measure this compound in all environmental media at ppb levels (EPA 1982a, 

1982b, 1986c, 1986d, 1988a; Giust et al. 1990; Ishida et al. 1981; NIOSH 1985b; van Lierop and van 

Veen 1988, 1989; Williams 1973). However, ubiquitous laboratory contamination with this compound 

prevents accurate determinations. Research efforts pertaining to solving contamination problems are a 

major research need. 

7.3.2 Ongoing Studies 

No ongoing studies in analytical chemistry were identified. 
DI(2-ETHYLHEXYL)PHTHALATE 223 

8. REGULATIONS AND ADVISORIES
 

The international, national, and state regulations and guidelines regarding DEHP in air, water, and other 

media are summarized in Table 8-1. 

An MRL of 1 mg/kg/day was derived for acute-duration oral exposure (#14 days) to DEHP in the 1993 

toxicological profile for DEHP. Based on a re-evaluation of the database, including consideration of 

recent studies, this MRL has been withdrawn. An acute oral MRL is not currently derived for DEHP due 

to insufficient data on male reproductive effects, a known critical end point based on longer duration 

studies. In particular, derivation of an acute oral MRL is precluded by a lack of dose-response 

information on development of the male reproductive system in offspring acutely exposed during 

gestation and/or lactation. As previously discussed in Reproductive and Developmental Toxicity 

(Section 2.2, Summary of Health Effects), morphological and other effects in androgen-sensitive tissues, 

as well as reduced fetal and neonatal testosterone levels and adult sexual behavioral changes, have been 

observed in male rat offspring exposed to DEHP during gestation and lactation for intermediate durations 

of exposure. 

An MRL of 0.1 mg/kg/day was derived for intermediate-duration (15–364 days) oral exposure to DEHP 

based on a NOAEL of 14 mg/kg/day for decreased fertility in mice (Lamb et al. 1987). Mice of both 

sexes were exposed to DEHP in the diet for up to 126 days in a continuous breeding reproductive toxicity 

study that also found reduced fertility at doses $140 mg/kg/day. This derivation used an uncertainty 

factor of 100 (10 for extrapolation from animals to humans and 10 for human variability). 

The Draft for Public Comment version of this profile used a LOAEL of 3.3 mg/kg/day for testicular 

pathology in male offspring of rats that were exposed to DEHP in drinking water throughout pregnancy 

and during postnatal days 1–21 (Arcadi et al. 1998) as the basis of a provisional intermediate-duration 

oral MRL of 0.01 mg/kg/day. The 3.3 mg/kg/day dose was classified as a serious LOAEL and was used 

to derive the MRL with an uncertainty factor of 300 (10 for the use of a LOAEL, 10 for interspecies 

extrapolation, and 3 for human variability). A component factor of 3 was used for human variability 

because DEHP was administered during the most sensitive period during development. The MRL was 

provisional because it was derived from a serious LOAEL, which is not conventional ASTDR 

methodology. The Arcadi et al. (1998) study was judged to be inadequate for MRL derivation because 

the NTP-CERHR Expert Panel on DEHP (NTP 2000b) concluded that the effect levels are unreliable, 

making them unsuitable for identifying a LOAEL. In particular, NTP (2000b) found that (1) the methods 
DI(2-ETHYLHEXYL)PHTHALATE 224 

8. REGULATIONS AND ADVISORIES 

used to verify and characterize the administered doses were not clearly described or completely reported, 

and could not be resolved, and (2) the study authors did not reconcile their blood DEHP concentration 

data with other studies. 

In the 1993 toxicological profile for DEHP, an MRL of 0.4 mg/kg/day was derived for intermediate oral 

exposure to DEHP based on a NOAEL of 44 mg/kg/day for fetal malformations from a developmental 

toxicity study in mice (Tyl et al. 1988). An uncertainty factor of 100 (10 for extrapolation from animals 

to humans and 10 for human variability) was used in that derivation. This MRL is higher than the 

intermediate MRL derived in this profile and is based on an inappropriate end point. In particular, the 

44 mg/kg/day developmental toxicity NOAEL is no longer a suitably sensitive basis for MRL derivation 

because of more recent evidence of testicular toxicity at a lower dose (38 mg/kg/day) in rats exposed to 

DEHP for 90 days (Poon et al. 1997). 

An MRL of 0.06 mg/kg/day was derived for chronic-duration ($365 days) oral exposure to DEHP based 

on a NOAEL of 5.8 mg/kg/day for testicular pathology in male rats that were exposed to DEHP in the 

diet for up to 104 weeks in a chronic toxicity study (David et al. 2000a). The LOAEL in this study was 

29 mg/kg/day for bilateral aspermatogenesis. The chronic MRL was derived by dividing the 

5.8 mg/kg/day NOAEL by an uncertainty factor of 100 (10 for extrapolation from animals to humans and 

10 for human variability). 

The EPA derived a chronic oral RfD of 0.02 mg/kg/day for DEHP based on a LOAEL of 19 mg/kg/day 

for hepatic effects in guinea pigs fed a diet containing DEHP for 1 year (Carpenter et al. 1953; IRIS 

2001). 
DI(2-ETHYLHEXYL)PHTHALATE 225 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to DEHP 

Agency	 Description Information Reference 

INTERNATIONAL 

Guidelines: 

IARC	 Carcinogenicity classification Group 3a IARC 2001 

NATIONAL 

Regulations and 

Guidelines: 

a. Air: 

ACGIH	 TLV-TWA 5 mg/m3 ACGIH 2001 

NIOSH	 IDLH 5,000 mg/m3 NIOSH 2001
 

REL (10-hour TWA) 5 mg/m3
 

STEL (15-minute TWA) 10 mg/m3
 

OSHA PEL (8-hour TWA) 5 mg/m3	 OSHA 2001b 

29CFR1910.1000 

PEL (8-hour TWA) for 5 mg/m3 OSHA 2001c 

construction workers 29CFR1926.55 

PEL (8-hour TWA) for 5 mg/m3 OSHA 2001a 

shipyard workers 29CFR1915.1000 

USC	 Listed as a hazardous air USC 2001
 

pollutant 42 USC 7412
 

b. Water 

EPA Drinking water standard 6 μg/L	 EPA 2001 

40CFR141.32(e)(62) 

Groundwater monitoring	 EPA 2001 

Suggested methods PQL 40CFR264, 

8060 20 μg/L Appendix IX 

8270 10 μg/L 

Health advisories EPA 2000 

10-4 cancer riskb 3x10-4 μg/L 

DWELc 7x10-4 μg/L 

MCL 6 μg/L	 EPA 2001 

40CFR141.61c 

MCLG Zero	 EPA 2001 

40CFR141.50(a)(21) 

Water quality criteria—human	 EPA 1999 

health for consumption of: 

Water and organism 1.8 μg/L 

Organism only 5.9 μg/L 
DI(2-ETHYLHEXYL)PHTHALATE 226 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to DEHP (continued) 

Agency	 Description Information Reference 

NATIONAL (cont.) 

c. Food 

FDA Indirect food additive—acrylic Use only as a flow FDA 2001h 

and modified acrylic plastics, promoter at a level not 21CFR177.1010 

semirigid and rigid to exceed 3 weight­ (a)(8) 

percent based on the 

monomers 

Indirect food additive— Alone or in FDA 2001h 

component of cellophane combination with other 21CFR177.1200(c) 

used for food packaging phthalates where total 

phthalates do not 

exceed 5% 

Indirect food additive— FDA 2001h 

plasticizer in resinous and 21CFR175.300(b)(3) 

polymeric coatings used as 

the food-contact surface of 

articles intended for use in 

producing, manufacturing, 

packing, processing, 

preparing, treating, packaging, 

transporting, or holding food 

Indirect food additive FDA 2001h 

—substances permitted for 21CFR175.105(c)(5) 

use in adhesives 

Indirect food additive—used FDA 2001h 

as a defoaming agent in the 21CFR176.210(d)(3) 

manufacture of paper and 

paperboard intended for use 

in packaging, transporting, or 

holding food 

Indirect food additive—used in Total residual FDA 2001h 

surface lubricants employed in lubricant remaining on 21CFR178.3910 

the manufacture of metallic the metallic article not (a)(2) 

articles that contact food to exceed 

0.015 mg/inch2

 of 

metallic food-contact 

surface 

Prior-sanctioned food For foods of high FDA 2001h 

ingredients—classified as a water content only 21CFR181.27 

plasticizer, when migrating 

from food packaging materials 
DI(2-ETHYLHEXYL)PHTHALATE 227 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to DEHP (continued) 

Agency Description Information Reference 

NATIONAL (cont.) 

d. Other 

ACGIH Carcinogenicity classification A3d ACGIH 2001 

DOT Category D noxious liquid 

substance 

Allowed to be carried 

by the Coast Guard 

DOT 2001 

33CFR151.47 

EPA Carcinogenicity classification 

RfC 

RfD 

Oral slope factor 

Drinking water unit risk 

Group B2e 

Not available 

2x10-2 mg/kg/day 

1.4x10-2 mg/kg/day 

4x10-7 (μg/L)-1 

IRIS 2001 

Health based limits for 

exclusion of waste-derived 

residues—concentration limits 

for residues 

3x101 mg/kg EPA 2001 

40CFR266, 

Appendix VII 

Identification and listing of 

hazardous waste—hazardous 

waste number 

U028 EPA 2001 

40CFR261.33 

Reportable quantity of a 

CERCLA hazardous 

substance under Section 

307(a) of the Clean Water Act, 

Section 112 of the Clean Air 

Act, and RCRA Section 3001 

100 pounds EPA 2001 

40CFR302.4 

Risk specific doses 

Unit risk 

Risk specific dose 

2.4x10-7 μg/m3 

4.2x101 μg/m3 

EPA 2001 

40CFR266, 

Appendix V 

Toxic chemical release 

reporting; community right-toknow—effective date for 

reporting 

01/01/87 EPA 2001 

40CFR372.65 

TSCA—health and safety data 

reportingf 

Effective date 

Sunset date 

10/04/82 

10/04/92 

EPA 2001 

40CFR716.120(c) 

TSCA—testing consent order 

Testing 

FR publication date 

Chemical fate 

01/09/89 

EPA 2001 

40CCFR799.5000 
DI(2-ETHYLHEXYL)PHTHALATE 228 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to DEHP (continued) 

Agency	 Description Information Reference 

STATE 

a. Air 

Idaho	 Toxic air pollutants ID Dept. of Health & 

carcinogenic increments Welfare 1999 

AACC (annual average) 4.2 μg/m3 

EL 2.8x10-2 pounds/hour 

New Hampshire Regulated toxic air pollutant BNA 2001
 

OEL 5 mg/m3
 

North Carolina Toxic air pollutant BNA 2001
 

24-hour chronic toxicant 0.03 mg/m3
 

Washington	 Acceptable source impact 2.5 μg/m3 WA Dept. of Ecology 

levels at 10-6 risk (annual 1998 

average) 

Wisconsin	 Hazardous air contaminants 250 pounds/year2 WI Dept. of Natural 

without acceptable ambient Resources 1997 

concentrations requiring 

application of best available 

control technology 

b. Water 

Alaska MCL 6 μg/L	 AK Dept. Environ. 

Conservation 1999 

Arizona	 Aquifer water quality standard 6 μg/L BNA 2001 

California	 Drinking water standard 4 μg/L HSDB 2001 

MCL 4 μg/L	 CA Dept. of Health 

Services 2000 

Colorado Groundwater organic chemical 6 μg/L CO Dept. of Public 

standard Health & Environ. 

1999 

Kentucky	 Maximum allowable instream 1.8 μg/L BNA 2001
 

concentration
 

Maine	 Drinking water guideline 25 μg/L HSDB 2001 

New Jersey	 Groundwater quality criteria 3 μg/L NJ Dept. of Environ. 

PQL 30 μg/L Protection 1993 

Rhode Island	 Groundwater quality standard 6 μg/L BNA 2001 

Preventive action limit 3 μg/L 

South Dakota MCL 6 μg/L	 SD Dept. of Environ. 

& Natural Resources 

1998 

Vermont Groundwater quality standard BNA 2001 

Enforcement standard 6.0 μg/L 

Preventive action level 3.0 μg/L 
DI(2-ETHYLHEXYL)PHTHALATE 229 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to DEHP (continued) 

Agency Description Information Reference 

STATE (cont.) 

c. Food No data 

d. Other 

Connecticut Direct exposure criteria for soil 

Residential 

BNA 2001 

Industrial/commercial 44 mg/kg 

410 mg/kg 

Massachusetts RfD 

Oral slope factor 

2x10-2 mg/kg/day 

1.4x10-2 (mg/kg/day)-1 

BNA 2001 

Minnesota Slope factor 

Health risk limit 

0.014 (mg/kg/day)-1 

20 μg/L 

BNA 2001 

a

Group 3: not classifiable as to its carcinogenicity to humans

b

10-4 cancer risk: The concentration of a chemical in drinking water corresponding to an estimated lifetime cancer
 

risk of 1 in 10,000.
 c

DWEL: A lifetime exposure concentration protective of adverse, non-cancer health effects, that assumes all of the
 

exposure to a contaminant is from drinking water.

d

A3: confirmed animal carcinogen with unknown relevance to humans
 e

Group B2: probable human carcinogen

f

All chemical substances within a category are subject to all the provisions of part 716 for the time period from the
 

effective date of the category until the sunset date. 

AACC = acceptable ambient concentration for a carcinogen; ACGIH = American Conference of Governmental
 

Industrial Hygienists; BNA = Bureau of National Affairs; CERCLA = Comprehensive Environmental Response
 

Compensation and Liability Act; CFR = Code of Federal Regulations; DOT = Department of Transportation;
 

DWEL = drinking water equivalent level; EL = emissions screening level; EPA = Environmental Protection Agency;
 

FDA = Food and Drug Administration; FR = Federal Register; HSDB = Hazardous Substances Data Bank;
 

IARC = International Agency for Research on Cancer; IDLH = immediately dangerous to life or health;
 

IRIS = Integrated Risk Information System; MCL = maximum contaminant level; MCLG = maximum contaminant
 

level goal; NIOSH = National Institute for Occupational Safety and Health; OEL = occupational exposure level;
 

OSHA = Occupational Safety and Health Administration; PEL = permissible exposure limit; PQL = practical
 

quantitation limits; RCRA = Resource Conservation and Recovery Act; REL = recommended exposure limit;
 

RfC = inhalation reference concentration; RfD = oral reference dose; STEL = short-term exposure limit;
 

TLV = threshold limit value; TSCA = Toxic Substances Control Act; TWA = time-weighted average; URF = unit risk
 

factor; USC = United States Code
 

_______________ 

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*Ward JM, Diwan BA, Ohshimna M, et al. 1986. Tumor-initiating and promoting activities of di(2­

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DI(2-ETHYLHEXYL)PHTHALATE 285 

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 a 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 which 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. 
DI(2-ETHYLHEXYL)PHTHALATE 286 

10. GLOSSARY 

Case Series—Describes the experience of a small number of individuals with the same disease or 

exposure. These may suggest potential topics for scientific research but are not actual research studies. 

Ceiling Value—A concentration of a substance that should not be exceeded, even instantaneously. 

Chronic Exposure—Exposure to a chemical for 365 days or more, as specified in the Toxicological 

Profiles. 

Cohort Study—A type of epidemiological study of a specific group or groups of people who have had a 

common insult (e.g., exposure to an agent suspected of causing disease or a common disease) and are 

followed forward from exposure to outcome. At least one exposed group is compared to one unexposed 

group. 

Cross-sectional Study—A type of epidemiological study of a group or groups which 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. 

Epigenetic—The nonmutagenic alteration of gene expression at the transcriptional ("turning genes on or 

off"), translational (modifying the stability of the genetic message), or the posttranslational (modification 

of the gene-encoded proteins) levels. 

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. 
DI(2-ETHYLHEXYL)PHTHALATE 287 

10. GLOSSARY 

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. 

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. 

Immunologic Toxicity—The occurrence of adverse effects on the immune system that may result from 

exposure to environmental agents such as chemicals. 

Immunological Effects—Functional changes in the immune response. 

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 which 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 which 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. 
DI(2-ETHYLHEXYL)PHTHALATE 288 

10. GLOSSARY 

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. 

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) which 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 odds ratio of greater than 1 is considered to indicate greater risk 

of disease in the exposed group compared to the unexposed. 

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 science of quantitatively predicting 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. 
DI(2-ETHYLHEXYL)PHTHALATE 289 

10. GLOSSARY 

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 whereby the 

physiologically-based model compartments represent real anatomic regions of the body. 

Physiologically Based Pharmacodynamic (PBPD) Model—A type of physiologically-based doseresponse model which quantitatively describes the relationship between target tissue dose and toxic end 

points. These models advance the importance of physiologically based models in that they clearly 

describe the biological effect (response) produced by the system following exposure to an exogenous 

substance. 

Physiologically Based Pharmacokinetic (PBPK) Model—Comprised of a series of compartments 

representing organs or tissue groups with realistic weights and blood 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) concentrations 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. 
DI(2-ETHYLHEXYL)PHTHALATE 290 

10. GLOSSARY 

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. 

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. 

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 min 

continually. No more than four excursions are allowed per day, and there must be at least 60 min 

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. 
DI(2-ETHYLHEXYL)PHTHALATE 291 

10. GLOSSARY 

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 study of 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 one can be used; 

however a reduced UF of three may be used on a case-by-case basis, three being the approximate 

logarithmic average of 10 and 1. 

Xenobiotic—Any chemical that is foreign to the biological system. 

DI(2-ETHYLHEXYL)PHTHALATE A-1 

APPENDIX A 

ATSDR MINIMAL RISK LEVEL 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 chemicalinduced 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. 
DI(2-ETHYLHEXYL)PHTHALATE A-2 

APPENDIX A 

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 

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 a hundredfold 

below levels that have been shown to be nontoxic in laboratory animals. 

Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the 

Division of Toxicology, expert panel peer reviews, and agencywide MRL Workgroup reviews, with 

participation from other federal agencies and comments from the public. They are subject to change as 

new information becomes available concomitant with updating the toxicological profiles. Thus, MRLs in 

the most recent toxicological profiles supersede previously published levels. For additional information 

regarding MRLs, please contact the Division of Toxicology, Agency for Toxic Substances and Disease 

Registry, 1600 Clifton Road, Mailstop E-29, Atlanta, Georgia 30333. 
DI(2-ETHYLHEXYL)PHTHALATE A-3 

APPENDIX A
 

MINIMAL RISK LEVEL WORKSHEET 

Chemical name: DEHP 

CAS number(s): 117-81-7 

Date: June 2002 

Profile status: Post Public Comment Final 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [X] Intermediate [ ] Chronic 

Key to figure: 131 

Species: Mouse 

MRL: 0.1 [X] mg/kg/day [ ] ppm [ ] mg/m3 

Reference: Lamb JC, Chapin RE, Teague J, et al. 1987. Reproductive effects of four phthalic acid esters 

in the mouse. Toxicol Appl Pharmacol 88:255-269. 

Experimental design: This is a reproductive toxicity study in which CD-1 Swiss mice were exposed to 

DEHP in the diet at calculated doses of 0, 14, 140, and 420 mg/kg/day. A continuous breeding protocol 

was used in which 11-week-old mice were exposed during a 7-day premating period and subsequently as 

breeding pairs for 98 days. There were 20 breeding pairs in each exposed group and 40 pairs in the 

control group. The pairs were segregated at the end of the 98-day breeding period so that females could 

deliver the final litter. The F0 mice were therefore exposed for a maximum possible duration of 105 

days. Clinical signs, food consumption, and body weight were evaluated during the breeding phase. The 

females were allowed to deliver their pups for determinations of fertility and reproductive performance; 

indices included number of pairs producing a litter/total number of breeding pairs, number of litters/pair, 

number of live pups/litter, proportion of pups born alive, and live birth weights. Because an effect on 

fertility was observed, a crossover mating study was performed in which high dose mice of each sex were 

mated to unexposed mice of the opposite sex at the end of the breeding period to determine the affected 

sex. In addition to the fertility/reproductive indices examined in the continuous breeding phase, the high 

dose F0 mice in the crossover study were evaluated for body weight, organ weights (liver, testis, 

epididymis, prostate, seminal vesicles, brain, pituitary, ovaries and oviduct, and/or uterus), and sperm 

indices (percent motile sperm, sperm concentration, and percent abnormal sperm). 

Effects noted in study and corresponding doses: No effects were observed at 14 mg/kg/day. Fertility 

was reduced at 140 mg/kg/day as indicated by significantly (p<0.01) reduced number of litters/pair, 

number of live pups/litter, and proportion of live pups; mean live pup weight was also significantly 

reduced. Exposure to 420 mg/kg/day caused significant infertility during the continuous breeding part of 

the study (0/18 fertile pairs) as well as in both sexes (0/16 fertile females and 4/20 fertile males) during 

the crossover mating part of the study. Other effects observed at 420 mg/kg/day in the crossover study 

included significantly reduced testis, epididymis, and prostate weights, percentages of motile sperm and 

abnormal sperm, and reduced sperm concentration in the males; significantly reduced combined weight 

of ovaries, oviducts and uterus in the females; and significantly increased liver weights in both sexes. All 

but one of the high dose males had some degree of bilateral atrophy of the seminiferous tubules, but no 

exposure-related reproductive histopathology was observed in the females. Considering the reduced 

fertility and reproductive organ weights in the high dose females, there is evidence that reproductive 

performance was impaired in both sexes at 420 mg/kg/day. Because the crossover mating study was only 
 

DI(2-ETHYLHEXYL)PHTHALATE A-4 

APPENDIX A 

conducted at the high dose, the reduced fertility observed at 140 mg/kg/day is not necessarily due to 

effects in both sexes. 

Dose and end point used for MRL derivation: 

[X] NOAEL [ ] LOAEL 

The lowest dose, 14 mg/kg/day, is a NOAEL for reproductive toxicity in the male and female mice. 

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? 

Yes. The mice were exposed to DEHP dietary concentrations of 0, 0.01, 0.1, and 0.3% (0, 100, 1,000, 

and 3,000 mg DEHP/kg diet). Using a food factor of 0.14 kg food/kg bw/day based on reported average 

food consumption (5.1 g/day) and body weight (36 g) values, doses are estimated to be 0, 14, 140, and 

420 mg/kg/day. 

Was a conversion used from intermittent to continuous exposure? NA 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: NA 

Other additional studies or pertinent information that lend support to this MRL: Other studies have 

established that testicular toxicity is a critical effect of DEHP. It is well documented that oral exposure 

to DEHP in adult rats and mice causes decreased weights of the testes, prostate, seminal vesicles, and 

epididymis, atrophy and degeneration of the seminiferous tubules, and/or altered sperm measures and 

reduced fertility (David et al. 2000a; Dostal et al. 1988; Ganning et al. 1991; Gray and Butterworth 1980; 

Gray and Gangolli 1986; Kluwe et al. 1982a; Lamb et al. 1987; Oishi 1986, 1994; Parmar et al. 1987, 

1995; Price et al. 1987; Sjoberg et al. 1986a, 1986b). The lowest reproductive effect levels in these 

studies are a NOAEL and LOAEL for testicular histopathology of 3.7 and 38 mg/kg/day, respectively, in 

rats exposed for 90 days (Poon et al. 1997), and 5.8 and 29 mg/kg/day, respectively, in rats exposed for 

104 weeks (David et al. 2000a). Because the 14 mg/kg/day NOAEL in the critical study (Lamb et al. 

1987) is higher than the NOAELs of 3.7 and 5.9 mg/kg/day (David et al. 2000a; Poon et al. 1997), and is 

based on an assessment of fertility rather than histological examination without evaluation of 

reproductive function, the 14 mg/kg/day NOAEL is the most appropriate basis for derivation of the 

intermediate duration MRL. 

Other studies have shown that gestational and lactational exposure to DEHP adversely affected the 

morphological development of the reproductive system, as well as caused reduced fetal and neonatal 

testosterone levels and adult sexual behavioral changes, in male rat offspring (Arcadi et al. 1998; Gray et 

al. 1999, 2000; Moore et al. 2001; Parks et al. 2000). One of these studies (Arcadi et al. 1998) was used 

as the basis of a provisional intermediate-duration oral MRL in the previous draft of the DEHP 

toxicological profile (i.e., the Draft for Public Comment). In the Arcadi et al. (1998) study, severe 

testicular histopathological changes were observed at 21–56 days of age in male offspring of rats that 

were exposed to DEHP in the drinking water at reported estimated doses of 3.3 or 33 mg/kg/day 

throughout pregnancy and continuing during postnatal days 1–21. The 3.3 mg/kg/day dose was classified 

as a serious LOAEL and was used to derive an MRL of 0.01 mg/kg/day by using an uncertainty factor of 
DI(2-ETHYLHEXYL)PHTHALATE A-5 

APPENDIX A 

300 (10 for the use of a LOAEL, 10 for interspecies extrapolation, and 3 for human variability). A 

component factor of 3 was used for human variability because DEHP was administered during the most 

sensitive period during development. The MRL was provisional because it was derived from a serious 

LOAEL, which is not conventional ATSDR methodology. The Arcadi study is now judged to be 

inadequate for MRL derivation because the NTP-CERHR Expert Panel on DEHP (NTP 2000b) 

concluded that the effect levels are unreliable and are unsuitable for identifying a LOAEL. In particular, 

NTP (2000b) found that (1) the methods used to verify and characterize the administered doses were not 

clearly described or completely reported, and could not be resolved, and (2) the study authors did not 

reconcile their blood DEHP concentration data with other studies. 

In the 1993 toxicological profile for DEHP, an MRL of 0.4 mg/kg/day was derived for intermediate oral 

exposure to DEHP based on a NOAEL of 44 mg/kg/day for fetal malformations from a developmental 

toxicity study in mice (Tyl et al. 1988). An uncertainty factor of 100 (10 for extrapolation from animals 

to humans and 10 for human variability) was used in this derivation. The 44 mg/kg/day NOAEL for 

developmental toxicity is no longer a suitable basis for MRL derivation because the more recent Poon et 

al. (1997) study found testicular toxicity at a lower dose (38 mg/kg/day) in rats exposed to DEHP for 

90 days (Poon et al. 1997). 

Agency Contact (Chemical Manager): Stephanie Miles-Richardson, D.V.M., Ph.D. 
DI(2-ETHYLHEXYL)PHTHALATE A-6 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical name: DEHP 

CAS number(s): 117-81-7 

Date: June 2002 

Profile status: Post Public Comment Final 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [ ] Intermediate [X] Chronic 

Key to figure: 161 

Species: Rat 

MRL: 0.06 [X] mg/kg/day [ ] ppm [ ] mg/m3 

Reference: David RM, Moore MR, Finney DC, et al. 2000a. Chronic toxicity of 

di(2-ethylhexyl)phthalate in rats. Toxicol Sci 55:433-443. 

Experimental design: Groups of F344 rats were fed a diet containing DEHP in concentrations of 0 ppm 

(80/sex), 100 ppm (50/sex), 500 ppm (55/sex), 2,500 ppm (65/sex) or 12,500 ppm (80/sex) for up to 

104 weeks. Reported average daily doses based on food consumption were 0, 5.8, 29, 147, or 

789 mg/kg/day in males and 0, 7.3, 36, 182, or 939 mg/kg/day in females. The animals were observed for 

clinical signs, moribundity, and mortality twice daily throughout the study. Body weights and food 

consumption were measured weekly for weeks 1–17 and every 4 weeks thereafter. Final body weight 

and organ weights (brain, lungs, spleen, kidneys, testes, and uterus) were measured at the end of the 

study. Comprehensive hematology, clinical chemistry, and urine analyses were performed on 10 rats/sex/ 

dose during weeks 26, 52, 78, and 104. Ten rats/sex from the control and two highest dose groups were 

sacrificed at week 78 for a complete necropsy and histological examination of tissues from major tissues. 

Animals that died during the study were also examined microscopically. Surviving animals were 

sacrificed during week 105 and the control and high-dose groups were subjected to comprehensive 

histological examination of tissues listed in EPA test guidelines for combined chronic 

toxicity/oncogenicity studies. Target tissues and gross lesions from the other dose groups were 

additionally examined at the end of the study. Effects on carcinogenicity, hepatomegaly, and peroxisome 

proliferation were reported by David et al. (1999). 

Effects noted in study and corresponding doses: No exposure-related effects were observed at 

5.8 mg/kg/day in the males or 7.3 mg/kg/day in the females. Bilateral aspermatogenesis was significantly 

(p�0.05) increased at �29 mg/kg/day. The incidences of bilateral aspermatogenesis were 37/64 (58%), 

34/50 (64%), 43/55 (78%), 48/65 (74%), and 62/64 (97%) in the control to high-dose males. The 

increase in aspermatogenesis was dose-related and is consistent with a significant reduction in relative 

testes weight that occurred at 789 mg/kg/day (59% less than controls). The examinations at week 

78 showed aspermatogenesis at 789, but not 147 mg/kg/day (no interim exams were performed in the 

lower dose groups), suggesting the possibility that the lesion was age- rather than treatment-related at 

29 and 147 mg/kg/day. Also observed in the high dose in males was a significantly increased incidence 

of castration cells in the pituitary gland, which are promoted by reduced testosterone secretions from the 

testes. Castration cells are vacuolated basophilic cells in the anterior pituitary gland usually observed 

after castration. Hepatic effects included significantly increased absolute and relative liver weights 

accompanied by increased peroxisome proliferation in males at �147 mg/kg/day and females at �182 mg/ 

kg/day, spongiosis hepatis in males at �147 mg/kg/day, and hepatocellular neoplasms in males at 
 

DI(2-ETHYLHEXYL)PHTHALATE A-7 

APPENDIX A 

�147 mg/kg/day and females at 939 mg/kg/day. Renal effects included significantly increased absolute 

and relative kidney weights in males at �147 mg/kg/day and females at �182 mg/kg/day, a dose-related 

increased incidence and severity of mineralization of the renal papilla in males at �5.8 mg/kg/day, 

increased severity of normally occurring chronic progressive nephropathy in males at 789 mg/kg/day, and 

increased severity of normally occurring renal tubule pigmentation in males at 789 mg/kg/day and 

females at 939 mg/kg/day. The renal lesions were unlikely to be toxicologically significant because (1) 

they are age- and/or species-related, (2) the increased mineralization in the kidneys was probably related 

to male rat-specific alpha2μ-globulin and hyaline droplet formation, and (3) the increased kidney weights 

may reflect peroxisome proliferation. Mean body weight gain was significantly lower than controls 

throughout the study in the males at 789 mg/kg/day and females at 939 mg/kg/day (15.0 and 15.5% 

lower, respectively, at the end of the study). 

Dose and end point used for MRL derivation: 

[X] NOAEL [ ] LOAEL 

The lowest dose, 5.8 mg/kg/day, is a NOAEL for testicular toxicity in the male rats. 

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? No. 

Was a conversion used from intermittent to continuous exposure? NA. 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: 

NA. 

Other additional studies or pertinent information that lend support to this MRL: Other studies have 

established that testicular toxicity is a critical effect of DEHP. It is well documented that oral exposure 

to DEHP in adult rats and mice caused decreased weights of the testes, prostate, seminal vesicles, and 

epididymis, atrophy and degeneration of the seminiferous tubules, and/or altered sperm measures and 

reduced fertility (Dostal et al. 1988; Ganning et al. 1991; Gray and Butterworth 1980; Gray and Gangolli 

1986; Kluwe et al. 1982a; Lamb et al. 1987; Oishi 1986, 1994; Parmar et al. 1987, 1995; Price et al. 

1987; Sjoberg et al. 1986a, 1986b). Additionally, gestational and lactational exposure to DEHP 

adversely affected the morphological development of the reproductive system, as well as caused reduced 

fetal and neonatal testosterone levels and adult sexual behavioral changes, in male rat offspring (Arcadi 

et al. 1998; Gray et al. 1999, 2000; Moore et al. 2001; Parks et al. 2000). The 5.8 mg/kg/day NOAEL 

and 29 mg/kg/day LOAEL for testicular histopathology in the chronic MRL study (David et al. 2000a) 

are similar to the testicular NOAEL and LOAEL values of 3.7 and 38 mg/kg/day, respectively, in rats 

exposed for 90 days (Poon et al. 1997), but are somewhat lower than the NOAEL and LOAEL of 14 and 

130 mg/kg/day, respectively, for reduced fertility in mice exposed for up to 105 days in the intermediateduration MRL study (Lamb et al. 1987). 

Agency Contact (Chemical Manager): Stephanie Miles-Richardson, D.V.M., Ph.D 
DI(2-ETHYLHEXYL)PHTHALATE 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, 

weight-of-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 they appear within the Discussion of Health Effects by 

Route of Exposure section, by route (inhalation, oral, 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. If data are located in the scientific literature, a table of genotoxicity information is 

included. 

The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using 

existing toxicokinetic, genotoxic, epigenetic, 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. 
DI(2-ETHYLHEXYL)PHTHALATE B-2 

APPENDIX B 

Interpretation of Minimal Risk Levels 

Where sufficient toxicologic information is available, we have derived minimal risk levels (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. They 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 the Environmental Protection Agency (EPA) 

provides (Barnes and Dourson 1988) to determine reference doses for lifetime exposure (RfDs). 

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 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 LSE Tables. 

Chapter 3 

Health Effects 

Tables and Figures for Levels of Significant Exposure (LSE) 

Tables (3-1, 3-2, and 3-3) and figures (3-1 and 3-2) 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, minimal risk levels 

(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 No-Observed-Adverse-Effect Levels 

(NOAELs), Lowest-Observed-Adverse-Effect Levels (LOAELs), or Cancer Effect Levels (CELs). 
DI(2-ETHYLHEXYL)PHTHALATE B-3 

APPENDIX B 

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. 

LEGEND 

See LSE Table 3-1 

(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. When sufficient 

data exists, 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 

Table 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 2 

"18r" data points in 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 

regimen 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 1,1,2,2-tetrachloroethane via 

inhalation for 6 hours per day, 5 days per week, for 3 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, 1 systemic effect (respiratory) was investigated. 
DI(2-ETHYLHEXYL)PHTHALATE B-4 

APPENDIX B 

(8)	 NOAEL A No-Observed-Adverse-Effect Level (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"). 

(9)	 LOAEL A Lowest-Observed-Adverse-Effect Level (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 Cancer Effect Level (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 the NOAEL of 3 ppm in key number 18 was used to derive an 

MRL of 0.005 ppm. 

LEGEND 

See Figure 3-1 

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 intermediate and chronic 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, 18r NOAEL is the critical end point for which an intermediate inhalation 

exposure MRL is based. As you can see from the LSE figure key, the open-circle symbol indicates 

to a NOAEL for the test species-rat. 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 38r is 1 of 3 studies for which Cancer Effect Levels were derived. The diamond 

symbol refers to a Cancer Effect Level for the test species-mouse. The number 38 corresponds to 

the entry in the LSE table. 
DI(2-ETHYLHEXYL)PHTHALATE B-5 

APPENDIX B 

(18)	 Estimated Upper-Bound Human Cancer Risk Levels This is the range associated with the 

upper-bound for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are 

derived from the EPA's Human Health Assessment Group's upper-bound estimates of the slope of 

the cancer dose response curve at low dose levels (q1*). 

(19)	 Key to LSE Figure The Key explains the abbreviations and symbols used in the figure. 
B-6 

SAMPLE 

6 Table 3-1. Levels of Significant Exposure to [Chemical x] – Inhalation 1 

Exposure

Key to frequency/figurea Species duration 

2 6 INTERMEDIATE EXPOSURE

5 6

3 6 Systemic 9 9

4 6 18 Rat 13 wk

5 d/wk6 hr/d 

CHRONIC EXPOSURECancer38 Rat 18 mo

5 d/wk7 hr/d 

39 Rat 89–104 wk

5 d/wk6 hr/d 

40 Mouse 79–103 wk

5 d/wk6 hr/d 

NOAEL

System (ppm) 

7 8 

9 9

Resp 3b 

LOAEL (effect) 

Less serious (ppm) Serious (ppm) Reference

9 10 

9 9

10 (hyperplasia) Nitschke et al.

1981 

11

9

20

1010 

(CEL, multiple

organs)

(CEL, lung tumors,

nasal tumors)

(CEL, lung tumors,

hemangiosarcomas) 

Wong et al. 1982 NTP 1982 NTP 1982 

a The number corresponds to entries in Figure 3-1.

6 b Used to derive an intermediate inhalation Minimal Risk Level (MRL) of 5 x 10-3 ppm; dose adjusted for intermittent exposure and divided by 12 an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability). 

DI(2-ETHYLHEXYL)PHTHALATE 

APPENDIX B 
DI(2-ETHYLHEXYL)PHTHALATE B-7 

APPENDIX B 

DI(2-ETHYLHEXYL)PHTHALATE C-1 

APPENDIX C 

ACRONYMS, ABBREVIATIONS, AND SYMBOLS 

ACOEM American College of Occupational and Environmental Medicine 

ACGIH American Conference of Governmental Industrial Hygienists 

ADI acceptable daily intake 

ADME absorption, distribution, metabolism, and excretion 

AED atomic emission detection 

AOEC Association of Occupational and Environmental Clinics 

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 

AP alkaline phosphatase 

APHA American Public Health Association 

AST aspartate aminotranferase 

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 

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 
 

DI(2-ETHYLHEXYL)PHTHALATE C-2 

APPENDIX C 

DOT/UN/ Department of Transportation/United Nations/

 NA/IMCO North America/International Maritime Dangerous Goods Code 

DWEL drinking water exposure level 

ECD electron capture detection 

ECG/EKG electrocardiogram 

EEG electroencephalogram 

EEGL Emergency Exposure Guidance Level 

EPA Environmental Protection Agency 

F Fahrenheit 

F1 first-filial generation 

FAO Food and Agricultural Organization of the United Nations 

FDA Food and Drug Administration 

FEMA Federal Emergency Management Agency 

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act 

FPD flame photometric detection 

fpm feet per minute 

FR Federal Register 

FSH follicle stimulating hormone 

g gram 

GC gas chromatography 

gd gestational day 

GLC gas liquid chromatography 

GPC gel permeation chromatography 

HPLC high-performance liquid chromatography 

HRGC high resolution gas chromatography 

HSDB Hazardous Substance Data Bank 

IARC International Agency for Research on Cancer 

IDLH immediately dangerous to life and health 

ILO International Labor Organization 

IRIS Integrated Risk Information System 

Kd adsorption ratio 

kg kilogram 

Koc organic carbon partition coefficient 

Kow octanol-water partition coefficient 

L liter 

LC liquid chromatography 

LCLo lethal concentration, low 

LC50 lethal concentration, 50% kill 

LDLo lethal dose, low 

LD50 lethal dose, 50% kill 

LDH lactic dehydrogenase 

LH luteinizing hormone 

LT50 lethal time, 50% kill 

LOAEL lowest-observed-adverse-effect level 

LSE Levels of Significant Exposure 

m meter 

MA trans,trans-muconic acid 

MAL maximum allowable level 

mCi millicurie 

MCL maximum contaminant level 

MCLG maximum contaminant level goal 
DI(2-ETHYLHEXYL)PHTHALATE 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 

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 

NHANES National Health and Nutrition Examination Survey 

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 

OPPTS Office of Prevention, Pesticides and Toxic Substances, EPA 

OPPT Office of Pollution Prevention and Toxics, EPA 

OR odds ratio 

OSHA Occupational Safety and Health Administration 

OSW Office of Solid Waste, EPA 

OW Office of Water 

OWRS Office of Water Regulations and Standards, EPA 

PAH polycyclic aromatic hydrocarbon 

PBPD physiologically based pharmacodynamic 
DI(2-ETHYLHEXYL)PHTHALATE C-4 

APPENDIX C 

PBPK physiologically based pharmacokinetic 

PCE polychromatic erythrocytes 

PEL permissible exposure limit 

PID photo ionization detector 

pg picogram 

pmol picomole 

PHS Public Health Service 

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 

RTECS Registry of Toxic Effects of Chemical Substances 

RQ reportable quantity 

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 

> greater than $ greater than or equal to 

= equal to 

< less than # less than or equal to 
DI(2-ETHYLHEXYL)PHTHALATE C-5 

APPENDIX C 

% 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 

DI(2-ETHYLHEXYL)PHTHALATE D-1 

APPENDIX D
 

INDEX
 

adipose tissue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106, 109, 124, 148, 213, 219, 223
 

adsorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192, 194
 

aerobic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11, 183, 193, 194
 

AHH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 
 

air . . . . . . . . . . . . . . . . . . . . 2-5, 7, 9, 11, 12, 23, 141, 142, 175, 180, 183, 185, 187-189, 191, 193, 195, 196, 200, 203, 204, 206,
 

208, 213, 220, 221, 223, 225, 227, 229, 230
 

ambient air . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12, 183, 203, 213
 

anaerobic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193, 194
 

androgen receptor .................................................................... 133, 140, 143, 165, 170
 

Antarctic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191, 193
 

antiandrogenic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16, 90, 132, 138-140, 143, 165, 170
 

aryl hydrocarbon hydroxylase (see AHH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 
 

bioaccumulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11, 183, 213
 

bioavailability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213 
 

bioconcentration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193, 212, 213
 

bioconcentration factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 
 

biodegradation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11, 183, 193, 194, 212
 

biomagnification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193, 213
 

biomarker . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139, 146, 147
 

blood . . . . . . . . . . . . . . . . . . . . . . 2, 4, 6, 8, 11, 12, 19, 67, 68, 87, 90, 106-108, 113, 116-121, 131, 141, 143, 144, 146-148, 153,
 

161, 168, 180, 183, 199, 209, 210, 213, 218, 219, 223, 226
 

body weight effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 
 

breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 
 

breast milk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4, 7, 88, 112, 143-145, 161, 166, 170, 204, 206
 

cancer . . . . . . . . . . . . . . . . . . . . . . 5, 6, 13-16, 20, 22, 23, 28, 91-93, 121, 122, 125, 127, 135, 136, 139, 141, 142, 155, 161-163,
 

167, 170, 174, 227, 231
 

carcinogen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6, 14, 15, 231 
 

carcinogenic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6, 14, 21, 22, 125, 158, 230
 

carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7, 14, 15, 91, 92, 94, 122, 126, 127, 135, 155, 162, 170, 227, 229, 231
 

carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 
 

cardiovascular effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 
 

Clean Water Act . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229 
 

Department of Health and Human Services (see DHHS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6, 14 
 

dermal effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80, 93 
 

DHHS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 
 

dialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4, 6, 68, 77, 108, 113, 152, 210
 

DNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13, 14, 69, 73, 76, 93-101, 124-127, 136, 146, 163
 

dog . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 
 

ECMO therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144, 209
 

effluents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189, 192, 194, 197
 

enantiomer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90, 166 
 

endocrine effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 
 

epigenetic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13, 70, 93, 97, 122 
 

estrogen receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 
 

estrogenic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85, 139 
 

exchange transfusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199, 209, 210
 

extracorporeal membrane oxygenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12, 67, 183, 199, 209
 

FDA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9, 92, 93, 108, 143-145, 153, 161, 166, 170, 183, 199, 202, 206, 210, 212, 228, 231
 

FEDRIP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171, 172, 214
 

fetus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7, 140 
 

fish . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3, 193, 198
 

follicle stimulating hormone (see FSH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 
 

Food and Drug Administration (see FDA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9, 202, 231
 

FSH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85, 129, 131, 134, 135, 138
 
DI(2-ETHYLHEXYL)PHTHALATE D-2 

APPENDIX D 

gap junctional intercellular communication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76, 77, 122, 125, 127, 134, 146, 170
 

gas chromatography (see GC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217, 219, 222
 

gastrointestinal effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 
 

GC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217-223
 

general population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11, 23, 146, 152, 168, 200, 202, 206
 

glutathione peroxidase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72, 73, 75 
 

groundwater . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2, 192, 196, 197, 212, 213, 227, 230
 

half-life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109, 113, 146, 147, 193
 

hematological effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 
 

Henry’s law . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185, 195
 

hepatic effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13, 14, 20, 24, 68-70, 76, 77, 144, 226
 

high performance liquid chromatography (see HPLC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217, 219
 

HPLC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217-220, 223
 

hydrolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67, 109, 110, 120, 129, 147, 169, 194
 

immune system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166 
 

immunological effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24, 81 
 

insects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 
 

Integrated Risk Information System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 
 

intermediate oral exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226 
 

kidney . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4, 6, 7, 20, 77-79, 96, 106-109, 124-127, 158-162
 

kidney effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6, 78, 160 
 

lake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69, 70, 72, 76, 120, 122, 123, 125, 159, 161, 162, 169, 188, 192
 

LD50 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29, 92 
 

leachate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78, 162, 189, 192, 197
 

leukemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 
 

LH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85, 134, 138
 

liver . . . . . . . . . . . . . . . . . . . . . 4, 6, 7, 12-15, 17, 20, 23, 24, 29, 68-70, 72-77, 88, 91, 93-96, 100, 101, 106-109, 115-119, 121­

128, 134-136, 142, 146-150, 153-156, 158-163, 167-170
 

lung . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13, 24, 104, 109, 144-146
 

luteinizing hormone (see LH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83, 129, 134
 

lymph . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 
 

lymphoreticular effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24, 81, 93 
 

marine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192, 197, 198
 

mass spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 
 

medical procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4, 7, 12, 121, 144, 167, 183, 209
 

MEHP . . . . . . . . . . . . . . . . . . . . . . 3, 4, 8, 67, 69, 86, 88, 90, 102, 104, 108-112, 116-118, 120, 121, 123-125, 127, 129-136, 138,
 

140, 142-145, 147, 148, 150, 153, 154, 163-165, 168, 169, 200, 219, 220
 

milk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4, 7, 88, 112, 143-145, 161, 166-168, 170, 198, 199, 202, 204, 206
 

Minimal Risk Levels (see MRL) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15, 16, 22 
 

MRL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16-20, 22, 84, 90, 159-162, 165, 225, 226
 

MRLs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15-17, 22, 23, 164 
 

musculoskeletal effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 
 

National Priorities List (see NPL) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1, 183 
 

neurobehavioral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81, 82, 138, 143, 167
 

neurodevelopmental . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144 
 

NIOSH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9, 174, 204, 217, 220, 221, 223, 224, 227, 231
 

NOAEL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17-21, 24, 28, 29, 84, 86, 87, 91, 160, 162, 165, 225, 226
 

NOAELs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18, 21, 22, 164 
 

NOES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204 
 

NPL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1, 12, 156, 183, 184, 189, 191, 215
 

ocean . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190 
 

ocular effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23, 80, 93 
 

pacifiers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7, 199, 200, 206, 207, 214
 

particulate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191, 199, 208
 

particulates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191-193, 196, 204, 212
 

partition coefficients ........................................................................... 116-118, 175
 

PBPD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 
 

PBPK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113-116, 164
 

peroxisomal proliferation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15, 68, 72, 76, 122, 136
 

peroxisome . . . . . . . . . . . . . . . . . . . . . . . . 13-15, 20, 24, 70, 74-77, 88, 91, 104, 122-127, 135, 136, 152, 156, 162, 163, 168, 169
 

pharmacodynamic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113, 153
 
DI(2-ETHYLHEXYL)PHTHALATE D-3 

APPENDIX D 

pharmacokinetic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113-115, 120, 164
 

photolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 
 

physiologically based pharmacodynamic (see PBPD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 
 

physiologically based pharmacokinetic (see PBPK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113, 115, 164
 

plasma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14, 67, 88, 109, 112, 113, 121, 130-132, 134, 199, 209, 210, 219
 

precipitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79, 218 
 

public health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1, 5, 9, 11, 13, 21, 22, 137, 156, 158, 211, 217, 223, 230
 

PVC . . . . . . . . . . . . . . . . . . . . 8, 11, 13, 24, 105, 121, 141, 142, 145, 153, 177, 180, 181, 196, 199, 200, 202-204, 206-208, 210,
 

211, 214, 220, 222
 

RCRA ..................................................................................... 181, 229, 231
 

reference dose (see RfD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 
 

regulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9, 10, 181, 225, 227, 228, 231
 

renal effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77, 78, 92, 162 
 

reportable quantity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229 
 

reproductive effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 
 

reproductive system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16-18, 85, 87, 89, 90, 121, 132, 139, 140, 143, 159, 164-167, 225
 

Resource Conservation and Recovery Act (see RCRA) ................................................... 181, 231
 

RfD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226, 229, 231
 

seal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198 
 

sediment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191, 194, 197, 198, 204, 220, 221
 

selenium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146 
 

serum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16, 67, 68, 74, 79, 85, 113, 128, 129, 138, 151, 155, 163, 199, 209, 210, 219
 

sludge ............................................................................. 189, 190, 194, 198, 222
 

soil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2, 3, 9, 185, 190-195, 197, 204, 212, 213, 220, 221, 231
 

solubility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12, 175, 183, 192, 195
 

surface water ........................................................................... 189, 196, 197, 213
 

T3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79, 151 
 

T4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79, 151 
 

testicular effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12, 15, 19, 82, 84-86, 128, 134, 136, 138, 143, 160, 167, 171
 

testicular toxicity . . . . . . . . . . . . . . . . . . . . . . 12, 15, 18, 83-86, 120, 124, 128-130, 133, 136, 138, 139, 142, 143, 145, 155, 162,
 

164, 170, 172, 226
 

thyroid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6, 12, 79, 129, 151, 158
 

thyroxine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 
 

time-weighted average (TWA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203, 208, 231
 

toxicokinetic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 
 

Toxics Release Inventory (TRI) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185, 212
 

toys . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2, 7, 8, 11, 141, 180, 199, 203, 206, 207, 214, 222
 

transport . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72, 75, 104, 137, 188, 191-193, 211, 212
 

TRI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177, 185, 187-190, 204, 205, 212
 

triglycerides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74, 163 
 

triiodothyronine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 
 

tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14, 15, 28, 29, 91, 92, 124, 126
 

TWA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227, 231
 

vapor phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 
 

vapor pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159-161, 175, 185, 191, 195
 

volatility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12, 183, 208
 

volatilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11, 192, 196
 

water . . . . . . . . . . . . . . . . . . . . 2-4, 7, 9, 11, 12, 19, 70, 89, 111, 117, 120, 121, 141, 143, 154, 167, 175, 183, 185-187, 189, 192­

197, 202-204, 206, 211-213, 220, 221, 224, 225, 227-231