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TOXICOLOGICAL PROFILE FOR
 

PHOSPHATE ESTER FLAME RETARDANTS
 


	


	

 

Prepared for:
	

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
	

Public Health Service
	

Agency for Toxic Substances and Disease Registry
	

September 2009 
 

 


 

PHOSPHATE ESTER FLAME RETARDANTS 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. 

This information is distributed solely for the purpose of pre dissemination public comment under 

applicable information quality guidelines. It has not been formally disseminated by the Agency for Toxic 

Substances and Disease Registry. It does not represent and should not be construed to represent any 

agency determination or policy. 

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PHOSPHATE ESTER FLAME RETARDANTS iii 

Toxicological profiles are revised and republished as necessary. For information regarding the update 

status of previously released profiles, contact ATSDR at: 

Agency for Toxic Substances and Disease Registry
	

Division of Toxicology and Environmental Medicine/Applied Toxicology Branch
	

1600 Clifton Road NE
	

Mailstop F-62
	

Atlanta, Georgia 30333
	

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PHOSPHATE ESTER FLAME RETARDANTS iv 

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v 

FOREWORD 

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

Toxic Substances and Disease Registry (A TSDR) 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 necesslll)'. 

The A TSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects 

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

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

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

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

The focus ofthe profiles is on health and toxicologic information. 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 ofsignificant 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 summlll)'. Data needs that are ofsignificance to 

protection ofpublic health are identified by A TSDR and EPA. 

Each profile includes the following: 

(A) The examination, summlll)', and interpretation ofavailable toxicologic information and 

epidemiologic evaluations on a toxic substance to ascertain the levels ofsignificant human 

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

(B) 	 A determination ofwhether adequate information on the health effects ofeach substance is 

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

significant risk to human health ofacute, subacute, and chronic health effects; and 

(C) 	 Where appropriate, identification oftoxicologic testing needed to identifY the types or levels of 

exposure that may present significant risk ofadverse 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 ofthe public. We pIan to 

revise these documents in response to public comments and as additional data become available. 

Therefore, we encourage comments that will make the toxicological profile series ofthe greatest use. 

Comments should be sent to: 

Agency for Toxic Substances and Disease Registry 

Division of Toxicology and Environmental Medicine 

1600 Clifton Road, N.E. 

Mail Stop F-62 

Atlanta, Georgia 30333 
VI 

The toxicological profiles are developed under the Comprehensive Environmental Response, 

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

I 04(i)(1) directs the Administrator ofATSDR to " ...effectuate and implement the health related 

authorities" ofthe statute. This inCludes the preparation oftoxicological profiles for hazardous substances 

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

significant potential threat to human health, as determined by ATSDR and the EPA. Section 104(i)(3) of 

CERCLA, as amended, directs the Administrator ofA TSDR to prepare a toxicological profile for each 

substance on the list. In addition, A TSDR has the authority to prepare toxicological profiles for substances 

not found at sites on the National Priorities List, in an effort to " ...establish and maintain inventory of 

literature, research, and studies on the health effects oftoxic substances" under CERCLA Section 

I 04(i)(1 XB), to respond to requests for consultation under section 104(iX 4), and as otherwise necessary to 

support the site-specific response actions conducted by ATSDR. 

This profile reflects ATSDR's assessment of all relevant toxicologic testing and information that 

has been peer-reviewed. Staffs ofthe 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 is being made available for public review. Final responsibility for the contents 

and views expressed in this toxicological profile resides with ATSDR. 

Howard Frumkin, M.D., Dr. P.H. VThomas R. Frieden, M.D., M.P.H. 

Director, National Center for Environmental Administrator, Agency for Toxic Substances and 

Health/Agency for Toxic Substances and Disease Disease Registry 

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PHOSPHATE ESTER FLAME RETARDANTS vii 

QUICK REFERENCE FOR HEALTH CARE PROVIDERS 

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

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

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

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

answers to often-asked questions. 

Primary Chapters/Sections of Interest 

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

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

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

the general health effects observed following exposure. 

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

and assesses the significance of toxicity data to human health. 

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

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

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

reported in this section. 

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

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

following exposure. 

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

issues: 

Section 1.6 How Can (Chemical X) Affect Children?
 

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

Section 3.7 Children’s Susceptibility
 

Section 6.6 Exposures of Children
 

Other Sections of Interest: 

Section 3.8 Biomarkers of Exposure and Effect 

Section 3.11 Methods for Reducing Toxic Effects 

ATSDR Information Center 

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

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

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

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

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

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

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PHOSPHATE ESTER FLAME RETARDANTS viii 

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

Toxicity; and numerous chemical-specific case studies. 

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

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

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

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

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

professionals treating patients exposed to hazardous materials. 

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

Other Agencies and Organizations 

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

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

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

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

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

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

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

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

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

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

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

1998 • Phone: 800-35-NIOSH. 

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

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

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

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

Referrals 

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

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

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

4976 • FAX: 202-347-4950 • e-mail: AOEC@AOEC.ORG • Web Page: http://www.aoec.org/. 

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

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

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

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

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PHOSPHATE ESTER FLAME RETARDANTS ix 

CONTRIBUTORS 

CHEMICAL MANAGER(S)/AUTHOR(S): 

G. Daniel Todd, Ph.D.
	

Dennis Jones, D.V.M
	

Jaclynn Lippe, M.P.H.
	

Jewell Crawford, M.D.
	

John Doyle, M.P.A.
	

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

Fernando T. Llados, Ph.D.
	

Steve Houghton, Ph.D.
	

Laura McIlroy, B.S.
	

SRC, Inc., North Syracuse, NY
	

THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS: 

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

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

end points. 

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

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

profile, and makes recommendations for derivation of MRLs. 

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

consistency across profiles and adherence to instructions in the Guidance. 

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

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PHOSPHATE ESTER FLAME RETARDANTS xi 

PEER REVIEW
 

A peer review panel was assembled for phosphate ester flame retardants. The panel consisted of the 

following members: 

1.		Sam Kacew, Ph.D., Associate Director of Toxicology, University of Ottawa, McLaughlin Center for 

Population Health, Ottawa, ON, Canada 

2.		Richard K. Miller, Ph.D., Professor of Environmental Medicine, University of Rochester School of 

Medicine and Dentistry, Department of Obstetrics and Gynecology, Rochester, NY 

3. Michael Pereira, Ph.D., Professor, Division of Hematology and Oncology, College of Medicine and 

Public Health, Ohio State University, Columbus, OH 

These experts collectively have knowledge of phosphate ester flame retardants' physical and chemical 

properties, toxicokinetics, key health end points, mechanisms of action, human and animal exposure, and 

quantification of risk to humans. All reviewers were selected in conformity with the conditions for peer 

review specified in Section 104(I)(13) of the Comprehensive Environmental Response, Compensation, 

and Liability Act, as amended. 

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

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

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

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

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

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

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PHOSPHATE ESTER FLAME RETARDANTS xii 

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PHOSPHATE ESTER FLAME RETARDANTS xiii 

CONTENTS 

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

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

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

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

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

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

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

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

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

1.1 WHAT ARE PHOSPHATE ESTER FLAME RETARDANTS?.................................................... 2
 

1.2 WHAT HAPPENS TO PHOSPHATE ESTER FLAME RETARDANTS WHEN THEY 

ENTER THE ENVIRONMENT? .................................................................................................... 2
 

1.3 HOW MIGHT I BE EXPOSED TO PHOSPHATE ESTER FLAME RETARDANTS? ............... 3
 

1.4 HOW CAN PHOSPHATE ESTER FLAME RETARDANTS ENTER AND LEAVE MY 

BODY? ............................................................................................................................................ 3
 

1.5 HOW CAN PHOSPHATE ESTER FLAME RETARDANTS AFFECT MY HEALTH? ............. 4
 

1.6 HOW CAN PHOSPHATE ESTER FLAME RETARDANTS AFFECT CHILDREN? ................. 6
 

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO PHOSPHATE ESTER 

FLAME RETARDANTS?............................................................................................................... 6
 

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

TO PHOSPHATE ESTER FLAME RETARDANTS? ................................................................... 7
 

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 

PROTECT HUMAN HEALTH? ..................................................................................................... 7
 

1.10 WHERE CAN I GET MORE INFORMATION?............................................................................ 8
 

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

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO PHOSPHATE ESTER 

FLAME RETARDANTS IN THE UNITED STATES ................................................................. 11
 

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

2.3 MINIMAL RISK LEVELS (MRLs) .............................................................................................. 16
 

3. HEALTH EFFECTS.............................................................................................................................. 35
 

3.1 INTRODUCTION ......................................................................................................................... 35
 

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE....................................... 35
 

3.2.1 Inhalation Exposure................................................................................................................. 36
 

3.2.1.1 Death ............................................................................................................................... 37
 

3.2.1.2 Systemic Effects .............................................................................................................. 38
 

3.2.1.3 Immunological and Lymphoreticular Effects .................................................................. 42
 

3.2.1.4 Neurological Effects........................................................................................................ 42
 

3.2.1.5 Reproductive Effects....................................................................................................... 42
 

3.2.1.6 Developmental Effects .................................................................................................... 42
 

3.2.1.7 Cancer ............................................................................................................................. 42
 

3.2.2 Oral Exposure.......................................................................................................................... 43
 

3.2.2.1 Death ............................................................................................................................... 43
 

3.2.2.2 Systemic Effects ............................................................................................................ 104
 

3.2.2.3 Immunological and Lymphoreticular Effects ................................................................ 115
 

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PHOSPHATE ESTER FLAME RETARDANTS xiv 

3.2.2.4 Neurological Effects...................................................................................................... 116
 

3.2.2.5 Reproductive Effects..................................................................................................... 119
 

3.2.2.6 Developmental Effects .................................................................................................. 121
 

3.2.2.7 Cancer ........................................................................................................................... 123
 

3.2.3 Dermal Exposure................................................................................................................... 125
 

3.2.3.1 Death ............................................................................................................................. 125
 

3.2.3.2 Systemic Effects ............................................................................................................ 126
 

3.2.3.3 Immunological and Lymphoreticular Effects ............................................................... 136
 

3.2.3.4 Neurological Effects...................................................................................................... 136
 

3.2.3.5 Reproductive Effects..................................................................................................... 137
 

3.2.3.6 Developmental Effects .................................................................................................. 137
 

3.2.3.7 Cancer ........................................................................................................................... 137
 

3.3 GENOTOXICITY ....................................................................................................................... 137
 

3.4 TOXICOKINETICS .................................................................................................................... 143
 

3.4.1 Absorption............................................................................................................................. 144
 

3.4.1.1 Inhalation Exposure ...................................................................................................... 144
 

3.4.1.2 Oral Exposure................................................................................................................ 144
 

3.4.1.3 Dermal Exposure........................................................................................................... 145
 

3.4.1.4 Other Routes of Exposure ............................................................................................. 146
 

3.4.2 Distribution............................................................................................................................ 146
 

3.4.2.1 Inhalation Exposure ...................................................................................................... 146
 

3.4.2.2 Oral Exposure................................................................................................................ 147
 

3.4.2.3 Dermal Exposure........................................................................................................... 148
 

3.4.2.4 Other Routes of Exposure ............................................................................................. 148
 

3.4.3 Metabolism............................................................................................................................ 150
 

3.4.4 Elimination and Excretion ..................................................................................................... 158
 

3.4.4.1 Inhalation Exposure ...................................................................................................... 158
 

3.4.4.2 Oral Exposure................................................................................................................ 158
 

3.4.4.3 Dermal Exposure........................................................................................................... 159
 

3.4.4.4 Other Routes of Exposure ............................................................................................. 160
 

3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models ............. 161
 

3.5 MECHANISMS OF ACTION ..................................................................................................... 164
 

3.5.1 Pharmacokinetic Mechanisms ............................................................................................... 164
 

3.5.2 Mechanisms of Toxicity........................................................................................................166
 

3.5.3 Animal-to-Human Extrapolations ......................................................................................... 167
 

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS ............................ 168
 

3.7 CHILDREN’S SUSCEPTIBILITY ............................................................................................. 170
 

3.8 BIOMARKERS OF EXPOSURE AND EFFECT ....................................................................... 172
 

3.8.1	 Biomarkers Used to Identify or Quantify Exposure to Phosphate Ester Flame 

Retardants.............................................................................................................................. 173
 

3.8.2	 Biomarkers Used to Characterize Effects Caused by Phosphate Ester Flame 

Retardants.............................................................................................................................. 174
 

3.9 INTERACTIONS WITH OTHER CHEMICALS....................................................................... 174
 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE ................................................. 174
 

3.11 METHODS FOR REDUCING TOXIC EFFECTS ..................................................................... 175
 

3.11.1 Reducing Peak Absorption Following Exposure .................................................................. 175
 

3.11.2 Reducing Body Burden ......................................................................................................... 176
 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects ................................................ 176
 

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PHOSPHATE ESTER FLAME RETARDANTS xv 

3.12 ADEQUACY OF THE DATABASE.......................................................................................... 176
 

3.12.1 Existing Information on Health Effects of Phosphate Ester Flame Retardants..................... 177
 

3.12.2 Identification of Data Needs.................................................................................................. 179
 

3.12.3 Ongoing Studies .................................................................................................................... 188
 

4. CHEMICAL AND PHYSICAL INFORMATION.............................................................................. 189
 

4.1 CHEMICAL IDENTITY............................................................................................................. 189
 

4.2 PHYSICAL AND CHEMICAL PROPERTIES.......................................................................... 189
 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL.......................................................... 197
 

5.1 PRODUCTION............................................................................................................................ 197
 

5.2 IMPORT/EXPORT...................................................................................................................... 198
 

5.3 USE.............................................................................................................................................. 198
 

5.4 DISPOSAL .................................................................................................................................. 201
 

6. POTENTIAL FOR HUMAN EXPOSURE ......................................................................................... 203
 

6.1 OVERVIEW................................................................................................................................ 203
 

6.2 RELEASES TO THE ENVIRONMENT .................................................................................... 206
 

6.2.1 Air.......................................................................................................................................... 206
 

6.2.2 Water..................................................................................................................................... 207
 

6.2.3 Soil ........................................................................................................................................ 207
 

6.3 ENVIRONMENTAL FATE........................................................................................................ 207
 

6.3.1 Transport and Partitioning..................................................................................................... 207
 

6.3.2 Transformation and Degradation........................................................................................... 208
 

6.3.2.1 Air ................................................................................................................................. 208
 

6.3.2.2 Water............................................................................................................................. 209
 

6.3.2.3 Sediment and Soil ......................................................................................................... 211
 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT ................................... 211
 

6.4.1 Air.......................................................................................................................................... 211
 

6.4.2 Water..................................................................................................................................... 212
 

6.4.3 Sediment and Soil.................................................................................................................. 215
 

6.4.4 Other Environmental Media.................................................................................................. 216
 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE.......................................... 220
 

6.6 EXPOSURES OF CHILDREN ...................................................................................................223
 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES................................................ 224
 

6.8 ADEQUACY OF THE DATABASE.......................................................................................... 225
 

6.8.1 Identification of Data Needs.................................................................................................. 225
 

6.8.2 Ongoing Studies .................................................................................................................... 227
 

7. ANALYTICAL METHODS................................................................................................................ 229
 

7.1 BIOLOGICAL MATERIALS ..................................................................................................... 229
 

7.2 ENVIRONMENTAL SAMPLES................................................................................................ 231
 

7.3 ADEQUACY OF THE DATABASE.......................................................................................... 233
 

7.3.1 Identification of Data Needs.................................................................................................. 234
 

7.3.2 Ongoing Studies .................................................................................................................... 235
 

8. REGULATIONS, ADVISORIES, AND GUIDELINES..................................................................... 237
 

9. REFERENCES .................................................................................................................................... 243
 

10. GLOSSARY ...................................................................................................................................... 271
 

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PHOSPHATE ESTER FLAME RETARDANTS xvi 

APPENDICES 

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

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

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

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

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PHOSPHATE ESTER FLAME RETARDANTS xvii 

LIST OF FIGURES
 

3-1. Levels of Significant Exposure to Selected Phosphate Esters – Inhalation........................................ 40
	

3-2. Levels of Significant Exposure to Tris(2-chloroethyl) Phosphate (TCEP) – Oral ............................. 59
	

3-3. Levels of Significant Exposure to Tri-n-butyl Phosphate (TnBP) – Oral .......................................... 79
	

3-4. Levels of Significant Exposure to Tris(2-butoxyethyl) Phosphate (TBEP) – Oral ............................ 87
	

3-5. Levels of Significant Exposure to Tris(1,3-dichloro-2-propyl) Phosphate (TDCP) – Oral................ 94
	

3-6. Levels of Significant Exposure to TPP, TCPP, and TiBP – Oral..................................................... 102
	

3-7. Proposed Scheme for TCEP Metabolism in Rats and Mice .............................................................152
	

3-8. Proposed Metabolic Pathway of TnBP in Rats.................................................................................154
	

3-9. Suggested Biotransformation Scheme of TnBP in Rats...................................................................156
	

3-10. Proposed Metabolic Pathway of TnBP in Yucatan® Minipigs.......................................................157
	

3-11. Conceptual Representation of a Physiologically Based Pharmacokinetic (PBPK) Model for a
	

Hypothetical Chemical Substance................................................................................................163
	

3-12. Existing Information on Health Effects of Phosphate Ester Flame Retardants..............................178
	

6-1. Frequency of NPL Sites with Phosphate Flame Retardants.............................................................204
	

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PHOSPHATE ESTER FLAME RETARDANTS xix 

LIST OF TABLES 

2-1. Incidence of Urinary Bladder Hyperplasia Induced by Tributyl Phosphate in Four Studies 

in Rats ................................................................................................................................................. 25
	

3-1. Levels of Significant Exposure to Phosphate Esters - Inhalation..................................................... 39
	

3-2. Levels of Significant Exposure to Tris(2-chloroethyl) Phosphate (TCEP) - Oral............................ 45
	

3-3. Levels of Significant Exposure to Tri-n-butyl Phosphate (TnBP) - Oral ......................................... 64
	

3-4. Levels of Significant Exposure to Tris(2-butoxyethyl) Phosphate (TBEP) - Oral........................... 83
	

3-5. Levels of Significant Exposure to Tris(1,3-dichloro-2-propyl) Phosphate (TDCP) - Oral .............. 89
	

3-6. Levels of Significant Exposure to TPP, TCPP, and TiBP - Oral...................................................... 97
	

3-7. Levels of Significant Exposure to Selected Phosphate Esters - Dermal......................................... 127
	

3-8. Genotoxicity of Phosphate Ester Flame Retardants In Vitro............................................................138
	

3-9 Genotoxicity of Phosphate Ester Flame Retardants In Vivo..............................................................141
	

4-1. Chemical Identity of Selected Phosphate Ester Flame Retardants...................................................190
	

4-2. Physical and Chemical Properties of Selected Phosphate Ester Flame Retardants..........................193
	

5-1. Applications of Phosphate Ester Flame Retardants..........................................................................199
	

6-1. Phosphate Ester Flame Retardant Levels in Food ............................................................................217
	

6-2. Dietary Phosphate Ester Flame Retardant Intake .............................................................................221
	

7-1. Analytical Methods for Determining Phosphate Ester Flame Retardants in Biological
	

Materials ...........................................................................................................................................230
	

7-2. Analytical Methods for Determining Phosphate Ester Flame Retardants in Environmental
	

Samples.............................................................................................................................................232
	

8-1. Regulations and Guidelines Applicable to Phosphate Ester Flame Retardants................................238
	

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PHOSPHATE ESTER FLAME RETARDANTS 1 

1. PUBLIC HEALTH STATEMENT
 

This public health statement tells you about phosphate ester flame retardants and the effects of 

exposure to them. 

This profile discusses the following phosphate ester flame retardants: tris(2-chloroethyl) 

phosphate (TCEP), tributyl phosphate (TnBP), tris(2-butoxyethyl) phosphate (TBEP), 

tris(1,3-dichloro-2-propyl) phosphate (TDCP), triphenyl phosphate (TPP), tris(2-chloroisopropyl) phosphate (TCPP), and triisobutyl phosphate (TiBP). 

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

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

long-term federal clean-up activities. Phosphate ester flame retardants have been found in at 

least 8 of the 1,699 current or former NPL sites. Although the total number of NPL sites 

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

which phosphate ester flame retardants are found may increase in the future as more sites are 

evaluated. This information is important because these sites may be sources of exposure and 

exposure to these substances may be harmful. 

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

container, such as a drum or bottle, it enters the environment. Such a release does not always 

lead to exposure. You can be exposed to a substance only when you come in contact with it. 

You may be exposed by breathing, eating, or drinking the substance, or by skin contact. 

If you are exposed to phosphate ester flame retardants, many factors will determine whether you 

will be harmed. These factors include the dose (how much), the duration (how long), and how 

you come in contact with them. You must also consider any other chemicals you are exposed to 

and your age, sex, diet, family traits, lifestyle, and state of health. 

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1. PUBLIC HEALTH STATEMENT 

1.1	 WHAT ARE PHOSPHATE ESTER FLAME RETARDANTS? 

Description Phosphate ester flame retardants are human-made chemicals added 

to consumer and industrial products for the purpose of reducing 

flammability. 

Phosphate ester flame retardants are composed of a group of 

chemicals with similar properties but slightly different structures. 

Phosphate esters are typically liquids at room temperature; however, 

some are solids. 

Uses Phosphate esters are flame retardants, plasticizers, hydraulic fluids, 

solvents, extraction agents, antifoam agents, and coatings for 

electronic devices. 

For more information on the physical and chemical properties of phosphate esters and their 

production, disposal and use, see Chapters 4 and 5. 

1.2	 WHAT HAPPENS TO PHOSPHATE ESTER FLAME RETARDANTS WHEN THEY 

ENTER THE ENVIRONMENT? 

Sources Phosphate ester flame retardants are released to the environment 

from industrial sources and disposal of consumer products containing 

flame retardants. 

Breakdown 

• Air 

• Water and soil 

Phosphate ester flame retardants can change chemical composition 

in the environment. 

There is no information available that suggests the selected 

phosphate ester flame retardants undergo transformation or 

degradation in the atmosphere. Particulate-phase phosphate esters 

are subject to wet and dry deposition, while semi-volatile phosphate 

esters have the potential to hydrolyze to diesters, monoesters, and 

phosphoric acid. 

Generally, most phosphate esters are poorly soluble in water and 

adsorb strongly to soils. These compounds are considered emerging 

pollutants due to their prevalence and persistence in the environment. 

Phosphate esters are subject to biodegradation in aquatic and 

terrestrial environments. 

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PHOSPHATE ESTER FLAME RETARDANTS 3 

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1.3 HOW MIGHT I BE EXPOSED TO PHOSPHATE ESTER FLAME RETARDANTS? 

Routes of exposure Humans can be exposed by a combination of oral, inhalation, and 

dermal routes. 

Food—primary source 

of exposure 

Ingesting contaminated food: Most foods have been found to contain 

trace amounts of phosphate ester flame retardants due to their wide 

use in plastics and presence in the environment. 

Air Breathing contaminated outdoor air: Hydraulic fluid is the primary 

source of phosphate esters in outdoor air. 

Breathing contaminated indoor air: Indoor air can contain phosphate 

ester flame retardants from certain plastics, adhesives, foams, or 

electronics. 

Water and soil Drinking water contaminated with phosphate esters due to leaching 

from plastics or industrial waste water discharge. 

By skin contact with contaminated soil: Hydraulic fluid spills or 

industrial waste water used for agriculture can result in the presence 

of phosphate esters in soil. 

Children Young children may be at a higher risk of exposure since they are 

more likely to put phosphate ester flame retardant treated materials in 

their mouths. 

1.4 HOW CAN PHOSPHATE ESTER FLAME RETARDANTS ENTER AND LEAVE MY 

BODY? 

Enter the body 

• Humans 

• Animals 

There is virtually no information about the entrance of these 

substances into the body. However, TDCP had been found in human 

tissues and body fluids, so we know that this substance can enter the 

body possibly by inhaling aerosols or dusts or ingesting contaminated 

food or water. 

Oral – Studies found that TDCP, TCEP, and TnBP can easily pass 

from the stomach and intestines to the blood stream. 

Dermal – Less amounts entered the body through the skin of rats and 

only very small amounts through the skin of pigs. 

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PHOSPHATE ESTER FLAME RETARDANTS 4 

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Leave the body 

• Humans 

• Animals 

There is no information on how these chemicals leave your body, but 

based on studies in animals, phosphate ester flame retardants may 

be broken down in the body and the breakdown product may be 

eliminated in the urine. However, there are no studies in humans to 

prove that this actually happens. 

Neither phosphate ester flame retardants nor their breakdown 

products seemed to accumulate in the body. Most breakdown 

products were eliminated in the urine in 2–3 days. 

1.5 HOW CAN PHOSPHATE ESTER FLAME RETARDANTS AFFECT MY HEALTH? 

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

Workers Long-term exposure of workers to TDCP or TPP was not associated 

with adverse health effects. No information was available regarding 

exposure to other phosphate ester flame retardants. 

General population Almost no information is available regarding health effects in 

members of the general population exposed to the phosphate ester 

flame retardants discussed in this profile. 

There have been a few cases of allergic reactions to consumer 

products that contain TPP, but a study that examined several 

hundred people exposed to plastics and glues that contained TPP did 

not find any allergic reactions. 

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PHOSPHATE ESTER FLAME RETARDANTS 5 

1. PUBLIC HEALTH STATEMENT 

Laboratory animals One way to learn about the effects of phosphate ester flame 

retardants is to see how they affect test animals. Almost all studies in 

animals have administered these substances orally and generally at 

levels much higher than what can be expected from environmental 

exposures. 

TCEP given to rats for 16 weeks or longer caused brain lesions. 

When given for 2 years, it also caused lesions in the kidneys. TCEP 

also decreased the fertility of mice that were exposed for 18 weeks 

before mating. 

TnBP induced lesions in the urinary bladder of rats when given for 

10 weeks or longer. 

TBEP caused liver lesions in rats after the rats ate food that 

contained TBEP for 18 weeks. 

Rats that ate food containing TDCP for 2 years developed lesions in 

the kidneys and liver. 

The few studies that examined the effects of TPP, TiBP, and TCPP in 

animals did not report significant adverse health effects. 

Cancer There is not enough information available to determine with certainty 

whether or not phosphate ester flame retardants produce cancer in 

humans. 

A study of workers employed in the manufacture of TDCP did not find 

significant associations between exposure to TDCP and cancer. No 

information was available regarding the carcinogenic potential of the 

other phosphate esters to humans. 

Rats that received oral doses of TCEP for 2 years developed kidney 

tumors. Feeding mice a diet that contained TCEP for 18 months 

induced tumors in the kidney, liver, and stomach, and also induced 

leukemia. Long-term administration of TnBP to rats and mice 

induced tumors in the urinary bladder and the liver, respectively. 

Feeding rats with a diet that contained TDCP for 2 years produced 

tumors in the liver, kidneys, testes, and adrenal gland. 

Neither the EPA nor the Department of Health and Human Services 

(DHHS) has classified the carcinogenic potential of the phosphate 

esters discussed in this profile. The International Agency for 

Research on Cancer (IARC) determined that TCEP is not classifiable 

as to its carcinogenicity to humans. 

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PHOSPHATE ESTER FLAME RETARDANTS 6 

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1.6 HOW CAN PHOSPHATE ESTER FLAME RETARDANTS AFFECT CHILDREN? 

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

conception to maturity at 18 years of age. 

Effects in humans There are no studies that examined the health effects of the 

phosphate ester flame retardants discussed in this profile on 

pregnant women or on their embryo or fetus. 

There are no studies that examined the health effects in children of 

the phosphate ester flame retardants discussed in this document. 

Laboratory animals In general, exposure of rodents during gestation to TCEP, TnBP, 

TBEP, TDCP, TPP, or TCPP did not result in adverse effects to the 

fetuses or newborn animals. 

However, continuous exposure of two generations of mice to TCEP 

reduced the number of male pups born alive in the third generation. 

A similar study with TnBP in rats found that pups born to exposed rats 

had lower body weight during the first weeks of life than pups born to 

untreated rats. 

Exposure of the fetus There is no information regarding transfer of phosphate ester flame 

retardants to the fetus across the placenta in pregnant women. 

Human breast milk No studies have been conducted to determine whether phosphate 

ester flame retardants can be detected in human breast milk from 

women exposed at work or from the general population. 

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO PHOSPHATE ESTER 

FLAME RETARDANTS? 

Food Avoid food that is generally high in phosphate ester content as 

indicated by the current market basket for the U.S. Total Diet study. 

Air Avoid installation or use of materials that are known to contain 

phosphate ester-based flame retardants in indoor environments to 

minimize exposure to them via air and particulate matter. 

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PHOSPHATE ESTER FLAME RETARDANTS	 7 

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

PHOSPHATE ESTER FLAME RETARDANTS? 

Detecting exposure Phosphate ester flame retardants can be measured in blood and 

urine, but this is not a routine test that can be performed in a doctor’s 

office. You should, however, see a physician if you believe that you 

have been exposed to high levels of these substances. 

No studies have been conducted to measure these chemicals in 

blood samples from groups of people representative of the U.S. 

general population. 

Measuring exposure The presence of phosphate ester flame retardants in your blood may 

indicate that you have been exposed to these substances and some 

amount entered your bloodstream. 

The presence of phosphate ester flame retardants in your blood does 

not necessarily indicate that adverse health effects will occur. 

Additional studies are needed to help to determine the health effects 

associated with exposure to these substances. 

1.9	 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 

PROTECT HUMAN HEALTH? 

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

Regulations can be enforced by law. The EPA, the Occupational Safety and Health 

Administration (OSHA), and the Food and Drug Administration (FDA) are some federal 

agencies that develop regulations for toxic substances. Recommendations provide valuable 

guidelines to protect public health, but cannot be enforced by law. The Agency for Toxic 

Substances and Disease Registry (ATSDR) and the National Institute for Occupational Safety 

and Health (NIOSH) are two federal organizations that develop recommendations for toxic 

substances. 

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

of a toxic substance in air, water, soil, or food that do not exceed a critical value. This critical 

value is usually based on levels that affect animals; they are then adjusted to levels that will help 

protect humans. Sometimes these not-to-exceed levels differ among federal organizations 

because they used different exposure times (an 8-hour workday or a 24-hour day), different 

animal studies, or other factors. 

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PHOSPHATE ESTER FLAME RETARDANTS 8 

1. PUBLIC HEALTH STATEMENT 

Recommendations and regulations are also updated periodically as more information becomes 

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

provides it. 

Some regulations and recommendations for phosphate ester flame retardants include the 

following: 

Levels in workplace air 

set by OSHA 

OSHA set a legal limit of 3 and 5 mg/m3 for TPP and TnBP, 

respectively, in air averaged over an 8-hour work day. 

Food The EPA has permitted TnBP, TBEP, and TPP for use in nonfood 

pesticide products. 

1.10 WHERE CAN I GET MORE INFORMATION? 

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

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

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

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

hazardous substances. 

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PHOSPHATE ESTER FLAME RETARDANTS 9 

1. PUBLIC HEALTH STATEMENT 

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

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

and technical assistance number at 1-800-CDCINFO (1-800-232-4636), by e-mail at 

cdcinfo@cdc.gov, or by writing to: 

Agency for Toxic Substances and Disease Registry 

Division of Toxicology and Environmental Medicine 

1600 Clifton Road NE 

Mailstop F-62 

Atlanta, GA 30333 

Fax: 1-770-488-4178 

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

National Technical Information Service (NTIS)
 

5285 Port Royal Road
 

Springfield, VA 22161
 

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

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

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PHOSPHATE ESTER FLAME RETARDANTS 10 

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PHOSPHATE ESTER FLAME RETARDANTS 11 

2. RELEVANCE TO PUBLIC HEALTH 

2.1	 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO PHOSPHATE ESTER 

FLAME RETARDANTS IN THE UNITED STATES 

Phosphate esters are a class of anthropogenic organic compounds found in the environment due to their 

release from commercial and industrial products. They are pervasive throughout the world due to their 

extensive industrial and commercial use since the 1940s. Phosphate esters represent an important class of 

commercial additives used as flame retardants, plasticizers, hydraulic fluids, solvents, extraction agents, 

antifoam agents, adhesives, and coatings for electronic devices. 

Human exposure to phosphate ester flame retardants can occur via ingestion of food and water, and 

through contact with water, air, or soil containing phosphate esters. The most likely route of exposure to 

the general population is through ingestion of food and water containing phosphate esters or inhalation of 

vapors or particulates released from flame retardant materials. The dermal route can account for exposure 

if contact with flame-retarded textiles occurs. Oral exposure could occur in young children from 

dissolution of phosphate ester treated materials since children are more likely to suck on these materials. 

The ranges of expected exposure through food are generally 0.5–20 ng/kg/day for adults and 0.1– 

40 ng/kg/day for children under 2 years of age. These estimated intakes are significantly lower than the 

doses administered to laboratory animals. Workers in industries that manufacture phosphate esters or 

products containing phosphate esters are subject to a greater exposure risk than the general population. 

Concentrations of phosphate esters in ambient outdoor air are not well known, as few studies address this 

subject. The presence of phosphate esters in outdoor air likely originates from hydraulic fluid 

volatilization and diffusion of plasticizers. Concentrations were in the low μg/m3 range when detected 

near airports and low ng/m3 range outside of office buildings. Indoor air is well documented to contain a 

wide array of phosphate esters at concentrations in the μg/m3 range. Concentrations measured indoors 

typically range from ng/m3 to μg/m3

. 

Surface water is the most likely place to find anthropogenic phosphate ester flame retardants. 

Concentrations of 0.5 μg/L are commonplace in rivers, lakes, and groundwater, but effluent and waste 

water have been documented to contain up to 15 μg/L of select phosphate esters, predominantly tributyl 

phosphate (TnBP) or triphenyl phosphate (TPP). Tris-(2-chloroethyl)-phosphate (TCEP) has also been 

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PHOSPHATE ESTER FLAME RETARDANTS 12 

2. RELEVANCE TO PUBLIC HEALTH 

found in water in above average concentrations. Groundwater is less likely to contain phosphate esters 

due to their potential to adsorb to soils and sediments. For a more complete discussion of phosphate ester 

flame retardants found in the environment, see Chapter 6. 

2.2 SUMMARY OF HEALTH EFFECTS 

Very limited information was located in the database available for review regarding adverse health effects 

in humans exposed to the phosphate ester flame retardants covered in this profile. Studies of subjects 

occupationally exposed to tris(1,3-dichloro-2-propyl) phosphate (TDCP) found no apparent medical 

conditions related to exposure. The time-weighted average exposure concentration was estimated to have 

been ≤0.4–0.5 μg/m3

. Examination of the mortality experience in 289 workers employed in the 

manufacture of TDCP also found no significant association between exposure and any specific cause of 

death. Examinations conducted over the years of small groups of operators in a TPP production plant did 

not reveal any usual frequency of symptoms, or physical or laboratory findings as compared to unexposed 

groups. The estimated weighted average concentration of TPP vapor mist and dust was 3.5 mg/m3

. A 

few individual cases of allergic dermal reactions to TPP have been reported. However, a much bigger 

study of 343 patients seen at a dermatology clinic reported that no individuals showed allergic reactions to 

TPP. No studies were located regarding immunological effects or on effects on human reproduction. In 

addition, no studies were available in pregnant women or children. 

The great majority of the studies in animals have been conducted by the oral route of exposure. However, 

two 3-week studies in rabbits exposed to TPP and tributoxyethyl phosphate (TBEP) by skin application 

evaluated hematology and clinical chemistry parameters and gross and microscopic morphology of tissues 

and found virtually no toxicity with daily dermal doses of up to 1,000 mg/kg/day of each substance. The 

only significant effect observed was slight edema, atonia, and desquamation at the application site of 

rabbits applied the lowest dose of 10 mg TBEP/kg/day. In rabbits treated with 1,000 mg TBEP/kg/day, 

microscopic examination of the treated sites showed squamous cell hyperplasia, hyperkeratosis, erosionsulcers, acute-subacute inflammation, and congestion and hemorrhage, in various combinations. 

The information available from oral studies does not support treating these chemicals as a class for 

purposes of risk assessment based on the different toxicities exhibited by each one of them. For TCEP, 

TnBP, TBEP, and TDCP, there was sufficient information to identify sensitive end points; this was not 

the case for TPP, triisobutyl phosphate (TiBP), or tri-(2-chloroisopropyl) phosphate (TCPP). Because of 

the structural similarity of some of these compounds, particularly TPP, to the potent neurotoxicant, tri-

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PHOSPHATE ESTER FLAME RETARDANTS 13 

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ortho cresyl phosphate (TOCP), it was thought that they might also induce organophosphate-induced 

delayed neurotoxicity (OPIDN). However, studies have shown that not to be the case for the alkyl 

substituted phosphate ester flame retardants discussed in this profile. Studies have also shown that TPP 

has only a fraction of the potency of TOCP for inducing OPIDN. 

TCEP induced brain lesions in rats in 16-week (175 mg/kg/day) and 2-year (88 mg/kg/day) studies; 

females appeared more sensitive than males. In the 16-week studies, the lesions were located in the 

hippocampus and thalamus, whereas dosing for 2 years involved primarily the brain stem and cerebral 

cortex. Cerebral ischemia and/or convulsive activity are potential mechanisms by which these lesions 

might occur. No such lesions were reported in studies with the other phosphate esters discussed in this 

profile. Decreased conduction velocity was reported in rats treated with 411 mg TnBP/kg/day for 

14 days, and this was accompanied by morphological alterations in the nerve. Acute high doses of TBEP 

induced abnormal gait, piloerection, and tremors in rats. Several studies measured red blood cell 

cholinesterase activity and only in a study in rats dosed with TBEP was there a statistically significant 

decrease (although the magnitude was not specified) after 9 weeks of treatment, but not after 18 weeks of 

treatment. No clinical signs were associated with the decrease in cholinesterase activity in that study. 

The kidney and urinary tract from rats were targets for some of the subject phosphate ester flame 

retardants of this profile. Administration of TCEP to rats for 16 weeks resulted in increases in absolute 

and relative kidney weight without inducing histological alterations in doses of up to 350 mg/kg/day. 

However, treatment for 2 years with 88 mg/kg/day induced renal tubule epithelial hyperplasia in male and 

female rats. Effects were also reported in mice, but at higher dose levels. The kidney was also a sensitive 

target for TDCP in rats. Relatively low dietary doses of 20 mg/kg/day significantly increased the 

incidence of hyperplasia of the convoluted tubular epithelium in male rats; females appeared slightly less 

sensitive. For TnBP, the urinary bladder of rats was the most sensitive target in intermediate- and 

chronic-duration oral studies. Urinary bladder hyperplasia was found to be reversible during a 10-week 

period in a control diet that followed a 10-week exposure period. Interestingly, doses of TnBP that 

induced nearly 100% incidence of urinary bladder hyperplasia following intermediate-duration exposure 

induced a much lower incidence of this lesion in a 2-year study. This appeared to be due to the fact that 

in the 2-year study, rats with malignant bladder tumors usually did not have any remaining uninvolved 

epithelium to evaluate for the presence or absence of hyperplasia. The latter suggested that urinary 

bladder hyperplasia may be a precursor of bladder tumors. 

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PHOSPHATE ESTER FLAME RETARDANTS 14 

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The liver was also a target for some of the phosphate ester flame retardants discussed in this document, 

although effects in some cases were limited to changes in organ weight. TCEP induced increases in liver 

weight without histological alterations in rats dosed with up to 350 mg TCEP/kg/day for 16 weeks. 

Extending the treatment for 2 years with doses of up to 88 mg TCEP/kg/day also resulted in only 

increases in organ weight. Similar findings were reported in rats dosed with TnBP in acute- and 

intermediate-duration studies and in intermediate- and chronic-duration studies in mice. TBEP induced 

histological alterations in the liver of rats in a 2-year study and the same was reported in rats dosed with 

TBEP for 18 weeks. In the single study available with TiBP, rats treated with up to 404 mg TiBP/kg/day 

for 13 weeks did not show gross or microscopic alterations in the liver. 

For the most part, standard toxicity studies did not report morphological alterations in the reproductive 

organs of rats and mice. Of the phosphate esters subject of this profile, TCEP, TnBP, TPP, and TDCP 

were also tested for effects on fertility. TCEP in doses ≥350mg/kg/day significantly reduced fertility in 

mice in a continuous breeding protocol study. Cross-mating experiments conducted to determine the 

affected sex showed that both sexes were adversely affected, but the males were relatively more sensitive, 

as all sperm end points examined (concentration, motility, and percent abnormal) were affected. In a 

2-generation reproductive toxicity study in rats dosed with 217 mg TnBP/kg/day, there were no 

significant reproductive effects in either the F0 or F1 generations, including mating and fertility, or on 

gross and microscopic appearance of the reproductive organs. TDCP was tested for its effects on fertility 

in male rabbits by dosing the rabbits with up to 200 mg TDCP/kg/day by gavage for 12 weeks and then 

mating the males with untreated females. Fertility was not affected and examination of sperm from the 

cauda epididymides for motility, morphology, and concentration did not show significant alterations. 

Fertility indices (number pregnant, corpora lutea, implantations, implantation efficiency, resorptions) 

were not affected in male or female rats dosed with up to 690 mg TPP/kg/day for 91 days before mating. 

Studies in which animals have been exposed to various phosphate ester flame retardants only during 

pregnancy suggest that developmental end points are not particularly sensitive to these substances. Doses 

of TCEP that produced maternal toxicity in rats and mice did not affect fetal parameters. However, in a 

continuous breeding protocol study in mice, the lowest dose tested (175 mg TCEP/kg/day) significantly 

decreased the number of live male F2 pups per litter. Studies conducted with TnBP also showed lack of 

developmental toxicity for this chemical even in the presence of frank maternal toxicity. However, in a 

2-generation reproductive study in mice, exposure to TnBP produced a significant reduction in F1 and 

F2 pup weight per litter during postnatal days 0–21. Significant reductions in maternal body weight also 

occurred at this level, which may have contributed to the decrease in pup weight. Studies in rats exposed 

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PHOSPHATE ESTER FLAME RETARDANTS 15 

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to TBEP or TDCP during pregnancy also reported no developmental effects at dose levels that 

significantly reduced weight gain in the dams. TPP was not a developmental toxicant in a study in which 

both male and female rats were dosed for 91 days before mating, and females continued being treated 

through gestation. A gestational exposure study with TCPP in rats also reported no significant 

developmental toxicity under the conditions of the study. 

Very limited information is available regarding the effects of the phosphate esters covered in this profile 

on the immune system. Gross and microscopic examinations of the thymus, spleen, and lymph nodes 

conducted in many of the toxicity studies available did not reveal significant treatment-related alterations. 

Parameters of immunocompetence were evaluated only in one study in rats dosed with up to 711 mg 

TPP/kg/day for 120 days. The only effects noted were increases in the levels of α- and β-globulins at 

6 months, which suggested increased hepatic activity. Assessment of the humoral response to the 

T-lymphocyte-dependent antigen sheep red blood cell (SRBC) did not indicate alterations in 

immunocompetence due to treatment with TPP. 

TCEP, TnBP, and TDCP have been tested for carcinogenicity in long-term oral bioassays. Doses of 

88 mg TCEP/kg/day significantly increased the incidence of renal tubule adenoma or carcinoma in male 

Fischer-344 rats and renal tubule adenomas in female Fischer-344 rats. Based on these findings, NTP 

concluded that there was clear evidence of carcinogenic activity for male and female Fischer-344/N rats. 

TCEP (350 mg/kg/day) also induced a nonsignificant increase in the incidence of a rare renal tubule 

neoplasm in male B6C3F1 mice, which led NTP to conclude that there was equivocal evidence of 

carcinogenic activity for male mice. TCEP increased, although not significantly, the incidence of tumors 

of the Harderian gland in female B6C3F1 mice; based on this, NTP concluded that there was equivocal 

evidence of carcinogenic activity for female mice. In a dietary study in ddY mice, TCEP increased the 

incidences of renal (1,333 mg/kg/day) and liver (267 mg/kg/day) tumors in male mice and forestomach 

tumors (1,333 mg/kg/day) and leukemia (267 mg/kg/day) in female mice. In dermal assays, TCEP 

showed no significant carcinogenic, initiating, or promoting activity on the skin of female Swiss mice. 

IARC evaluated TCEP and concluded that the chemical is not classifiable as to its carcinogenicity to 

humans. 

TnBP significantly increased the incidence of combined papillomas, squamous cell carcinomas, and 

transitional cell carcinomas in the urinary bladder of male Sprague-Dawley rats at 143 mg/kg/day and of 

hepatocellular adenomas in male CD-1 mice at 585 mg/kg/day. TDCP significantly increased the 

incidence of neoplastic nodules in the liver of male and female Sprague-Dawley rats and the incidence of 

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PHOSPHATE ESTER FLAME RETARDANTS 16 

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hepatocellular carcinomas in male rats dosed with 20 mg/kg/day. Doses of ≥20 mg TDCP/kg/day also 

increased the incidence of renal cortical tumors in male and female rats and interstitial cell tumors in the 

testes in males; the incidence of adrenocortical adenomas was also significantly increased in females 

dosed with 80 mg TDCP/kg/day. 

The EPA has not evaluated the carcinogenicity of the phosphate ester flame retardants discussed in this 

profile. 

2.3 MINIMAL RISK LEVELS (MRLs) 

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

flame retardants. An MRL is defined as an estimate of daily human exposure to a substance that is likely 

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

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

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

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

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

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

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

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

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

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

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

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

significant human exposure improve, these MRLs will be revised. 

Inhalation MRLs 

Although some human data were available in two reports of occupational exposure to TDCP (Stauffer 

Chemical Co. 1983) and in a report of occupational exposure to TPP (Sutton et al. 1960), the data were 

inadequate for derivation of inhalation MRLs. 

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PHOSPHATE ESTER FLAME RETARDANTS 17 

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Stauffer Chemical Co. (1983) conducted a retrospective cohort study to examine the mortality experience 

of 289 workers employed in the manufacture of TDCP. Exposure levels were <8 ppb. The overall 

mortality of the cohort was 75% of that expected in a comparable population of U.S. males. There were 

three deaths attributed to lung cancer, which was higher than the 0.8 expected. However, one case was 

found to have not been exposed to TDCP, a second case worked only 2 years before onset of the disease, 

and all three cases were cigarette smokers. The investigators concluded that there was insufficient 

evidence to establish a causal relationship between lung cancer and TDCP. ATSDR does not derive 

MRLs based on death or cancer; therefore, even if the exposure concentration of 8 ppb had been 

considered a reliable no-observed-adverse-effect level (NOAEL), an inhalation MRL based on this 

limited survey would have not been derived. 

Stauffer Chem Co. (1983) also conducted a morbidity survey to identify adverse health effects among 

workers occupationally exposed to TDCP. The survey was based on an analysis of the physical 

examination reports of 93 exposed and 31 non-exposed workers examined in 1981 and found no apparent 

medical conditions related to exposure to TDCP. Time-weighted average breathing zone sampling 

conducted in 1978 and 1979 showed that the concentration in the process area or in other areas was ≤7– 

8 ppb (0.4–0.5 μg/m3

). The evaluation included tests for respiratory and cardiovascular functions, 

urinalyses and evaluation of hematology and clinical chemistry parameters. Limitations of the survey 

noted by the investigators included the fact that the number of non-exposed workers was only one third 

that of the exposed workers. Secondly, since payroll records were unavailable prior to 1975, some 

workers classified as non-exposed could have been exposed prior to 1975. Thirdly, since a higher 

percentage of exposed workers were employed before 1975 than non-exposed, and some of the exposed 

workers could have had potentially a long duration of exposure, the maximum effect of any harmful 

exposure should be observed among the exposed workers. These limitations, plus the lack of control for 

confounding, render the study inadequate for MRL derivation. 

Sutton et al. (1960) reported that red blood cell cholinesterase activity was significantly reduced (18%) in 

a small group (n=6) of regular operators in a TPP production plant compared to unexposed subjects. 

They also noted that the variability both within and between individuals was great enough so that the 

small depressions in cholinesterase activity were not sufficient to identify individuals with TPP exposure. 

Health evaluations of this group and of others (the total number of workers examined was not specified) 

conducted over the years did not reveal any unusual frequency of symptoms, or physical or laboratory 

findings as compared to unexposed groups. Sutton et al. (1960) estimated that workers may have been 

exposed to a weighted average concentration of TPP vapor mist and dust of 3.5 mg/m3

. The lack of 

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PHOSPHATE ESTER FLAME RETARDANTS 18 

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information regarding the total number of workers that participated in the health surveys, lack of detailed 

presentation of the results of the surveys, and uncertainty regarding the estimation of exposure levels 

make this report unsuitable for MRL derivation. 

Toxicity information from animal studies available in the literature reviewed was limited to acute highdose experiments aimed primarily at determining lethal concentrations, and is therefore inadequate for 

MRL derivation. 

Oral MRLs 

No studies were located on health effects in humans exposed orally to the phosphate ester flame 

retardants discussed in this profile. Therefore, the discussion of derivation of MRLs for these compounds 

is based purely on results from animal studies. As previously mentioned, the information available from 

oral studies does not support treating these chemicals as a class for purposes of risk assessment based on 

the different toxicities exhibited by each one of them. 

TCEP. An acute-duration oral MRL for TCEP was not derived due to inadequacies of the database. The 

few studies available did not identify a target for TCEP toxicity. The lowest lowest-observed-adverseeffect level (LOAEL) in the studies available was 200 mg TCEP/kg/day for death of 7/30 pregnant Wistar 

rats (0/23 in the control group) in a developmental study in which the rats were exposed to TCEP by 

gavage on gestational days (Gd) 7–15 (Kawashima et al. 1983a). That dose level, however, did not 

produce developmental effects, including neurobehavioral evaluations in the pups. Other information 

available include LD50 data (Eldefrawi et al. 1977; Smyth et al. 1951), data from a developmental study of 

CD-1 mice in which the single dose level tested on Gd 6–13, 940 mg TCEP/kg/day, significantly reduced 

weight gain in the dams between Gd 6 and postnatal day (Pnd) 3, but produced no developmental effects 

in the progeny (Hardin et al. 1987), and a dose-range finding study in which CD-1 mice treated by gavage 

with doses of up to 1,000 mg TCEP/kg/day for 14 days did not show clinical signs or significant 

alterations in body weight or water consumption (NTP 1991b). Adverse neurological effects were 

reported in two studies. Female Fischer-344 rats administered a single gavage dose of 275 mg TCEP/kg 

(only dose level tested) suffered seizures within 60–90 minutes of dosing (Tilson et al. 1990). This 

treatment resulted in mild impairment in the acquisition of a reference memory task in a water maze, and 

in performing a repeated acquisition task in a water maze. In a 16-day gavage study, B6C3F1 mice given 

350 or 700 mg TCEP/kg/day exhibited ataxia and convulsive movements during the first 3 days of dosing 

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PHOSPHATE ESTER FLAME RETARDANTS 19 

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(NTP 1991a). These studies do not identify a clear target for TCEP, and the studies that provide 

information other than lethal doses are unsuitable for dose-response assessments. 

•	 An MRL of 0.6 mg/kg/day was derived for intermediate-duration oral exposure (15–364 days) to 

TCEP based on necrosis of hippocampal neurons in female rats. 

Although a limited number of intermediate-duration oral studies with TCEP were available for review, 

the data were sufficient for derivation of an intermediate-duration oral MRL. NTP (1991a) conducted 

studies in rats and mice administered TCEP by gavage 5 days/week for 16 days or 16 weeks, Anonymous 

(1977) conducted a 3-month dietary study in rats, and NTP (1991b) conducted a reproductive study in 

mice using a continuous breeding protocol; dosing was by daily gavage. The hippocampus from female 

rats was a target for TCEP toxicity in the 16-week gavage study in rats (NTP 1991a). Necrosis of neurons 

of the hippocampus was seen in 10/10 females and in 2/10 males treated with TCEP at 350 mg/kg/day 

and in 8/10 females treated with 175 mg/kg/day; no lesions were seen at ≤88 mg/kg/day. The affected 

neurons were mainly in the dorsomedial portion of the pyramidal row of the hippocampus. The more 

severe lesions showed mineral deposits in the affected areas. Females dosed with 350 mg/kg/day also 

showed neuronal necrosis in the thalamus. No brain lesions were seen in mice treated with up to 700 mg 

TCEP/kg/day for 16 weeks. It is worth noting that the unpublished 3-month dietary study in male and 

female rats administered up to 506 and 586 mg TCEP/kg/day, respectively, does not mention the 

occurrence of brain lesions, but it is unclear in the report available whether the brain was examined 

microscopically (Anonymous 1977). 

In the NTP (1991a) study, treatment of rats and mice with TCEP also produced dose-related increases in 

absolute and relative liver and kidney weight in female rats dosed by gavage for 16 days or 16 weeks, in 

both cases without histological alterations; changes >10% relative to controls were generally achieved in 

the highest-dose groups. Mice dosed by gavage with 700 mg TCEP/kg/day for 16 weeks showed 

enlargement of the nuclei of epithelial cells in the renal tubules. In the absence of histopathology, the 

weight changes in the liver and kidneys from rats in the intermediate-duration studies could be considered 

not adverse; however, results from a chronic-duration study suggest that in the kidneys, but not the liver, a 

progression into more severe effects takes place. Based on the latter observation, the increase in absolute 

kidney weight in rats in the 16-week gavage studies is considered a minimal LOAEL (175 mg/kg/day); 

the corresponding NOAEL is 88 mg/kg/day. 

In the reproductive study using a continuous breeding protocol, mice were dosed by gavage with 0, 175, 

350, or 700 mg TCEP/kg/day (NTP 1991b). Treatment with ≥350 mg TCEP/kg/day significantly 

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PHOSPHATE ESTER FLAME RETARDANTS 20 

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decreased the number of F1 litters produced by the parental generation. Only 2 out of 18 pairs delivered a 

third litter in the high-dose group versus 37/38 in the controls, and 13 out of 18 pairs delivered a fifth 

litter in the mid-dose group. Treatment with TCEP also induced significant and dose-related reductions in 

the number of live pups per litter at ≥350 mg TCEP/kg/day and in the number of live F2 male pups/litter 

at ≥175 mg TCEP/kg/day (dose-related). Based on the effect on F2 pups, a serious developmental 

LOAEL of 175 mg TCEP/kg/day was identified in this study; a developmental NOAEL was not defined. 

Data sets for necrosis of hippocampal neurons and changes in absolute kidney weight in female rats 

reported in the NTP (1991a) study and decreased number of live F2 pups reported in the NTP (1991b) 

study were analyzed using the benchmark dose (BMD) approach to determine the point of departure for 

MRL derivation. Models in the EPA Benchmark Software (BMDS version 2.1) were fit to the three data 

sets. In each data set, adequate model fit is judged by three criteria: goodness-of-fit (p>0.1), visual 

inspection of the dose-response curve, and scaled residual at the data point (except the control) closest to 

the predefined BMR. The data set for changes in absolute kidney weight in female rats in the NTP 

(1991a) proved not suitable for benchmark modeling even after dropping the two highest doses (out of 

five dose levels tested). Of the two data sets remaining, the best fit for the incidence of necrosis in 

hippocampal neurons in female rats (NTP 1991a) was obtained with the log-logistic model (BMD10 

143.41 mg/kg/day; BMDL10 85.07 mg/kg/day), whereas the linear model provided the best fit for the 

decrease in live male F2 pups in the continuous breeding protocol study (BMD10 242.19 mg/kg/day; 

BMDL10 167.83 mg/kg/day) (NTP 1991b). The lower BMDL10 of 85.07 mg/kg/day is more health 

protective and was selected as the point of departure for MRL derivation. Multiplying the BMDL10 of 

85.07 mg/kg/day by 5/7, to adjust for continuous exposure, results in a duration-adjusted BMDL10 of 

60.76 mg/kg/day. Applying an uncertainty factor of 100 (10 for animal to human extrapolation and 10 for 

human variability) to the duration-adjusted BMDL10 of 60.76 mg/kg/day results in an intermediateduration oral MRL of 0.6 mg/kg/day for TCEP. A detailed description of the NTP (1991a) study and of 

the MRL derivation is presented in Appendix A. 

If the changes in absolute kidney weight in female rats in the NTP (1991a) study had been used as a basis 

for MRL derivation using a NOAEL/LOAEL approach, the NOAEL would have been 88 mg 

TCEP/kg/day (<10% increase in kidney weight). The next highest dose, 175 mg/kg/day, induced a 16% 

increase in absolute kidney weight. Applying an uncertainty factor of 100 (10 for animal to human 

extrapolation and 10 for human variability) to the duration-adjusted NOAEL of 62.85 mg/kg/day 

(88 mg/kg/day x 5/7) would have resulted in an MRL of 0.6 mg/kg/day for TCEP, which is identical to 

the MRL based on brain lesions in female rats derived using the BMD approach. 

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PHOSPHATE ESTER FLAME RETARDANTS 21 

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•	 An MRL of 0.3 mg/kg/day was been derived for chronic-duration oral exposure (365 days and 

longer) to TCEP based on renal tubule lesions in female rats. 

The chronic-duration database for TCEP was limited to the NTP (1991a) 2-year bioassay in rats and mice. 

Fischer-344 rats were treated by gavage 5 days/week with 0, 44, or 88 mg TCEP/kg/day and B6C3F1 

mice were dosed similarly with 0, 175, or 350 mg TCEP/kg/day. Animals were monitored for clinical 

signs, body weight gain, hematology and clinical chemistry parameters (week 66 and at termination), and 

gross and microscopic changes in tissues and organs at week 66 and at termination. Nonneoplastic effects 

in mice were limited to an increased incidence of karyomegaly of the cells in the proximal convoluted 

tubules of the inner cortex and outer stripe of the outer medulla at ≥175 mg TCEP/kg/day. In rats, one of 

the principal nonneoplastic alterations attributed to administration of the test chemical was a significant 

increase in renal tubule epithelial hyperplasia in the convoluted tubules of the cortex in high-dose males 

and females; the respective incidences were 0/50, 2/50, and 24/50, and 0/50, 3/50, and 16/50. In addition 

to the kidney lesions, high-dose female rats showed degenerative lesions in the brain. The degenerative 

lesions were located in the cerebral cortex and brain stem, involved both the gray and white matter, and 

were focally distributed. Specifically, the lesions were in the thalamus, hypothalamus, basal ganglia, and 

frontal and parietal cortex. Other affected structures included the cingulate cortex, olfactory cortex, 

superior colliculus, hippocampus, geniculate body, globus pallidus, ventral pallidum, and amygdaloid 

nuclear region. The lesions varied in severity from minimal to marked, and often involved extensive 

areas. Active lesions were characterized by degeneration and necrosis with hemorrhage, while resolving 

lesions exhibited loss of neurons and neuropil, proliferation of glial cells, capillary hyperplasia, 

hypertrophy of the tunica media of small vessels, and hemosiderin-laden macrophages. Brain lesions 

were already observed at the 66-month interim sacrifice. Incidences of lesions in specific areas ranged 

from 24 to 38%. However, the reporting of the data (no individual animal data) in the NTP (1991a) study 

did not allow the determination of whether individual animals had more than one lesion type. The lesion 

with the highest incidence was cerebrum gliosis with an incidence of 19/50 (38%); the incidences in the 

control and low-dose groups were 0/50 and 0/49, respectively. 

The incidences of cerebrum gliosis in female rats and of renal epithelial hyperplasia in both male and 

female rats reported in the NTP (1991a) study were analyzed using the BMD approach for MRL 

derivation. Models in the EPA BMDS (version 2.1) were fit to the three data sets. The best fit for the 

incidence of renal tubule hyperplasia in male rats was obtained with the log-logistic model, which 

identified a BMD10 and BMDL10 of 54.80 and 43.58 mg TCEP/kg/day, respectively. The gamma model 

provided the best fit for the incidence of renal lesions in female rats; a BMD10 and BMDL10 of 53.09 and 

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PHOSPHATE ESTER FLAME RETARDANTS 22 

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36.09 mg TCEP/kg/day, respectively, were identified. The data set for incidences of cerebrum gliosis in 

female rats was best fitted with the log-logistic model, which defined a BMD10 and BMDL10 of 80.04 and 

59.86 mg TCEP/kg/day, respectively. The BMDL10 of 36.09 mg TCEP/kg/day for renal tubular lesions in 

female rats is selected as the point of departure for MRL derivation on the basis of being more health 

protective. The slightly higher BMDL10 obtained with the male rat data set does not seem to indicate that 

female rats are more sensitive than males. Multiplying the BMDL10 of 36.09 mg/kg/day by 5/7, to adjust 

for continuous exposure, results in a duration-adjusted BMDL10 of 25.78 mg/kg/day. Applying an 

uncertainty factor of 100 (10 for animal to human extrapolation and 10 for human variability) to the 

duration-adjusted BMDL10 of 25.78 mg/kg/day yields a chronic-duration oral MRL of 0.3 mg/kg/day for 

TCEP. A detailed description of the NTP (1991a) study and of the MRL derivation can be found in 

Appendix A. 

TnBP 

•	 An MRL of 1.1 mg/kg/day was derived for acute-duration oral exposure (14 days or less) to 

TnBP based on reduced body weight gain in pregnant rats. 

Few acute-duration oral studies were available for review. One study conducted hematological and 

clinical chemistry tests and histological examinations of the brain, heart, kidneys, liver, lungs, spleen, 

ovaries, and testes from Sprague-Dawley rats following a 14-day gavage regime with 0, 137, or 411 mg 

TnBP/kg/day (Laham et al. 1984b). Significant findings in high-dose rats included decreased hemoglobin 

in females, increased absolute and relative liver weight in males and females, increased serum potassium 

in females, decreased absolute and relative spleen weight, and degenerative changes in the testes. 

Decreased nerve conduction velocity accompanied by morphological alterations in the sciatic nerve was 

also reported in Sprague-Dawley rats dosed with 411 mg TnBP/kg/day for 14 days; the NOAEL was 

274 mg TnBP/kg/day (Laham et al. 1983). In a developmental study, pregnant Wistar rats were exposed 

to 0, 62.5, 125, 250, or 500 mg TnBP/kg/day on Gd 7–17; sacrifices were conducted on Gd 20 (Noda et 

al. 1994). Rats exposed to 500 mg/kg/day showed piloerection, wetting of abdominal hair with urine, and 

salivation during the treatment, but these signs disappeared after the last treatment. Final maternal weight 

was reduced 6–9% in the two highest dose groups. Adjusted body weight gain (body weight gain minus 

gravid uterus weight) from Gd 0 to 20 was reduced 13% at 125 mg/kg/day, 39% at 250 mg/kg/day, and 

63% at 500 mg/kg/day. Food consumption was also reduced starting on Gd 7. Liver weight was 

increased 6% at 500 mg/kg/day and kidney weight was not significantly affected. Spleen weight was 

reduced 11% at 500 mg/kg/day. Gravid uterus weight was not affected. All pregnant rats had living 

fetuses on Gd 20. There was no significant difference between the groups in the number of corpora lutea, 

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PHOSPHATE ESTER FLAME RETARDANTS 23 

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implants or living fetuses, incidence of dead or resorbed fetuses, sex ratio, or body weight of the living 

fetuses. There was only one malformation that occurred in the groups exposed to 125 mg/kg/day in 

which there were conjoined twins. No visceral anomalies attributed to treatment with TnBP were 

reported. Based on a significant reduction in maternal body weight gain at ≥125 mg/kg/day, a maternal 

NOAEL and LOAEL of 62.5 and 125 mg/kg/day, respectively, were defined in this study; the highest 

dose tested, 500 mg/kg/day, was a developmental NOAEL. Since the Noda et al. (1994) study identified 

the most sensitive end point, it was selected as the principal study for the derivation of an acute-duration 

oral MRL for TnBP. 

Data from Noda et al. (1994) were analyzed using the BMD approach for MRL derivation. BMD models 

in the EPA BMDS (version 2.1) (linear, polynomial, power, and Hill models) were fit to the maternal 

body weight gain data to determine potential points of departure for the MRL (details of the modeling are 

presented in Appendix A). In the absence of a clear criteria as to what level of change in weight gain 

during pregnancy should be considered adverse, the benchmark response (BMR) was defined as a change 

in mean body weight gain equal to one standard deviation from the control mean (EPA 2000). The linear 

model provided the best fit. The corresponding BMD1SD was 130.32 mg/kg/day; the corresponding 

BMDL1SD was 111.47 mg/kg/day. Applying an uncertainty factor of 100 (10 for animal to human 

extrapolation and 10 for human variability) to the BMDL1SD results in an acute-duration oral MRL of 

1.1 mg/kg/day for TnBP. 

•	 An MRL of 0.02 mg/kg/day was derived for intermediate-duration oral exposure (15–364 days) 

to TnBP based on urinary bladder lesions in male rats. 

Intermediate-duration oral studies with TnBP identified the urinary bladder as the most sensitive target for 

TnBP toxicity. Increased incidence of urothelial hyperplasia was reported in male Sprague-Dawley rats 

(females not tested) dosed via the diet with approximately 33 mg TnBP/kg/day for 10 weeks (Arnold et 

al. 1997), male Sprague-Dawley rats dosed with 68.1 mg TnBP/kg/day in the diet for 90 days (FMC 

1985a), and in male and female F0 and F1 Sprague-Dawley rats dosed with 51 mg TnBP/kg/day in the diet 

for 10 weeks in a 2-generation reproductive study (Tyl et al. 1997). The NOAELs were in the range of 9– 

15 mg TnBP/kg/day. An additional study that also reported urothelial hyperplasia in rats used somewhat 

higher doses (200, or 333 mg/kg/day for 18 weeks) (Laham et al. 1985a). Mice appeared to be less 

sensitive than rats as evidenced by a NOAEL and LOAEL of 95 and 382 mg/kg/day, respectively, for 

urinary bladder hyperplasia in male mice (Auletta 1991). Arnold et al. (1997) also demonstrated that 

hyperplastic effects were reversible upon cessation of treatment and that acidification of the urine with 

ammonium chloride did not completely inhibit the proliferative changes, but the hyperplastic changes 

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PHOSPHATE ESTER FLAME RETARDANTS 24 

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were milder when TnBP was coadministered with ammonium chloride. Also consistently reported in 

intermediate-duration oral studies with TnBP were increases in liver weight, generally with histological 

alterations observed only at the highest dose levels (FMC 1985a; Laham et al. 1985a; Oishi et al. 1982; 

Tyl et al. 1997). In a 2-generation reproductive study in rats dosed through the diet with up to 217 mg 

TnBP/kg/day, fertility indices were not significantly affected, but that dose level significantly decreased 

F1 and F2 pup weight during the preweaning periods (Tyl et al. 1997). In a 13-week gavage study, 

excessive salivation occurred frequently in rats after dosing with 100 mg TnBP/kg/day, and almost all the 

time in rats dosed with 325 mg TnBP/kg/day (Healy et al. 1995). In that study, neither motor activity nor 

functional observational battery (FOB) results obtained during the study were affected by treatment with 

up to 325 mg TnBP/kg/day. In addition, histological evaluations of unspecified nervous tissues were 

unremarkable (Healy et al. 1995). 

As indicated above, urothelial hyperplasia was the most sensitive end point in the intermediate-duration 

studies with TnBP and will serve as the basis for the derivation of an intermediate-duration oral MRL for 

TnBP. Of the four studies that described the lesion in rats, only the studies by Arnold et al. (1997), FMC 

(1985a), and Tyl et al. (1997) are considered for further analysis on the basis that they identified a 

NOAEL; the lowest dose used by Laham et al. (1985a) induced hyperplasia in 100% of the rats. The data 

are summarized in Table 2-1, which also includes the data set from the 2-year study of Auletta et al. 

(1998a). The data set from Tyl et al. (1997) corresponds to incidences in the parental generation (F0). 

Incidences in F1 females were virtually the same as in F0 females, whereas incidences in mid-dose 

F1 males were slightly lower than in F0 males. 

Incidence data for urothelial hyperplasia in male rats from the Arnold et al. (1997) study, for urothelial 

hyperplasia in F0 males and females from the Tyl et al. (1997), and for urothelial hyperplasia in male rats 

from the FMC (1985a) study were analyzed using the BMD approach for MRL derivation (further details 

of the modeling are presented in Appendix A). Models in the EPA Benchmark Dose Software (BMDS 

version 2.1) (gamma, logistic, log-logistic, multi-stage, probit, log-probit, quantal linear, Weibull models) 

were fit to urothelial hyperplasia data to determine potential points of departure for the MRL. Comparing 

across data sets, and using the established criteria for model selection, the BMDL10 of 1.96 mg/kg/day 

obtained with the Multistage model for the incidence data reported by Arnold et al. (1997) is selected as 

point of departure for the MRL. Applying an uncertainty factor of 100 (10 for animal to human 

extrapolation and 10 for human variability) to the BMDL10 yields an intermediate-duration oral MRL of 

0.02 mg/kg/day for TnBP. 

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PHOSPHATE ESTER FLAME RETARDANTS 25 

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Table 2-1. Incidence of Urinary Bladder Hyperplasia Induced by Tributyl 

Phosphate in Four Studies in Rats
 

NOAEL LOAEL BMDL10 

Arnold et al. (1997)–10 weeks 

Dose (mg/kg/day) 0 9 33 143 1.96 

Incidence 0/10 0/10 8/10 10/10 

FMC (1985a)–13 weeks 

Dose (mg/kg/day) 012 0.6 2.8 13.8 68.1 360 

Males 0/10 0/10 0/10 0/10 10/10 10/10 2.60 

Tyl et al. (1997)–10 weeks 

Dose (mg/kg/day) 0 15 51 217 

Males 0/30 1/29 22/29 30/30 13.77 

Females 0/30 2/29 21/30 30/30 10.50 

Auletta et al. (1998a)–2 years 

Dose (mg/kg/day) 0 9 33 143 

Males 3/50 3/50 12/49 17/49 23.51 

Females 1/50 1/50 5/49 29/49 19.85 

BMDL10 = The 95% lower confidence limit on the dose associated with a 10% extra risk; LOAEL = lowest-observedadverse-effect level; NOAEL = no-observed-adverse-effect level 

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PHOSPHATE ESTER FLAME RETARDANTS 26 

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•	 The intermediate-duration oral MRL of 0.02 mg/kg/day for TnBP was adopted as chronicduration (365 days or longer) oral MRL for TnBP. 

Only two chronic-duration oral studies were located for TnBP, one in Sprague-Dawley rats (Auletta et al. 

1998a) and one in CD-1mice (Auletta et al. 1998b). As in the intermediate-duration studies, the urinary 

bladder from rats was the most sensitive target for TnBP toxicity. Rats were dosed via the diet for 

2 years, whereas mice were treated for 18 months. Male rats received doses of 0, 9, 33, or 143 mg 

TnBP/kg/day, whereas females received doses of 0, 12, 42, or 182 mg TnBP/kg/day. The doses for male 

and female mice were 0, 28.9, 169, or 585 mg/kg/day and 0, 24.1, 206, or 711 mg/kg/day, respectively. 

At termination, the incidences of trace to severe urinary bladder hyperplasia in male rats were 3/50, 3/50, 

12/49, and 17/49 with increasing doses. The corresponding incidences in female rats were 1/50, 1/50, 

5/49, and 29/49. Urinary bladder hyperplasia was not observed in mice. Based on these findings, the 

increased incidence of urothelial hyperplasia in rats was used to determine the point of departure for 

derivation of a chronic-duration oral MRL for TnBP. 

Incidence data for urinary bladder hyperplasia in male and female rats exposed to TnBP (Auletta et al. 

1998a) were analyzed using the BMD approach for MRL derivation. Models in the EPA BMDS 

(version 2.1) (gamma, logistic, log-logistic, multi-stage, probit, log-probit, quantal linear, Weibull 

models) were fit to the urinary bladder lesion data to determine potential points of departure for the MRL. 

Comparing across models showed that the Gamma model provided the best fit for the incidence data in 

male rats, whereas the Multistage 1-degree polynomial provided the best fit for the incidence data in 

female rats. This analysis yielded respective BMDL10 values of 23.51 and 19.85 mg TnBP/kg/day. As 

seen in Table 2-1, these values are higher than the BMDL10 values obtained in the analyses of the 

incidences of urinary bladder hyperplasia reported in the intermediate-duration studies (Arnold et al. 

1997; Tyl et al. 1997). As the data show, the incidences of urinary bladder hyperplasia at comparable 

high doses are higher in the intermediate-duration studies than in the chronic-duration study. A likely 

explanation for this phenomenon is provided in the chronic study by the observation that rats with 

malignant bladder tumors usually did not have any remaining uninvolved epithelium to evaluate for the 

presence or absence of hyperplasia (Auletta et al. 1998a). Whether urinary bladder hyperplasia is a 

potential precursor of urinary bladder tumors is not known for certain, but the data are suggestive. The 

lower incidence of the lesion in the chronic-duration study may be indicating that the hyperplasia 

transformed into neoplasia. As shown in Table 2-1, dose levels that did not increase the incidence of 

urothelial hyperplasia in the intermediate-duration studies (NOAELs ranged from 9 to 15 mg/kg/day) also 

did not increase the incidence of urinary bladder hyperplasia in the chronic-duration study (NOAEL was 

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PHOSPHATE ESTER FLAME RETARDANTS 27 

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9 mg/kg/day) and did not increase the incidence of neoplastic lesions; thus, the NOAEL from 

intermediate-duration studies would also be protective for chronic exposure. Therefore the intermediateduration oral MRL of 0.02 mg/kg/day based on a BMDL10 of 1.96 mg/kg/day is adopted also as chronicduration oral MRL for TnBP. 

TBEP 

•	 An MRL of 4.8 mg/kg/day was derived for acute-duration oral exposure (14 days or less) to 

TBEP based on reduced body weight gain in pregnant rats. 

Three acute-duration oral studies were located in the literature reviewed. In a gestational exposure study 

rats were administered 0, 250, 500, or 1,500 mg TBEP/kg/day on Gd 6–15 (Monsanto Co. 1985b). The 

highest dose tested induced overt toxicity in the dams, including wet haircoat matting or staining with 

urine, and brown material or blood on the face, neck, thorax, and/or anogenital area; this was observed in 

approximately half of the high-dose rats. Following dosing on Gd 6, two high-dose rats were ataxic, had 

reduced righting reflex, and/or were lethargic. Terminal body weight of high-dose dams (unadjusted for 

uterine content) was significantly reduced, but only by 6% relative to controls. In high-dose dams, weight 

gain was significantly reduced from Gd 6 on, and during treatment (Gd 6–15), weight gain was reduced 

35%. Food consumption data were not provided. The maternal NOAEL in the study was 500 mg/kg/day 

and the developmental NOAEL was 1,500 mg/kg/day based on no evidence of fetotoxicity or 

teratogenicity. A single gavage dose study in Sprague-Dawley rats measured caudal nerve conduction 

velocity 3 weeks following exposure and also performed microscopic examination of the sciatic nerve 

(Laham et al. 1985b). During the week after dosing, females dosed with ≥1,750 mg/kg showed slight 

tremors and piloerection, whereas those treated with 3,200 mg/kg exhibited tremors and abnormal gait; 

males appeared to be somewhat less sensitive. Examination of the sciatic nerve showed nerve 

degeneration in females dosed with ≥2,000 mg/kg. The NOAEL for males and females was 3,200 and 

1,500 mg/kg, respectively. In an additional acute-duration study, Sprague-Dawley rats (10/sex/dose) 

were treated with up to 100 mg TBEP/kg/day by gavage in corn oil for 14 days (Komsta et al. 1989). End 

points monitored included clinical signs, body weight, hematology and clinical chemistry at termination, 

organ weights (brain, heart, liver, kidneys, and spleen), microsomal liver enzyme activities, and gross and 

microscopic morphology of all major tissues and organs. The results did not show any significant 

differences between the treated and control groups for any of the parameters evaluated. However, 

because no adverse effects were reported, the Komsta et al. (1989) study is not a suitable basis for an 

MRL. The developmental study is a well-conducted study and the maternal changes in weight gain 

during the treatment period were used to determine the point of departure for MRL derivation. 

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PHOSPHATE ESTER FLAME RETARDANTS 28 

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Data from Monsanto Co. (1985b) were analyzed using the BMD approach for MRL derivation. BMD 

models in the EPA BMDS (version 2.1) (linear, polynomial, power, and Hill models) were fit to the 

maternal body weight gain data to determine potential points of departure for the MRL. The multistage 

3-degree polynomial model provided the best fit (details of the modeling are presented in Appendix A). 

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

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

deviation from the control mean (EPA 2000). The corresponding BMD1SD was 824.97 mg/kg/day; the 

corresponding BMDL1SD was 477.25 mg/kg/day. Applying an uncertainty factor of 100 (10 for animal to 

human extrapolation and 10 for human variability) to the BMDL1SD results in an acute-duration oral MRL 

of 4.8 mg/kg/day for TBEP. 

•	 An MRL of 0.2 mg/kg/day was derived for intermediate-duration oral exposure (15–365 days) to 

TBEP based on hepatocyte hypertrophy in male rats. 

Only one intermediate-duration oral study was located for TBEP. In that study, groups of SpragueDawley rats (20/sex/group) were fed a diet containing 0, 300, 3,000, or 10,000 ppm TBEP for 

approximately 18 weeks (Reyna and Thacke 1987a). This corresponds to doses of approximately 0, 17.3, 

173, or 578 mg/kg/day for males and 0, 21, 209, or 698 for females using food intake and body weight 

data from the study. End points monitored included clinical signs, body weight, food consumption, 

clinical chemistry and hematology (weeks 9 and 18), organ weights (brain, liver, kidneys, testes with 

epididymides), and gross and microscopic examination of all the major organs and tissues of controls and 

high-dose rats plus target tissues defined by the high-dose group and gross lesions from all necropsied 

animals. A detailed description of the study is provided in Appendix A. There were no treatment-related 

mortalities or adverse clinical signs throughout the study. Body weight was not significantly affected by 

treatment with the TBEP. Food consumption was lower in high-dose males and females and mid-dose 

males during the first week of the study, but was comparable to controls for the remainder of the study. 

The most sensitive organ was the liver. Absolute and relative liver weight was increased in high-dose 

males and females, but not significantly. Histopathology was restricted to the liver of males and consisted 

of increased incidence of periportal hepatocellular hypertrophy (0/10, 0/10, 3/10, 7/10 with increasing 

TBEP doses) and periportal vacuolization (1/10, 2/10, 6/10, 7/10). In the same study, although presented 

separately, the investigators measured tail nerve conduction velocity at the end of the treatment period 

(Reyna and Thacke 1987b). Following these measurements, the sciatic, tibial, and plantar nerves were 

processed for light microscopy. A significant reduction in nerve conduction velocity was measured only 

in high-dose females. Since both the absolute and relative refractory periods were decreased (the opposite 

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PHOSPHATE ESTER FLAME RETARDANTS 29 

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of what would be expected in the case of a reduction in conduction velocity), the effect was not seen in 

males, and morphology of the nerves was unremarkable, the decrease in conduction velocity in females 

appeared questionable. 

Although the increased incidences of periportal hepatocyte hypertrophy and vacuolization may represent 

adaptive responses of the cell and not necessarily an adverse effect, the lack of chronic data makes it 

impossible to predict whether these changes may progress into more severe lesions under a longer 

exposure regime. Incidence data for periportal hepatocyte hypertrophy and vacuolization in male rats 

exposed to TBEP (Reyna and Thacke 1987a) were analyzed using the BMD approach for MRL derivation 

(further details of the modeling are presented in Appendix A). Models in the EPA BMDS (version 2.1) 

(gamma, logistic, log-logistic, multi-stage, probit, log-probit, quantal linear, Weibull models) were fit to 

the hepatocyte hypertrophy and hepatocyte vacuolization reported in male rats to determine the point of 

departure for the MRL. Comparing across models using using established criteria for model selection, the 

best fit for the hepatocyte hypertrophy data was provided by the Log logistic model; the BMD10 and 

BMDL10 were 80.62 and 21.92 mg TBEP/kg/day, respectively. The best fit for the incidence of 

hepatocyte vacuolization was provided by the Log logistic model, which estimated a BMD10 and BMDL10 

of 22.02 and 8.88 mg TBEP/kg/day, respectively. Since hypertrophy is a more valid physiological end 

point than vacuolization, the BMDL10 of 21.92 mg/kg/day is selected as the point of departure for the 

intermediate-duration MRL. Applying an uncertainty factor of 100 (10 for animal to human extrapolation 

and 10 for human variability) to the BMDL10 results in an intermediate-duration oral MRL of 

0.2 mg/kg/day for TBEP. 

No chronic-duration oral studies with TBEP were located; therefore, a chronic-duration oral MRL was 

not derived for this compound. 

TDCP. An acute-duration oral MRL was not derived for TDCP due to an insufficient database. Other 

than lethal dose studies, only one study, a developmental study in rats, was available for review for TDCP 

(Stauffer Chemical Co. 1981b). Pregnant rats were treated by gavage with 0, 25, 100, or 400 mg 

TDCP/kg/day on Gd 6–15; sacrifices were conducted on Gd 19. Compound-related clinical signs were 

observed during treatment mainly in the high-dose group consisting of urine stains, hunched appearance, 

and salivation in almost all rats in this group, and alopecia in approximately half of the rats in the group. 

Final body weight of the high-dose group was significantly lower (16%) than in controls. During Gd 6– 

11, body weight gain of the mid-dose group was approximately 29% lower than controls and rats in the 

high-dose group lost weight. During the posttreatment days, weight gain was comparable among all 

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PHOSPHATE ESTER FLAME RETARDANTS 30 

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groups. Food consumption during treatment days was significantly lower in the mid- and high-dose rats, 

but posttreatment values were comparable among groups. There was no significant effect on the numbers 

of corpora lutea or implantations. A statistically higher incidence of resorptions was found in high-dose 

rats, but the number per litter was not significantly affected. Fetal viability was significantly decreased in 

high-dose rats. Mean fetal weight and length were significantly lower in high-dose rats. Decreased 

skeletal development (incomplete ossification of various bones) was noted in high-dose fetuses. This 

single study gives a very limited picture regarding the acute toxicity of TDCP since it provides virtually 

no information on maternal effects other than body weight changes. Acute-duration oral MRLs were 

derived for TnBP and TBEP based on effects on maternal body weight in gestational exposure studies 

(Monsanto Co. 1985b; Noda et al. 1994), but in both cases, there was additional information regarding the 

chemical from studies that evaluated gross and microscopic morphology of a number of organs and 

tissues and conducted hematological and clinical chemistry tests (Komsta et al. 1989; Laham et al. 

1984b). 

•	 An MRL of 0.05 mg/kg/day has been derived for intermediate-duration oral exposure (15– 

364 days) to TDCP based on increased absolute kidney weight in male rats. 

Limited intermediate-duration studies were available. In a study in male rabbits, the animals were 

administered doses of 0, 2, 20, or 200 mg TDCP/kg/day by gavage for 12 weeks (Anonymous 1977). 

During the last week of treatment, male fertility was tested by mating the males with untreated females. 

Fertility was assessed by sacrificing the females at mid-gestation and evaluating their uteri. After the 

mating period, the males were sacrificed and sperm from the cauda epididymides were analyzed for 

motility, morphology, and concentration. Blood was also collected for hematology and clinical chemistry 

tests. The pituitary, liver, kidneys, and reproductive tract were processed for microscopic examination. 

The treatment-related effects appeared to be a significant increase in relative liver weight (23%) and in 

absolute kidney weight (14%). Neither gross necropsy nor microscopic examinations revealed significant 

alterations in the organs examined. The fact that only a small number of organs were examined and no 

adverse effects were reported other than possibly minimal LOAELs for changes in liver and kidney 

weights, and the lack of information in female animals, limit the usefulness of the study for risk 

assessment. In the 2-year bioassay in rats conducted by Stauffer Chemical Co. (1981a), hematology and 

clinical chemistry tests, as well as urine analyses were conducted after 3 and 6 months of treatment; 

however, no gross or microscopic examination of the tissues was conducted at these times. Body weights 

were reduced in males and females 5–7% relative to controls at the 3- and 6-month time points. Body 

weight was reduced 12% in high-dose males on week 50. Hematology tests showed significant 

reductions in hemoglobin and hematocrit in high-dose males both at 3 and 6 months and of hemoglobin in 

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PHOSPHATE ESTER FLAME RETARDANTS 31 

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females at 6 months. High-dose males also showed a reduction in red blood cell count at 6 months. At 

12 months, there were significant reductions in hemoglobin in high-dose males (10.6%) and females 

(7.5%) and in red cell counts in high-dose males (10.7%). None of these alterations were observed after 

24 months of treatment with TDCP. Prothrombin times and partial thromboplastin times showed 

considerable variability from interval to interval and no consistent pattern of differences between treated 

and control rats were apparent during the study. Serum alkaline phosphatase levels were lower than 

controls in high-dose rats both at the 3- and 6-month intervals. Blood urea nitrogen (BUN) values in 

treated rats were not significantly different than in controls. Other clinical chemistry tests showed no 

consistent dose-related differences between controls and treated rats that could be attributed to treatment 

with TDCP. The most significant observations at 12 months were dose-related increases in absolute 

kidney and liver weights which achieved significance at the highest dose level; these changes in organ 

weights were not accompanied by histopathology. Changes in kidney weight were more marked than 

those in liver weight, 48% increase in high-dose males and 39% increase in high-dose females relative to 

controls. At the lowest dose, kidney weight was increased 12% in males relative to controls. In mid-dose 

males, absolute thyroid and liver weight were increased by 14 and 12%, respectively; the corresponding 

increases in high-dose males were 25 and 26%. Since the kidney was the most sensitive end point in rats 

exposed to TDCP for 24 months in the same study, it would appear that the increase in kidney weight 

observed at 12 months is a continuum of the same spectrum of health effects used to derive the chronicduration MRL (see below) and may in fact be a precursor to the renal tubule hyperplasia seen in rats 

exposed to TDCP for 24 months. Since the hematological changes observed during the first year of the 

study are of questionable toxicological significance, it is appropriate to use the changes in absolute kidney 

weight at the 12-month time point as the basis for derivation of an intermediate-duration oral MRL for 

TDCP. 

Although ATSDR typically defines intermediate duration to be from 15 to 364 days, using a 1-year 

(365 days) study, which is 1 day longer, is not a significantly different time frame. In addition, using a 

365-day end point is protective of intermediate-duration exposure. 

Data from Stauffer Chemical Co. (1981a) were analyzed using the BMD approach for MRL derivation. 

BMD models in the EPA BMDS (version 2.1) (linear, polynomial, power, and Hill models) were fit to the 

absolute kidney weight male and female datasets to determine potential points of departure for the MRL. 

In the absence of a clear criteria as to what level of change in kidney weight should be considered 

adverse, the BMR was defined as a change in mean kidney weight equal to one standard deviation from 

the control mean (EPA 2000). Based on the criteria for model selection, the Hill model provided the best 

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PHOSPHATE ESTER FLAME RETARDANTS 32 

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fit for the male data set, whereas the Linear model provided the best fit for the female data set. The 

corresponding BMDL1SD values were 4.69 and 13.49 mg/kg/day. In order to be health protective, the 

male BMDL1SD of 4.69 mg/kg/day is preferred as point of departure over the female BMDL1SD of 

13.49 mg/kg/day. Applying an uncertainty factor of 100 (10 for animal to human extrapolation and 10 for 

human variability) to the BMDL1SD of 4.69 mg/kg/day yields an intermediate-duration oral MRL of 

0.05 mg/kg/day for TDCP. Details of the modeling are presented in Appendix A. 

•	 An MRL of 0.02 mg/kg/day has been derived for chronic-duration oral exposure (365 days and 

longer) to TDCP based on renal tubule hyperplasia in male rats. 

A chronic-duration study with TDCP was available for review. In that study, groups of male and female 

Sprague-Dawley rats (60/sex/dose) were fed a diet that provided 0, 5, 20, or 80 mg TDCP/kg/day for 

24 months (Stauffer Chemical Co. 1981a). End points monitored included lethality, clinical signs, body 

weight, food consumption, hematology, clinical chemistry and urinalysis (periodically throughout the 

study), gross necropsy, and histopathology at termination and at 12 months (10 rats/sex/dose). The most 

sensitive organs affected by treatment with TDCP appeared to be the liver and kidneys. At termination, 

gross observations revealed masses, nodules, and raised areas in the liver of high-dose rats; enlargement 

of the kidney in mid- and high-dose males and high-dose females plus higher incidence of discolorations, 

surface irregularities, masses, nodules, and cysts in treated rats than in controls; and higher incidence of 

small seminal vesicles and testicular enlargement, masses, nodules, flaccidity, and discolorations in midand high-dose males. Nonneoplastic lesions that were significantly increased in treated rats were 

foci/areas of hepatocellular alterations (high-dose males and females), dilation of liver sinusoids (highdose males and females), hyperplasia of convoluted tubular epithelium of the kidney (high-dose males 

and females, mid-dose males), and chronic nephropathy (high-dose males and females). None of these 

alterations were seen at the 12-month interim sacrifice. Hyperplasia of the renal convoluted tubular 

epithelium was the most sensitive effect and occurred with incidences of 2/45, 10/49, 28/48, and 24/46 in 

males as the doses increased; the corresponding incidences in females were 0/49, 1/48, 3/48, and 22/50. 

Based on the incidences of the lesion in males, a LOAEL of 20 mg TDCP/kg/day was defined; the 

NOAEL was 5 mg/kg/day. Examination of these incidences shows that males were clearly more sensitive 

than females. Therefore, the data set for hyperplasia of the renal convoluted tubular epithelium in males 

served as the basis for determining the point of departure for MRL derivation. A detailed description of 

the study and modeling of the data is provided in Appendix A. 

Incidence data for renal tubule epithelial hyperplasia in male rats exposed to TDCP (Stauffer Chemical 

Co. 1981a) were analyzed using the BMD approach for MRL derivation. Models in the EPA BMDS 

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PHOSPHATE ESTER FLAME RETARDANTS 33 

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(version 2.1) (gamma, logistic, log-logistic, multi-stage, probit, log-probit, quantal linear, Weibull 

models) were fit to the renal tubular epithelial hyperplasia data in male rats to determine potential points 

of departure for the MRL. Since an adequate fit to the data set could not be obtained with any of the 

models, the high-dose was dropped, in accordance with EPA (2000) guidance. Comparing across models, 

the Multistage 1-degree polynomial model provided the best fit to the renal epithelial hyperplasia data 

after dropping the highest dose. From this model, the predicted dose associated with a 10% extra risk 

(BMD10) was 2.60 mg TDCP/kg/day; the lower 95% confidence limit on this dose (BMDL10) was 

1.94 mg TDCP/kg/day. Applying an uncertainty factor of 100 (10 for animal to human extrapolation and 

10 for human variability) to the BMDL10 of 1.94 mg/kg/day yields a chronic-duration oral MRL of 

0.02 mg/kg/day for TDCP. 

TPP. No MRLs were derived for TPP due to inadequacies of the database available for review; 

specifically, no toxicity was reported. Information regarding acute exposure to TPP was limited to lethal 

dose studies aimed mainly at determining LD50 values. Information regarding intermediate-duration 

exposure was limited to an early study by Sutton et al. (1960) who treated rats with up to 416 mg 

TPP/kg/day via the diet for 35 days and reported no hematological effects or alterations in body weight or 

in the weight of the liver and kidneys; no further end points were evaluated. In a 4-month dietary study, 

doses of 345 mg TPP/kg/day reduced weight gain of rats by 11%, but doses of up to 711 mg TPP/kg/day 

had no significant effect on the results of a battery of behavioral tests administered at monthly intervals 

during treatment (Sobotka et al. 1986). In a study in which male and female rats received doses of up to 

690 mg TPP/kg/day for 90 days before mating and during gestation, there were no significant effects on 

reproductive parameters or on fetal parameters assessed on Gd 20 (Welsh et al. 1987). Indices of 

immunocompetence, including the humoral response to immunization with SRBC were also not 

significantly affected in rats exposed to up to 711 mg TPP/kg/day for 120 days (Hinton et al. 1996). No 

chronic-duration studies with TPP were located in the literature available for review. 

TiBP. No MRLs were derived for TiBP due to lack of adequate information. Only one study with TiBP 

was available for review. In that study, male and female rats received doses of up to 346 and 404 mg 

TiBP/kg/day, respectively, for 13 weeks in the diet (Naylor and Ribelin 1990). End points evaluated 

included clinical signs, body weight, food consumption, hematology and clinical chemistry, selected 

organ weights, and gross and microscopic evaluation of all major organs and tissues. The only reported 

effects were a statistically significant decrease in neutrophil count in high-dose males and an increase in 

mean corpuscular hemoglobin (MCH) in high-dose males and in mean corpuscular hemoglobin 

concentration (MCHC) in mid- (68 mg/kg/day) and high-dose males. Clinical chemistry tests also 

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PHOSPHATE ESTER FLAME RETARDANTS 34 

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showed a statistically significant increase in serum cholesterol in high-dose males. In the absence of any 

other significant alterations, the toxicological significance of the reported effects is unknown and not 

suitable for MRL derivation. 

TCPP. No MRLs were derived for TCPP due to lack of adequate information. Only one study was 

available for review (Kawasaki et al. 1982). That study determined a 96-hour LD50 of 1,500 mg TCPP/kg 

in female rats and reported that exposure to up to 1,000 mg TCPP/kg/day by gavage for 7 days had no 

significant effect on the relative weights of the brain, heart, lungs, liver, spleen, kidneys, or adrenals. In 

another experiment, exposure of pregnant rats to up to 893 mg TCPP/kg/day by gavage on Gd 0–20, 

followed by sacrifice on Gd 20, did not result in fetotoxicity or teratogenicity. Some dams were allowed 

to give birth and their offspring were monitored for 4 weeks after weaning. Neonatal growth and viability 

during this period was comparable among groups. The information available is not suitable for MRL 

derivation. 

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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 phosphate ester 

flame retardants. It contains descriptions and evaluations of toxicological studies and epidemiological 

investigations and provides conclusions, where possible, on the relevance of toxicity and toxicokinetic 

data to public health. 

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

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 

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

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

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

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

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

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

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

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

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

or death). "Less serious" effects are those that are not expected to produce 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 

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PHOSPHATE ESTER FLAME RETARDANTS 36 

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

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

effects to human health. 

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

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

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

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

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

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

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

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

This profile discusses the following phosphate ester flame retardants: tris(2-chloroethyl) phosphate 

(TCEP), tributyl phosphate (TnBP), tris(2-butoxyethyl) phosphate (TBEP), tris(1,3-dichloro-2-propyl) 

phosphate (TDCP), triphenyl phosphate (TPP), tris(2-chloroisopropyl) phosphate (TCPP), and triisobutyl 

phosphate (TiBP). 

Although the industrial properties of the selected phosphate ester flame retardants have been known for 

many decades, there is relatively little information on their adverse health effects in the peer-review 

literature. In contrast, a significant amount of studies performed or sponsored by industry remain 

unpublished, although many of them can be obtained from the EPA. ATSDR has made an effort to 

include all of the relevant information in this profile for the chemicals mentioned above. However, it is 

important to note that the quality of the microfiche that contain the unpublished studies varied greatly; 

some are unreadable and others could not be used due to being “sanitized” by the manufacturer, thus 

making it impossible to determine the identity of the chemical being tested. 

3.2.1 Inhalation Exposure 

No studies were located regarding adverse health effects in the general population due to inhalation 

exposure to the subject phosphate ester flame retardants of this profile and very limited information was 

located regarding people occupationally exposed to these substances. 

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PHOSPHATE ESTER FLAME RETARDANTS 37 

3. HEALTH EFFECTS 

Data in animals were limited to brief summaries of exposures to high concentrations of the chemicals 

(vapors, aerosols, dusts) aimed primarily to estimate lethal concentrations. Therefore, only this 

information is presented in Section 3.2.1. 

3.2.1.1 Death 

No reports of death in humans following inhalation exposure to the subject phosphate ester flame 

retardants were located in the literature reviewed. See Section 3.2.1.7, Cancer, for information regarding 

cancer mortality among workers exposed to TDCP. 

An LC50 of >5,000 mg/m3 was estimated in rats exposed for 4 hours to an aerosol of TCEP (Anonymous 

1977). All rats survived through the exposure and the observation period of 14 days, and gross necropsy 

did not reveal compound-related effects. FMC (1976) reported that the lowest LC50 following a 1-hour 

exposure of rats to vapors of TnBP was 28,000 mg/m3

. Studies conducted by Eastman Kodak Co. (1968) 

reported that one out of three rats died following exposure to TnBP at a concentration of 41,382 mg/m3

; 

no deaths or clinical signs of toxicity occurred at 10.89 mg/m3

. MacKellar (1976) reported an LC50 of 

<200,000 mg/m3 for TnBP in rats, as exposure to 200,000 mg/m3 of TnBP killed 100% of the rats. 

An LC50 of >9,800 mg/m3 was reported for rats exposed for 1 hour to an aerosol of TDCP (Stauffer 

Chemical Co. 1981b). All rats survived through the exposure and 14-day observation period, and gross 

necropsy did not reveal compound-related effects. Exposure of rats for 4 hours to an aerosol of TBEP at a 

nominal concentration of 5,000 mg/m3 resulted in the death of 4/5 males and 3/3 females at the end of a 

14-day observation period (Mobil Oil Corporation 1981). Clinical signs of toxicity included lethargy, 

brown discharge from the mouth, and labored breathing. 

An LC50 >200,000 mg/m3 was described for TPP in rats in a summary of an acute inhalation study (FMC 

1982). Rats were exposed for 1 hour to dusts of TPP and were observed for 14 days. All rats survived 

through the exposure and observation period, and gross necropsy did not reveal compound-related effects. 

Exposure of rats to up to 83,350 mg/m3 of vapors of TiBP for 6 hours induced gasping; prostration; 

yellow hair, ears, and feet; and red eyes during exposure, but no deaths occurred (Eastman Kodak Co. 

1990). However, all rats exposed to this concentration died 48 hours following the exposure. 

Additional information regarding LC50 values and lethal concentrations of the selected phosphate ester 

flame retardants can be found in IPCS (1991a, 1991b, 1998, 2000b). 

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PHOSPHATE ESTER FLAME RETARDANTS 38 

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Lethal exposure concentrations and LC50 values are presented in Table 3-1 and plotted in Figure 3-1. 

3.2.1.2 Systemic Effects 

Respiratory Effects. Stauffer Chem Co. (1983) conducted a morbidity survey to identify adverse 

health effects among workers occupationally exposed to TDCP. The survey was based on an analysis of 

the physical examination reports of 93 exposed and 31 non-exposed workers examined in 1981. The 

evaluation included a self administered 175 item questionnaire, clinical studies including pulmonary 

function tests, a chest x-rays and electrocardiograms (EKG), and laboratory test including urinalyses, 

hematology and clinical chemistry parameters. Time-weighted average breathing zone sampling 

conducted in 1978 and 1979 showed that the concentration in the process area or in other areas was ≤7– 

8 ppb (0.4–0.5 μg/m3

). Analysis of alcohol consumption habits showed that there were significantly more 

non drinkers among non-exposed individuals and a higher daily alcohol consumption among exposed 

workers than non-exposed. There were no significant differences between the groups regarding smoking 

habits. In general, prevalence rates for positive responses to the questionnaire tended to be higher among 

non-exposed workers. From the respiratory section of the questionnaire, the main focus of the survey, 

exposed workers showed a 2-fold excess for bringing up phlegm first thing in the morning and for having 

a stuffy nose or post-nasal drip in the summer. Results from the chest x-rays showed no significant 

differences between exposed and non-exposed workers. Results from the pulmonary tests showed a six 

times greater percentage of abnormal pulmonary tests in non-exposed workers than in exposed workers; 

the impairment occurred primarily in FEV1. Based on these findings, the investigators concluded that it 

was apparent that workers exposed to TDCP were not at increased risk for respiratory conditions. 

Limitations of the survey (which also apply to other end points mentioned below) noted by the 

investigators included the fact that the number of non-exposed workers was only one third that of of the 

exposed workers. Secondly, since payroll records were unavailable prior to 1975, some of the workers 

classified as non-exposed could have been exposed prior to 1975. Thirdly, since a higher percentage of 

exposed workers were employed before 1975 than non-exposed, and some of the exposed workers could 

have had potentially a long duration of exposure, the maximum effect of any harmful exposure should be 

observed among the exposed workers. 

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205

5000

184

41382

152

83350

194

28000

155

200000

176

200000

143

5000

168

9800

Table 3-1 Levels of Significant Exposure to Selected Phosphate Esters - Inhalation 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/m3) (mg/m3) (mg/m3) Chemical Form 

ACUTE EXPOSURE Death 

1 Rat 4 hr 5000 (LC50 is greater than Anonymous 1977 (NS) 5000 mg/m3) 115-96-8 

2 Rat 6 hr 41382 (1/3 deaths) Eastman Kodak Co. 196

(NS) (NS) 126-73-8 

3 Rat 6 hr 83350 (3/3 deaths 48 hours Eastman Kodak Co. 199

(NS) (NS) after exposure) 126-71-6 

4 Rat 1 hr 28000 (LC50) FMC 1976 (Wistar) (NS) 126-73-8 

5 Rat 1 hr 200000 (LC50 was greater than FMC 1982 (Wistar) (NS) 200000 mg/m3) 115-86-6 

6 Rat 1 hr 200000 (LC50 is less than MacKeller 1976 (NS) (NS) 200000 mg/m3) 126-73-8 

7 Rat 4 hr 5000 (7/8 deaths in 14 days) Mobil Oil Corporation 19

(Sprague- (NS) 78-51-3 Dawley) 

8 Rat 1 hr 9800 (1-hr LC50 is greater Stauffer Chemical Co. 1

(Sprague- (NS) than 9800 mg/m3) 13674-87-8 Dawley) 

hr = hour(s); LC50 = lethal concentration, 50% kill; LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; NS = not specified 
1000

10000

100000

1E+6

Death

1r

2r

3r

4r

5r 6r

7r

8r

mg/m3

Figure 3-1 Levels of Significant Exposure to Selected Phosphate Esters - Inhalation

Acute (≤14 days)

c-Cat

d-Dog

r-Rat

p-Pig

q-Cow

 -Humans

k-Monkey

m-Mouse

h-Rabbit

a-Sheep

f-Ferret

j-Pigeon

e-Gerbil

s-Hamster

g-Guinea Pig

n-Mink

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

 LOAEL, Less Serious-Animals

 NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

 LOAEL, Less Serious-Humans

 NOAEL - Humans

 LD50/LC50

 Minimal Risk Level

 for effects

 other than

 Cancer

TPP TnBP

TnBP

TnBP

TiBP

TCEP TBEP

TDCP

PHOSPHATE ESTER FLAME RETARDANTS

3. HEALTH EFFECTS

40

***DRAFT FOR PUBLIC COMMENT***
 

 

 

 

 

 

 

 

 

 

PHOSPHATE ESTER FLAME RETARDANTS 41 

3. HEALTH EFFECTS 

Sutton et al. (1960) reported the results of health evaluations of men engaged in the manufacture and use 

of TPP. The workers could have been exposed to up to 29 mg/m3 TPP mist and vapor or dust for short 

period of time, but the investigators estimated a weighted average exposure concentration of 3.5 mg/m3

. 

Although the total number of men evaluated was not indicated, review of medical records and chest x-ray 

tests did not reveal respiratory alterations attributable to exposure to TPP. Review of the medical records, 

illnesses, and examinations of 11 plant operators found no cases of respiratory tract irritation. 

Cardiovascular Effects. In the survey conducted by Stauffer Chem Co. (1983), workers exposed to 

TDCP had twice as many abnormal EKG tracings as non-exposed workers. The principal abnormalities 

observed were sinus bradycardia, sinus arrhythmias, left axis deviation and incomplete right bundle 

branch block. However, from the health questionnaire information, a lower percentage of these workers 

had a history of heart trouble than non-exposed workers, but a higher percent had a history of “other” 

chest trouble. In addition, exposed workers had a lower prevalence of diseases of the circulatory system. 

The review of medical evaluations of workers exposed to TTP conducted by Sutton et al. (1960) did not 

reveal electrocardiographic alterations attributable to occupational exposure to TPP. 

Hematological Effects. Hematology tests (complete blood counts with differentials) carried out in 

the morbidy survey conducted by Stauffer Chem Co. (1983) showed no statitistically significant 

differences between workers exposed to TDCP and non-exposed workers. Health evaluations of workers 

exposed to TPP that included hematology tests (hemoglobin, cell volume, white blood cell count, and 

differential) did not show deviations from the normal range attributable to exposure to TPP (Sutton et al. 

1960). 

Hepatic Effects. Results of the liver function tests performed on the workers studied by Stauffer 

Chem Co. (1983) showed that workers exposed to TDCP had a higher percentage of abnormal total 

bilirubin and total protein values than non-exposed workers. However, non-exposed workers had higher 

serum aspartate aminotransferase (AST) and alkaline phosphatase values. Health evaluations conducted 

in workers exposed to TPP did not reveal alterations in liver function as assessed by the cephalin 

cholesterol flocculation test (Sutton et al. 1960). 

Renal Effects. In the morbidity survey conducted by Stauffer Chem Co. (1983), there was a 

considerably greater percentage of workers exposed to TDCP with abnormal BUN values than nonexposed workers, 14.1 versus 0.0%; creatinine values were similar for both groups. The results also 

showed that a greater percentage of non-exposed workers (25.8%) had abnormal urine results 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

 

 

 

 

PHOSPHATE ESTER FLAME RETARDANTS 42 

3. HEALTH EFFECTS 

(unspecified) than exposed workers (6.7%). Examination of the urine of workers exposed to TPP did not 

reveal any abnormalities that could be attributed to exposure to the chemical (Sutton et al. 1960). 

Dermal Effects. A higher prevalence of dermatitis was reported among TDCP workers compared 

with non-exposed workers in the morbidity survey conducted by Stauffer Chem Co. (1983); no further 

details were provided. No cases of dermatitis were observed among 11 workers exposed to TPP that were 

evaluated by Sutton et al. (1960). 

3.2.1.3 Immunological and Lymphoreticular Effects 

No information was located regarding immunological and lymphoreticular effects in humans or animals 

following inhalation exposure to the phosphate ester flame retardants discussed in this profile. 

3.2.1.4 Neurological Effects 

Examination of 32 men who were assigned to jobs in which they occasionally handled bags of TPP and 

had a mean length of exposure of 7.4 years revealed no cases of neurological disease (Sutton et al. 1960). 

Examination of 11 of the men with the highest exposure who were working regularly at the time of the 

evaluations showed no evidence of neurological disease (Sutton et al. 1960). However, red blood cell 

cholinesterase activity was significantly reduced (18%) in this group of workers compared to unexposed 

subjects. Yet, Sutton et al. (1960) noted that the variability both within and between individuals was 

great enough so that the small depressions in cholinesterase activity were not sufficient to identify 

individuals with TPP exposure. 

No studies were located regarding the following effects: 

3.2.1.5 Reproductive Effects 

3.2.1.6 Developmental Effects 

3.2.1.7 Cancer 

Stauffer Chemical Co. (1983) conducted a retrospective cohort study to examine the mortality experience 

of 289 workers employed in the manufacture of TDCP. The study period was established as January 

1956 through December 1980. The cohort included active, terminated, retired, and deceased employees. 

Full-shift, time weighted average breathing zone sampling conducted from December, 1978 to May, 1979 

showed that exposure levels were <8 ppb. Of the total cohort, only 42 workers had been employed 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

 

 

 

 

 

PHOSPHATE ESTER FLAME RETARDANTS 43 

3. HEALTH EFFECTS 

≥15 years. The overall mortality of the cohort was 75% of that expected in a comparable population of 

U.S. males, which probably reflected the healthy worker effect. There were three deaths attributed to 

lung cancer, which was higher than the 0.8 expected. However, based on the fact that one case was found 

to have not been exposed to TDCP, a second case worked only 2 years before onset of the disease, and all 

three cases were cigarette smokers, the investigators conluded that there was insufficient evidence to 

establish a causal relationship between lung cancer and TDCP. Considering the small size of the cohort, 

the investigators recommended continued surveillance of the group. Without providing further details, 

Stauffer Chem Co. (1983) stated that in the morbidity survey conducted among TDCP workers, there was 

an excess of benign neoplasms, primarily lipomas, relative to non-exposed workers. 

3.2.2 Oral Exposure 

3.2.2.1 Death 

No reports of deaths of humans following oral exposure to the phosphate ester flame retardants subject of 

this profile were located in the reviewed literature. 

Oral LD50 values between 46.4 and 100 mg/kg and between 46.4 and 1,000 mg/kg were reported for 

TCEP in male and female rats, respectively (Anonymous 1977). Other LD50 values reported for TCEP in 

rats were 1,230 and 1,410 mg/kg (Eldefrawi et al. 1977; Smyth et al. 1951). In a gestational exposure 

study, 7/30 rats dosed with 200 mg TCEP/kg/day died during the study; no deaths occurred in a group 

treated with 100 mg/kg/day (Kawashima et al. 1983a). In a 16-week duration study in which rats were 

treated with TCEP by gavage 5 days/week, 5/10 males and 3/10 females died on week 16 (NTP 1991a). 

LD50 values and/or lethal doses ranging from 1,400 to 3,200 mg/kg were reported for TnBP in rats (Dow 

Chemical Co. 1956; Eastman Kodak Co. 1968; EI Dupont Denemours 1953a; Johannsen et al. 1977; 

Stauffer Chemical Co. 1973; Union Carbide Corp 1943). MacKellar (1976) reported that all rats 

(unspecified number) treated once with 20,000 mg TnBP/kg died. Eastman Kodak Co. (1968) also 

reported an LD50 between 400 and 800 mg/kg for TnBP in mice. In a gestational exposure study, all five 

pregnant rats dosed with 800 mg TnBP/kg/day died after five or six treatments (Noda et al. 1994). These 

rats showed marked reduction in body weight and food consumption, piloerection, wetting of abdominal 

hair with urine, and salivation. In a 13-week gavage study, 7/24 rats died at unspecified times before the 

end of the study (Healy et al. 1995). Gross examination of these rats showed a pale, frothy material in the 

trachea and/or lungs, suggesting that deaths may have been due to aspiration of saliva. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

PHOSPHATE ESTER FLAME RETARDANTS 44 

3. HEALTH EFFECTS 

Oral LD50 values of 13,278 and 5,383 mg/kg were reported for TBEP in male and female rats, 

respectively (Mobil Oil Corporation 1976a). Clinical signs of toxicity observed included ataxia, labored 

breathing, red stains on the nose or eyes, rough coat, soft feces, urine stains, depression, prostration, and 

tremors. Gross necropsy of animals that died during the study revealed reddened intestines and/or 

reddened stomach linings. Without providing any details, Eldefrawi et al. (1977) reported an estimated 

oral LD50 of 2,830 mg/kg for TDCP in rats. 

An oral LD50 of 10,800 mg/kg was described in rats administered TPP by capsule and observed for 

14 days (Johannsen et al. 1977). Without providing further details, EF Houghton and Co. (1996) and 

FMC (1982) reported LD50 values >6,400 and >20,000 mg/kg, respectively, for TPP in rats. Oral LD50 

values >3,200 and >6400 mg/kg were described for TiBP in rats and mice, respectively (Eastman Kodak 

Co. 1990). Mortality in rats occurred between 2.5 hours and 2 days following administration of TiBP and 

clinical signs of toxicity included ataxia, jerking, and white foam at the mouth. Mortality in mice 

occurred between 2 and 3 hours following administration of TiBP, and clinical signs of toxicity included 

ataxia. In a study conducted by Monsanto Co. (1989a, 1989b), a single dose of 5,000 mg/kg killed only 

1/10 rats within a 14-day observation period. Clinical signs of toxicity observed 24 hours after dosing 

included dry rales, hypoactivity, and red nasal discharge. 

Oral LD50 values of 2,000 and 1,260 mg/kg were reported for TCPP in male and female rats, respectively 

(Anonymous 1977). Spasm, salivation, ataxia, and spasmodic jumping were noticed in the rats. 

Kawasaki et al. (1982) reported a 96-hour oral LD50 of 1,500 mg/kg for TCPP in female rats. Tremors 

and wheezing were evident 30 minutes after dosing in rats that died. Rats that did not die after 5 hours 

did not do so later. In rats dosed once with 200, 500, or 2,000 mg TCPP/kg, all five high-dose females 

died (Stropp 1996). There were no other mortalities at any other dose level. Clinical signs observed in 

high-dose females included apathy, spasms, blood-crusted snout, and lateral position. No clinical signs of 

toxicity were observed in either sex at 200 or 500 mg/kg, and body weight was not affected. At necropsy, 

reddened lungs were observed in animals that died during the study; however, no surviving animals 

showed pathological changes upon sacrifice. 

Additional information regarding LD50 values and lethal doses of phosphate ester flame retardants can be 

found in IPCS (1991a, 1991b, 1998, 2000b). 

Oral LD50 values and oral lethal doses for the selected phosphate ester flame retardants are presented in 

Tables 3-2, 3-3, 3-4, 3-5, and 3-6 and plotted in Figures 3-2, 3-3, 3-4, 3-5, and 3-6. 

***DRAFT FOR PUBLIC COMMENT*** 
209

46.446.4

83

1230

68

200

82

1410

66

940

93

1000

64

275

Table 3-2 Levels of Significant Exposure to Tris(2-chloroethyl) Phosphate (TCEP) - Oral 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

ACUTE EXPOSURE Death 

1 Rat once 46.4 M (LD50 is between 46.4 Anonymous 1977 (Sprague- (NS) and 100 mg/kg) 115-96-8 Dawley) 

46.4 F (LD50 is between 46.4 

and 1000 mg/kg) 

2 Rat once 1230 (LD50) Eldefrawi et al. 1977 (albino) (G) 115-96-8 

3 Rat 9 d 200 F (7/30 pregnant rats died, Kawashima et al. 1983a Gd 7-15 (Wistar) 1 x/d 0/23 in controls) 115-96-8 

(GO) 

4 Rat once 1410 (LD50) Smyth et al. 1951 (albino) (G) 115-96-8 

Systemic 

5 Mouse 8 d 

Bd Wt 940 F (12% reduced weight Hardin et al. 1987 Gd 6-13 (CD-1) 

gain between Gd 6 and 1 x/d 115-96-8 Pnd 3) (G) 

6 Mouse 14 d Bd Wt 1000 NTP 1991b 1 x/d (CD-1) 115-96-8 (GO) 

Neurological 

7 Rat once 275 F (convulsions; loss of Tilson et al. 1990 (Fischer- 344) (GO) hippocampal cells) 115-96-8 
10

175 300

67

200

65

940

13

350

Table 3-2 Levels of Significant Exposure to Tris(2-chloroethyl) Phosphate (TCEP) - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

8 Mouse 3 d 175 300 (ataxia, convulsions) NTP 1991a 1 x/d (B6C3F1) 115-96-8 (GO) 

Developmental 

9 Rat 9 d 200 F Kawashima et al. 1983a 

(Wistar) Gd 7-15 

1 x/d 115-96-8 (GO) 

10 Mouse 8 d 940 F Hardin et al. 1987 

Gd 6-13 (CD-1) 1 x/d 115-96-8 (G) 

INTERMEDIATE EXPOSURE Death 

11 Rat 16 wk 350 (5/10 males and 3/10 NTP 1991a 5 d/wk (Fischer- 344) 1 x/d females died on week 115-96-8 16) (GO) 
103

586586586586586586586586586586192

506

586586

Table 3-2 Levels of Significant Exposure to Tris(2-chloroethyl) Phosphate (TCEP) - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

Systemic 

12 Rat 3 mo Resp 586 F Anonymous 1977 

(Sprague- ad lib 

115-96-8 Dawley) (F) 

Cardio 586 F Gastro 586 F Hemato 586 F Musc/skel 586 F Hepatic 586 F Renal 586 F Endocr 586 F Dermal 586 F Ocular 586 F Bd Wt 192 M 506 M (13% reduction in final

body weight)

Metab 586 FOther 586 F
12

35035035035088

175

88

175

350350350350

Table 3-2 Levels of Significant Exposure to Tris(2-chloroethyl) Phosphate (TCEP) - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

13 Rat 16 wk NTP 1991a 

Resp 350 5 d/wk (Fischer- 344) 

1 x/d 115-96-8 

(GO) 

Cardio 350 Gastro 350 Musc/skel 350 Hepatic 88 175 (>10% increase in

absolute liver weight)

Renal 88 F 175 F (>10% increased

absolute and relativekidney weight)

Endocr 350Dermal 350Bd Wt 350Other 350
3

35035035035035088

175

350350350350

14 

Table 3-2 Levels of Significant Exposure to Tris(2-chloroethyl) Phosphate (TCEP) - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

Rat 16 d Resp 350 NTP 1991a 

5 d/wk (Fischer- 344) 1x/d 115-96-8 (GO) 

Cardio 350 Gastro 350 Musc/skel 350 Hepatic 350 Renal 88 M 175 M (increased absolute and

relative kidney weight)

Endocr 350Dermal 350Bd Wt 350Other 350
17

700700700700700350

700

700700700700

15 

Table 3-2 Levels of Significant Exposure to Tris(2-chloroethyl) Phosphate (TCEP) - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

Mouse 16 wk Resp 700 NTP 1991a (B6C3F1) 5 d/wk 

1 x/d 115-96-8 (GO) 

Cardio 700 Gastro 700 Musc/skel 700 Hepatic 700 Renal 350 M 700 (nuclear enlargement of

epithelial cells in renaltubules)

Endocr 700Dermal 700Bd Wt 700Other 700
8

700700700700700700700700700700

104

586

15

350

Table 3-2 Levels of Significant Exposure to Tris(2-chloroethyl) Phosphate (TCEP) - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ 

Duration/ 

a Frequency Key to Species (Route) Figure (Strain) System 

Resp 

Cardio Gastro Musc/skel Hepatic Renal Endocr Dermal Bd Wt Other 

16 d 5 d/wk 1 x/d (GO) 3 mo ad lib (F) 16 d 5 d/wk 1 x/d (GO) 

LOAEL 

NOAEL Less Serious Serious Reference

(mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

NTP 1991a 

700 

115-96-8 

700

700700

700700

700

700

700700586 F Anonymous 1977 

115-96-8 

350 NTP 1991a 

115-96-8 

16 Mouse 

(B6C3F1) 

Immuno/ Lymphoret 

17 Rat 

(SpragueDawley) 

18 Rat 

(Fischer- 344) 
6

350

18

700

9

700

105

586

14

88

175

7

350

140

700

Table 3-2 Levels of Significant Exposure to Tris(2-chloroethyl) Phosphate (TCEP) - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

19 Rat 16 d 350 NTP 1991a 

(Fischer- 344) 5 d/wk 

1 x/d 115-96-8 (GO) 

20 Mouse 16 wk NTP 1991a 

700 5 d/wk (B6C3F1) 

1 x/d 115-96-8 (GO) 

21 Mouse 16 d NTP 1991a 

(B6C3F1) 5 d/wk 700 

1 x/d 115-96-8 (GO) 

Neurological 

22 Rat 3 mo 586 F Anonymous 1977 

ad lib (Sprague- 

115-96-8 Dawley) (F) 

23 Rat 16 wk b 88 F 175 F (necrosis of hippocampal NTP 1991a 5 d/wk (Fischer- 344) 1 x/d neurons) 115-96-8

(GO)

24 Rat 16 d NTP 1991a 

350 5 d/wk (Fischer- 344) 

1 x/d 115-96-8(GO)

25 Mouse 16 d NTP 1991a 

700 (B6C3F1) 1 x/d 

115-96-8 (GO) 
19

700

106

506586

16

350

5

350

11

700

20

700

Table 3-2 Levels of Significant Exposure to Tris(2-chloroethyl) Phosphate (TCEP) - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a Frequency Reference Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

26 Mouse 16 wk 700 NTP 1991a 5 d/wk (B6C3F1) 1 x/d 115-96-8 

(GO) 

Reproductive 

27 Rat 3 mo 506 M Anonymous 1977 ad lib (Sprague- 115-96-8 Dawley) (F) 586 F 

28 Rat 16 wk 350 NTP 1991a 5 d/wk (Fischer- 344) 1 x/d 115-96-8 

(GO) 

29 Rat 16 d 350 NTP 1991a 5 d/wk (Fischer- 344) 1 x/d 115-96-8 

(GO) 

30 Mouse 16 d 700 NTP 1991a 5 d/wk (B6C3F1) 1 x/d 115-96-8 

(GO) 

31 Mouse 16 wk 700 NTP 1991a 5 d/wk (B6C3F1) 1 x/d 115-96-8 

(GO) 
91

175

350

92

175

Table 3-2 Levels of Significant Exposure to Tris(2-chloroethyl) Phosphate (TCEP) - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

32 Mouse 18 wk 175 350 (decreased number of F1 NTP 1991b 1 x/d (CD-1) litters) 115-96-8 (GO) 

Developmental 

33 Mouse 18 wk 175 (decreased number of NTP 1991b 1 x/d (CD-1) live male F2 pups per 115-96-8 (GO) litter) 
21

88888888888844

88

8888888888

Table 3-2 Levels of Significant Exposure to Tris(2-chloroethyl) Phosphate (TCEP) - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a Frequency Reference Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

CHRONIC EXPOSURE Systemic 

34 Rat 104 wk Resp 88 NTP 1991a 

5 d/wk (Fischer- 344) 1x/d 115-96-8 (GO) 

Cardio 88Gastro 88Hemato 88Musc/skel 88Hepatic 88

c

Renal 44 88 (renal tubule epithelium

hyperplasia)

Endocr 88Dermal 88Ocular 88Bd Wt 88Other 88
26

350350350350350350

175

350350350350350

213

267

1333

Table 3-2 Levels of Significant Exposure to Tris(2-chloroethyl) Phosphate (TCEP) - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

35 Mouse 104 wk NTP 1991a 

Resp 350 (B6C3F1) 5 d/wk 

1 x/d 115-96-8 

(GO) 

Cardio 350 Gastro 350 Hemato 350 Musc/skel 350 Hepatic 350 Renal 175 (nuclear enlargement in

tubule cells)

Endocr 350Dermal 350Ocular 350Bd Wt 350Other 350

36 Mouse 18 mo Bd Wt 267 1333 (32% reduction in final Takada et al. 1989 (albino) ad libitum body weight) 115-96-8 (F) 
22

88

27

350

23

44

88

28

350

24

88

29

350

Table 3-2 Levels of Significant Exposure to Tris(2-chloroethyl) Phosphate (TCEP) - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a Frequency Reference Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

Immuno/ Lymphoret 

37 Rat 104 wk 88 NTP 1991a 

(Fischer- 344) 5 d/wk 

1x/d 115-96-8 (GO) 

Mouse 104 wk

5 d/wk

38 350 NTP 1991a 

(B6C3F1) 

1 x/d 115-96-8 (GO) 

Neurological 

39 Rat 104 wk 44 F 88 F (degenerative lesions in NTP 1991a 5 d/wk (Fischer- 344) cerebral cortex and brain 

stem) 1x/d 115-96-8 (GO) 

40 Mouse 104 wk NTP 1991a 

350 5 d/wk (B6C3F1) 

1 x/d 115-96-8 

(GO) 

Reproductive 

41 Rat 104 wk 88 NTP 1991a 

(Fischer- 344) 5 d/wk 

1x/d 115-96-8 

(GO) 

42 Mouse 104 wk 350 NTP 1991a 

5 d/wk (B6C3F1) 1 x/d 115-96-8 

(GO) 
25

88

139

350350

212

267267

Table 3-2 Levels of Significant Exposure to Tris(2-chloroethyl) Phosphate (TCEP) - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a Frequency Key to Species NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

Cancer 

43 Rat 104 wk 88 (CEL:renal tubule NTP 1991a 5 d/wk (Fischer- 344) 1x/d adenomas) 115-96-8 

(GO) 

44 Mouse 104 wk 

350 M (CEL: renal adenoma NTP 1991a 5 d/wk (B6C3F1) 

1x/d and adenocarcinoma) 115-96-8 

(GO) 

350 F (CEL: harderian gland 

tumors) 

45 Mouse 18 mo 267 M (CEL:hepatocellular Takada et al. 1989 (albino) ad libitum adenoma/carcinoma) 115-96-8 (F) 

267 F (CEL: leukemia) 

a The number corresponds to entries in Figure 3-2. b Used to derive an intermediate-duration oral minimal risk level (MRL) of 0.6 mg/kg/day; the MRL was derived by adjusting the BMDL10 of 85.07 mg/kg/day for co(85.07 mg/kg/day 5/7) and dividing by an uncertainty factor of 100 (10 for animal to human extrapolation and 10 for human variability). c Used to derive a chronic-duration MRL of 0.3 mg/kg/day; the MRL was derived by adjusting the BMDL10 of 36.09 mg/kg/day for continuous exposure (36.09 x 5/7an uncertainty factor of 100 (10 for animal to human extrapolation and 10 for human variability). ad lib = ad libitum; Bd Wt = body weight; Cardio = cardiovascular; CEL = cancer effect level; d = day(s); Endocr = endocrine; (F) = feed; F = Female; (G) = gavage; gastrointestinal; Gd = gestation day; (GO) = gavage in oil; Hemato = hematological; LD50 = lethal dose, 50% kill; LOAEL = lowest-observed-adverse-effect level; M month(s); Musc/skel = musculoskeletal; NOAEL = no-observed-adverse-effect level; NS = not specified; pnd = post-natal day; Resp = respiratory; wk = week(s); x = 
10

100

1000

10000

Death

1r 1r

2r

3r

4r

Body Weight

5m 6m

Neurological

8m

8m 7r

Developmental

10m

9r

mg/kg/day

Figure 3-2 Levels of Significant Exposure to Tris(2-chloroethyl) Phosphate (TCEP) - Oral

Acute (≤14 days)

c-Cat

d-Dog

r-Rat

p-Pig

q-Cow

 -Humans

k-Monkey

m-Mouse

h-Rabbit

a-Sheep

f-Ferret

j-Pigeon

e-Gerbil

s-Hamster

g-Guinea Pig

n-Mink

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

 LOAEL, Less Serious-Animals

 NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

 LOAEL, Less Serious-Humans

 NOAEL - Humans

 LD50/LC50

 Minimal Risk Level

 for effects

 other than

 Cancer

Systemic

PHOSPHATE ESTER FLAME RETARDANTS

3. HEALTH EFFECTS

59

***DRAFT FOR PUBLIC COMMENT***
0.1

1

10

100

1000

Death

11r

Respiratory

15m 16m

12r

13r 14r

Cardiovascular

15m 16m

12r

13r 14r

Gastrointestinal

15m 16m

12r

13r 14r

Hematological

12r

Musculoskeletal

15m 16m

12r

13r 14r

Hepatic

15m 16m

12r

13r

13r

14r

Renal

15m

15m

16m

12r

13r

13r

14r

14r

Endocrine

15m

mg/kg/day

Figure 3-2 Levels of Significant Exposure to Tris(2-chloroethyl) Phosphate (TCEP) - Oral (Continued)

Intermediate (15-364 days)

c-Cat

d-Dog

r-Rat

p-Pig

q-Cow

 -Humans

k-Monkey

m-Mouse

h-Rabbit

a-Sheep

f-Ferret

j-Pigeon

e-Gerbil

s-Hamster

g-Guinea Pig

n-Mink

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

 LOAEL, Less Serious-Animals

 NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

 LOAEL, Less Serious-Humans

 NOAEL - Humans

 LD50/LC50

 Minimal Risk Level

 for effects

 other than

 Cancer

Systemic

PHOSPHATE ESTER FLAME RETARDANTS

3. HEALTH EFFECTS

60

***DRAFT FOR PUBLIC COMMENT***
0.1

1

10

100

1000

Endocrine

16m

12r

13r 14r

Dermal

15m 16m

12r

13r 14r

Ocular

12r

Body Weight

15m 16m

12r

12r

13r 14r

Metabolic

12r

Other

15m 16m

12r

13r 14r

Immuno/Lymphor

20m 21m

17r

18r 19r

Neurological

25m 26m

22r

23r

23r

24r

Reproductive

30m 31m

32m

32m

27r 27r

mg/kg/day

Figure 3-2 Levels of Significant Exposure to Tris(2-chloroethyl) Phosphate (TCEP) - Oral (Continued)

Intermediate (15-364 days)

c-Cat

d-Dog

r-Rat

p-Pig

q-Cow

 -Humans

k-Monkey

m-Mouse

h-Rabbit

a-Sheep

f-Ferret

j-Pigeon

e-Gerbil

s-Hamster

g-Guinea Pig

n-Mink

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

 LOAEL, Less Serious-Animals

 NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

 LOAEL, Less Serious-Humans

 NOAEL - Humans

 LD50/LC50

 Minimal Risk Level

 for effects

 other than

 Cancer

Systemic

PHOSPHATE ESTER FLAME RETARDANTS

3. HEALTH EFFECTS

61

***DRAFT FOR PUBLIC COMMENT***
0.1

1

10

100

1000

Reproductive

28r 29r

Developmental

33m

mg/kg/day

Figure 3-2 Levels of Significant Exposure to Tris(2-chloroethyl) Phosphate (TCEP) - Oral (Continued)

Intermediate (15-364 days)

c-Cat

d-Dog

r-Rat

p-Pig

q-Cow

 -Humans

k-Monkey

m-Mouse

h-Rabbit

a-Sheep

f-Ferret

j-Pigeon

e-Gerbil

s-Hamster

g-Guinea Pig

n-Mink

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

 LOAEL, Less Serious-Animals

 NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

 LOAEL, Less Serious-Humans

 NOAEL - Humans

 LD50/LC50

 Minimal Risk Level

 for effects

 other than

 Cancer

PHOSPHATE ESTER FLAME RETARDANTS

3. HEALTH EFFECTS

62

***DRAFT FOR PUBLIC COMMENT***
0.1

1

10

100

1000

10000

Respiratory

35m

34r

Cardiovascular

35m

34r

Gastrointestinal

35m

34r

Hematological

35m

34r

Musculoskeletal

35m

34r

Hepatic

35m

34r

Renal

35m

34r

34r

Endocrine

35m

34r

Dermal

35m

34r

Ocular

35m

34r

Body Weight

35m

36m

36m

34r

Other

35m

34r

Immuno/Lymphor

38m

37r

Neurological

40m

39r

39r

Reproductive

42m

41r

Cancer *

44m 44m

45m 45m

43r

mg/kg/day

Figure 3-2 Levels of Significant Exposure to Tris(2-chloroethyl) Phosphate (TCEP) - Oral (Continued)

Chronic (≥365 days)

c-Cat

d-Dog

r-Rat

p-Pig

q-Cow

 -Humans

k-Monkey

m-Mouse

h-Rabbit

a-Sheep

f-Ferret

j-Pigeon

e-Gerbil

s-Hamster

g-Guinea Pig

n-Mink

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

 LOAEL, Less Serious-Animals

 NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

 LOAEL, Less Serious-Humans

 NOAEL - Humans

 LD50/LC50

 Minimal Risk Level

 for effects

 other than

 Cancer

*Doses represent the lowest dose tested per study that produced a tumorigenic

response and do not imply the existence of a threshold for the cancer endpoint.

Systemic

PHOSPHATE ESTER FLAME RETARDANTS

3. HEALTH EFFECTS

63

***DRAFT FOR PUBLIC COMMENT***
170

2000

179

1600

173

2250

138

1400

174

20000

47

800

185

3160

189

3200

Table 3-3 Levels of Significant Exposure to Tri-n-butyl Phosphate (TnBP) - Oral 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL 

Duration/ 

a Frequency Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/kg) (mg/kg) (mg/kg) 

ACUTE EXPOSURE Death 

1 Rat once 2000 (2/2 died) (NS) (GO) 

2 Rat once 1600 (LD50 is 1600-3200 (NS) (NS) mg/kg) 

3 Rat once 2250 (lethal dose) (NS) (NS) 

4 Rat once 1400 (14-day LD50) (Sprague- (GO)

Dawley)

5 Rat once 20000 (all rats died) (NS) (NS) 

6 Rat 11 d 800 F (5/5 dead pregnant rats Gd 7-17 (Wistar) after 5 or 6 treatments) 1 x/d

(GO)

7 Rat once 3160 M (LD50) (Sprague- (G)

Dawley)

8 Rat once 3200 (LD50) (NS) (G) 

Reference Chemical Form 

Dow Chemical Co. 1956 126-73-8 Eastman Kodak Co. 196126-73-8 EI Dupont Denemours 11953b 126-73-8 Johannsen et al. 1977 126-73-8 MacKeller 1976 126-73-8 Noda et al. 1994 126-73-8 Stauffer Chemical Co. 1126-73-8 Union Carbide Corp 194126-73-8 
180

400

37

411

54

411411137 411137

411

411411

137

46

100

200

Table 3-3 Levels of Significant Exposure to Tri-n-butyl Phosphate (TnBP) - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg) (mg/kg) (mg/kg) Chemical Form 

9 Mouse once 400 (LD50 is 400-800 mg/kg) Eastman Kodak Co. 196

(NS) (NS) 126-73-8 

Systemic 

10 Rat 14 d Bd Wt 411 Laham et al. 1983 1x/d (Sprague- 126-73-8 Dawley) (G) 

11 Rat 14 d Laham et al. 1984b 

Resp 411 1 x/d (Sprague- 

126-73-8 Dawley) (G) 

Cardio 411Hemato 137 F 411 F (decreased hemoglobin)Hepatic 137 411 (increased absolute and

relative liver weight) 

Renal 411Bd Wt 411Metab 137 F (increased serum

potassium) 

12 Rat 11 d Bd Wt 100 F 200 F (37% reduced adjusted Noda et al. 1994 Gd 7-17 (Wistar) 1 x/d body weight gain on Gd 126-73-8 0-20) (GO) 
48

50050062.5

125

55

137

411

50

325

1000

38

274

411

57

411

56

137

411

Table 3-3 Levels of Significant Exposure to Tri-n-butyl Phosphate (TnBP) - Oral (continued) 

LOAEL 

a 

Key to Species 

Figure (Strain) 

13 Rat 

(Wistar) 

Exposure/ 

Duration/ 

Frequency 

(Route) System 

Hepatic 

RenalBd Wt

NOAEL 

(mg/kg/day) 

500 F 

500 F 

b

62.5 F 

137 F 325 274 411 137 M 

Less Serious Serious 

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

125 F (13% reduced adjusted

body weight gain on Gd0-20)

411 F (decreased absolute and

relative spleen weight)

1000 (decreased motor activity 

11 hours postdosing) 

411 (decreased nerve

conduction velocity)

411 M (degenerative changes in

seminiferous tubules)

11 d Gd 7-17 1 x/d (GO) 14 d 1 x/d (G) once (GO) 14 d 1x/d (G) 14 d 1 x/d (G) 14 d 1 x/d (G) 

Reference Chemical Form 

Noda et al. 1994 126-73-8 Laham et al. 1984b 126-73-8 Healy et al. 1995 126-73-8 Laham et al. 1983 126-73-8 Laham et al. 1984b 126-73-8 Laham et al. 1984b 126-73-8 

***DRAFT FOR PUBLIC COMMENT***

Immuno/ Lymphoret 

14 Rat 

(SpragueDawley) 

Neurological 

15 16 17 

Rat (SpragueDawley) Rat (SpragueDawley) Rat (SpragueDawley) 

Reproductive 

18 Rat 

(SpragueDawley) 
45

400

49

500

52

325

36

14314333

143

9 33

39

182

Table 3-3 Levels of Significant Exposure to Tri-n-butyl Phosphate (TnBP) - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a Frequency Reference Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

Developmental 

19 Rat 11 d Noda et al. 1994 

400 F (Wistar) Gd 7-17 

1 x/d 126-73-8 (GO) 

Rat 11 d

Gd 7-17

20 500 F Noda et al. 1994 

(Wistar) 

1 x/d 126-73-8 (GO) 

INTERMEDIATE EXPOSURE Death 

21 Rat 13 wk 325 (7/24 deaths before end Healy et al. 1995 1x/d (Sprague- of the study) 126-73-8 Dawley) (GO) 

Systemic 

22 Rat 10 wk Gastro 143 M Arnold et al. 1997 

(Sprague- ad lib 

126-73-8 Dawley) (F) 

Renal 143 M Bd Wt 33 M 143 M (final body weight

reduced more than 10%relative to controls)

c,d Other 9 M 33 M (urothelial hyperplasia) 

23 Rat 12 mo Hemato 182 F Auletta et al. 1998a ad lib (Sprague- 126-73-8 Dawley) (F) 
122

42342342368.1

360

42313.8

68.1

42342342342368.1

360

68.1

360

13.8

68.1

Table 3-3 Levels of Significant Exposure to Tri-n-butyl Phosphate (TnBP) - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a Frequency Reference Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

24 Rat 90 d FMC 1985a 

Resp 423 F (Sprague- ad lib 

126-73-8 Dawley) (F) 

Cardio 423 F Gastro 423 F Hemato 68.1 M 360 M (increased activated

partial thromboplastintime)

Musc/skel 423 F Hepatic 13.8 M 68.1 M (increased absolute and

relative liver weight)

Renal 423 FEndocr 423 FDermal 423 FOcular 423 FBd Wt 68.1 M 360 M (14% reduction in final

body weight) 

Metab 68.1 M 360 M (increased serum

calcium)

Other 13.8 M 68.1 M (urinary bladder epithelial

cell hyperplasia)
53

100

325

60

333333333333200

333

333333200

333

333

200

Table 3-3 Levels of Significant Exposure to Tri-n-butyl Phosphate (TnBP) - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

25 Rat 13 wk Bd Wt 100 325 (final body weight Healy et al. 1995 1x/d (Sprague- reduced 15-20%) 126-73-8 Dawley) (GO) 

26 Rat 18 wk Laham et al. 1985a 

Resp 333 (Sprague- 5 d/wk 

1 x/d 126-73-8 Dawley) 

(G) 

Cardio 333Gastro 333Hemato 333Hepatic 200 F 333 F (increase absolute and

relative liver weight) 

Renal 333Endocr 333Bd Wt 200 M 333 M (14% reduction in final

body weight) 

Metab 333 Other 200 (epithelial hyperplasia of

the urinary bladder)
43

460460460 783

58

460

460460460

460

Table 3-3 Levels of Significant Exposure to Tri-n-butyl Phosphate (TnBP) - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ 

Duration/ 

a Frequency Key to Species (Route) Figure (Strain) 

27 Rat 10 wk 

ad lib (Wistar) (F) 

28 Rat 9 wk 

ad lib (Wistar) (F) 

LOAEL 

NOAEL Less Serious Serious Reference

System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

Hemato 460 M (increased coagulation Oishi et al. 1980 

time) 126-73-8 

Renal 460 M (increased BUN) 

Bd Wt 460 M (17% reduction in final 783 M (31% reduction in final 

body weight) body weight) 

Hemato 460 M Oishi et al. 1982 

126-73-8 

Hepatic 460 M (increase in absolute and 

relative liver weight; slight histopathology) 

Renal 460 M (increased BUN) Bd Wt 460 M (11% decrease in final 

body weight) 

Metab 460 M 
40

51

217

51

217

51

217

15

51

29 

Table 3-3 Levels of Significant Exposure to Tri-n-butyl Phosphate (TnBP) - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a Frequency Reference Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

Rat 70-110 d Hepatic 51 F 217 F (hepatic centrilobular Tyl et al. 1997 Gd 1-20 (Sprague- Ld 1-20 hypertrophy in F0 126-73-8 Dawley) females) ad lib 

(F) 

Renal 51 M 217 M (renal pelvic epithelial

hyperplasia in F1 males)

Bd Wt 51 217 (greater than 10%

reduction in body weightin F0 generation)

Other 15 51 (bladder hyperplasia in

F0 generation)
118

177617761776382

1478

177695 3821776177617761776382

1478

95

382

86

711

123

423

Table 3-3 Levels of Significant Exposure to Tri-n-butyl Phosphate (TnBP) - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

30 Mouse 13 wk Resp 1776 F Auletta 1991 ad lib (CD-1) 126-73-8 (F) 

Cardio 1776 FGastro 1776 FHemato 382 M 1478 M (increased platelet

counts) 

Musc/skel 1776 FHepatic 95 M 382 M (hepatocyte hypertrophy)Renal 1776 FEndocr 1776 FOcular 1776 FBd Wt 1776 FMetab 382 M 1478 M (increased serum

calcium) 

Other 95 M 382 M (urinary bladder epithelial

hyperplasia)

31 Mouse 12 mo Hemato 711 F Auletta et al. 1998b ad lib (CD-1) 126-73-8 (F) 

Immuno/ Lymphoret 

32 Rat 90 d FMC 1985a 

423 F ad lib (Sprague- 

126-73-8 Dawley) (F) 
61

333

59

460

119

1776

124

423

51

32.5 100

62

333

120

1776

Table 3-3 Levels of Significant Exposure to Tri-n-butyl Phosphate (TnBP) - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

33 Rat 18 wk 333 Laham et al. 1985a 

(Sprague- 5 d/wk 

1 x/d 126-73-8 Dawley) 

(G) 

34 Rat 9 wk Oishi et al. 1982 

460 M ad lib (Wistar) 

126-73-8 (F) 

35 Mouse 13 wk 1776 F Auletta 1991 

ad lib (CD-1) 

126-73-8 (F) 

Neurological 

36 Rat 90 d FMC 1985a 

423 F ad lib (Sprague- 

126-73-8 Dawley) (F) 

37 Rat 13 wk 32.5 100 (excessive salivation) Healy et al. 1995 1x/d (Sprague- 126-73-8 Dawley) (GO) 

38 Rat 18 wk 333 Laham et al. 1985a 

5 d/wk (Sprague- 1 x/d 126-73-8 Dawley) (G) 

39 Mouse 13 wk 1776 F Auletta 1991 

(CD-1) ad lib 

126-73-8 (F) 
125

360423

63

333

41

217

121

14781776

42

51

217

Table 3-3 Levels of Significant Exposure to Tri-n-butyl Phosphate (TnBP) - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

a 

Key to Species 

Figure (Strain) 

Reproductive 

40 Rat 

(SpragueDawley) 

41 Rat 

(SpragueDawley) 

42 Rat 

(SpragueDawley) 

43 Mouse 

(CD-1) 

Developmental 

44 Rat 

(SpragueDawley) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

90 d ad lib (F) 18 wk 5 d/wk 1 x/d (G) 70-110 d Gd 1-20 Ld 1-20 ad lib (F) 13 wk ad lib (F) 70-110 d Gd 1-20 Ld 1-20 ad lib (F) 

NOAEL 

System (mg/kg/day) 

360 M 423 F 333 217 

1478 M 1776 F 

51 

LOAEL 

Less Serious Serious 

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

217 (reduced F1 and F2 pup 

weight during preweaning period) 

Reference Chemical Form 

FMC 1985a 126-73-8 Laham et al. 1985a 126-73-8 Tyl et al. 1997 126-73-8 

Auletta 1991 126-73-8 Tyl et al. 1997 126-73-8 
31

18218218218218218218218218218212

42 182

9

33

Table 3-3 Levels of Significant Exposure to Tri-n-butyl Phosphate (TnBP) - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ 

Duration/ 

a Frequency Key to Species (Route) Figure (Strain) 

CHRONIC EXPOSURE Systemic 

45 Rat 2 yr 

ad lib (SpragueDawley) (F) 

LOAEL 

NOAEL Less Serious Serious Reference

System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

Resp 182 F Auletta et al. 1998a 

126-73-8 

Cardio 182 F Gastro 182 F Hemato 182 F Musc/skel 182 F Hepatic 182 F Renal 182 F Endocr 182 F Dermal 182 F Ocular 182 F Bd Wt 12 F 42 F (12% reduction in final 182 F (20% reduction in final 

body weight) body weight) 

Other 9 M 33 M (urinary bladder 

hyperplasia) 
85

71171171171171128.9

169

711711711711711711

32

182

87

711

Table 3-3 Levels of Significant Exposure to Tri-n-butyl Phosphate (TnBP) - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ 

Duration/ 

a Frequency Key to Species (Route) Figure (Strain) 

46 Mouse 18 mo 

ad lib (CD-1) (F) 

Immuno/ Lymphoret 

47 Rat 2 yr 

ad lib (SpragueDawley) (F) 

48 Mouse 18 mo 

ad lib (CD-1) (F) 

System 

Resp Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr Dermal Ocular Bd Wt Other 

LOAEL 

NOAEL Less Serious Serious Reference

(mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

711 Auletta et al. 1998b 

126-73-8 

711 F711 F711 F711

28.9 M 169 M (increased absolute and

relative liver weight)

711

711 F711 F711711 F711

182 F Auletta et al. 1998a 

126-73-8 

Auletta et al. 1998b 

711 F 

126-73-8 
33

182

88

711

34

143182

89

585711

35

143

Table 3-3 Levels of Significant Exposure to Tri-n-butyl Phosphate (TnBP) - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

Neurological 

49 Rat 2 yr 182 F Auletta et al. 1998a 

(Sprague- ad lib 

126-73-8 Dawley) (F) 

50 Mouse 18 mo 711 F Auletta et al. 1998b 

ad lib (CD-1) 

126-73-8 (F) 

Reproductive 

51 Rat 2 yr 143 M Auletta et al. 1998a 

ad lib (Sprague- 

126-73-8 Dawley) (F) 

182 F 

52 Mouse 18 mo 585 M Auletta et al. 1998b 

ad lib (CD-1) 

126-73-8 (F) 

711 F 

Cancer 

53 Rat 2 yr 143 M (CEL: urinary bladder Auletta et al. 1998a ad lib (Sprague- papillomas and 126-73-8 Dawley) (F) carcinomas) 
90

585

54 

Table 3-3 Levels of Significant Exposure to Tri-n-butyl Phosphate (TnBP) - Oral (continued) 

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

Mouse 18 mo 585 M (CEL: hepatocellular Auletta et al. 1998b ad lib (CD-1) adenomas) 126-73-8 (F) 

***DRAFT FOR PUBLIC COMMENT***

a The number corresponds to entries in Figure 3-3. b Used to derive an acute-duration oral MRL of 1.1 mg/kg/day; the MRL was derived by dividing the BMDL1SD of 111.47 mg/kg/day by an uncertainty factor of 100 human extrapolation and 10 for human variability). c Used to derive an intermediate-duration oral MRL of 0.02 mg/kg/day; the MRL was derived by dividing the BMDL10 of 1.96 mg/kg/day by an uncertainty factor of to human extrapolation and 10 for human variability). d ATSDR adopted the intermediate-duration oral MRL also as chronic-duration oral MRL for TnBP. ad lib = ad libitum; Bd Wt = body weight; (C) = capsule; Cardio = cardiovascular; CEL = cancer effect level; d = day(s); Endocr = endocrine; (F) = feed; F = Female; Gastro = gastrointestinal; Gd = gestation day; (GO) = gavage in oil; Hemato = hematological; Ld = lactation day; LD50 = lethal dose, 50% kill; LOAEL = lowest-observed-adverse-effect level; M = male; Metab = metabolic; mo = month(s); Musc/skel = musculoskeletal; NOAEL = no-observed-adverse-effect level; NS Resp = respiratory; wk = week(s); x = time(s); yr = year(s) 
1

10

100

1000

10000

100000

Death

9m

1r

2r

3r

4r

5r

6r

7r 8r

Respiratory

11r

Cardiovascular

11r

Hematological

11r

11r

Hepatic

11r

11r

13r

Renal

11r

13r

Body Weight

10r 11r

12r

12r

13r

13r

Metabolic

11r

Immuno/Lymphor

14r

14r

Neurological

15r

15r

16r

16r

17r

Reproductive

18r

18r

Developmental

19r

20r

mg/kg/day

Figure 3-3 Levels of Significant Exposure to Tri-n-butyl Phosphate (TnBP) - Oral

Acute (≤14 days)

c-Cat

d-Dog

r-Rat

p-Pig

q-Cow

 -Humans

k-Monkey

m-Mouse

h-Rabbit

a-Sheep

f-Ferret

j-Pigeon

e-Gerbil

s-Hamster

g-Guinea Pig

n-Mink

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

 LOAEL, Less Serious-Animals

 NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

 LOAEL, Less Serious-Humans

 NOAEL - Humans

 LD50/LC50

 Minimal Risk Level

 for effects

 other than

 Cancer

Systemic

PHOSPHATE ESTER FLAME RETARDANTS

3. HEALTH EFFECTS 

79

***DRAFT FOR PUBLIC COMMENT***
0.01

0.1

1

10

100

1000

10000

Death

21r

Respiratory

30m

24r

26r

Cardiovascular

30m

24r

26r

Gastrointestinal

30m

22r

24r

26r

Hematological

30m

30m

31m

23r

24r

24r 26r

27r 28r

Musculoskeletal

30m

24r

Hepatic

30m

30m

24r

24r

26r

26r

28r

29r

29r

Renal

30m

22r

24r

26r

27r 28r

29r

29r

Endocrine

30m

24r

26r

Dermal

24r

Ocular

30m

24r

Body Weight

30m

22r

22r

24r

24r

25r

25r

26r

26r

27r

27r

mg/kg/day

Figure 3-3 Levels of Significant Exposure to Tri-n-butyl Phosphate (TnBP) - Oral (Continued)

Intermediate (15-364 days)

c-Cat

d-Dog

r-Rat

p-Pig

q-Cow

 -Humans

k-Monkey

m-Mouse

h-Rabbit

a-Sheep

f-Ferret

j-Pigeon

e-Gerbil

s-Hamster

g-Guinea Pig

n-Mink

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

 LOAEL, Less Serious-Animals

 NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

 LOAEL, Less Serious-Humans

 NOAEL - Humans

 LD50/LC50

 Minimal Risk Level

 for effects

 other than

 Cancer

Systemic

PHOSPHATE ESTER FLAME RETARDANTS

3. HEALTH EFFECTS 

80

***DRAFT FOR PUBLIC COMMENT***
0.01

0.1

1

10

100

1000

10000

Body Weight

28r

29r

29r

Metabolic

30m

30m

24r

24r 26r

28r

Other

30m

30m

22r

22r

24r

24r

26r

29r

29r

Immuno/Lymphor

35m

32r

33r

34r

Neurological

39m

36r

37r

37r

38r

Reproductive

43m 43m

40r 40r 41r

42r

Developmental

44r

44r

mg/kg/day

Figure 3-3 Levels of Significant Exposure to Tri-n-butyl Phosphate (TnBP) - Oral (Continued)

Intermediate (15-364 days)

c-Cat

d-Dog

r-Rat

p-Pig

q-Cow

 -Humans

k-Monkey

m-Mouse

h-Rabbit

a-Sheep

f-Ferret

j-Pigeon

e-Gerbil

s-Hamster

g-Guinea Pig

n-Mink

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

 LOAEL, Less Serious-Animals

 NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

 LOAEL, Less Serious-Humans

 NOAEL - Humans

 LD50/LC50

 Minimal Risk Level

 for effects

 other than

 Cancer

Systemic

PHOSPHATE ESTER FLAME RETARDANTS

3. HEALTH EFFECTS 

81

***DRAFT FOR PUBLIC COMMENT***
0.01

0.1

1

10

100

1000

Respiratory

46m

45r

Cardiovascular

46m

45r

Gastrointestinal

46m

45r

Hematological

46m

45r

Musculoskeletal

46m

45r

Hepatic

46m

46m 45r

Renal

46m

45r

Endocrine

46m

45r

Dermal

46m

45r

Ocular

46m

45r

Body Weight

46m

45r

45r

45r

Other

46m

45r

45r

Immuno/Lymphor

48m

47r

Neurological

50m

49r

Reproductive

52m

52m

51r

51r

Cancer *

54m

53r

mg/kg/day

Figure 3-3 Levels of Significant Exposure to Tri-n-butyl Phosphate (TNBP) - Oral (Continued)

Chronic (365 days)

c-Cat

d-Dog

r-Rat

p-Pig

q-Cow

 -Humans

k-Monkey

m-Mouse

h-Rabbit

a-Sheep

f-Ferret

j-Pigeon

e-Gerbil

s-Hamster

g-Guinea Pig

n-Mink

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

 LOAEL, Less Serious-Animals

 NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

 LOAEL, Less Serious-Humans

 NOAEL - Humans

 LD50/LC50

 Minimal Risk Level

 for effects

 other than

 Cancer

Systemic

*Doses represent the lowest dose tested per study that produced a tumorigenic

response and do not imply the existence of a threshold for the cancer endpoint.

PHOSPHATE ESTER FLAME RETARDANTS

3. HEALTH EFFECTS 

82

***DRAFT FOR PUBLIC COMMENT***
142

132785383

78

100100100100100100100100100100100

112

500

1500

79

100

Table 3-4 Levels of Significant Exposure to Tris(2-butoxyethyl) Phosphate (TBEP) - Oral 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

ACUTE EXPOSURE Death 

1 Rat Once 13278 M (LD50) Mobil Oil Corporation 19

(Fischer- 344) (G) 78-51-3 

5383 F (LD50) 

Systemic 

2 Rat 14 d Komsta et al. 1989 

Resp 100 (Sprague- 1 x/d 

78-51-3 Dawley) (GO) 

Cardio 100Gastro 100Hemato 100Musc/skel 100Hepatic 100Renal 100Endocr 100Dermal 100Bd Wt 100Metab 100

3 Rat 10 d b Bd Wt 500 F 1500 F (weight gain reduced Monsanto Co. 1985b Gd 6-15 (CD) 1 x/d 35% during Gd 6-15) 78-51-3

(GO)

Immuno/ Lymphoret 

4 Rat 14 d Komsta et al. 1989 

100 (Sprague- 1 x/d 

78-51-3 Dawley) (GO) 
80

100

77

1500

1750

3200

81

100

111

1500

Table 3-4 Levels of Significant Exposure to Tris(2-butoxyethyl) Phosphate (TBEP) - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

Neurological 

5 Rat 14 d 100 Komsta et al. 1989 

(Sprague- 1 x/d 

78-51-3 Dawley) (GO) 

6 Rat once 1500 F 1750 F (slight tremors and 3200 F (abnormal gait, tremors) Laham et al. 1985b (Sprague- (G) piloerection) 78-51-3 Dawley) 

Reproductive 

7 Rat 14 d 100 Komsta et al. 1989 

1 x/d (Sprague- 

78-51-3 Dawley) (GO) 

Developmental 

8 Rat 10 d 1500 F Monsanto Co. 1985b 

(CD) Gd 6-15 

1 x/d 78-51-3 (GO) 
98

698698698173

578

69817.3

173

698698698698698698698

99

698

100

698

Table 3-4 Levels of Significant Exposure to Tris(2-butoxyethyl) Phosphate (TBEP) - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

INTERMEDIATE EXPOSURE Systemic 

9 Rat 18 wk Reyna and Thake 1987

Resp 698 F (Sprague- ad lib 

78-51-3 Dawley) (F) 

Cardio 698 F Gastro 698 F Hemato 173 M 578 M (increased platelet

counts)

Musc/skel 698 F 

c

Hepatic 17.3 M 173 M (periportal hepatocelllar

hypertrophy)

Renal 698 FEndocr 698 FDermal 698 FOcular 698 FBd Wt 698 FMetab 698 FOther 698 F

Immuno/ Lymphoret 

10 Rat 18 wk Reyna and Thake 1987

698 F ad lib (Sprague- 

78-51-3 Dawley) (F) 

Neurological 

11 Rat 18 wk Reyna and Thake 1987

698 M (Sprague- ad lib 

78-51-3 Dawley) (F) 
102

209

698

101

578698

Table 3-4 Levels of Significant Exposure to Tris(2-butoxyethyl) Phosphate (TBEP) - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

12 Rat 18 wk 209 F 698 F (reduced conduction Reyna and Thake 1987

ad lib (Sprague- velocity in tail nerve) 78-51-3 Dawley) (F) 

Reproductive 

13 Rat 18 wk 578 M Reyna and Thake 1987

(Sprague- ad lib 

78-51-3 Dawley) (F) 

698 F 

a The number corresponds to entries in Figure 3-4. b Used to derive and acute-duration oral MRL of 4.8 mg/kg/day; the MRL was derived by dividing the BMDL1SD of 477.25 mg/kg/day by an uncertainty factor of 10human extrapolation and 10 for human variability). c Used to derive an intermediate-duration oral MRL of 0.2 mg/kg/day; the MRL was derived by dividing the BMDL10 of 21.92 mg/kg/day by an uncertainty factor of to human extrapolation and 10 for human variability). ad lib = ad libitum; Bd Wt = body weight; Cardio = cardiovascular; d = day(s); Endocr = endocrine; (F) = feed; F = Female; (G) = gavage; Gastro = gastrointestinal; day; (GO) = gavage in oil; Hemato = hematological; LD50 = lethal dose, 50% kill; LOAEL = lowest-observed-adverse-effect level; M = male; Metab = metabolic; Mumusculoskeletal; NOAEL = no-observed-adverse-effect level; Resp = respiratory; wk = week(s); x = time(s) 
1

10

100

1000

10000

100000

Death

1r

1r

Respiratory

2r

Cardiovascular

2r

Gastrointestinal

2r

Hematological

2r

Musculoskeletal

2r

Hepatic

2r

Renal

2r

Endocrine

2r

Dermal

2r

Body Weight

2r

3r

3r

Metabolic

2r

Immuno/Lymphor

4r

Neurological

5r

6r

6r 6r

Reproductive

7r

Developmental

8r

mg/kg/day

Figure 3-4 Levels of Significant Exposure to Tris(2-butoxyethyl) Phosphate (TBEP) - Oral

Acute (≤14 days)

c-Cat

d-Dog

r-Rat

p-Pig

q-Cow

 -Humans

k-Monkey

m-Mouse

h-Rabbit

a-Sheep

f-Ferret

j-Pigeon

e-Gerbil

s-Hamster

g-Guinea Pig

n-Mink

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

 LOAEL, Less Serious-Animals

 NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

 LOAEL, Less Serious-Humans

 NOAEL - Humans

 LD50/LC50

 Minimal Risk Level

 for effects

 other than

 Cancer

Systemic

PHOSPHATE ESTER FLAME RETARDANTS

3. HEALTH EFFECTS

87

***DRAFT FOR PUBLIC COMMENT***
0.1

1

10

100

1000

Respiratory

9r

Cardiovascular

9r

Gastrointestinal

9r

Hematological

9r

9r

Musculoskeletal

9r

Hepatic

9r

9r

Renal

9r

Endocrine

9r

Dermal

9r

Ocular

9r

Body Weight

9r

Metabolic

9r

Other

9r

Immuno/Lymphor

10r

Neurological

11r

12r

12r

Reproductive

13r

13r

mg/kg/day

Figure 3-4 Levels of Significant Exposure to Tris(2-butoxyethyl) Phosphate (TBEP) - Oral (Continued)

Intermediate (15-364 days)

c-Cat

d-Dog

r-Rat

p-Pig

q-Cow

 -Humans

k-Monkey

m-Mouse

h-Rabbit

a-Sheep

f-Ferret

j-Pigeon

e-Gerbil

s-Hamster

g-Guinea Pig

n-Mink

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

 LOAEL, Less Serious-Animals

 NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

 LOAEL, Less Serious-Humans

 NOAEL - Humans

 LD50/LC50

 Minimal Risk Level

 for effects

 other than

 Cancer

Systemic

PHOSPHATE ESTER FLAME RETARDANTS

3. HEALTH EFFECTS

88

***DRAFT FOR PUBLIC COMMENT***
84

2830

218

25

100

219

100 400

Table 3-5 Levels of Significant Exposure to Tris(1,3-dichloro-2-propyl) Phosphate (TDCP) - Oral 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

ACUTE EXPOSURE Death 

1 Rat once 2830 (LD50) Eldefrawi et al. 1977 (albino) (G) 13674-87-8 

Systemic 

2 Rat 10 d Bd Wt 25 F 100 F (29% decreased weight Stauffer Chemical Co. 1

Gd 6-15 (Sprague- 1 x/d gain on Gd 6-11) 13674-87-8 Dawley)

(GO)

Developmental 

3 Rat 10 d 100 F 400 F (reduced fetal viability) Stauffer Chemical Co. 1

Gd 6-15 (Sprague- 1 x/d 13674-87-8 Dawley)

(GO)
220

80808020

80

805

205

5

20

808020

80

Table 3-5 Levels of Significant Exposure to Tris(1,3-dichloro-2-propyl) Phosphate (TDCP) - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

INTERMEDIATE EXPOSURE Systemic 

4 Rat 12 mo Resp 80 Stauffer Chemical Co. 1

ad lib (Sprague- 13674-87-8 Dawley) (F) 

Cardio 80 Gastro 80 Hemato 20 M 80 M (10.6% reduction in

hemoglobin and red cellcount at 12 months)

Musc/skel 80 Hepatic 5 M 20 M (12% increase in

absolute liver weight)

b

Renal 5 M (12% increase in

absolute kidney weight)

Endocr 5 M 20 M (14% increase in

absolute thyroid weight)

Dermal 80 Ocular 80 Bd Wt 20 M 80 M (12% reduction in body

weight on week 50)
203

20020

200

20

200

200200200

221

80

222

80

223

80

202

200

Table 3-5 Levels of Significant Exposure to Tris(1,3-dichloro-2-propyl) Phosphate (TDCP) - Oral (continued) 

Exposure/ 

Duration/ 

a Frequency Key to Species (Route) Figure (Strain) 

LOAEL 

System 

Hemato Hepatic Renal Endocr Bd Wt Other 

NOAEL 

(mg/kg/day) 

200 M 

20 M 20 M 

200 M 200 M 200 M 

80 80 80 

200 M 

Less Serious Serious 

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

200 M (23% increase in relative 

liver weight) 

200 M (14% increase in 

absolute kidney weight) 

Reference Chemical Form 

Anonymous 1977 13674-87-8 

Stauffer Chemical Co. 113674-87-8 Stauffer Chemical Co. 113674-87-8 Stauffer Chemical Co. 113674-87-8 

Anonymous 1977 13674-87-8 

***DRAFT FOR PUBLIC COMMENT***

5 Rabbit 

(New Zealand) 

Immuno/ Lymphoret 

6 Rat 

(SpragueDawley) 

Neurological 

7 Rat 

(SpragueDawley) 

Reproductive 

8 Rat 

(SpragueDawley) 

9 Rabbit 

(New Zealand) 

12 wk 1 x/d (GO) 12 mo ad lib (F) 12 mo ad lib (F) 12 mo ad lib (F) 12 wk 1 x/d (GO) 
130

80808020

80

8020

80

5

20

808020

80

20

80

Table 3-5 Levels of Significant Exposure to Tris(1,3-dichloro-2-propyl) Phosphate (TDCP) - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

CHRONIC EXPOSURE Systemic 

10 Rat 24 mo Resp 80 Stauffer Chemical Co. 1

ad lib (Sprague- 13674-87-8 Dawley) (F) 

Cardio 80 Gastro 80 Hemato 20 80 (reduced hemoglobin,

hematocrit, and totalerythrocyte count)

Musc/skel 80 Hepatic 20 80 (foci/areas of

hepatocellularalterations;dilation ofsinusoids)

c

Renal 5 M 20 M (hyperplasia of

convoluted tubularepithelium)

Endocr 80 Dermal 80 Ocular 20 80 (accelerated

development ofsacculation along retinalarterioles)

Bd Wt 20 80 (21-24% reduction in final 

body weight) 
131

80

132

80

133

80

134

2020

Table 3-5 Levels of Significant Exposure to Tris(1,3-dichloro-2-propyl) Phosphate (TDCP) - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

Immuno/ Lymphoret 

11 Rat 24 mo 80 Stauffer Chemical Co. 1

(Sprague- ad lib 

13674-87-8 Dawley) (F) 

Neurological 

12 Rat 24 mo 80 Stauffer Chemical Co. 1

ad lib (Sprague- 

13674-87-8 Dawley) (F) 

Reproductive 

13 Rat 24 mo 80 Stauffer Chemical Co. 1

(Sprague- ad lib 

13674-87-8 Dawley) (F) 

Cancer 

14 Rat 24 mo 20 M (CEL: testicular interstitial Stauffer Chemical Co. 1

ad lib (Sprague- cell tumors) 13674-87-8 Dawley) (F) 

20 (CEL: renal cortical 

tumors) 

a The number corresponds to entries in Figure 3-5. b Used to derive an intermediate-duration oral MRL of 0.05 mg/kg/day; the MRL was derived by dividing the BMDL1SD of 4.69 mg/kg/day by an uncertainty factor oanimal to human extrapolation and 10 for human variability). c Used to derive a chronic-duration oral MRL of 0.02 mg/kg/day; the MRL was derived by dividing the BMDL10 of 1.94 mg/kg/day by an uncertainty factor of 100 (1human extrapolation and 10 for human variability). ad lib = ad libitum; Bd Wt = body weight; Cardio = cardiovascular; CEL = cancer effect level; d = day(s); Endocr = endocrine; (F) = feed; F = Female; (G) = gavage; gastrointestinal; Gd = gestation day; (GO) = gavage in oil; Hemato = hematological; LD50 = lethal dose, 50% kill; LOAEL = lowest-observed-adverse-effect level; M month(s); Musc/skel = musculoskeletal; NOAEL = no-observed-adverse-effect level; NS = not specified; wk = week(s); x = time(s) 
10

100

1000

10000

Death

1r

Body Weight

2r

2r

Developmental

3r

3r

mg/kg/day

Figure 3-5 Levels of Significant Exposure to Tris(1,3-dichloro-2-propyl) Phosphate (TDCP) - Oral

Acute (≤14 days)

c-Cat

d-Dog

r-Rat

p-Pig

q-Cow

 -Humans

k-Monkey

m-Mouse

h-Rabbit

a-Sheep

f-Ferret

j-Pigeon

e-Gerbil

s-Hamster

g-Guinea Pig

n-Mink

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

 LOAEL, Less Serious-Animals

 NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

 LOAEL, Less Serious-Humans

 NOAEL - Humans

 LD50/LC50

 Minimal Risk Level

 for effects

 other than

 Cancer

Systemic

PHOSPHATE ESTER FLAME RETARDANTS 94 ***DRAFT FOR PUBLIC COMMENT*** 3. HEALTH EFFECTS
0.01

0.1

1

10

100

1000

Respiratory

4r

Cardiovascular

4r

Gastrointestinal

4r

Hematological

4r

4r

5h

Musculoskeletal

4r

Hepatic

4r

4r

5h

5h

Renal

4r

5h

5h

Endocrine

4r

4r

5h

Dermal

4r

Ocular

4r

Body Weight

4r

4r

5h

Other

5h

Immuno/Lymphor

6r

Neurological

7r

Reproductive

8r

9h

mg/kg/day

Figure 3-5 Levels of Significant Exposure to Tris(1,3-dichloro-2-propyl) Phosphate (TDCP) - Oral (Continued)

Intermediate (15-364 days)

c-Cat

d-Dog

r-Rat

p-Pig

q-Cow

 -Humans

k-Monkey

m-Mouse

h-Rabbit

a-Sheep

f-Ferret

j-Pigeon

e-Gerbil

s-Hamster

g-Guinea Pig

n-Mink

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

 LOAEL, Less Serious-Animals

 NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

 LOAEL, Less Serious-Humans

 NOAEL - Humans

 LD50/LC50

 Minimal Risk Level

 for effects

 other than

 Cancer

Systemic

PHOSPHATE ESTER FLAME RETARDANTS 95 ***DRAFT FOR PUBLIC COMMENT*** 3. HEALTH EFFECTS
0.01

0.1

1

10

100

Respiratory

10r

Cardiovascular

10r

Gastrointestinal

10r

Hematological

10r

10r

Musculoskeletal

10r

Hepatic

10r

10r

Renal

10r

10r

Endocrine

10r

Dermal

10r

Ocular

10r

10r

Body Weight

10r

10r

Immuno/Lymphor

11r

Neurological

12r

Reproductive

13r

Cancer *

14r 14r

mg/kg/day

Figure 3-5 Levels of Significant Exposure to Tris(1,3-dichloro-2-propyl) Phosphate (TDCP) - Oral (Continued)

Chronic (≥365 days)

c-Cat

d-Dog

r-Rat

p-Pig

q-Cow

 -Humans

k-Monkey

m-Mouse

h-Rabbit

a-Sheep

f-Ferret

j-Pigeon

e-Gerbil

s-Hamster

g-Guinea Pig

n-Mink

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

 LOAEL, Less Serious-Animals

 NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

 LOAEL, Less Serious-Humans

 NOAEL - Humans

 LD50/LC50

 Minimal Risk Level

 for effects

 other than

 Cancer

*Doses represent the lowest dose tested per study that produced a tumorigenic

response and do not imply the existence of a threshold for the cancer endpoint.

Systemic

PHOSPHATE ESTER FLAME RETARDANTS 96 ***DRAFT FOR PUBLIC COMMENT*** 3. HEALTH EFFECTS
204

20001260

149

3200

158

6400

154

20000

135

10800

114

1500

145

5000

Table 3-6 Levels of Significant Exposure to TPP, TCPP, and TiBP - Oral 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL 

Duration/ 

a Frequency Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

ACUTE EXPOSURE Death 

1 Rat once 2000 M (4-6 hr LD50) (Sprague- (NS)

Dawley) 1260 F (5-hr LD50) 

2 Rat once 3200 (LD50s between 3200 (NS) (G) and 6400 mg/kg were 

estimated) 

3 Rat once 6400 (LD50 is greater than (NS) (NS) 6400 mg/kg) 

4 Rat once 20000 (LD50 is greater than (Wistar) (GW) 20000 mg/kg) 

5 Rat once 10800 (14-day LD50) (Sprague- (C)

Dawley)

6 Rat once 1500 F (96-hr LD50) (Wistar) (GO) 7 Rat once 5000 (LD50 is greater than (Sprague- (G) 5000 mg/kg) Dawley) 

Reference Chemical Form 

Anonymous 1977 13674-84-5 Eastman Kodak Co. 199126-71-6 EF Houghton & Co. 199115-86-6 FMC 1982 115-86-6 Johannsen et al. 1977 115-86-6 Kawasaki et al. 1982 13674-84-5 Monsanto Co. 1989a, 1126-71-6 
144

500632

150

6400

115

1000

117

893

Table 3-6 Levels of Significant Exposure to TPP, TCPP, and TiBP - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

8 Rat once 500 M (LD50 is greater than 500 Stropp 1996 (Wistar) (GO) mg/kg) 13674-84-5 

632 F (3-6 hr LD50) 

9 Mouse once 6400 (LD50s between 6400 Eastman Kodak Co. 199

(NS) (G) and 12800 mg/kg were 126-71-6 

estimated) 

Systemic 

10 Rat 7 d Bd Wt 1000 F Kawasaki et al. 1982 1 x/d (Wistar) 13674-84-5 (GO) 

INTERMEDIATE EXPOSURE Systemic 

11 Rat 20 d Bd Wt 893 F Kawasaki et al. 1982 Gd 0-20 (Wistar) ad lib 13674-84-5 

(F) 
94

40440440468

346

40468

346

404404404404404404404

73

161

345

Table 3-6 Levels of Significant Exposure to TPP, TCPP, and TiBP - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/

a Frequency Reference Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

12 Rat 13 wk Resp 404 F Naylor and Ribelin 1990 

(Sprague- ad lib 

126-71-6 Dawley) (F) 

Cardio 404 F Gastro 404 F Hemato 68 M 346 M (decreased neutrophil

count; increased MCHand MCHC)

Musc/skel 404 F Hepatic 68 M 346 M (increased serum

cholesterol)

Renal 404 FEndocr 404 FDermal 404 FOcular 404 FBd Wt 404 FMetab 404 FOther 404 F

13 Rat 4 mo Bd Wt 161 M 345 M (11% reduced body Sobotka et al. 1986 ad lib (Sprague- weight gain) 115-86-6 Dawley) (F) 
76

416416416416

74

711

95

404

96

404

72

711

141

893

Table 3-6 Levels of Significant Exposure to TPP, TCPP, and TiBP - Oral (continued) 

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Exposure/ LOAEL

Duration/

a

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

14 Rat 35 d Hemato 416 M Sutton et al. 1960 ad lib (Holtzman) 115-86-6 (F) 

Hepatic 416 M Renal 416 M Bd Wt 416 M 

Immuno/ Lymphoret 

15 Rat 120 d 711 Hinton et al. 1996 ad lib (Sprague- 115-86-6 Dawley) (F) 

16 Rat 13 wk 404 F Naylor and Ribelin 1990 ad lib (Sprague- 126-71-6 Dawley) (F) 

Neurological 

17 Rat 13 wk 404 F Naylor and Ribelin 1990 ad lib (Sprague- 126-71-6 Dawley) (F) 

18 Rat 4 mo 711 M Sobotka et al. 1986 ad lib (Sprague- 115-86-6 Dawley) (F) 

Reproductive 

19 Rat 20 d 893 F Kawasaki et al. 1982 Gd 0-20 (Wistar) ad lib 13674-84-5 

(F) 
97

346404

70

690

116

893

71

690

Table 3-6 Levels of Significant Exposure to TPP, TCPP, and TiBP - Oral (continued) 

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Exposure/ LOAEL

Duration/

a Frequency Key to Species NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

20 Rat 13 wk 346 M Naylor and Ribelin 1990 

(Sprague- ad lib 

126-71-6 Dawley) (F) 

404 F 

21 Rat 111 d 690 F Welsh et al. 1987 

(Sprague- ad lib 

115-86-6 Dawley) (F) 

Developmental 

22 Rat 20 d Kawasaki et al. 1982 

893 F Gd 0-20 (Wistar) 

ad lib 13674-84-5 (F) 

23 Rat 111 d 690 F Welsh et al. 1987 

(Sprague- ad lib 

115-86-6 Dawley) (F) 

ad lib = ad libitum; Bd Wt = body weight; (C) = capsule; Cardio = cardiovascular; d = day(s); Endocr = endocrine; (F) = feed; F = Female; (G) = gavage; Gastro = ga= gestation day; (GO) = gavage in oil; (GW) = gavage in water; Hemato = hematological; hr = hour(s); LD50 = lethal dose, 50% kill; LOAEL = lowest-observed-adve= male; Metab = metabolic; Musc/skel = musculoskeletal; NOAEL = no-observed-adverse-effect level; NS = not specified; Resp = respiratory; wk = week(s); x = tim
100

1000

10000

100000

Death

9m

1r

1r

2r

3r

4r

5r

6r

7r

8r

8r

Body Weight

10r

mg/kg/day

Figure 3-6 Levels of Significant Exposure to TPP, TCPP, And TiBP - Oral

Acute (≤14 days)

c-Cat

d-Dog

r-Rat

p-Pig

q-Cow

 -Humans

k-Monkey

m-Mouse

h-Rabbit

a-Sheep

f-Ferret

j-Pigeon

e-Gerbil

s-Hamster

g-Guinea Pig

n-Mink

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

 LOAEL, Less Serious-Animals

 NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

 LOAEL, Less Serious-Humans

 NOAEL - Humans

 LD50/LC50

 Minimal Risk Level

 for effects

 other than

 Cancer

TPP

TPP

TPP

TiBP TiBP

TiBP

TCPP

TCPP

TCPP

TCPP

TCPP

TCPP

Systemic

PHOSPHATE ESTER FLAME RETARDANTS

3. HEALTH EFFECTS 

102

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10

100

1000

Respiratory

12r

Cardiovascular

12r

Gastrointestinal

12r

Hematological

12r

12r

14r

Musculoskeletal

12r

Hepatic

12r

12r

14r

Renal

12r 14r

Endocrine

12r

Dermal

12r

Ocular

12r

Body Weight

11r

12r

13r

13r

14r

Metabolic

12r

Other

12r

Immuno/Lymphor

15r

16r

Neurological

17r

18r

Reproductive

19r

20r

20r

21r

Developmental

22r

23r

mg/kg/day

Figure 3-6 Levels of Significant Exposure to TPP, TCPP, And TiBP - Oral (Continued)

Intermediate (15-364 days)

c-Cat

d-Dog

r-Rat

p-Pig

q-Cow

 -Humans

k-Monkey

m-Mouse

h-Rabbit

a-Sheep

f-Ferret

j-Pigeon

e-Gerbil

s-Hamster

g-Guinea Pig

n-Mink

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

 LOAEL, Less Serious-Animals

 NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

 LOAEL, Less Serious-Humans

 NOAEL - Humans

 LD50/LC50

 Minimal Risk Level

 for effects

 other than

 Cancer

TiBP TiBP TiBP

TiBP

TiBP

TiBP

TiBP TiBP TiBP TiBP

TiBP

TiBP TiBP

TiBP TiBP

TiBP TiBP

TiBP

TiBP

TCPP TCPP TCPP

TPP

TPP

TPP

TPP

TPP

TPP

TPP

TPP TPP TPP

Systemic

PHOSPHATE ESTER FLAME RETARDANTS

3. HEALTH EFFECTS 

103

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PHOSPHATE ESTER FLAME RETARDANTS 104 

3. HEALTH EFFECTS 

3.2.2.2 Systemic Effects 

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

species and duration category are recorded in Tables 3-2, 3-3, 3-4, 3-5, and 3-6 and plotted in Figures 3-2, 

3-3, 3-4, 3-5, and 3-6. 

Respiratory Effects. The respiratory tract of animals has been examined in many repeated oral dose 

studies of the phosphate ester flame retardants discussed in this profile and no significant histological 

alterations have been reported. For example, no effects were noted in rats dosed daily with 350 mg 

TCEP/kg/day by gavage for up to 16 weeks (NTP 1991a) or in rats receiving dietary doses of up to 

596 mg TCEP/kg/day for 3 months (Anonymous 1977). Similarly, mice dosed daily with up to 

700 mg TCEP/kg/day for up to 16 weeks showed no alterations in the respiratory tract (NTP 1991a). No 

respiratory alterations were reported in rats or mice dosed with up to 88 or 350 mg TCEP/kg/day, 

respectively, for 2 years (NTP 1991a). 

In studies with TnBP, treatment of rats with up to 411 mg/kg/day for 14 days (Laham et al. 1984b), 

423 mg/kg/day for 90 days (FMC 1985a), 333 mg/kg/day for 18 weeks (Laham et al. 1985a), or 

182 mg/kg/day for 2 years (Auletta et al. 1998a) did not result in alterations in the respiratory tract. 

Similar findings were reported in mice dosed with up to 1,776 mg/kg/day for 13 weeks (Auletta et al. 

1991) or 711 mg/kg/day for 18 months (Auletta et al. 1998b). 

Rats dosed with up to 100 mg TBEP/kg/day for 14 days (Komsta et al. 1989) or 698 mg TBEP/kg/day for 

18 weeks (Reyna and Thacke 1987a) showed no histological alterations in the respiratory tract. Doses of 

up to 404 mg TiBP/kg/day for 13 weeks also had no significant effect on the respiratory tract of rats 

(Naylor and Ribelin 1990). Administration of up to 80 mg TDCP/kg/day to rats for 2 years did not 

induce respiratory tract alterations (Stauffer Chemical Co. 1981a). 

Cardiovascular Effects. Evaluations of the cardiovascular system have been limited to monitoring 

the weight and gross and microscopic appearance of the heart of animals. No significant alterations in 

these parameters were reported in the studies mentioned above. 

Gastrointestinal Effects. No alterations were observed in the gastrointestinal tract of rats dosed 

daily with 350 mg TCEP/kg/day by gavage for up to 16 weeks (NTP 1991a) or in rats receiving dietary 

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PHOSPHATE ESTER FLAME RETARDANTS 105 

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doses of up to 596 mg TCEP/kg/day for 3 months (Anonymous 1977). Mice dosed daily with up to 

700 mg TCEP/kg/day for up to 16 weeks showed no alterations in the gastrointestinal tract (NTP 1991a). 

No apparent alterations were reported in rats or mice dosed with up to 88 or 350 mg TCEP/kg/day, 

respectively, for 2 years (NTP 1991a). 

Rats dosed with up to 143 mg TnBP/kg/day in the diet for 10 weeks showed no significant alterations in 

the stomach (Arnold et al. 1997). Similar findings were reported in rats administered up to 423 mg 

TnBP/kg/day in the diet for 90 days (FMC 1985a) or 333 mg/kg/day by gavage for 18 weeks (Laham et 

al. 1985a). No alterations in the gastrointestinal tract were reported in mice treated with dietary doses of 

up to 1,776 mg TnBP/kg/day for 13 weeks (Auletta 1991). Longer-term studies also found a lack of 

significant alterations in the gastrointestinal tract of rats dosed with up to 182 mg TnBP/kg/day (Auletta 

et al. 1998a) for 2 years or mice dosed with up to 711 mg TnBP/kg/day for 18 months (Auletta et al. 

1998b). 

TBEP administered to rats by gavage in doses of up to 100 mg/kg/day for 14 days (Komsta et al. 1989) or 

in dietary doses of up to 698 mg/kg/day for 18 weeks (Reyna and Thacke 1987a) did not induce gross or 

microscopic alterations in the gastrointestinal tract. TDCP in dietary doses of up to 80 mg/kg/day for 

24 months also did not induce these alterations (Stauffer Chemical Co. 1981a). Administration of doses 

of up to 404 mg TiBP/kg/day to rats in the diet for up to 13 weeks did not result in alterations in the 

gastrointestinal tract (Naylor and Ribelin 1990). 

Hematological Effects. No significant alteration in hematological parameters were reported in rats 

fed diets that provided up to 586 mg TCEP/kg/day for 3 months (Anonymous 1977) or in rats treated by 

gavage with up to 88 mg TCEP/kg/day for 2 years (NTP 1991a). Similar results were reported in mice 

dosed by gavage with up to 350 mg TCEP/kg/day for 2 years (NTP 1991a). 

More information is available for TnBP. Laham et al. (1984b) reported a significant decrease in 

hemoglobin in female rats, but not male rats, dosed with 411 mg TnBP/kg/day for 14 days. At 

137 mg/kg/day, females also showed a decrease in mean corpuscular hemoglobin (MCH) and mean 

corpuscular hemoglobin concentration (MCHC), but hemoglobin concentration was not elevated in highdose females. A 90-day dietary study reported a significant increase in activated partial thromboplastin 

time in male rats dosed with 360 mg TnBP/kg/day at termination but not at the midpoint; this effect was 

not present in female rats that received doses of up to 423 mg TnBP/kg/day (FMC 1985a). The NOAEL 

in males was 68.1 mg/kg/day. Oishi et al. (1980) also reported an increase in coagulation time in rats 

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PHOSPHATE ESTER FLAME RETARDANTS 106 

3. HEALTH EFFECTS 

dosed with 460 mg TnBP/kg/day (lowest dose tested) for 10 weeks. In a 2-year study in rats dosed via 

the diet with up to 182 mg TnBP/kg/day, interim evaluations conducted at 12 months showed no 

significant alterations in hematological parameters (Auletta et al. 1988a). Similar results were reported in 

an 18-week study in rats dosed with up to 333 mg TnBP/kg/day (Laham et al. 1985a). Evaluation of 

hematological parameters in mice showed an increase in platelet counts in males dosed with 1,478 mg 

TnBP/kg/day for 13 weeks (Auletta et al. 1991), but there was no evidence of hematological alterations at 

9 months or at termination in mice dosed with up to 711 mg/kg/day in an 18-month study, although it 

appears that evaluations were limited to red blood cell and leukocyte total counts only (Auletta et al. 

1988b). 

Data for TDCP indicate that treatment of rabbits by gavage with up to 200 mg TDCP/kg/day for 12 weeks 

did not result in significant alterations in hematological parameters (Anonymous 1977). In the 2-year 

bioassay in rats, hemoglobin, hematocrit, and total erythrocyte values were often significantly lower than 

controls in high-dose rats (80 mg/kg/day), and the differences with the control group were usually more 

pronounced in males (Stauffer Chemical Co. 1981a). Hemoglobin and hematocrit were significantly 

reduced in high-dose males both at 3 and 6 months and hemoglobin was reduced in high-dose females at 

6 months. High-dose males also showed a reduction in red blood cell count at 6 months. At 12 months, 

there were significant reductions in hemoglobin in high-dose males (10.6%) and females (7.5%) and in 

red cell counts in high-dose males (10.7%). None of these alterations were observed after 24 months of 

treatment with TDCP. At 24 months, prothrombin times and partial thromboplastin times were 

significantly elevated in high-dose males; the NOAEL was 20 mg/kg/day. 

Two studies were available that provided information for TBEP. No significant hematological alterations 

were reported in rats dosed daily by gavage with up to 100 mg TBEP/kg/day for 14 days (Komsta et al. 

1989). In an 18-week study, dietary administration of TBEP resulted in statistically significant 

hematological changes that included decreased leukocyte counts (lymphocytes) in high-dose males 

(578 mg/kg/day) on week 9, increased platelet counts in high-dose males and females (698 mg/kg/day) on 

weeks 9 and 18, and increased platelet counts in mid-dose males (173 mg/kg/day) only on week 9 (Reyna 

and Thacke 1987a). 

Even less information is available for the remaining phosphate ester flame retardants discussed in this 

profile. Decreased neutrophil count and increased MCH and MCHC were reported in male rats treated 

with dietary doses of 346 mg TiBP/kg/day for 13 weeks; the NOAEL was 68 mg/kg/day (Naylor and 

Ribelin 1990). Sutton et al. (1960) reported that dietary doses of up to 416 mg TPP/kg/day for 35 days 

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PHOSPHATE ESTER FLAME RETARDANTS 107 

3. HEALTH EFFECTS 

did not alter hematological parameters in rats (red blood cell and leukocyte counts, hemoglobin content, 

and cell volume). 

Musculoskeletal Effects. No alterations in gross or microscopic morphology of bone or skeletal 

muscle have been reported in any of the studies of the phosphate ester flame retardants summarized in 

this profile. No effects were noted in rats dosed daily with 350 mg TCEP/kg/day by gavage for up to 

16 weeks (NTP 1991a) or in rats receiving dietary doses of up to 596 mg TCEP/kg/day for 3 months 

(Anonymous 1977). Similarly, mice dosed daily with up to 700 mg TCEP/kg/day for up to 16 weeks 

showed no alterations in bone or muscle (NTP 1991a). No effects were reported in rats or mice dosed 

with up to 88 or 350 mg TCEP/kg/day, respectively, for 2 years (NTP 1991a). 

Dietary administration of 423 mg TnBP/kg/day to rats for 90 days (FMC 1985a), 182 mg/kg/day to rats 

for 2 years (Auletta et al. 1998a), 1,776 mg TnBP/kg/day to mice for 13 weeks (Auletta 1991), or 

711 mg/kg/day to mice for 18 months (Auletta et al. 1998b) did not result in alterations in bone or muscle. 

Similar results were reported in rats treated with 80 mg TDCP/kg/day for 2 years (Stauffer Chemical Co. 

1981a), rats treated with 100 mg TBEP/kg/day for 14 days (Komsta et al. 1989), rats treated with 698 mg 

TBEP/kg/day for 18 weeks (Reyna and Thacke 1987a), or rats dosed with 404 mg TiBP/kg/day for 

13 weeks (Naylor and Ribelin 1990). 

Hepatic Effects. Administration of 350 mg TCEP/kg/day by gavage 5 days/week for 16 days to rats 

resulted in a significant increase (10%) in absolute and relative liver weight in females; doses of 

≥175 mg/kg/day and 350 mg/kg/day produced similar effects in females and males, respectively, after 

61 weeks of dosing; however, gross or microscopic examination of the liver did not show lesions (NTP 

1991a). Dietary administration of up to 586 mg TCEP/kg/day for 3 months to rats did not produce 

significant changes in liver weight or in gross or microscopic appearance of the liver (Anonymous 1977). 

Mice administered up to 700 mg TCEP/kg/day for 16 days by gavage had no significant changes in liver 

weight or in gross or microscopic appearance of the liver, but similar dosing with ≥175mg TCEP/kg/day 

for 16 weeks induced a significant increase in absolute and relative liver weight of females (NTP 1991a); 

the NOAEL was 88 mg/kg/day. No significant gross or microscopic alterations were reported in the liver 

in the latter experiment. In the 2-year bioassay, the liver did not appear to be a particularly sensitive 

target for TCEP. The only significant effect reported was an increase in absolute and relative liver weight 

in rats dosed with 88 mg TCEP/kg/day at week 66 interim sacrifice; the NOAEL was 44 mg/kg/day (NTP 

1991a). Clinical chemistry tests, as well as gross and microscopic examination of the liver, did not reveal 

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PHOSPHATE ESTER FLAME RETARDANTS 108 

3. HEALTH EFFECTS 

significant chemical-related alterations. In mice, doses of up 350 mg TCEP/kg/day had no significant 

effect on liver parameters (NTP 1991a). 

Treatment of male and female rats with 411 mg TnBP/kg/day by gavage for 14 days resulted in a 

significant increase in absolute and relative liver weight, and gross examination revealed slight liver 

enlargement; however, microscopic evaluation of liver tissue did not show significant alterations (Laham 

et al. 1984b). The NOAEL for liver weight was 137 mg/kg/day. In a developmental study, treatment of 

pregnant rats with up to 500 mg TnBP/kg/day on gestation days (Gd) 7–17 resulted in a 6% increase in 

absolute liver weight on Gd 20; no other liver parameter was evaluated in this study (Noda et al. 1994). 

In a 90-day study in rats, consumption of a diet containing 1,000 ppm TnBP (68.1 mg/kg/day for males 

and 80.9 mg/kg/day for females) resulted in a significant increase in absolute and relative liver weight in 

males; the NOAEL was 13.8 mg/kg/day (FMC 1985a). Increases in serum transaminases were observed 

at the midpoint in the study and at termination mainly in rats that consumed 5,000 ppm TnBP in the diet 

(360 and 423 mg/kg/day in males and females, respectively); histological evaluation of the liver did not 

reveal lesions. In a similar study, dosing rats by gavage with 333 mg TnBP/kg/day for 18 weeks induced 

a significant increase in absolute and relative liver weight in females; the NOAEL was 200 mg/kg/day 

(Laham et al. 1985a). Clinical chemistry tests as well histological examination of the liver were 

unremarkable. In a 2-generation reproductive study in rats, dietary doses of approximately ≥51mg 

TnBP/kg/day for 110 days induced a significant increase in the incidence of hepatic centrilobular 

hyperplasia only in parental females (Tyl et al. 1997); the NOAEL was 15 mg/kg/day. F1 females treated 

similarly showed the lesion, but at a higher dose level of 217 mg TnBP/kg/day. In an intermediateduration study in mice, dietary doses of ≥382 mg/kg/day significantly increased the incidence of 

centrilobular hepatocyte hypertrophy in males (Auletta et al. 1998b). Clinical chemistry tests showed 

significantly elevated serum alanine aminotransferase (ALT) and alkaline phosphatase (AP) activities in 

males dosed with 1,478 mg TnBP/kg/day and females dosed with 1,776 mg/kg/day. The NOAEL for 

hepatocyte hyperplasia in males was 95 mg/kg/day. 

The liver was not a sensitive target in male or female rats dosed with up to 143 and 182 mg TnBP/kg/day, 

respectively, for 2 years, as judged by a lack of treatment-related gross or microscopic alterations in the 

liver at termination (Auletta et al. 1998a). In a similar 18-month study in mice, nonneoplastic effects 

were limited to significant increases in absolute and relative liver weight in males and females at dietary 

doses of ≥169 and ≥206 mg TnBP/kg/day, respectively (Auletta et al. 1998b). 

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PHOSPHATE ESTER FLAME RETARDANTS 109 

3. HEALTH EFFECTS 

Less information is available for the remaining phosphate ester flame retardants subject of this profile. 

Komsta et al. (1989) conducted liver function tests, measured microsomal enzyme activities, and 

evaluated the gross and microscopic appearance of the liver of rats dosed by gavage with up to 100 mg 

TBEP/kg/day for 14 days and reported no significant alterations in any of the parameters examined. 

However, in an 18-week dietary study in rats, treatment of males with ≥173 mg TBEP/kg/day resulted in 

a significant increase in periportal hepatocellular vacuolization (Reyna and Thacke 1987a). At the next 

highest dose level, 578 mg/kg/day, the incidence of periportal hepatocellular hypertrophy was also 

significantly elevated. This was accompanied by elevations in serum gamma-glutamyl transferase (GGT) 

activity on weeks 9 and 18 of the study. No significant histopathology was reported in female rats. The 

hepatic NOAEL in males was 17.3 mg TBEP/kg/day. 

In a 12-week study with TDCP in rabbits, daily gavage doses of up to 200 mg/kg/day had no significant 

effect on clinical chemistry tests or on gross or microscopic morphology of the liver (Anonymous 1977). 

In the Stauffer Chemical Co. (1981a) bioassay, absolute liver weight was significantly increased in highdose (80 mg/kg/day) males and females (26 and 23.5%, respectively) at the 12 month interval, but there 

were no significant histoplogical alterations. In that study, extending the treatment to 24 months resulted 

in a significantly increased incidence of foci/areas of hepatocellular alterations and of dilated sinusoids in 

high-dose (80 mg/kg/day) males and females (Stauffer Chemical Co. 1981a). Gross observations 

revealed masses, nodules, and raised areas in the liver of rats in the 80 mg/kg/day groups. Clinical 

chemistry tests showed no consistent alterations throughout the study. 

In a 13-week dietary study with TiBP in rats, clinical chemistry tests at termination showed a significant 

increase in serum cholesterol in males dosed with 346 mg/kg/day. The NOAEL was 68 mg/kg/day; no 

other clinical chemistry parameter was affected (Naylor and Ribelin 1990). Neither gross nor 

microscopic examination of the liver showed treatment-related effects. The NOAEL in females was 

404 mg/kg/day. In an early study in rats, Sutton et al. (1960) reported that dietary administration of up to 

approximately 416 mg TPP/kg/day for 35 days had no significant effect on the weight of the liver; no 

other hepatic parameter was evaluated in this study. 

Renal Effects. Treatment of male and female rats with 350 mg TCEP/kg/day by gavage 5 days/week 

for 16 days significantly increased the absolute and relative weight of the kidneys in males, whereas 

similar treatment with ≥175 mg TCEP/kg/day for 16 weeks increased absolute and relative kidney weight 

in both males and females (NTP 1991a); no kidney histopathology was reported in either case. In a 

3-month dietary study in rats, doses of up to 586 mg TCEP/kg/day did not alter kidney weight or gross or 

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PHOSPHATE ESTER FLAME RETARDANTS 110 

3. HEALTH EFFECTS 

microscopic morphology (Anonymous 1977). Treatment of mice with up to 700 mg TCEP/kg/day by 

gavage for 16 days did not produce alterations in the kidneys, but similar treatment with 700 mg/kg/day 

for 16 weeks significantly reduced absolute and relative kidney weight in males (NTP 1991a). Light 

microscopy showed enlargement of the nuclei of epithelial cells in the renal tubules in all males and 

females treated with 700 mg/kg/day. These lesions were observed primarily in the proximal convoluted 

tubules of the inner cortex and outer stripe of the outer medulla, and to a lesser extent, in the outer portion 

of the loops of Henle in the outer medulla. The NOAEL was 350 mg/kg/day. 

In the 2-year bioassay in rats, the principal nonneoplastic alterations attributed to administration of TCEP 

were seen in the kidneys and consisted of focal hyperplasia of the renal tubule epithelium in high-dose 

(88 mg/kg/day) males and females; this occurred in the convoluted tubules of the cortex. The lesions 

were focal or multifocal and were characterized by stratification of the epithelial cells with partial to 

complete obliteration of the tubule lumens. The NOAEL was 44 mg/kg/day. In mice, the principal 

nonneoplastic effect associated with administration of TCEP also occurred in the kidneys. The incidence 

of karyomegaly (nuclear enlargement) of the cells in the proximal convoluted tubules of the inner cortex 

and outer stripe of the outer medulla was significantly increased in mid- (175 mg/kg/day) and high-dose 

(350 mg/kg/day) males and females (NTP 1991a). 

Daily gavage doses of up to 411 mg TnBP did not induce significant alteration in the weight or 

morphology of the kidneys (Laham et al. 1984b). Similar findings were reported in studies in rats dosed 

with up to 143 mg TnBP/kg/day for 10 weeks (Arnold et al. 1997), 423 mg/kg/day for 90 days (FMC 

1985a), or 333 mg/kg/day for 18 weeks (Laham et al. 1985a). Dose related increases in blood urea 

nitrogen (BUN) were reported in rats dosed via the diet with ≥460mg TnBP/kg/day for 9–10 weeks 

(Oishi et al. 1980, 1982), but histopathologic evaluations apparently were not conducted. Increased 

incidence of renal pelvic epithelial hyperplasia was reported in F1 males treated with 217 mg 

TnBP/kg/day in a 2-generation reproductive study (Tyl et al. 1997); the NOAEL was 51 mg/kg/day. No 

significant kidney alterations were reported in mice dosed with up to 1,776 mg TnBP/kg/day for 13 weeks 

(Auletta et al. 1991), in mice dosed with up to 711 mg/kg/day for 18 months (Auletta et al. 1998b), or in 

rats dosed with up to 182 mg/kg/day for 2 years (Auletta et al. 1998a). 

Dosing of male rabbits by gavage with 200 mg TDCP/kg/day for 12 weeks induced a significant increase 

in absolute kidney weight, but did not induce gross or microscopic alterations in the kidneys (Anonymous 

1977). In a 2-year bioassay in rats (0, 5, 20, or 80 mg/kg/day), the kidneys appeared to be the target for 

TDCP (Stauffer Chemical Co. 1981a). At the 12-month interval males and females exhibited dose-related 

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PHOSPHATE ESTER FLAME RETARDANTS 111 

3. HEALTH EFFECTS 

increases in absolute kidney weight which achieved statistical significance in the high-dose groups; 

effects were more pronounced in males than in females. Relative to controls, absolute kidney weight 

increased 12, 17, and 48% in the low-, mid-, and high-dose males, respectively. However, no significant 

histological alterations were seen at this time point. Necropsy at 24 months revealed enlargement of the 

kidney in mid- and high-dose males and high-dose females, plus higher incidence of discolorations, 

surface irregularities, masses, nodules, and cysts in treated rats than in controls. Light microscopy 

revealed a significant increase in the incidence of hyperplasia of the convoluted tubular epithelium in 

males dosed with ≥20 mg TDCP/kg/day. High-dose females also exhibited this lesion and both high-dose 

males and females showed increased incidence of chronic nephropathy. BUN was significantly elevated 

in some mid- and high-dose rats at 18 and 24 months, which was consistent with the microscopic 

evidence of renal pathology. 

Dosing of rats with up to 100 mg TBEP/kg/day for 14 days (Komsta et al. 1989) or 698 mg/kg/day for 

18 weeks (Reyna and Thacke 1987a) did not induce renal alterations, and neither did administration of up 

to 404 mg TiBP/kg/day for 13 weeks (Naylor and Ribelin 1990). Sutton et al. (1960) reported that a 

35-day dietary regime of up to 416 mg TPP/kg/day did not significantly alter the weight of the kidney in 

rats, but histological examinations were not conducted. 

Endocrine Effects. Endocrine parameters evaluated in the toxicity studies available generally 

consisted of the weight and gross and microscopic morphology of endocrine glands (i.e., thyroid, 

pituitary, adrenals). For the most part, no significant alterations were reported following oral exposure to 

the phosphate ester flame retardants discussed in this profile. No effects were noted in rats dosed daily 

with 350 mg TCEP/kg/day by gavage for up to 16 weeks (NTP 1991a) or in rats receiving dietary doses 

of up to 596 mg TCEP/kg/day for 3 months (Anonymous 1977). Similarly, mice dosed daily with up to 

700 mg TCEP/kg/day for up to 16 weeks showed no alterations in the endocrine glands (NTP 1991a). No 

alterations in endocrine glands were reported in rats or mice dosed with up to 88 or 350 mg TCEP/kg/day, 

respectively, for 2 years (NTP 1991a). 

No significant alteration in endocrine glands were noted in rats dosed with up to 423 mg TnBP/kg/day for 

90 days (FMC 1985a) or 182 mg/kg/day for 2 years (Auletta et al. 1998a), or in mice dosed with up to 

1,776 mg/kg/day for 13 weeks (Auletta et al. 1991) or 711 mg/kg/day for 18 months (Auletta et al. 

1998b). Dosing of rabbits with up to 200 mg TDCP/kg/day for 12 weeks did not produce alterations in 

the pituitary gland (Anonymous 1977). Significant increases in absolute thyroid weight were reported in 

rats dosed with up to 80 mg TDCP/kg/day for 12 or 24 months, but there were no significant histological 

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PHOSPHATE ESTER FLAME RETARDANTS 112 

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alterations (Stauffer Chemical Co. 1981a). Rats dosed with 100 mg TBEP/kg/day for 14 days (Komsta et 

al. 1989) or rats dosed with 698 mg TBEP/kg/day for 18 weeks also showed no histological alterations in 

the thyroid gland (Reyna and Thacke 1987a). A single study with TiBP reported no significant endocrine 

gland alterations in rats dosed with up to 404 mg/kg/day for 13 weeks (Naylor and Ribelin 1990). 

Dermal Effects. Many of the oral toxicity studies described above conducted gross and microscopic 

examinations of the skin and none reported chemical-related alterations. 

Ocular Effects. The eyes were examined in many toxicity studies with the phosphate ester flame 

retardants discussed in this profile and, with one exception, no significant alterations were reported. In 

the 24-month dietary study in rats dosed with 0, 20, or 80 mg TDCP/kg/day conducted by Stauffer 

Chemical Co. (1981a), ophthalmological examinations performed at 18 and 24 months revealed 

sacculations along the course of the retinal arterioles in one mid-dose male, four high-dose males, and 

four high-dose females, primarily at 24 months. Stauffer Chemical Co. (1981a) stated that this type of 

lesion is observed occasionally in old untreated rats and that, in this study, there appeared to have been an 

acceleration of this abnormal arteriolar process in some treated animals. 

Body Weight Effects. Body weight was monitored in virtually all of the toxicity studies already 

described. Food consumption was not always reported, but when information was provided, it was 

usually in absolute terms (i.e., g/day); few studies also provided relative intake (i.e., g/kg body 

weight/day. It should also be noted that differences in food consumption, and consequently in body 

weight gain, between gavage and dietary studies may be due, in part, to poor palatability of the feed. 

Body weight was not significantly affected in intermediate- and chronic duration gavage studies in rats 

and mice conducted by NTP (1991a). In the intermediate-duration studies, rats and mice received doses 

of up to 350 and 700 mg TCEP/kg/day for 16 weeks; the corresponding doses in the 2-year study were 

88 and 350 mg TCEP/kg/day. However, in a 3-month dietary study, male and female rats dosed with 

506 and 586 mg TCEP/kg/day, respectively, had a final body weight 11–18% lower than controls 

(Anonymous 1977). The lower body weight was associated with a significant reduction in food 

consumption by the end of the study. In a gestational exposure study, Hardin et al. (1987) reported that 

pregnant rats dosed with 940 mg TCEP/kg/day on Gd 6–13 experienced a 12% reduction in body weight 

gain between Gd 6 and postnatal day 3 relative to controls; food consumption data were not available. 

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Administration of up to 411 mg TnBP/kg/day by gavage for 14 days to rats had no significant effect on 

body weight (Laham et al. 1984b), but administration of 125 mg/kg/day to pregnant rats on Gd 7–17 

reduced adjusted body weight gain on Gd 0–20 by 13% relative to controls and 200 mg TnBP/kg/day 

reduced the same parameter by 37% (Noda et al. 1994). Food consumption was also significantly 

reduced. Final body weight was reduced between 10 and 20% relative to controls in rats dosed with 

143 mg TnBP/kg/day in the diet for 10 weeks (Arnold et al. 1997), 217 mg/TnBP/kg/day in the diet for 

70-110 days (Tyl et al. 1997), 360–423 mg TnBP/kg/day in the diet for 3 months (FMC 1985a), 460 mg 

TnBP/kg/day in the diet for 9 weeks (Oishi et al. 1980), 325 mg TnBP/kg/day by gavage for 13 weeks 

(Healy et al. 1995), 333 mg TnBP/kg/day by gavage for 18 weeks (Laham et al. 1985a), or 42 mg 

TnBP/kg/day in the diet for 2 years (Auletta et al. 1998a); some reduction in food consumption was 

reported in all of these studies except in Laham et al. (1985a), who did not provide information in that 

regard. Mice dosed via the diet with up to 1,776 mg TnBP/kg/day for 13 weeks (Auletta et al. 1991) or 

711 mg TnBP/kg/day for 18 months (Auletta et al. 1998b) did not experience significant alterations in 

body weight compared to controls. 

Weight gain was significantly reduced (29%) on Gd 6–11 in pregnant rats dosed with 100 mg 

TDCP/kg/day; and on Gd 6–15, rats dosed with 400 mg/kg/day lost weight (Stauffer Chemical Co. 

1981b). Food consumption during treatment days was significantly reduced relative to controls. Body 

weight gain was not affected in rabbits dosed by gavage with up to 200 mg TDCP/kg/day for 12 weeks 

(Anonymous 1977). In the 2-year bioassay, final body weight of male and female rats was reduced 21– 

24% relative to controls (Stauffer Chemical Co. 1981a). There was no consistent pattern of differences 

among groups over time regarding food consumption. 

Studies with TBEP showed no significant alterations in body weight in rats treated with gavage doses of 

up to 100 mg/kg/day for 14 days (Komsta et al. 1989) or up to 698 mg/kg/day in the food for 18 weeks 

(Reyna and Thake 1987a). TiBP also did not alter weight gain in rats in dietary doses of up to 

404 mg/kg/day for 13 weeks (Naylor and Ribelin 1990). TPP administered to rats in doses of up to 

416 mg/kg/day in the food for 35 days had no significant effect on weight gain (Sutton et al. 1960), but 

345 mg TPP/kg/day, also administered in the food, reduced weight gain by 11% (Sobotka et al. 1986); 

food consumption was not significantly altered in the latter study. TCPP administered to rats in gavage 

doses of up to 1,000 mg/kg/day for 7 days did not significantly affect weight gain (Kawasaki et al. 1982). 

Metabolic Effects. Alterations in metabolic effects, principally in mean levels of serum electrolytes, 

have been reported in studies with some phosphate ester flame retardants subject of this profile. The 

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toxicological significance of these effects is unknown. No significant alterations in serum electrolytes or 

glucose were reported in rats dosed with up to 586 mg TCEP/kg/day for 3 months (Anonymous 1977). 

Female rats dosed with ≥137 mg TnBP/kg/day for 14 days showed a dose-related increase in serum 

potassium levels, whereas no such effect was seen in males (Laham et al. 1984b); neither glucose nor 

other serum electrolytes were affected. In a 90-day study, male rats treated with 360 mg TnBP/kg/day 

had a significant increase in serum calcium levels at termination (FMC 1985a), but treatment of rats with 

up to 333 mg TnBP/kg/day for 18 weeks did not affect serum electrolytes, including calcium (Laham et 

al. 1985a). Neither sodium nor potassium levels were altered in rats dosed with 460 mg TnBP for 

9 weeks (Oishi et al. 1982). Dosing of male and female mice with 1,478 and 1,776 mg TnBP/kg/day, 

respectively, for 13 weeks induced a significant increase in serum calcium at termination; the respective 

NOAELs were 382 and 461 mg/kg/day (Auletta et al. 1991). No significant alterations in serum 

electrolytes were reported in rats dosed with up to 100 mg TBEP/kg/day for 14 days (Komsta et al. 1989), 

698 mg TBEP/kg/day for 18 weeks (Reyna and Thacke 19897a), or 404 mg TiBP/kg/day for 13 weeks 

(Naylor and Ribelin 1990). 

Other Systemic Effects. The urinary bladder of rats appears to be a sensitive target for TnBP. 

Treatment of male rats with TnBP in the diet for 10 weeks produced urothelial hyperplasia (Arnold et al. 

1997). The incidence of simple hyperplasia was significantly increased at ≥33mg TnBP/kg day, whereas 

the incidence of papillary and nodular hyperplasia was significantly increased at 143 mg/kg/day. 

Simultaneous administration of ammonium chloride (to acidify the urine and thus prevent the formation 

of magnesium ammonium phosphate crystals) did not prevent the proliferative changes in the bladder 

epithelium, but the hyperplastic effects were milder. Removing the rats from the experimental diet for 

10 weeks after treatment led to healing, but the ulcer repair process was accompanied by submucosal 

fibrosis. The NOAEL was 9 mg TnBP/kg/day. FMC (1985a) also reported increased incidence of 

minimal to moderate hyperplasia of the transitional cell epithelium and males appeared more sensitive 

than females. The incidence of urinary bladder hyperplasia was significantly increased in males dosed 

with ≥68.1 mg TnBP/kg/day, and the NOAEL was 13.8 mg/kg/day; increased incidence in females 

occurred at 423 mg/kg/day. Laham et al. (1985a) also reported this lesion in an 18-week gavage study. 

All treated rats (6/6 compared with 0/6 in controls) showed diffuse hyperplasia of the bladder epithelium; 

severity appeared greater in males. The epithelium of treated rats showed a greater frequency of 

prominent nucleoli compared to controls and was thicker than in controls, particularly in males. The 

lowest dose of TnBP in this study was 200 mg/kg/day. Tyl et al. (1997) also reported bladder epithelial in 

male and female rats dosed with ≥51 mg TnBP/kg/day for 70–110 days via the diet; the NOAEL was 

15 mg/kg/day. In the 2-year study, a significant increase in urinary bladder hyperplasia was seen in males 

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dosed with ≥33 mg TnBP/kg/day; the NOAEL was 9 mg/kg/day. Rats with benign tumors also had 

hyperplasia present; however, rats with malignant bladder tumors usually did not have any remaining 

uninvolved epithelium to evaluate for the presence or absence of hyperplasia. This led Auletta et al. 

(1991a) to speculate that the bladder hyperplasia and papillomas could represent a progression of a 

hyperplastic lesion to neoplasia. Urinary bladder lesions were not seen in mice or in rats exposed to other 

phosphate ester flame retardants subject of this profile. 

3.2.2.3 Immunological and Lymphoreticular Effects 

The information available does not suggest that the immunological system of rodents is especially 

sensitive to the effects of orally administered phosphate ester flame retardants discussed in this profile, 

although it should be mentioned that, for the most part, the testing has been limited to measurements of 

the weight of the thymus and spleen and gross and microscopic examinations of these organs and lymph 

nodes. 

In studies with TCEP that evaluated the parameters mentioned above, no significant effects were noted in 

rats dosed daily with 350 mg TCEP/kg/day by gavage for up to 16 weeks (NTP 1991a) or in rats 

receiving dietary doses of up to 596 mg TCEP/kg/day for 3 months (Anonymous 1977). Similarly, mice 

dosed daily with up to 700 mg TCEP/kg/day for up to 16 weeks showed no alterations in lymphoreticular 

tissues (NTP 1991a). Similar findings were reported in rats or mice dosed with up to 88 or 350 mg 

TCEP/kg/day, respectively, for 2 years (NTP 1991a). 

TnBP administered by gavage to rats in doses of 411 mg/kg/day for 14 days produced a significant 

decrease in absolute and relative spleen weight, but microscopic morphology was unremarkable (Laham 

et al. 1984b). Rats dosed with 423 mg/kg/day for 90 days (FMC 1985a), 333 mg/kg/day for 18 weeks 

(Laham et al. 1985a), or 182 mg/kg/day for 2 years (Auletta et al. 1998a) showed no significant 

alterations in lymphoid tissues. Similar findings were reported in mice dosed with up to 1,776 mg/kg/day 

for 13 weeks (Auletta et al. 1991) or 711 mg/kg/day for 18 months (Auletta et al. 1998b). 

The same results were reported for TBEP given to rats by gavage in doses of up to 100 mg/kg/day for 

14 days (Komsta et al. 1989) or in the diet in doses of up to 698 mg/kg/day for 18 weeks (Reyna and 

Thake 1987a). No significant alterations were observed in lymphoreticular organs of rats dosed via the 

diet with up to 404 mg TiBP/kg/day for 13 weeks (Naylor and Ribelin 1990) or up to 80 mg 

TDCP/kg/day for 12 or 24 months (Stauffer Chemical Co. 1981a). 

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Parameters of immunocompetence were evaluated in rats treated with dietary doses of up to 711 mg 

TPP/kg/day for 120 days (Hinton et al. 1996). Beginning on day 60, groups of rats were immunized with 

sheep red blood cells (SRBC). Secondary and tertiary immunizations were performed at successive 

21-day intervals. Serum was analyzed for total and relative amount of proteins. At termination, the 

weights of the spleen and thymus were measured. Treatment with TPP did not significantly affect the 

weight or the microscopic appearance of the thymus or spleen. Separate evaluations of B- and 

T-lymphocyte regions in lymphoid organs showed no significant effects on distribution and proliferation. 

Total serum protein determination showed no significant effects of TPP, although there was a positive 

trend with increasing dose. At 6 months, all treated male groups had significantly increased β-globulins 

and females had increased α-globulins, but no significant differences were seen at termination. 

Assessment of the humoral response to the T-lymphocyte-dependent antigen SRBC did not indicate 

alterations in immunocompetence due to treatment with TPP. 

The highest NOAEL values and all LOAEL values from each reliable study for immunological and 

lymphoreticular effects in each species and duration category are recorded in Tables 3-2, 3-3, 3-4, 3-5, 

and 3-6 and plotted in Figures 3-2, 3-3, 3-4, 3-5, and 3-6. 

3.2.2.4 Neurological Effects 

Acute-, intermediate-, and chronic-duration exposure of rats to TCEP has produced adverse neurological 

effects including morphological and behavioral effects. Tilson et al. (1990) administered a single dose of 

275 mg TCEP/kg by gavage to female rats and reported that the animals suffered seizures within 60– 

90 minutes of dosing, characterized by facial twitching, myoclonic motions of the jaw, forelimb clonus, 

and whole body jerks. Necropsy conducted 7 days after dosing showed severe damage to the CA1 and 

CA3 regions of the hippocampus. TCEP also produced some necrosis in the lateral and medial thalamic 

nuclei. In a separate experiment, treated rats were trained on a spatial memory task in a water maze 

3 weeks after dosing and were killed 2 days after training for histological evaluation. The results showed 

that the treated rats were mildly impaired in the acquisition of a reference memory task in the water maze, 

and were consistently impaired in performing a repeated acquisition task in the water maze. In a 16-day 

study in mice dosed daily by gavage, mice given 350 or 700 mg TCEP/kg/day exhibited ataxia and 

convulsions during the first 3 days of dosing; the NOAEL was 175 mg/kg/day (NTP 1991a). Neither 

gross nor microscopic examination of the brain at termination showed significant alterations, but it was 

not specifically indicated whether the hippocampus was examined. 

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In a 16-week study, administration of ≥175 mg TCEP/kg/day, 5 days/week to male and female rats 

induced ataxia, convulsions, excessive salivation, and gasping in some females and reduced serum 

cholinesterase activity by 25–41% (NTP 1991a). Examination of the hippocampus at termination 

revealed necrosis in 10/10 females and 2/10 males dosed with 350 mg/kg/day (the highest dose tested) 

and in 8/10 females dosed with 175 mg/kg/day; the NOAEL for these effects was 88 mg/kg/day. None of 

these effects were observed in rats dosed by gavage with the same doses for 16 days (NTP 1991a). 

Dietary doses of up to 586 mg TCEP/kg/day for 3 months did not induce alterations in the brain and did 

not affect the activity of red blood cell cholinesterase (Anonymous 1977). 

In the 2-year NTP (1991a) study (0, 44, or 88 mg/kg/day by gavage 5 days/week), there were no clinical 

signs in rats attributable to administration of TCEP, but treatment with TCEP resulted in degenerative 

lesions in the brain, mainly in high-dose females. The degenerative lesions were located in the cerebral 

cortex and brain stem, involved both the gray and white matter and were focally distributed. Specifically, 

the lesions were in the thalamus, hypothalamus, basal ganglia, and frontal and parietal cortex. Other 

affected structures included the cingulate cortex, olfactory cortex, superior colliculus, hippocampus, 

geniculate body, globus pallidus, ventral pallidum, and amygdaloid nuclear region. The lesions varied in 

severity from minimal to marked and often involved extensive areas. Active lesions were characterized 

by degeneration and necrosis with hemorrhage, while resolving lesions exhibited loss of neurons and 

neuropil, proliferation of glial cells, capillary hyperplasia, hypertrophy of the tunica media of small 

vessels, and hemosiderin-laden macrophages. Mice treated similarly with up to 350 mg TCEP/kg/day did 

not exhibit brain lesions. 

Studies with TnBP showed that a single gavage dose of 1,000 mg/kg/day induced a significant reduction 

in motor activity in rats 11 hours postdosing, but that was comparable to controls on days 7 and 

14 postdosing (Healy et al. 1995); the NOAEL was 325 mg/kg/day. A FOB performed at various time 

points during the 14-day study occasionally revealed differences between high-dose rats and controls 

(data not shown), which the investigators attributed to nonspecific toxicity rather than to neurotoxicity. In 

another acute-duration study, Laham et al. (1983) reported decreased caudal nerve conduction velocity in 

rats dosed with 411 mg TnBP/kg/day 2 days after a 14-day daily dosing. Two weeks after the last dose, 

light and electron microscopy of the nerve showed retraction of Schwann cell processes surrounding 

unmyelinated fibers. The NOAEL was 274 mg/kg/day. This dosing protocol did not alter brain weight or 

the gross or microscopic appearance of the brain, and red blood cell acetylcholinesterase activity was not 

significantly reduced (Laham et al. 1984b). There were no signs of toxicity in any of the 14-day studies. 

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Dosing male and female rats with up to 360 and 423 mg TnBP/kg/day, respectively, for 90 days had no 

significant effect on the gross or microscopic morphology of the brain, spinal cord, or sciatic nerve, or on 

red blood cell or brain cholinesterase activities measured on day 45 and at termination (FMC 1985a). In 

another 90-day study in rats treated daily by gavage with TnBP, Healy et al. (1995) reported that 

postdosing salivation occurred rarely at 32.5 mg/kg/day, frequently at 100 mg/kg/day, and almost all the 

time at 325 mg/kg/day. An FOB conducted at various times during the dosing period showed no 

significant alterations, and light microscopy of unspecified tissues of the nervous system was 

unremarkable. In yet another intermediate-duration study, gavage doses of up to 333 mg TnBP/kg/day 

for 18 weeks reduced red blood cell cholinesterase only by 9% in females and had no significant effect on 

brain weight or morphology (Laham et al. 1985a). Dietary treatment of rats with up to 182 mg 

TnBP/kg/day for 2 years (Auletta et al. 1998b) or mice with up to 711 mg/kg/day for 18 months did not 

induce clinical signs or produce histopathology in the brain, spinal cord, or sciatic nerve. 

Less information is available for other phosphate ester flame retardants. Female rats administered a 

single gavage dose of ≥3,200 mg TBEP/kg showed abnormal gait, piloerection, and tremors during the 

first week after dosing; these signs were also seen in some females dosed with 1,750 mg/kg (Laham et al. 

1985b). Males exhibited similar signs at ≥8,000 mg/kg. Exposure of rats to up to 100 mg TBEP/kg/day 

by gavage for 14 days did not produce alterations in the weight or histology of the brain (Komsta et al. 

1989). In the only long-term studies available with TBEP, 18-week dosing of male and female rats with 

up to 578 and 698 mg TBEP/kg/day, respectively, did not produce adverse clinical signs or induce gross 

or microscopic alterations in the brain or sciatic nerve (Reyna and Thacke 1987a), but induced a reduction 

in nerve conduction velocity in females (Reyna and Thake 1987b). Red blood cell cholinesterase activity 

was significantly reduced in all treated groups of females at week 9, but not at week 18; the magnitude of 

the reduction was not provided (Reyna and Thacke 1987a). 

The only information available for TDCP is that from a 24-month bioassay in which rats received dietary 

doses of 0, 20, or 80 mg TDCP/kg/day (Stauffer Chemical Co. 1981a). TDCP did not induce clinical 

signs or morphological alterations in the brain or spinal cord. Changes in red blood cell cholinesterase 

measured throughout the study were inconsistent. 

Administration of dietary doses of up to 346 and 404 mg TiBP/kg/day to male and female rats, 

respectively, for 13 weeks did not induce clinical signs or produce morphological alterations in the brain, 

spinal cord, or sciatic nerve (Naylor and Ribelin 1990). A 4-month study with TPP in rats receiving up to 

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711 mg TPP/kg/day via the diet reported no treatment-related effects in a battery of behavioral tests 

administered at various intervals, which included assessment of motility, balance, coordination, and 

muscular strength (Sobotka et al. 1986). 

The highest NOAEL values and all LOAEL values from each reliable study for neurological effects in 

each species and duration category are recorded in Tables 3-2, 3-3, 3-4, 3-5, and 3-6 and plotted in 

Figures 3-2, 3-3, 3-4, 3-5, and 3-6. 

3.2.2.5 Reproductive Effects 

No significant alterations were noted in the weight or gross or microscopic appearance of the reproductive 

organs of male or female rats dosed daily with 350 mg TCEP/kg/day by gavage for up to 16 weeks (NTP 

1991a) or of rats receiving dietary doses of up to 596 mg TCEP/kg/day for 3 months (Anonymous 1977). 

Similarly, mice dosed daily with up to 700 mg TCEP/kg/day for up to 16 weeks showed no alterations in 

the reproductive organs (NTP 1991a). No alterations were reported in the reproductive organs of rats or 

mice dosed by gavage with up to 88 or 350 mg TCEP/kg/day, respectively, for 2 years (NTP 1991a). 

The effects of TCEP on fertility of CD-1 mice were examined in a continuous breeding protocol study 

(NTP 1991b). Pairs of mice were administered TCEP in doses of 0, 175, 350, or 700 mg/kg/day by 

gavage in corn oil for 1 week during cohabitation, 14 weeks postmating, and 3 additional weeks. End 

points evaluated included clinical signs, body weight, fertility, litters per pair, live pups per litter, 

proportion of pups born alive, sex ratio, and neonatal pup weight. The last F1 litter was reared by the dam 

until weaning, after which time the F1 rats were treated as were the F0 generation. The F1 rats were used 

to assess second generation fertility. Dosing with TCEP significantly reduced the number of litters 

produced by mid- and high-dose F0 mice. Only 2/18 pairs delivered a third litter in the high-dose group 

versus 37/38 in the controls. The number of pairs that delivered a fifth litter in the mid-dose group was 

also significantly reduced. Cumulative days to litter were also significantly increased in the high-dose 

group starting with the second litter. Cross-mating experiments conducted with controls and high-dose 

mice to determine the affected sex showed that both sexes were adversely affected, but the males were 

relatively more sensitive, as all sperm end points examined (concentration, motility, and percent 

abnormal) were affected. Mating of the F1 generation showed no significant effect on pregnancy or 

fertility indices. 

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Daily administration of 411 mg TnBP/kg/day by gavage for 14 days to male and female rats induced 

degenerative changes in about 50% of the seminiferous tubules in one out of four males examined 

(Laham et al. 1984b). The tubules showed varying degrees of aspermatogenesis; spermatocytes and 

spermatids were the cells most frequently affected. The NOAEL was 137 mg/kg/day. No significant 

alterations were reported in the ovaries. No significant gross or microscopic alterations were reported in 

the reproductive organs of male and female rats that received dietary doses of up to 423 mg TnBP/kg/day 

for 90 days (FMC 1985a) or 333 mg/kg/day by daily gavage for 18 weeks (Laham et al. 1985a), or in 

mice dosed with up to 1,776 mg/kg/day in the diet for 90 days (Auletta et al. 1991). In a 2-generation 

reproductive toxicity study in rats dosed with up to 217 mg TnBP/kg/day, there were no significant 

reproductive effects in either the F0 or F1 generations, including mating and fertility, and no effects on 

gross and microscopic appearance of the reproductive organs (Tyl et al. 1997). In rats dosed for 2 years 

with up to 182 mg TnBP/kg/day (Auletta et al. 1998a) or mice dosed with up to 711 mg TnBP/kg/day for 

18 months (Auletta et al. 1998b), examination of the reproductive organs showed no significant gross or 

microscopic alterations. 

Daily administration of up to 100 mg TBEP/kg/day to rats by gavage for 14 days did not significantly 

affect the weight or gross or microscopic morphology of the testes or ovaries (Komsta et al. 1989). 

Similar findings were reported in rats that consumed doses of up to 698 mg TBEP/kg/day via the diet for 

18 weeks (Reyna and Thacke 1987a). 

TDCP was tested for its effects on fertility in male rabbits (Anonymous 1977) by dosing the rabbits by 

gavage with up to 200 mg TDCP/kg/day for 12 weeks. During the last week of treatment, male fertility 

was tested by mating the males with untreated females. Fertility was assessed by sacrificing the females 

at mid-gestation and evaluating their uteri. After the mating period, the males were sacrificed and sperm 

from the cauda epididymides were analyzed for motility, morphology, and concentration. The results 

showed no alterations in mating behavior, fertility, or sperm quantity and quality. Neither gross necropsy 

nor microscopic examinations revealed significant alterations in the reproductive tract. In the 2-year 

bioassay with TDCP, dietary doses of up to 80 mg TDCP/kg/day had no significant effect on the gross or 

microscopic morphology of the reproductive organs of males or females (Stauffer Chemical Co. 1981a). 

Fertility indices (number pregnant, corpora lutea, implantations, implantation efficiency, resorptions) 

were not affected in male or female rats dosed with up to 690 mg TPP/kg/day through the diet for 91 days 

before mating (Welsh et al. 1987). Feeding rats a diet that provided up to 404 mg TiBP/kg/day for 

13 weeks also did not affect the gross or microscopic anatomy of the reproductive organs. Dietary 

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administration of up to 893 mg TCPP/kg/day to rats on Gd 0–20 had no significant effect on the number 

of implantations or resorptions (Kawasaki et al. 1982). 

The highest NOAEL values and all LOAEL values from each reliable study for reproductive effects in 

each species and duration category are recorded in Tables 3-2, 3-3, 3-4, 3-5, and 3-6 and plotted in 

Figures 3-2, 3-3, 3-4, 3-5, and 3-6. 

3.2.2.6 Developmental Effects 

The developmental effects of TCEP have been studied in rats and mice. In rats, administration of up to 

200 mg TCEP/kg/day by gavage in oil on Gd 7–15 did not significantly affect the number of live fetuses, 

sex ratio, or fetal weight measured on Gd 20 (Kawashima et al. 1983a). In addition, treatment with TCEP 

had no significant effect on the incidence of skeletal malformations or on postnatal viability monitored up 

to postnatal week 10. Behavioral and motor tests conducted on the offspring, including open field 

activity, performance in a water maze, balance, pain reflexes, and hearing reflexes, did not reveal 

significant differences between treated and control rats. Hardin et al. (1987) conducted a preliminary 

assay of developmental toxicity of TCEP in mice dosed by gavage with 940 mg TCEP/kg/day (only dose 

level tested) on Gd 6–13. At delivery, the number of live pups was recorded and live pups were weighed 

as a litter. Neither live pups nor dead pups were systematically examined for malformations. Dosing 

with TCEP had no significant effects on the number of viable litters, number of live pups born per litter, 

percent survival of pups, birth weight, or pup weight gain. In the continuous breeding protocol study 

conducted by NTP (1991b), treatment of the F0 generation with ≥350 mg TCEP/kg/day significantly 

reduced the number of live pups per litter. In addition, the number of F2 male pups per litter born to the 

treated F1 generation was significantly lower than in controls in the groups dosed with ≥175mg 

TCEP/kg/day, the lowest dose level tested; a developmental NOAEL was not identified in the study. 

Studies conducted by Noda et al. (1994) with TnBP showed lack of developmental toxicity for this 

chemical even in the presence of frank maternal toxicity. Treatment of pregnant female rats by gavage on 

Gd 7–17 with up to 500 mg/kg/day resulted in piloerection, wetting of abdominal hair with urine, and 

salivation during the treatment, but these effects disappeared after the last treatment. Adjusted body 

weight gain from Gd 0–20 was reduced 13% at 125 mg/kg/day, 39% at 250 mg/kg/day, and 63% at 

500 mg/kg/day. Gravid uterus weight was not affected. All pregnant rats had living fetuses on Gd 20. 

There was no significant difference between groups in the number of corpora lutea, implants or living 

fetuses, incidence of dead or resorbed fetuses, sex ratio, or body weight of the living fetuses. There was 

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PHOSPHATE ESTER FLAME RETARDANTS 122 

3. HEALTH EFFECTS 

only one malformation that occurred in the 125 mg/kg/day group in which there were conjoined twins. 

No increases in visceral anomalies were reported. In a 2-generation reproduction study, the only 

significant developmental effect attributed to treatment with TnBP was a reduction in F1 and F2 pup 

weight per litter measured 5 times from postnatal days 0–21 at maternal doses of approximately 

217 mg/kg/day; the number of pups per litter was comparable among groups (Tyl et al. 1997). Significant 

reductions in maternal body weight also occurred at this level, which may have contributed to the 

decrease in pup weight. 

Monsanto (1985b) conducted a gestational exposure study with TBEP. Pregnant rats were treated with up 

to 1,500 mg TBEP/kg/day by gavage on Gd 6–15 and sacrifices were conducted on Gd 20. Immediately 

after sacrifice, the uterus and ovaries were exposed and the number and location of viable and nonviable 

fetuses, early and late resorptions, and number of total implantations and corpora lutea were recorded. 

Fetuses were weighed, sexed, and examined for external malformations and variations. Fetuses were then 

prepared for visceral and skeletal examinations. No significant alterations were reported in any of the 

developmental parameters evaluated. Some dams in the 1,500 mg/kg/day group occasionally exhibited 

signs of toxicity after dosing such as ataxia and lethargy, and gained significantly less weight than control 

rats. 

A study with TDCP evaluated litter data, and fetal development (visceral abnormalities and skeletal 

anomalies) following exposure of pregnant rats to up to 0, 25, 100, or 400 mg TDCP/kg/day on Gd 6–15 

(Stauffer Chemical Co. 1978f); sacrifices were conducted on Gd 19. There was no effect on number of 

corpora lutea or implantations. A statistically higher incidence of resorptions was found in rats dosed 

with 400 mg/kg/day, but the number per litter was not statistically increased. Fetal viability was 

significantly decreased in high-dose rats (86.6 vs. 93.3% in controls). Mean fetal weight and length were 

lower in high-dose rats, but the difference with controls was <10%. Decreased skeletal development 

(incomplete ossification of various bones) was noted in high-dose fetuses. Maternal final body weight of 

the high-dose group was significantly lower (16%) than in controls. During Gd 6–11, body weight gain 

of the mid-dose group was significantly lower (30%) than controls, and high-dose rats lost weight. A 

developmental NOAEL of 100 mg/kg/day was defined in this study; the maternal NOAEL was 

25 mg/kg/day. 

Information regarding developmental effects of TPP is available in a study by Welsh et al. (1987). Male 

and female rats were fed a diet containing TPP for 91 days before mating and the females continued in the 

experimental diets during gestation and lactation. Cesarean sections were performed on Gd 20. The 

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PHOSPHATE ESTER FLAME RETARDANTS 123 

3. HEALTH EFFECTS 

investigators estimated that during Gd 0–20, the females consumed up to 690 mg TPP/kg/day. Treatment 

with TPP had no significant effect on fetal parameters (viability, early or late deaths, fetal weight, length 

or distribution) or skeletal anomalies. Although the incidence of some specific soft-tissue variations 

seemed higher in treated rats than in controls, Welsh et al. (1987) stated that because the baseline 

incidence in controls was also high and there was no clear dose-response, the significance of the finding 

was unclear. Dietary administration of up to 893 mg TCPP/kg/day to rats on Gd 0–20 had no significant 

effects on fetal weight or incidences of external malformations (Kawasaki et al. 1982). Cervical ribs, 

missing ribs, and delayed ossification of sternebrae were more frequent in the treated groups but the 

difference with controls was not significant. Neonatal growth and viability during the 4 weeks after 

weaning was comparable among groups. 

The highest NOAEL values and all LOAEL values from each reliable study for developmental effects in 

each species and duration category are recorded in Tables 3-2, 3-3, 3-4, 3-5, and 3-6 and plotted in 

Figures 3-2, 3-3, 3-4, 3-5, and 3-6. 

3.2.2.7 Cancer 

Information regarding the carcinogenic potential of TCEP, TnBP, and TDCP was available in the 

literature reviewed. 

NTP (1991a) conducted 2-year bioassays in Fischer-344/N rats and B6C3F1 mice. Rats were dosed by 

gavage once per day, 5 days/week for 104 weeks with 0, 44, or 88 mg TCEP/kg/day. Survival was 

reduced in high-dose males and females. Females that died early frequently had brain lesions, while 

males did not. Interim sacrifices (10/sex/group) on week 66 revealed an adenoma of the renal tubule in 

one high-dose male; no other neoplastic lesions were reported at this time point. Treatment with TCEP 

resulted in the following significant increased incidences of neoplastic lesions (overall rates): (1) renal 

tubule adenomas (1/50, 5/50, 24/50) renal tubule adenoma or carcinomas (2/50, 5/50, 25/50) in high-dose 

males; and renal tubule adenomas (0/50, 2/50, 5/50) in high-dose females (the adenomas occurred in the 

cortex and consisted of cells morphologically similar to those in foci of renal tubule epithelial 

hyperplasia); (2) benign granular cell tumors of the brain in high-dose males (0/50, 0/50, 3/50); and 

(3) follicular cell adenoma or carcinoma of the thyroid in high-dose females (0/50, 3/50, 4/50). 

Mononuclear cell leukemia was also elevated in treated rats, but the incidences were within the range of 

historical controls. NTP (1991a) concluded that there was clear evidence of carcinogenic activity for 

male and female rats based on the increased incidence of renal tubule adenomas. 

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PHOSPHATE ESTER FLAME RETARDANTS 124 

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Mice were treated in the same manner with doses of 0, 175, or 350 mg TCEP/kg/day (NTP 1991a). 

Survival rate in mice was not significantly affected by treatment with TCEP. An initial analysis of the 

kidneys showed adenomas of the renal tubule in one control male, one high-dose male, and one low-dose 

female, and a carcinoma in a second high-dose male. Because of the rare occurrence of renal tubule 

neoplasms in male B6C3F1 mice, the remaining portions of the kidneys were processed to produce 

additional sections per mouse for light microscopy examination. The results of a combined initial and 

second analysis of incidences of renal neoplasms yielded the following results: male adenomas 1/50, 

1/50, 3/50; male adenocarcinoma, 0/50, 0/50, 1/50; and female adenoma, 0/50, 1/49, 0/50. Based on these 

results, NTP (1991a) concluded that there was equivocal evidence of carcinogenic activity for male mice. 

Female mice showed an increased incidence of tumors of the Harderian gland (3/50, 8/50, 7/50, not 

significant) which became significant at the high-dose if data for the interim evaluation and termination 

were combined (3/59, 8/60, 10/60). Based on these results, NTP (1991a) concluded that there was 

equivocal carcinogenic activity for female mice. 

Takada et al. (1989) also conducted a bioassay with TCEP in ddY mice. Mice were fed TCEP in the diet 

at 0, 0.012, 0.06, 0.3, and 1.5% for 18 months. Assuming a mean body weight of 0.045 kg and daily food 

consumption of 0.004 kg/day from graphs in the paper, the diet provided approximately 0, 11, 53, 267, 

and 1,333 mg TCEP/kg/day. Treatment with TCEP significantly increased the incidences of renal cell 

adenomas and carcinomas in high-dose males (2/50, 0/49, 2/49, 5/47, and 41/50), hepatocellular 

adenoma/carcinoma in the two highest male groups (4/50, 5/49, 7/49, 12/47, and 19/50), forestomach 

papillomas/squamous cell carcinomas in high-dose females (0/49, 0/49, 0/50, 1/49, and 7/50), and 

leukemia in the two highest female groups (1/49, 3/49, 6/50, 9/49, and 9/50). 

Auletta et al. (1998a; 1998b) examined the carcinogenicity of TnBP in Sprague-Dawley rats and CD1 mice. TnBP was administered in the diet to rats at levels that provided 0, 9, 33, or 143 mg TnBP/kg/day 

to males and 0, 12, 42, or 182 mg TnBP/kg/day to females. Treatment with TnBP did not affect survival. 

Neoplastic lesions were restricted to the urinary bladder. The incidence of urinary bladder papillomas 

was significantly increased in high-dose males and females; transitional cell carcinomas were also 

significantly increased in males. The incidences of combined papillomas, squamous cell carcinoma, and 

transitional cell carcinomas was 0/50, 0/50, 2/49, and 30/49 in males and 0/50, 0/50, 0/49, and 2/49 in 

females. Most of the hyperplastic and neoplastic lesions were not associated with calculi, but when 

calculi were present, they were usually associated with hyperplasia and/or neoplasia. Rats found to have 

papillomas (benign tumors) often had hyperplasia present. In contrast, rats with malignant bladder tumors 

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PHOSPHATE ESTER FLAME RETARDANTS 125 

3. HEALTH EFFECTS 

usually did not have any remaining uninvolved epithelium to evaluate for the presence or absence of 

hyperplasia. 

In mice, the experimental diets provided doses of 0, 28.9, 169, or 585 mg TnBP/kg/day to males and 0, 

24.1, 206, or 711 mg TnBP/kg/day to females. Survival was not affected by treatment with TnBP. 

Increased incidence of neoplasms was seen only in the liver of male mice. The incidences of 

hepatocellular adenomas in males were 3/50, 6/50, 7/50, and 10/50 with increasing doses; the highest 

dose level achieved statistical significance. The incidence of malignant liver tumors was comparable 

between controls and treated males. In females, there was no significant association between tumor 

incidences and treatment with TnBP. 

TDCP was tested only in rats (Stauffer Chemical Co. 1981a). Male and female Sprague-Dawley rats 

were fed a diet that provided 0, 20, or 80 mg TDCP/kg/day for 2 years. Mortality was comparable among 

groups during the first year of the study, but it increased in high-dose males during the second year and 

was significantly higher than controls at termination. The incidence of neoplastic nodules in the liver of 

high-dose males and females was significantly increased (2/45, 7/48, 1/48, 13/46 in males and 1/49, 1/47, 

4/46, 8/50 in females) and the incidence of hepatocellular carcinomas was also increased in high-dose 

males (1/45, 2/48, 3/48, 7/46). In the kidney, both mid- and high-dose males and females had 

significantly increased incidence of renal cortical tumors (1/45, 3/49, 9/48, 22/36 in males; 0/49, 1/48, 

8/48, 25/50 in females). In the testes, interstitial cell tumors were significantly increased in mid- and 

high-dose males (7/43, 8/48, 23/47, 32/45), whereas adrenocortical adenomas were significantly increased 

in high-dose females (8/48, 5/27, 2/33, 19/49). 

3.2.3 Dermal Exposure 

3.2.3.1 Death 

No reports of deaths in humans following dermal exposure to the selected phosphate ester flame 

retardants were located in the reviewed literature. 

No deaths occurred among an unspecified number of rabbits applied a dose of 5,000 mg TCEP/kg and 

observed for 14 days (Anonymous 1977). Application of 10–20 mL TnBP/kg to guinea pigs for 24 hours 

under occluded conditions resulted in an estimated dermal LD50 between 9,727 and 19,454 mg/kg 

(Eastman Kodak Co. 1968). Other studies reported dermal LD50 values >3,100, >10,000, and 

>4,640 mg/kg for TnBP in rabbits (Johannsen et al. 1977; MacKellar 1976; Stouffer Chemical Co. 1973). 

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PHOSPHATE ESTER FLAME RETARDANTS 126 

3. HEALTH EFFECTS 

No deaths were reported in rabbits applied a dose of 4,640 mg TDCP/kg to the skin for 24 hours and 

observed for 14 days (Stauffer Chemical Co. 1981b). Application of 23,700 mg TDCP/kg also did not 

cause lethality among rabbits, but induced signs of cholinergic stimulation (Stauffer Chemical Co. 

1981b). Dermal LD50 values >5,000 and >10,000 mg/kg were estimated for TiBP in guinea pigs and 

rabbits, respectively (Eastman Kodak Co. 1990; Monsanto Co. 1989a, 1989b). Johannsen et al. (1977) 

reported that the dermal LD50 for TPP in rabbits was >7,900 mg/kg, whereas FMC (1982) estimated an 

oral LD50 >10,000 mg/kg for TPP in rabbits. Additional information regarding acute lethal doses or LD50 

values of dermally-applied phosphate ester flame retardants can be found in IPCS (1991a, 1991b, 1998, 

2000b). 

Dermal lethal doses and/or dermal LD50 values are presented in Table 3-7. 

3.2.3.2 Systemic Effects 

With the exception of dermal and ocular effects, most of the information summarized below is derived 

from two 3-week studies of TBEP and TPP in rabbits (Monsanto Co. 1979, 1985d). 

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

species and duration category are recorded in Table 3-7. 

Respiratory Effects. The only relevant information is that application of up to 1,000 mg TPP/kg/day 

onto a clipped intact or abraded area of the back of rabbits 5 days/week for 3 weeks did not result in gross 

or microscopic alterations in the lungs (Monsanto Co. 1979). 

Cardiovascular Effects. A 3-week study reported that daily applications of up to 1,000 mg 

TPP/kg/day onto the clipped intact or abraded area of the back of rabbits had no effect on the gross or 

microscopic morphology of the heart (Monsanto Co. 1979). 

Gastrointestinal Effects. No gross or microscopic alterations were reported in the gastrointestinal 

tract of rabbits that received daily applications of up to 1,000 mg TPP/kg/day on a clipped intact or 

abraded area on the back 5 days/week for 3 weeks (Monsanto Co. 1979). 

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182

mg/kg

151

mg/kg

208 mg/kg/day153

mg/kg

136 mg/kg137 mg/day175

mg/kg

146

mg/kg

Table 3-7 Levels of Significant Exposure to Selected Phosphate Esters - Dermal 

Exposure/ LOAEL

Duration/

Species Frequency Reference (Route) (Strain) System NOAEL Less Serious Serious Chemical Form 

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ACUTE EXPOSURE 

Death 

Gn Pig 24 hr Eastman Kodak Co. 196

9727 (LD50 is 9727-19454 (NS) (NS) mg/kg mg/kg) 126-73-8

Gn Pig once Eastman Kodak Co. 199

10000 (the LD50 was greater (NS) (NS) mg/kg than 10000 mg/kg) 126-71-6 

Rabbit Anonymous 1977 5000 (LD50 is greater than (New (NS) 

Zealand) mg/kg/day 5000 mg/kg) 115-96-8 Rabbit once FMC 1982 10000 (LD50 is greater than (NS) (NS) mg/kg 10000 mg/kg) 115-86-6 Rabbit 24 hr Johannsen et al. 1977 7900 B (The LD50 was greater (New than 7900 mg/kg) 115-86-6 Zealand) mg/kg 

Rabbit 24 hr Johannsen et al. 1977 3100 B (the LD50 was greater (New than 3100 mg/kg) 126-73-8 Zealand) mg/day Rabbit MacKeller 1976 10000 (LD50 is greater than (NS) (NS) mg/kg 10000 mg/kg) 126-73-8 

Rabbit NS Monsanto Co. 1989a, 1

5000 (the LD50 was greater (NS) (NS) mg/kg than 5000 mg/kg) 126-71-6 
186 mg/kg

167 mg/kg210

mg/kg/day

197

mg/kg

181

g/kg

169

mg/kg

215

mg

Table 3-7 Levels of Significant Exposure to Selected Phosphate Esters - Dermal (continued) 

Exposure/ LOAEL

Duration/

Species Frequency Reference (Route) (Strain) System NOAEL Less Serious Serious Chemical Form 

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Rabbit (New Zealand) Rabbit (New Zealand) Rabbit (NS) 

Systemic 

Rat (NS) Gn Pig (NS) Gn Pig (NS) Gn Pig (Hartley) 

24 h Stauffer Chemical Co. 1

4640 (LD50 is greater than (NS) mg/kg 4640 mg/kg) 126-73-8 

24 h Stauffer Chemical Co. 1

4640 (LD50 is greater than (NS) mg/kg 4640 mg/kg) 13674-87-8 

once Stauffer Chemical Co. 1

23700 (LD50 is greater than (NS) mg/kg/day 23700 mg/kg) 13674-87-8 

Dermal Akzo Chemical Inc 1991 750 (NS) mg/kg 126-73-8

24 hr Dermal Eastman Kodak Co. 196

20 (severe skin irritation) (NS) 126-73-8 g/kg 

once Dermal Eastman Kodak Co. 199

5000 (moderate edema) (NS) mg/kg 126-71-6

Dermal Socma 1990 0.3 B (NS) 

mg 126-73-8
206 mg

171

Percent (%)

172

Percent (%)

201 ml156

ml

157

ml

200 ml

Table 3-7 Levels of Significant Exposure to Selected Phosphate Esters - Dermal (continued) 

Exposure/ LOAEL

Duration/

Species Frequency Reference (Route) (Strain) System NOAEL Less Serious Serious Chemical Form 

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Rabbit once Ocular 10 Anonymous 1977 (New (NS) 

mg 115-96-8 Zealand) 

Rabbit Ocular Dow Chemical Co. 1956 100 (moderate immediate (NS) (NS) Percent (%) pain with slight 126-73-8 conjunctival irritation) 

Rabbit Dermal Dow Chemical Co. 1956 10 (slight hyperemia and (NS) (NS) Percent (%) moderate necrosis) 126-73-8 

Rabbit 24 hr Dermal FMC 1979, 1981 0.5 B (mild skin irritation) (New (NS) 126-73-8 Zealand) ml 

Rabbit once Dermal FMC 1982 0.5 (NS) (NS) ml 115-86-6Rabbit once Ocular FMC 1982 0.1 (mild eye irritation) (NS) (NS) ml 115-86-6

Rabbit 4 hr Dermal Mobil Oil Corporation 19

0.5 (mild skin irritation) (New (NS) 126-73-8 Zealand) ml 
148 ml

188 ml191

ml

199

mg

214

mg/kg

Table 3-7 Levels of Significant Exposure to Selected Phosphate Esters - Dermal (continued) 

Exposure/ LOAEL

Duration/

Species Frequency Reference (Route) (Strain) System NOAEL Less Serious Serious Chemical Form 

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Rabbit 4 hr Dermal Monsanto Co. 1989a, 1

0.5 B (slight erythema) (New (NS) 126-71-6 Zealand) ml 

Rabbit once Ocular Stauffer Chemical Co. 1

0.1 (New (NS) ml 126-73-8 Zealand) 

Rabbit once Ocular Union Carbide Corp 194

0.02 (necrosis) (NS) (NS) ml 126-73-8

Immuno/ Lymphoret 

Gn Pig Dermal Socma 1990 0.3 B (Hartley) (NS) 

mg 126-73-8

Neurological 

Rabbit once Stauffer Chemical Co. 1

23700 (diarrhea, pupillary (NS) (NS) mg/kg constriction, depressed 13674-87-8 RBC cholinesterase) 
126 mg/kg/day 

mg/kg/day

mg/kg/day

mg/kg/day

mg/kg/day

mg/kg/day

mg/kg/day

mg/kg/day

mg/kg/day

mg/kg/day

mg/kg/day

Table 3-7 Levels of Significant Exposure to Selected Phosphate Esters - Dermal (continued) 

Exposure/ LOAEL

Duration/

Species Frequency Reference (Route) (Strain) System NOAEL Less Serious Serious Chemical Form 

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INTERMEDIATE EXPOSURE 

Systemic 

Rabbit 3 wk Resp (New 5 d/wk 

Zealand) 1 x/d 

Cardio 

Gastro 

Hemato 

Musc/skel 

Hepatic 

Renal 

Endocr 

Dermal 

Ocular 

Bd Wt 

Monsanto Co. 1979 

1000 B 

mg/kg/day 115-86-6 

1000 B 

mg/kg/day 

1000 B 

mg/kg/day 

1000 B 

mg/kg/day 

1000 B 

mg/kg/day 

1000 B 

mg/kg/day 

1000 B 

mg/kg/day 

1000 B 

mg/kg/day 

1000 B 

mg/kg/day 

1000 B 

mg/kg/day 

1000 B 

mg/kg/day 
mg/kg/day

113 mg/kg/day

mg/kg/day

mg/kg/day

mg/kg/day

mg/kg/day

127 mg/kg/day128 mg/kg/day216 mg/kg/day 

Table 3-7 Levels of Significant Exposure to Selected Phosphate Esters - Dermal (continued) 

Exposure/ LOAEL

Duration/

Species Frequency Reference (Route) (Strain) System NOAEL Less Serious Serious Chemical Form 

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Metab 1000 B 

mg/kg/day 

Rabbit 3 wk Hemato Monsanto Co. 1985d 1000 B (New 5 d/wk 1 x/d mg/kg/day 78-51-3 Zealand) 

Hepatic 1000 B 

mg/kg/day 

Renal 1000 B 

mg/kg/day 

Dermal 10 B (slight edema, atonia, 

mg/kg/day desquamation) 

Bd Wt 1000 B 

mg/kg/day 

Immuno/ Lymphoret 

Rabbit 3 wk Monsanto Co. 1979 

1000 B (New 5 d/wk 

1 x/d mg/kg/day 115-86-6 Zealand) 

Neurological 

Rabbit 3 wk Monsanto Co. 1979 

1000 B (New 5 d/wk 

1 x/d mg/kg/day 115-86-6 Zealand) 

Rabbit 3 wk Monsanto Co. 1985d 

1000 B (New 5 d/wk 

1 x/d mg/kg/day 78-51-3 Zealand) 
129 mg/kg/day 

Table 3-7 Levels of Significant Exposure to Selected Phosphate Esters - Dermal (continued) 

Exposure/ LOAEL

Duration/

Species Frequency Reference (Route) (Strain) System NOAEL Less Serious Serious Chemical Form 

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Reproductive 

Rabbit 3 wk Monsanto Co. 1979 

1000 B (New 5 d/wk 

mg/kg/day 115-86-6 Zealand) 1 x/d 

Bd Wt = body weight; Cardio = cardiovascular; d = day(s); Endocr = endocrine; ; F = Female; Gastro = gastrointestinal; Gn Pig = guinea pig; Hemato = hematologicLD50 = lethal dose, 50% kill; LOAEL = lowest-observed-adverse-effect level; M = male; Metab = metabolic; NOAEL = no-observed-adverse-effect level; NS = not srespiratory; wk = week(s); x = time(s) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

PHOSPHATE ESTER FLAME RETARDANTS 134 

3. HEALTH EFFECTS 

Hematological Effects. Hematology tests done on blood collected at termination from rabbits treated 

dermally with up to 1,000 mg TBEP/kg/day 5 days/week for 3 weeks did not reveal any significant 

deviation from normal limits (Monsanto Co. 1985d). Similar results were reported in rabbits exposed to 

TPP (Monsanto Co. 1979). 

Musculoskeletal Effects. There were no gross or microscopic alterations in skeletal muscle from 

rabbits that received daily application of up to 1,000 mg TPP/kg/day 5 days/week for 3 weeks onto the 

clipped intact and abraded area of the back (Monsanto Co. 1979). 

Hepatic Effects. Application of up to 1,000 mg TBEP/kg/day to the unabraded clipped skin of rabbits 

5 days/week for 3 weeks did not result in alterations in liver weight, liver function tests, or the gross or 

microscopic appearance of the liver (Monsanto Co. 1985d). The same results were obtained in rabbits 

exposed to up to 1,000 mg TPP/kg/day (Monsanto Co. 1979). 

Renal Effects. Application of up to 1,000 mg/kg/day of TBEP or TPP to the clipped skin on the back 

of rabbits 5 days/week for 3 weeks did not result in alterations in kidney weight or the gross or 

microscopic appearance of the kidney (Monsanto Co. 1985d). 

Endocrine Effects. Application of up to 1,000 mg TPP/kg/day to a clipped intact or abraded area of 

the skin of rabbits 5 days/week for 3 weeks had no significant effect on the gross or morphological 

appearance of the adrenal, thyroid, and pituitary (Monsanto Co. 1979). 

Dermal Effects. Without providing any further details, IPCS (1991a, 1991b) stated that there have 

been reports of skin irritation among subjects occupationally exposed to TnBP. Several studies provide 

information regarding dermal effects of TnBP in animals. Application of 750 mg TnBP/kg to the skin of 

rats did not produce irritation (Akzo Chemical Inc 1991). In guinea pigs, application of a dose of 

20,000 mg TnBP/kg for 24 hours produced severe skin irritation (Eastman Kodak Co. 1968), but 

application of 0.3 mg once per week for 3 weeks did not produce skin irritation (SOCMA 1990). 

Application of TnBP as a 10% emulsion for 20 times on the ear and 6 times on the abdomen produced 

moderate exfoliation on the ear and slight hyperemia and slight exfoliation on the abdomen (Dow 

Chemical Co. 1956). Similar application of TnBP neat produced slight hyperemia and moderate necrosis 

on the ear after the 5th application. All signs of toxicity were reversed within 2–3 weeks after treatment 

(Dow Chemical Co. 1956). Both FMC (1979, 1981) and Mobil Oil Corporation (1979b) reported that 

application of 0.5 mL TnBP for 4–24 hours produced mild skin irritation in rabbits. Moderate edema was 

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PHOSPHATE ESTER FLAME RETARDANTS 135 

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reported in guinea pigs that received an application of 5,000 mg TiBP/kg to the skin (Eastman Kodak Co. 

1990) and mild, reversible skin irritation was reported in rabbits applied 0.5 mL TiBP and observed for 7– 

14 days (Monsanto Co. 1989a, 1989b). Application of 0.5 mL TPP to the clipped, intact, or abraded skin 

of rabbits did not result in the formation of erythema or edema (FMC 1982). 

In the 3-week study with TBEP in rabbits (Monsanto Co. 1985d), the undiluted test material was applied 

to the unabraded dorsal skin clipped of hair in doses of 0, 10, 100, or 1,000 mg/kg/day; the area was 

covered for 6 hours after each application. Gross necropsy showed slight to moderate erythema in the 

treated rabbits during the study; the incidence and severity was dose-related during the second and third 

week of the study. Atonia and desquamation were also more pronounced in treated rabbits (incidence and 

severity were dose-related). Slight fissuring became evident over time in some mid-dose and most highdose rabbits. Eschar formation was also seen in treated rabbits. Exfoliation also occurred in mid- and 

high-dose animals. Microscopic evaluation of sites from high-dose rabbits showed squamous cell 

hyperplasia, hyperkeratosis, erosions-ulcers, acute-subacute inflammation, and congestion and 

hemorrhage, in various combinations. 

In the 3-week study with TPP, there were no treatment-related alterations in the intact or abraded skin of 

rabbits applied up to 1,000 mg TPP/kg/day for 3 weeks (Monsanto Co. 1979). 

Ocular Effects. Application of 10 mg or 0.1 mL of TCEP into the lower eyelid of rabbits did not 

produce significant eye irritation (Anonymous 1977). Application of neat TnBP to the eye of rabbits 

induced slight conjunctival irritation which subsided within 24 hours (Dow Chemical Co. 1956). Union 

Carbide (1943) reported that application of 0.02 mL TnBP to the eye of rabbits induced necrosis, but a 

report by Stauffer Chemical Co. (1973) indicates that application of 10 mg or 0.1 mL TnBP to the eye of 

rabbits did not induce signs of eye irritation. There is not enough information in either report to explain 

this apparent discrepancy. Instillation of 0.1 mL TPP into the eye of rabbits produced mild irritation only 

when the eye remained unwashed after application (FMC 1982). No ocular effects were reported in 

rabbits that received daily skin applications of up to 1,000 mg TPP/kg/day 5 days/week for 3 weeks 

(Monsanto Co. 1979). 

Body Weight Effects. Application of up to 1,000 mg/kg/day of TBEP or TPP to a clipped area of 

intact or abraded the dorsal skin of rabbits 5 days/week for 3 weeks did not affect food consumption, 

body weight, or body weight gain (Monsanto Co. 1979, 1985d). 

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PHOSPHATE ESTER FLAME RETARDANTS 136 

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Metabolic Effects. Application of up to 1,000 mg TPP/kg/day to a clipped area of intact or abraded 

dorsal skin of rabbits 5 days/week for 3 weeks had no significant effect on serum levels of glucose, 

calcium, or inorganic phosphorus (Monsanto Co. 1979). 

3.2.3.3 Immunological and Lymphoreticular Effects 

No studies were located regarding immunological and lymphoreticular effects in humans following 

dermal exposure to the selected phosphate ester flame retardants. 

A study in which 0.3 mg TnBP was applied to the skin of guinea pigs once per week for 3 weeks showed 

that under the conditions of the study, TnBP was nonsensitizing (SOCMA 1990). A 3-week study in 

which rabbits were applied up to 1,000 mg TPP/kg/day 5 days/week to an area of intact or abraded dorsal 

skin did not report gross or microscopic changes in the spleen, thymus, or lymph nodes (Monsanto Co. 

1979). 

These two values are presented in Table 3-7. 

3.2.3.4 Neurological Effects 

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

subject phosphate ester flame retardants of this profile. 

Application of up to 1,000 mg TEBP/kg/day to the clipped unabraded dorsal skin of rabbits 5 days/week 

for 3 weeks did not induce clinical signs nor did it alter the activities of red blood cell (RBC) or brain 

cholinesterase or affect brain weight (Monsanto Co. 1985d). In the study with TPP, there were no 

alterations in brain weight or in gross and microscopic morphology of the brain, spinal cord, or sciatic 

nerve (Monsanto Co. 1979). However, at termination, there was a dose-related decrease in RBC and 

brain cholinesterase activities, which achieved statistical significance in the high-dose group 

(1,000 mg/kg/day, other groups were 10 and 100 mg/kg/day), but there were no clinical signs of increased 

cholinergic activity. 

The doses of 1,000 mg/kg/day of TBEP and TPP are presented as NOAELs for neurological effects in 

Table 3-7. 

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3.2.3.5 Reproductive Effects 

No studies were located regarding reproductive effects in humans exposed to the selected phosphate ester 

flame retardants by any route of exposure. 

The only relevant information regarding reproductive effects in animals is that in a 3-week study in 

rabbits applied up to 1,000 mg TPP/kg/day to the dorsal skin 5 days/week, there were no morphological 

alterations in the ovaries, uterus, prostate, or testes (Monsanto Co. 1979). This value is presented as a 

NOAEL in Table 3-7. 

3.2.3.6 Developmental Effects 

No studies were located regarding developmental effects in humans or animals following dermal 

exposure to the subject phosphate ester flame retardants of this profile. 

3.2.3.7 Cancer 

Only information regarding TCEP was located in the literature. Sala et al. (1982) studied the initiation/ 

promotion properties of TCEP in female Swiss mice. In the initiation study, mice received a single 

application of 71 mg of TCEP to the dorsal clipped skin and then repeated applications of 12-O-tetradecanoyl-phorbol-13-acetate (TPA). In the promotion studies, mice received, for 78 weeks, twice weekly 

applications of TCEP (21 mg) in acetone onto the area of dorsal skin after initiation with 7,12-dimethylbenz(a)anthracene (DMBA). TCEP was also tested for complete carcinogenicity by treating the mice 

twice weekly without any initiation treatment. TCEP was negative as an initiator, promoter, and complete 

skin carcinogen. However, TCEP by itself increased the incidence (not significantly) of lung adenomas 

in mice relative to a group initiated with DMBA and promoted with TCEP. The investigators had no 

explanation for the role of DMBA in decreasing the incidence of lung tumors. 

3.3 GENOTOXICITY 

For the most part, the phosphate ester flame retardants subject of this profile have provided negative 

evidence of mutagenicity in in vitro tests with prokaryotic organisms (i.e., Salmonella typhimurium) and 

mammalian cell systems. In vivo studies have, for the most part, also provided negative results. 

Tables 3-8 and 3-9 provide a summary of genotoxicity data for these test systems. 

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PHOSPHATE ESTER FLAME RETARDANTS 138 

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Table 3-8. Genotoxicity of Phosphate Ester Flame Retardants In Vitro 

Results 

With Without 

Species (test system) Compound End point activation activation Reference 

Prokaryotic organisms: 

Salmonella TBEP Gene mutation – – Abe and Urano 1994 

typhimurium, TA98 

S. typhimurium, TA09, TBEP Gene mutation – – Monsanto Co. 1985e 

TA100, TA1535, and 

TA1537 

S. typhimurium, TCEP Gene mutation – – Föllmann and Wober 

TA97a, TA98, TA100, 2006 

TA104, TA1535, 

TA1537, and TA1538 

S. typhimurium, TCEP Gene mutation – No data Haworth et al. 1983 

TA1535, TA1537, 

TA98, and TA100 

S. typhimurium, TA98 TCEP Gene mutation – – Abe and Urano 1994 

S. typhimurium, TCEP Gene mutation ± ± Nakamura et al. 1979; 

TA100, TA1535, NTP 1991a 

TA1537, and TA98 

S. typhimurium, TA98, TCEP Gene mutation – – Tennant and Ashby 

TA100, TA1535, 1991 

TA1537, and/or TA97 

S. typhimurium, TCPP Gene mutation – – Föllmann and Wober 

TA97a, TA98, TA100, 2006 

TA104, TA1535, 

TA1537, TA1538 

S. typhimurium, TA98 TCPP Gene mutation – – Abe and Urano 1994 

S. typhimurium, TA97, TCPP Gene mutation – – Zeiger et al. 1992 

TA98, TA100, TA102, 

TA104, TA1535, 

TA1537, and TA1538 

S. typhimurium, strain TDCP Gene mutation + No data NTP 1983 

n/a 

S. typhimurium, TA100 TDCP Gene mutation + No data Gold et al. 1978 

S. typhimurium, TA100 TDCP Gene mutation – – Søderlund et al. 1985 

S. typhimurium TDCP Gene mutation + + Mortelmans et al. 

TA1535, TA1537, 1986 

TA97, TA98, and 

TA100 

S. typhimurium, TA100 TDCP Gene mutation ± – Lynn et al. 1981 

S. typhimurium, TA100 TDCP Gene mutation ± ± Brusick et al. 1979 

S. typhimurium, TDC Gene mutation – – Brusick et al. 1979 

TA11535 

S. typhimurium, TA100 TDCP Gene mutation – No data Dybing et al. 1983 

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PHOSPHATE ESTER FLAME RETARDANTS 139 

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Table 3-8. Genotoxicity of Phosphate Ester Flame Retardants In Vitro 

Results 

With Without 

Species (test system) Compound End point activation activation Reference 

S. typhimurium, TA98, TDCP Gene mutation – – Stauffer Chemical Co. 

TA100, TA1535, 1981b 

TA1537, and TA1538/ 

Saccharomyces 

cerevisiae strain D4 

S. typhimurium, TA98, TiBP Gene mutation – – Stegeman et al. 1992 

TA100, TA1535, 

TA1537 

S. typhimurium, TA98 TnBP Gene mutation – No data Abe and Urano 1994 

S. typhimurium, TA102 TnBP Gene mutation – – Watanabe et al. 1996 

and TA2638 

Escherichia coli, TnBP Gene mutation – – Watanabe et al. 1996 

Wp2/pKM1010 and 

WP2 uvrA/pKM101 

S. typhimurium, strain TPP Gene mutation – No data NTP 1982
 

n/a
 

S. typhimurium, TA98, TPP Gene mutation – – Zeiger et al. 1987 

TA100, TA1535, 

TA1537, and/or TA97 

Mammalian cells: 

Chinese hamster ovary TBEP Forward gene – – Monsanto Co. 1985c 

(CHO) cells (HGPRT) mutation 

Mouse L5178Y TBEP Gene mutation – – Mobil Oil Corp 1991 

Lymphoma cells 

Chinese hamster V79 TCEP Cytotoxicity, + – Föllmann and Wober 

cells neutral red 2006 

uptake assay 

Chinese hamster V79 TCEP DNA damage, – – Föllmann and Wober 

cells Comet 2006 

analysis, 

CHO cells TCEP Chromosomal – – Galloway et al. 1987; 

aberrations NTP 1991a 

CHO cells TCEP Chromosomal ± – Galloway et al. 1987; 

aberrations, NTP 1991a 

sister 

chromatid 

exchange 

Chinese hamster V79 TCEP Forward gene – – Sala et al. 1982
 

cells mutation
 

Chinese hamster V79 TCEP Sister + + Sala et al. 1982
 

cells chromatid 

exchange
 

Mouse C3H10T1/2 TCEP Transformation – – Sala et al. 1982
 

cells assay
 

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PHOSPHATE ESTER FLAME RETARDANTS 140 

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Table 3-8. Genotoxicity of Phosphate Ester Flame Retardants In Vitro 

Results 

With Without 

Species (test system) Compound End point activation activation Reference 

Syrian hamster embryo TCEP Transformation + + Sala et al. 1982 

cells assay 

Chinese hamster V79 TCPP Cytotoxicity, + – Föllmann and Wober 

cells neutral red 2006 

uptake assay 

Chinese hamster V79 TCPP DNA damage, – – Föllmann and Wober 

cells Comet 2006 

analysis, 

Chinese hamster V79 TDCP Gene mutation – No data Søderlund et al. 1985 

cells 

Syrian hamster cells TDCP Transformation No data + Søderlund et al. 1985 

assay 

Mouse L5178Y TDCP Gene mutation – – Brusick et al. 1979 

Lymphoma cells 

Mouse L5178Y TDCP Sister ± ± Brusick et al. 1979 

lymphoma cells chromatid 

exchange 

Mouse L5178Y TDCP Chromosomal + + Brusick et al. 1979 

lymphoma cells aberrations 

Mouse BALB/3T3 cells TDCP Transformation – – Brusick et al. 1979 

assay 

Chinese hamster V79 TDCP Gene mutation – No data Dybing et al. 1983 

cells 

Mouse L5178Y TDCP Gene mutation ± – Stauffer Chemical Co. 

lymphoma cells 1981b 

CHO cells TnBP Gene mutation – – Batt et al. 1992 

CHO cells TnBP Chromosomal – – Batt et al. 1992 

aberrations 

+ = positive result; C = negative result; ± = weak or equivocal result; TBEP = tributoxyethyl phosphate; 

TCEP = tris-(2-chloroethyl)-phosphate; TCPP = tri-(2-chloroisopropyl) phosphate; TDCP = tris(1,3 dichloro-2-propyl) 

phosphate; TiBP = triisobutyl phosphate; TnBP = tributyl phosphate; TPP = triphenyl phosphate 

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PHOSPHATE ESTER FLAME RETARDANTS 141 

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Table 3-9 Genotoxicity of Phosphate Ester Flame Retardants In Vivo 

Species (test system) Compound End point Results Reference 

Chinese hamster TCEP Chromosomal ± Sala et al. 1982 

(male/female, aberrations, 

2/sex/dose) micronucleus assay 

Drosophila TCEP Gene mutation, spot – Vogel and Nivard 

melanogaster test 1993 

Mouse (male, Charles TDCP Chromosomal – Brusick et al. 1979 

River CD; eight per aberrations, bone 

treatment) marrow cytogenic assay 

D. melanogaster TDCP Gene mutation, sex­ – Brusick et al. 1979 

(modifed Muller five linked recessive lethal 

stock) assay 

D. melanogaster TDCP Gene mutation, sex­ – Stauffer Chemical Co. 

(males, 25/dose) linked recessive lethal 1981b 

assay 

Mouse (Male CD-1; TDCP Chromosomal – Stauffer Chemical Co. 

6/dose) aberrations, bone 1981b 

marrow cytogenic assay 

Mouse (male/female TiBP Chromosomal – Flowers and Garrett 

CD1; 15/sex/dose) aberrations, 1992 

micronucleus assay 

Rat (male/female, TnBP Chromosomal – Batt et al. 1992 

strain and number not aberrations 

reported) 

+ = positive result; C = negative result; ± = equivocal result; TCEP = tris-(2-chloroethyl)-phosphate; TDCP = tris(1,3 

dichloro-2-propyl) phosphate; TiBP = triisobutyl phosphate; TnBP = tributyl phosphate 

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PHOSPHATE ESTER FLAME RETARDANTS 142 

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In vitro Exposure Studies. In vitro studies with phosphate ester flame retardants have provided mixed 

results. In general, TBEP, TCEP, TCPP, TiBP, TnBP, and TPP have been found to be nonmutagenic in 

S. typhimurium with and without metabolic activation (Abe and Urano 1994; Brusick et al. 1979; 

Föllmann and Wober 2006; Monsanto Co. 1985e; Segeman et al. 1992; Søderlund et al. 1985; Stauffer 

Chemical Co. 1981b; Tennant and Ashby 1991; Watanabe et al. 1996; Zeiger et al. 1987, 1992). 

Additionally, in a study conducted by Watanabe et al. (1996), TnBP was found to be nonmutagenic in 

Escherichia coli. Studies of TCEP conducted by Nakamura et al. (1979) provided weak evidence of 

mutagenicity for this compound. Studies with TDCP have demonstrated mixed results in S. typhimurium, 

probably reflecting differences in methodology. Positive results were determined for an unreported strain 

with metabolic activation (NTP 1983), for strain TA100 with metabolic activation (Gold et al. 1978; Lynn 

et al. 1981), and for strains TA1535, TA1537, TA97, TA98, and TA100 with and without metabolic 

activation (Mortelmans et al. 1986). Conversely, negative results were determined for strain TA100 with 

and without metabolic activation in a study conducted by Søderlund et al. (1985), and equivocal results 

were noted in studies conducted with and without metabolic activation by Brusick et al. (1979). 

Studies with mammalian cells in vitro have also provided mixed results. TBEP was not genotoxic in 

Chinese hamster ovary cells or in mouse L5178Y lymphoma cells in assays conducted with and without 

metabolic activation (Mobil Oil Corporation 1991; Monsanto Co. 1985c). TnBP also produced negative 

results in tests for chromosomal aberrations and gene mutation in Chinese hamster ovary cells with and 

without metabolic activation (Batt et al. 1992). Results for TCEP, TCPP, and TCDP were mixed. 

In a neutral red uptake assay in Chinese hamster V79 cells, Föllmann and Wober (2006) reported positive 

results for TCEP and TCPP in the presence of metabolic activation only. Negative results were also 

reported in this study for TCEP and TCPP in a comet analysis of V79 cells both in the presence and 

absence of metabolic activation. TCEP did not induce chromosomal aberrations in Chinese hamster 

ovary cells in tests with and without metabolic activation (Galloway et al. 1987; NTP 1991a). However, 

in studies conducted by Sala et al. (1982), TCEP was found to be positive for sister chromatid exchange 

in Chinese hamster V79 cells as well as in a transformation assay in Syrian hamster embryo cells. 

Although a positive result was obtained in the sister chromatid exchange assay, no clear concentrationresponse was evident. Results from studies conducted by Sala et al. (1982) also showed TCEP to be 

negative in a test for forward gene mutation in Chinese hamster V79 cells, and negative in a 

transformation assay in mouse C3H10T1/2 cells. Sala et al. (1982) speculated that the negative result 

seen in mouse C3H10T1/2 cells in comparison with the positive result in Syrian hamster cells could have 

been due to the high metabolic activity known to occur naturally in hamster cells. 

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PHOSPHATE ESTER FLAME RETARDANTS 143 

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In vitro studies with TDCP in mammalian cells provided negative results for gene mutation in Chinese 

hamster V79 cells, mouse L5178Y lymphoma cells, and mouse BALB/3T3 cells (Brusick et al. 1979; 

Dybing et al. 1983; Søderlund et al. 1985). In a chromosomal aberration study conducted on mouse 

L5178Y lymphoma cells, positive results were demonstrated with and without metabolic activation 

(Brusick et al. 1979). Søderlund et al. (1985) also provided positive results in a gene mutation study in 

Syrian hamster cells in the absence of metabolic activation only. Equivocal results were obtained in a 

gene mutation assay (Stauffer Chemical Co. 1981b) and in a chromosomal aberration study (Brusick et al. 

1979) in mouse L5178Y lymphoma cells. The classification of equivocal was based on the variability of 

the results and on weak positive results. 

In vivo Exposure Studies. The relatively few studies available for review that examined the potential in 

vivo genotoxicity of the phosphate ester flame retardants discussed in this profile were negative 

(Table 3-9). In a micronucleus assay conducted on Chinese hamsters with TCEP, study results were 

equivocal (Sala et al. 1982). This result was due to a difference in response between sexes and dose 

variations which made analysis difficult. TDCP was negative for gene mutations in sex-linked recessive 

studies conducted on Drosophila melanogaster (Brusick et al. 1979; Stauffer Chemical Co. 1981b), as 

well as in a gene mutation spot test (Bruisck et al. 1979). Results for chromosomal aberrations in rats 

were negative in a study conducted with TnBP (Batt et al. 1992). Chromosomal aberration studies were 

also negative in CD-1 mice for TDCP (Brusick et al. 1979; Stauffer Chemical Co. 1981b) and TiBP 

(Flowers and Garrett 1992). 

3.4 TOXICOKINETICS 

Almost all of the information regarding toxicokinetics of the subject phosphate ester flame retardants is 

derived from studies with TDCP, TCEP, and TnBP in animals. TDCP, TCEP, and TnBP were well 

absorbed in rats following oral dosing. Significant amounts of TDCP and TnBP were also absorbed 

through rat skin; however, TnBP was poorly absorbed through pig skin. Oral and dermal absorption of 

the remaining phosphate ester flame retardants covered in this profile can be inferred from toxicity 

studies, but rates are not available. None of these substances showed preferential accumulation in 

specific tissues or organs. Analyses of excreta, mostly from rats, indicated that TDCP, TCEP, and TnBP 

undergo extensive metabolism by Phase I and Phase II enzymatic systems and the metabolic products are 

rapidly excreted, principally in the urine. Species and gender differences in metabolism and excretion 

were reported for TCEP. Female rats excreted less of a high-dose of TCEP than did males, and mice 

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PHOSPHATE ESTER FLAME RETARDANTS 144 

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eliminated TCEP faster than did male or female rats. An in vitro study showed that both liver slices and 

microsomes from humans and male rats metabolized TCEP to the same main metabolites; female liver 

microsomes did not appear to metabolize TCEP. No physiologically based pharmacokinetic (PBPK) 

models have been developed for any of the phosphate ester flame retardants covered in this profile. 

3.4.1 Absorption 

3.4.1.1 Inhalation Exposure 

The only relevant information available in humans regarding the phosphate ester flame retardants 

discussed in this profile is that male volunteers who inhaled small particles of TPP at a flow rate of 

18 L/second retained a mean of 41% of the inhaled TPP in the lungs (Landhal et al. 1951, 1952). 

Retention increased as particle size and flow rate increased. No pertinent information was found from 

studies in animals. 

3.4.1.2 Oral Exposure 

No information was located regarding absorption of phosphate ester flame retardants in humans following 

oral exposure. The fact that TDCP was detected in adipose tissue and seminal fluid from members of the 

general population (Hudec et al. 1981; LeBel and Williams 1986) suggests that this substance was 

absorbed, most likely through consumption of contaminated food or water, the main sources of exposure 

for the general population. 

TDCP. A study in which male Sprague-Dawley rats were administered 0.2, 2, or 20 μmol TDCP/kg 

(0.086, 0.86, or 8.6 mg/kg) showed that better than 90% of the administered dose was absorbed from the 

gastrointestinal tract within 24 hours after dosing, regardless of the dose (Nomeir et al. 1981). 

TCEP. Administration of a single gavage dose of 175 mg 14C-TCEP/kg to male and female Fischer344 rats resulted in rapid absorption from the stomach (Herr et al. 1991). Analysis of radioactivity in 

plasma over a 4-hour period showed that unmetabolized TCEP accounted for an average of 43.6% of the 

total radioactivity across time points and sexes. The concentration of TCEP in plasma reached a 

maximum early and did not vary significantly from 5 minutes to 4 hours after dosing. It appeared that at 

early time points plasma from female rats had twice as much TCEP than that from males, but because 

only three rats per sex were used, it was not possible to determine whether the difference was statistically 

significant. 

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TnBP. Analysis of the urine, expired air, and tissues of male and female Sprague-Dawley rats following 

gavage administration of single or repeated doses of 10 or 350 mg 14C-TnBP/kg yielded a maximum 

combined radioactivity of approximately 90% of the administered dose in females dosed repeatedly with 

350 mg TnBP/kg/day (SOCMA 1992). Approximately 6% of the administered 14C was found in the 

feces, but it is not possible to determine whether this amount correspond to unabsorbed parent compound 

or absorbed material secreted in the bile. The half-life for the 14C-TnBP-derived radioactivity in blood 

was estimated to be approximately 25 hours for both dosing regimes. 

3.4.1.3 Dermal Exposure 

No studies were located regarding absorption of the selected phosphate ester flame retardants in humans 

following dermal exposure. 

TDCP. Measurements of 14C-TDCP-derived radioactivity in tissues from male Sprague-Dawley rats 

4 hours after application of the compound in methanol to a shaved area of 4 cm2 in the back showed that 

the chemical was readily absorbed through the skin (Nomeir et al. 1981). The rate of absorption was not 

estimated. 

TnBP. Application of 10 or 350 mg 14C-TnBP/kg to a 2 cm2 shaved area of the skin of male and female 

Sprague-Dawley rats for 6 hours followed by washing with soap and water resulted in absorption of at 

least 53% (high-dose females) of the applied dose, which was the radioactivity recovered in combined 

urine, feces, expired air, and tissues (SOCMA 1992). 

In a study in Yucatan® minipigs, males and females were applied a dose of 10 or 350 mg 14C-TnBP to a 

lightly clipped area of the skin for 6 hours after which time the area was washed with soap and water 

(SOCMA 1992). Excreta were collected for up to 168 hours after dosing. Analysis of urine and feces 

samples showed only ≤4% of the applied dose in excreta. In low-dose animals, 57–64% of the applied 

dose of 14C was recovered at the dosing site (includes dosed site plus dose wash plus dose wrappings). In 

high-dose minipigs, 87–92% of the applied 14C was recovered at the dosing site. Compared to rats, 

minipigs absorbed about 10 times less TnBP than rats. 

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PHOSPHATE ESTER FLAME RETARDANTS 146 

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3.4.1.4 Other Routes of Exposure 

TDCP. Hughes et al. (2001) studied the dermal absorption of TDCP in an in vitro preparation of skin 

from adult hairless mice mounted on a flow-through diffusion cell. 14C-TDCP in acetone in 

concentrations of 20, 100, or 200 pmol were applied to the skin and receptor fluid was collected over a 

24-hour period. At this time, the skin was washed with ethanol to remove unabsorbed TDCP. For all 

doses, the greatest percent of the dose was absorbed between 6 and 12 hours. The 24-hour cumulative 

percent of the dose in the receptor fluid was 57, 45, and 39% for the 20, 100, and 200 pmol solutions, 

respectively. Washing with ethanol removed 11–25% of the applied radioactivity, whereas 28–35% of 

the applied radioactivity remained in the skin. Analysis of homogenates of the skin and receptor fluid 

showed the presence of parent compound and a minor unknown peak. 

TnBP. Marzulli et al. (1965) studied the in vitro dermal absorption of a series of organic phosphates 

using sheets of anterior forearm stratum corneum conjunctum from humans mounted in diffusion cells. 

The chemicals comprised TnBP and other organic phosphates with shorter alkyl chain. TnBP was found 

to penetrate the skin at a maximum steady state rate of 0.18 μg/cm2

/minute, which was slower than the 

rates determined for the other organic phosphates tested, indicating that chain length was an important 

factor in dermal absorption of organic phosphates. 

Intravenous administration of a single dose on 5 mg 14C-TnBP/kg to male or female Sprague-Dawley rats 

showed that 14C declined in plasma during the first 4 hours and then increased to reach a plateau between 

4 and 24 hours; this was followed by a gradual decline of radioactivity in plasma that reached about 5% 

of the peak at 96 hours after dosing (SOCMA 1992). No significant differences were noted between 

males and females. The investigators suggested that 14C during the first 4 hours may reflect unchanged 

TnBP with a short half-life in blood of approximately 1.3 hours. The mean terminal half-life of 14C 

estimated from urinary excretion data was approximately 29 hours, suggesting that the TnBP metabolites 

rapidly disappear from plasma due to tissue uptake followed by slower excretion into the urine. 

3.4.2 Distribution 

3.4.2.1 Inhalation Exposure 

No relevant information was located regarding distribution of the selected phosphate ester flame 

retardants in humans or animals following inhalation exposure. 

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3.4.2.2 Oral Exposure 

As mentioned previously, TDCP was detected in adipose tissue and seminal fluid from members of the 

general population (Hudec et al. 1981; LeBel and Williams 1986); no further relevant information was 

located. 

The tissue distribution of an equimolar dose of 14C-labeled TCPP, TCEP, and TDCP was studied in male 

Wistar rats (Minegishi et al. 1988). The rats received a single dose of 50 μmol/kg (~14 mg/kg) by gavage 

and sacrifices were conducted at various times during a 7-day period. Elimination half-lives from blood 

appeared to have two phases. The first phase ranged from 12 to 14 hours, whereas the second phase 

ranged from 42 to 59 hours for the three chemicals. The average times at which each chemical reached 

the maximum concentration in various tissues were 5.7 hours for TCPP, 6 hours for TCEP, and 9.6 hours 

for TDCP. In general, low tissue/blood ratios were recorded in the brain, heart, muscle, and testes. 

Moderate ratios were obtained in adipose tissue, the spleen, and lung; high ratios were recorded in the 

liver and kidneys. The highest amounts of radioactivity in the liver and kidney were detected during the 

first 12 hours after dosing. Seven days after dosing, for the three flame retardants, the highest amount of 

radioactivity was found in the liver. The longest elimination half-lives from any tissue corresponded to 

adipose tissue and ranged from 87 hours for TCEP to 103 hours for TCPP. 

TCEP. The distribution of 14C-TCEP into seven brain regions from male and female Fischer-344 rats was 

studied by Herr et al. (1991). The brain areas analyzed were: cerebellum, brainstem, caudate, 

hypothalamus, cortex, hippocampus, and midbrain. Two hours after administration of single doses of 

175, 350 or 700 mg TCEP/kg, all brain areas had dose-related TCEP-derived radioactivity. No 

preferential distribution was found across brain regions, sexes, or doses. Twenty-four hours after dosing, 

all brain areas had similar amounts of radioactivity; at this time, mean brain/blood ratios of 0.3 and 

0.7 were determined for the 175 and 350 mg/kg dose groups, respectively, providing no evidence of 

bioaccumulation. Twenty-four hours after 14 days of dosing with 175 mg TCEP/kg/day, radioactivity 

could be quantified in blood and in all brains areas. Again, no preferential accumulation was observed in 

any specific brain area. At this time, the average brain/blood ratio was only 0.4, indicating that no 

accumulation occurred even after repeated dosing. Analysis of blood and brain tissues 72 hours after a 

single dose of TCEP showed brain/blood ratios of approximately 0.5, indicating that no differential 

elimination of radioactivity existed among the various brain areas. Extraction of cortical tissue 2 hours 

after a single dose of 14C-TCEP showed that the radioactivity was primarily parent compound. However, 

when cortical tissues from selected treatment groups were pooled to maximize detection of 14C, a 

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PHOSPHATE ESTER FLAME RETARDANTS 148 

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metabolite could be detected, and there was evidence that the parent compound/metabolite ratio was 

greater in cortical tissue of female rats than of male rats. 

TnBP. Administration of a single dose of 10 or 350 mg 14C-TnBP/kg or eight consecutive doses of 10 or 

350 mg 14C-TnBP/kg/day to male or female Sprague-Dawley rats by gavage in corn oil resulted in only 

≤1% of the administered radioactivity detected in tissues 168 hours after dosing (SOCMA 1992), 

suggesting little or no accumulation of parent compound or metabolites at the time of tissue analysis. 

TDCP. A study in which male Sprague-Dawley rats were administered a single oral dose of 0.2, 2, or 

20 μmol TDCP/kg (0.086, 0.86, or 8.6 mg/kg) showed that distribution of radioactivity to tissues, 

determined 24 hours after dosing, was unaffected by the size of the dose and that the liver and kidneys 

had the highest concentration of radioactivity (Nomeir et al. 1981). 

3.4.2.3 Dermal Exposure 

No relevant information was found in human studies. 

TDCP. Application of 0.86 mg 14C-TDCP/kg to a 4-cm2 shaved area of the skin of rats resulted in 

tissue/blood ratios similar to those estimated in an experiment in which rats were injected TDCP 

intravenously (see Section 3.4.2.4 below), suggesting that tissue distribution is independent of the route of 

administration (Nomeir et al. 1981). Four hours after the application, the concentration in tissues, in 

decreasing order was: liver > lung > skin > blood > kidneys > adipose > muscle. 

TnBP. Application for 6 hours of 10 or 350 mg 14C-TnBP/kg to a 2-cm2 area of the back of male or 

female Sprague-Dawley rats followed by washing with soap and water resulted in ≤1% of the applied 

radioactivity in tissues 168 hours after dosing (SOCMA 1992). 

3.4.2.4 Other Routes of Exposure 

TDCP. The distribution of 14C-TDCP-derived radioactivity was studied in male Sprague-Dawley rats 

administered a single intravenous injection of 14C-TDCP (Lynn et al. 1981). Tissue samples (all major 

tissues and organs) were collected at five time intervals up to 120 hours after dosing. TDCP disappeared 

rapidly from plasma with a half-life of <5 minutes. This was paralleled by a rapid rise in the 

concentration of the major metabolite of TDCP, bis(1,3-dichloro-2-propyl) phosphate (BDCP, see 

Section 3.4.3). After 2 hours, the concentration of BDCP declined with a half-life of approximately 4– 

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PHOSPHATE ESTER FLAME RETARDANTS 149 

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6 hours. In most tissues, the concentrations of TDCP were initially (at 5 minutes) high, but declined 

considerably by 30 minutes; 8 hours after dosing, TDCP was detected only in fat tissue. No TDCP was 

detected in any tissues studied ≥24 hours after dosing. BDCP was also quantified in each of the tissues 

studied. The highest concentration of the metabolite was observed in the lung, liver, blood, and kidneys. 

BDCP could be detected in tissues within 5 minutes of dosing and up to 24 hours later, but not in 

quantifiable amounts 5 days after dosing. The highest concentrations of radiolabel were measured in the 

kidneys, lung, and liver. Five minutes after dosing, 46.4% of the administered TDCP had been 

metabolized and 16% of the phosphate was recovered as BDCP. By 30 minutes, 82% of the whole-body 

radiolabel was present as metabolite and 27% of the administered phosphate was recovered as BDCP. At 

8, 24, and 120 hours after dosing, 55.7, 59, and 63% of the administered phosphate was recovered as 

BDCP, respectively. 

A similar study was conducted by Nomeir et al. (1981). Intravenous injection of 14C-TDCP to male 

Sprague-Dawley rats resulted in initially high concentrations of radioactivity in the lung, liver, kidneys, 

and blood, whereas the lowest concentrations were found in muscle, skin, and adipose tissue. The 

relatively high concentration of radioactivity in the lung was thought to be the product of a first-pass 

effect. Except for the skin, radioactivity decreased in most tissues by 7 hours after dosing. By day 10, the 

remaining radioactivity was only 1–5% of that measured 15 minutes after dosing. Tissue fractioning 

studies showed that radiolabel derived from the parent compound significantly decreased in most tissues 

within the first 2 hours following apparent exponential decay rates with half-lives of 3–4 hours; 

elimination half-lives from the lung and adipose tissues were 1.5 and 5.4 hours, respectively. One day 

after dosing, only 20–30% of the radioactivity remaining in tissues was the parent compound. The 

clearance of the remaining radioactivity followed a single exponential decay with a half-life much longer 

than that observed for TDCP. 

Morales and Matthews (1980) studied the subcellular distribution of TDCP in male CD-1 mice. Mice 

received a single intravenous injection of 14C-TDCP and 6 hours later, the covalent binding of 

radioactivity to DNA, RNA, and protein from liver, muscle, and kidney was monitored. The highest 

concentration of radioactivity was found in the liver. In each tissue in which it was measured, the 

concentration of TDCP-derived bound radioactivity was highest in low molecular weight RNA followed 

in decreasing concentration by protein, rRNA, and DNA. 

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PHOSPHATE ESTER FLAME RETARDANTS 150 

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TnBP. Administration of a single intravenous dose of 5 mg 14C-TnBP/kg into the tail vein of male or 

female Sprague-Dawley rats resulted in ≤1% of the applied radioactivity in tissues 168 hours after dosing 

(SOCMA 1992). 

3.4.3 Metabolism 

TDCP. Lynn et al. (1981) studied the metabolism of TDCP in male Sprague-Dawley rats. Analysis by 

high-pressure liquid chromatography (HPLC)/liquid scintillation counting of the urine of rats following 

an intraperitoneal dose of 14C-TDCP showed a major component (approximately 69% of the radioactivity) 

identified as BDCP. A second component was identified as the dimethyl derivative of 1,3-dichloro2-propyl phosphate. Analysis without derivatization of chloroform extracts of the urine of rats by gas 

chromatography/mass spectrometry (GC/MS) showed that the major component was 1,3-dichloro2-propanol. Analysis over a 5-day period of excreta from rats injected intravenously with 14C-TDCP also 

showed BDCP to be a major component of the urine, feces, and bile. A metabolic scheme was not 

proposed, but Lynn et al. (1981) noted that the formation of the mono- and diester-metabolites was likely 

to proceed by either mixed function oxidase reactions, hydrolase reactions, and/or glutathione 

S-alkyltransferase reactions. Similar studies in rats conducted by Nomeir et al. (1981) also showed that 

the major metabolite excreted in the urine was BDCP, which accounted for 67.2% of the total 

radioactivity in the urine. Approximately 32% of the 14C-TDCP-derived radioactivity in the urine was an 

unidentified polar metabolite, whereas only 0.29% was 1,3-dichloro-2-propyl phosphate and 0.45% was 

unchanged parent compound. 

In vitro studies with rat liver fractions showed that TDCP was metabolized by enzymes located in the 

microsomal and soluble fractions, and to a lesser extent, by enzymes in the mitochondrial fraction 

(Nomeir et al. 1981). It appeared that TDCP was metabolized via oxidative and conjugation reactions. 

Experiments using the 10,000 g supernatant in the presence and absence of various cofactors showed that 

little metabolism (6.4%) occurred in the absence of cofactors. In contrast, addition of GSH or NADPH 

markedly increased metabolism (28 and 26%, respectively), with the highest rate being observed in the 

presence of both cofactors (34.7%). Metabolism also increased steadily for up to 2 hours. Experiments 

with the isolated microsomal fraction showed that this fraction metabolized TDCP to 1,3-dichloro2-propanol, 3-chloro-1,2-propanediol, BDCP, and at least one unidentified metabolite. In the soluble 

fraction, TDCP was metabolized to one metabolite, which was probably a glutathione conjugate formed 

with the intact TDCP molecule. 

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TCEP. HPLC analyses of the cumulative 24-hour urine of male and female Fischer-344 rats and male 

B6C3F1 mice following a gavage dose of 175 mg 14C-TCEP/kg showed the presence of up to six peaks 

(Burka et al. 1991). Although qualitatively similar, the profiles showed quantitative differences between 

rats and mice and between male and female rats. The major peak in both species accounted for 70% of 

the total radioactivity in urine from male mice, but only 50% in both male and female rats. In contrast, 

both male and female rat urine contained approximately 2 times more of a peak eluting at 9.7 minutes 

than did urine from mice, whereas urine from female rats contained more of a peak eluted at 12.9 minutes 

(12%) than either male rats (4%) or male mice (7%). Characterization of urinary metabolites by nuclear 

magnetic resonance and MS showed that the major metabolite in female rat urine was bis(2-chloroethyl) 

carboxymethyl phosphate (BCCP). This metabolite co-chromatographed with the major metabolite found 

in both male rats and mouse urine. Two additional metabolites that were identified in female rat urine 

were bis(2-chloroethyl) hydrogen phosphate (BCHP) and the glucuronide of bis(2-chloroethyl) 

2-hydroxyethyl phosphate (BCGP); both BCHP and BCGP also co-chromatographed with metabolites 

found in mouse and male rat urine. Experiments pretreating male rats with inhibitors of the enzyme 

aldehyde dehydrogenase showed increased TCEP-induced toxicity, whereas preadministration of SK 

525A, a mixed-function oxidase inhibitor, slowed elimination of 14C in urine and inhibited production of 

BCCP, but did not increase neurotoxicity. Burka et al. (1991) took these observations to imply that a 

metabolite rather than unmetabolized TCEP produces neurotoxicity. This, however, seems to conflict 

with results of studies of distribution of 14C in brains of rats that reported that at the time of seizures, most 

of the TCEP-derived radioactivity present in brain tissue was in the form of parent compound (Herr et al. 

1991). A metabolic scheme proposed by Burka et al. (1991) is shown in Figure 3-7. 

Differences in the metabolism of TCEP between male and female Fischer-344 rats have also been 

reported in in vitro studies. In a study that also included liver preparations from humans, Chapman et al. 

(1991) reported that both liver slices and microsomes from humans and male rats metabolized TCEP to 

bis(2-chloroethyl) hydrogen phosphate, 2-chloroethanol, and three unidentified metabolites. TCEP was 

metabolized by liver slices from female rats, but liver microsomes from female rats did not appear to 

metabolize TCEP. Additional experiments suggested that a substantial TCEP-hydrolyzing activity in rat 

liver was localized in the cytosol. The overall rate of TCEP metabolism by male rat liver slices was 

1.7 times greater than for female rat liver slices. TCEP was metabolized by rat plasma, without sex 

differences, but not by human plasma or whole blood. In all studies, the major metabolites were 

bis(2-chloroethyl) hydrogen phosphate and 2-chloroethanol. Since BCCP and BCGP were produced in 

vivo in rats (Burka et al. 1991), but no significant amounts were produced in vitro, Chapman et al. (1991) 

suggested that in vivo α-oxidation of TCEP may occur extrahepatically. Studies with enzyme inhibitors 

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PHOSPHATE ESTER FLAME RETARDANTS 152 

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Figure 3-7. Proposed Scheme for TCEP Metabolism in Rats and Mice 

O 

ClCH2CH2OP(OCH2CH2Cl)2 

TCEP 

Hyd Ox 

O HO O CHCH2OP(OCH2CH2Cl)2 HOP(OCH2CH2Cl)2 Cl
 

BCHP
 -HCl 

Hyd 

O O 

HOOCCH2OP(OCH2CH2Cl)2 OCHCH2OP(OCH2CH2Cl)2 

Ox 

BCCP 

Red 

O O 

Glu-OCH2CH2OP(OCH2CH2Cl)2 HOCH2CH2OP(OCH2CH2Cl)2 

BCGP 

BCCP = bis(2-chloroethyl) carboxymethyl phosphate; BCGP =bis(2-chloroethyl) 2-hydroxyethyl phosphate; 

BCHP = bis(2-chloroethyl) hydrogen phosphate; GT = glucuronyl transferase; Hyd = hydrolysis; Ox = oxidation; 

Red = reduction 

Source: Burka et al. 1991 

GT 

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PHOSPHATE ESTER FLAME RETARDANTS 153 

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(male rats only) suggested that cytochrome P-450 was responsible for approximately 38% of the total 

microsomal TCEP hydrolytic activity. The remaining microsomal TCEP hydrolytic activity appeared to 

be associated with a B-esterase. Chapman et al. (1991) noted that B-esterases are present in rat serum, 

but not human serum, which would be consistent with the finding in their study of hydrolysis of TCEP by 

rat serum, but not human plasma. 

TnBP. Analyses of urine samples from male Wistar rats administered a single intraperitoneal dose of 

250 mg 14C-TnBP revealed 11 phosphorus-containing metabolites (Suzuki et al. 1984a). The major 

metabolites were dibutyl hydrogen phosphate, butyl dihydrogen phosphate, and butyl bis(3-hydroxybutyl) 

phosphate; no glucuronide or cysteine conjugates could be detected, which suggested that biotransformation of TnBP in rats is carried out mainly by phase I reactions. However, in a subsequent study, 

Suzuki et al. (1984b) detected several S-containing metabolites in crude extracts of urine from rats treated 

with TnBP intraperitoneally. The main metabolites were (3-oxobutyl)- and (3-hydroxybutyl) mercapturic 

acids, and traces of (2-oxobutyl)- and (2-hydroxybutyl) mercapturic acids. The results also suggested that 

TnBP undergoes transalkylation of 3-hydroxybutyl or 3-oxobutyl moieties after oxidation of the original 

butyl moieties. Based on these findings, Suzuki et al. (1984b) proposed a metabolic scheme for TnBP 

shown in Figure 3-8. 

SOCMA (1992) also studied the metabolism of TnBP in male and female Sprague-Dawley rats following 

administration of intravenous, dermal, or oral (single or repeated doses of 10 or 350 mg/kg) doses. Urine, 

feces, and expired air were collected at various times up to 168 hours after dosing (rats sacrificed); blood 

was collected at termination. Because blood at collection contained <5% of the administered dose, blood 

samples were not chromatographed. HPLC analyses of urine showed the presence of 10 radioactive 

peaks, and 6 of them contained radioactivity ≥5% of the administered dose. None of the fecal samples 

contained >5% of the administered radioactivity. In general, the chromatographic profiles of all samples 

were similar, with differences only in the relative concentration of the peaks. Usually, the majority of the 

radioactivity in the urine was contained in the more polar peaks. Incubation of urine with 

β-glucuronidase produced no changes in the profile, suggesting that phase II metabolism was not a 

significant biotransformation route for TnBP. Differences in chromatographic profiles from rats in the 

various groups appeared greater between individual animals than among treatment groups or between 

male and female rats. However, profiles from female rats treated with multiple doses or a single high 

dose of TnBP showed higher concentrations of less polar metabolites than profiles from similarly treated 

males. From the 10 detected radioactive peaks, 18 metabolites were characterized. The three metabolites 

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P 

OBu 3OH 

P 

OBu 

OBu P 

OBu 

MFO OH MFO 2OH MFO 

TnBP O O OBu O OBu 

OBu OBu OBu 

GSH 

GSR 

Urine 

GSH 

GSR 

Urine 

O P 

OBu 

OBu 

OH 

O P 

OBu 

OBu 

OH 

OH 

O P 

OBu 

PH 

O P 

OBu 

OBu 

OBu 

O P 

OBu 

OH 

OH 

O P 

OBu 

OH 

OH 

MFO MFO MFO 

GSH GSR Urine 

Urine 

=O GSH 

GSR 

Urine 

OBu 

2OH 

OH 

G: gluathione or N-acetyl-L-cysteine 

CH2COCH2CH3 CH2CHCH2CH3 

OH 

CH2CH2COCH3 CH2CH2CHCH3 

R: OH 

 

PHOSPHATE ESTER FLAME RETARDANTS 154 

3. HEALTH EFFECTS 

Figure 3-8. Proposed Metabolic Pathway of TnBP in Rats 

MFO = mixed function oxidase; GSH = glutathione; GSR = reduced glutathione; TnBP = tributyl phosphate 

Source: Suzuki et al. 1984b 

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PHOSPHATE ESTER FLAME RETARDANTS 155 

3. HEALTH EFFECTS 

present in the highest concentrations in most of the samples were butyl 3-hydroxybutyl hydrogen 

phosphate (M8-4 in Figure 3-9), dibutyl hydrogen phosphate (M7), and butyl butanoic acid hydrogen 

phosphate (M8-6). Other metabolites were phase I metabolites produced by oxidation (acid, keto, 

hydroxylated) or enzymatic hydrolysis of the butyl chains of TnBP. SOCMA (1992) proposed a scheme 

in which the butyl groups of TnBP are oxidized metabolically to alcoholic, ketonic, and acidic groups. 

The oxidized butyl groups are then enzymatically hydrolyzed with sequential loss proceeding from the trisubstituted to the di-, mono-, and finally to unsubstituted phosphoric acid. The degree of oxidation or 

extent of hydrolysis of the detected metabolites was found to be independent on dosing, treatment, or sex 

of the animal. The metabolic scheme is presented in Figure 3-9. 

SOCMA et al. (1994) also studied the metabolism of TnBP in Yucatan® minipigs following 

administration of 14C-TnBP in a single intravenous injection (5 mg/kg) or after application of chemical 

(10 or 350 mg/kg) to the skin for 6 hours, as done in the rat experiments. Excreta were collected for up to 

168 hours after dosing. Only urine samples from animals dosed intravenously were analyzed for 

metabolites since fecal samples from pigs treated intravenously or dermally, or urine samples from pigs 

treated dermally contained <5% of the administered dose. HPLC profiles of urine showed four major 

peaks, which were characterized as two diasteromeric pairs of glucuronides of two precursor metabolites, 

a monohydroxy and a dihydroxy dibutyl phosphate. Neither time of sample collection or gender appeared 

to qualitatively change the distribution or type of the excreted metabolites. Unchanged TnBP was found 

at ≤0.4% of the administered dose. Hydrolysis of urine samples with β-glucuronidase followed by 

derivatization reactions and GC analysis showed that two peaks with mass spectra corresponding to 

2-hydroxybutyl dibutyl phosphate and dibutyl phosphate. Based on these results, SOCMA (1994) 

proposed a metabolic scheme, shown in Figure 3-10, that involves phase I and phase II reactions. The 

parent chemical is assumed to be oxidized by mixed function oxidases to produce the monohydroxyl and 

dihydroxyl species, which are substrates for glucuronide formation. 

TPP. Sasaki et al. (1984) provided some information regarding the in vitro metabolism of TPP by a rat 

liver preparation. Rat liver microsomes were able to metabolize TPP in the presence (91% of substrate) 

and absence (66% of substrate) of NADPH. This suggested that an arylesterase in the microsomes also 

contributed to the metabolism of TPP. Sasaki et al. (1984) also reported that the soluble fraction from rat 

liver also metabolized (15%) TPP. Experiments to identify metabolites of TPP were not conducted. 

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Figure 3-9. Suggested Biotransformation Scheme of TnBP in Rats 

O O O

(CH3CH2CH2CH2O)3

O

P [(CH3CH2CH2CH2O)2POCH2CH2CH2CH2OH]	 (CH3CH2CH2CH2O)2POCH2CH2CH2COH 

(M5) (TnBP; M1) 

OCH2CH2CCH3 

O 

CH3CH2CH2CH2OPOCH2CH2CH2CH2CO2H 

(M6) O 

O O 

[(CH3CH2CH2CH2O)2POCH2CHCH2CH3] 

O OH 

[(CH3CH2CH2CH2O)2POCH2CCH2CH3] 

O OH O O 

(CH3CH2CH2CH2O)2POCH2CH2CHCH3 [(CH3CH2CH2CH2O)2POCH2CH2CCH3] 

(M2) 

O 

(CH3CH2CH2CH2O)POH 

O O 

CH3CH2CH2CH2OPOCH2CH2CH2CH2OH 

(DBP; M7) 

CH3CH2CH2CH2OPOCH2CH2CH2CO2H 

(M8-2) OH (M8-6) OH 

O OH O 

CH3CH2CH2CH2OPOCH2CHCH2CH3 CH3CH2CH2CH2OPOCH

O

2CCH2CH3 

(M8-3) OH (M8-1) OH 

O OH O O 

CH3CH2CH2CH2OPOCH2CH2CHCH3 [CH3CH2CH2CH2OPOCH2CH2CCH3] 

(M8-4) OH OH 

OH O O 

CH3CH2CHCH2OPOCH2CH2CCH3 

O 

CH2CH2CH2CH2OPOCH2CO2H 

(M8-5) OH (M10-8) OH 

O 

(CH3CH2CH2CH2O)P(OH)2 

(HO)2POCH2CH2CH2CH2OH 

O 

(HO)2POCH2CH2CHCH3 

O 

(HO)2POCH2CHCH2CH3 

O 

OH 

OH 

[(HO)2POCH2CH2CH2CO2H] 

O 

(HO)2POCH2CH2CCH3 

O 

(HO)2POCH2CCH2CH3 

O 

O 

OH 

H3PO4 

(MBP; M10-4) 

(M10-5) 

(M10-7) 

(M10-6) 

(M10-3) 

(M10-2) 

PHOSPHATE ESTER FLAME RETARDANTS 156 

3. HEALTH EFFECTS 

(M10-1) 

[ ] = not observed; DBP = dibutyl phosphate; MBP = monobutyl phosphate; TnBP = tributyl phosphate 

Source: SOCMA 1992 

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Figure 3-10. Proposed Metabolic Pathway of TnBP in Yucatan ® Minipigs 

O 

CH3CH2CH2CH2 O	 P O CH2CH2CH2CH3 

CH2CH2CH2CH3 

[MFO] [MFO] 

O O 

CH3CH2CH2CH2 O P 

CH2CHCH2CH3 

O CH2CH2CH2CH3 CH3CH2CH2CH2 O P 

CH2CHCH2CH2OH 

O CH2CH2CH2CH3 

OH OH 

UDPGT UDPGT 

O O 

CH3CH2CH2CH2 O	 P O CH2CH2CH2CH3 CH3CH2CH2CH2 O P O CH2CH2CH2CH3 

CH2CHCH2CH3 CH2CHCH2CH2OH 

H H 

O O 

OH 

OH 

OH

CO2

O O 

OH 

OH 

OH

CO2

O = mixed function oxidase; TnBP = tributyl phosphate; UDPGT = uridine diphosphate glucuronyl transferases 

urce: SOCMA 1994 

MF

So

PHOSPHATE ESTER FLAME RETARDANTS 157 

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PHOSPHATE ESTER FLAME RETARDANTS 158 

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3.4.4 Elimination and Excretion 

No studies were located regarding elimination and excretion of the selected phosphate ester flame 

retardants or metabolites in humans following any route of exposure. 

3.4.4.1 Inhalation Exposure 

No pertinent information was located regarding excretion of phosphate ester flame retardants in animals 

following inhalation exposure. 

3.4.4.2 Oral Exposure 

Minegishi et al. (1988) compared the excretion of TDCP, TCPP, and TCEP in male Wistar rats during a 

7-day period following gavage administration of a single equimolar dose of 50 μmol/kg of 14C-labeled 

compound. During the 7-day period, the cumulative excretion of radiolabel in urine followed the order 

TCEP > TCPP > TDCP. Almost all (~90%) of the administered TCEP was excreted in the urine, whereas 

~60% of TCPP and ~40% of TDCP were excreted in the urine. The order of excretion was TDCP 

(~40%) > TCPP > TCEP in feces, and TDCP (~18%) > TCPP > TCEP in expired air. For the three 

compounds, recovery within the 7 days was almost 100%. Experiments in rats with cannulated bile ducts 

showed that peak biliary excretion occurred approximately 2 hours after dosing with TCPP and TCEP, 

whereas the peak for TDCP was reached at approximately 6 hours after dosing. As a percent of the 

administered dose, 45% of TCPP, 40% of TDCP, and 25% of TCEP were excreted in the bile in 48 hours. 

Since the biliary/fecal excretion ratios for TCEP and TCPP exceeded 1, it appeared that enterohepatic 

circulation occurred for these two compounds. 

TCEP. Excretion of 14C was studied in female Fischer-344 rats by collecting urine, feces, exhaled 

volatiles, and CO2 over a 3-day period following gavage administration of 175 or 350 mg 14C-TCEP/kg 

(Herr et al. 1991). The major portion of either dose was excreted in the urine within 24 hours. Only ≤1% 

of the radioactivity was excreted in expired air or as 14C-CO2 in 72 hours. Less than 10% of the 

radiolabel was excreted in feces over 3 days. Additional experiments were conducted to compare 

excretion between male and female rats over a 24-hour period. No significant differences were seen 

between males and females administered 175 mg TCEP/kg. However, females dosed with 350 mg 

TCEP/kg excreted significantly less cumulative 14C in urine than males at the 8- and 24-hour time points. 

Also, high-dose female rats excreted less cumulative 14C in urine than low-dose females at the 4-, 12-, and 

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PHOSPHATE ESTER FLAME RETARDANTS 159 

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24-hour time points. High-dose females also excreted less cumulative 14C in feces over the 24-hour 

period than males. 

Further studies of the metabolism and excretion of TCEP were conducted by Burka et al. (1991). In that 

study, cumulative 24-hour excretion of 14C-TCEP-derived radioactivity was measured in the urine and 

feces of male and female Fisher-344 rats and male B6C3F1 mice following a gavage dose of 175 mg 

TCEP/kg. In rats, >75% of the administered 14C was eliminated in the urine and <10% was eliminated in 

the feces over 24 hours; no significant differences were seen between males and females. However, male 

mice eliminated 14C 3 times faster than rats during the first 8 hours. Administration of nine consecutive 

oral doses to rats did not change the elimination rate of 14C in urine. The elimination of 14C in urine of 

female rats followed first-order kinetics with mean half-lives of 6.2, 6.1, and 6.5 hours after one, four, and 

seven doses, respectively. The corresponding half-lives in male rats were 7.6, 7.8, and 7.1 hours. The 

difference between males and females was statistically significant after one and four doses, but not after 

seven doses. 

TnBP. Administration of a single dose of 14 mg 14C-TnBP by gavage to male Wistar rats resulted in 50% 

of the 14C recovered in the urine, 10% in exhaled air, and 6% in feces within 1 day (Suzuki et al. 1984a). 

This was compared with corresponding values of 70, 7, and 7% after administration of the same dose by 

intraperitoneal injection (Suzuki et al. 1984a). 

The excretion of 14C-TnBP-derived radioactivity was also studied in male and female Sprague-Dawley 

rats over a 168-hour period following administration by gavage of a single dose of 10 or 350 mg TnBP/kg 

or eight consecutive doses of 10 or 350 mg/kg/day (SOCMA 1992). Analyses of excreta showed that the 

major portions of the administered doses were eliminated within 48 hours in urine and feces. The ratio of 

radioactivity urine/feces ranged from about 4 in single- low-dose males to 14 in repeated-high-dose 

females. Excretion of radioactivity in expired was low ranging from 3.6% in repeated-high-dose females 

to 8.3% in single-high-dose males. 

3.4.4.3 Dermal Exposure 

TnBP. SOCMA (1992) studied the excretion of 14C-TnBP-derived radioactivity in Sprague-Dawley rats 

over a 168-hour period after application of 10 or 350 mg TnBP/kg to a 2-cm2 area of the skin for 6 hours 

followed by washing with soap and water. The major portion of the recoverable dose was excreted in the 

urine and feces within 48 hours. In males, over the 168-hour period, approximately 29 and 40% of the 

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PHOSPHATE ESTER FLAME RETARDANTS 160 

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applied low- and high-dose, respectively, was recovered in urine and 3 and 7% in feces. In females, 

approximately 32 and 44% of the applied low- and high-dose, respectively, was recovered in urine and 

3 and 7% in feces. In both the low- and high-dose groups, between 24% (high-dose females) and 43% 

(low-dose females) of the applied 14C was recovered in the wash. Radioactivity in expired air comprised 

≤2% of the applied dose. No significant differences in excretion were seen between males and females. 

Yucatan® minipigs excreted in the urine and feces ≤4% of a dermal dose of 10 or 350 mg of 14C-TnBP/kg 

applied to the skin for 6 hours, indicating that dermal absorption of TnBP in this species is about 10 times 

lower than in rats under similar experimental conditions (SOCMA 1992). 

3.4.4.4 Other Routes of Exposure 

TDCP. In male Sprague-Dawley rats administered a single intravenous injection of 14C-TDCP, the 

primary route of excretion of radiolabel was the urine with significantly lesser amounts being excreted in 

the feces and in expired CO2 (Lynn et al. 1981). Approximately 62% of the radiolabel in the composite 

urine and 51% in composite feces over a 5-day period was found to be BDCP. On a molar basis, BDCP 

excreted in the urine and feces accounted for approximately 63% of the administered dose of TDCP. 

Only trace amounts of the parent compound were detected in the urine and feces. Experiments in rats 

with cannulated bile ducts showed that approximately one third of the administered radiolabel was 

excreted via the bile in 24 hours. Comparison of rats with cannulated bile ducts with normal rats showed 

that at least 67% of the radiolabel excreted in the bile was reabsorbed. 

Similar results were reported by Nomeir et al. (1981) who also administered 14C-TCDP to male SpragueDawley rats intravenously. In their study, approximately 47 and 21% of the administered radiolabel was 

excreted in the urine and feces, respectively, within 10 days of administration. The major metabolite 

excreted in the urine was BDCP. Experiments with bile duct-cannulated rats suggested that a portion of 

the radioactivity excreted in the bile was reabsorbed from the gastrointestinal tract and excreted in the 

urine. Nomeir et al. (1981) also showed that approximately 20% of an intravenous dose of TDCP was 

exhaled as CO2 during the first 24 hours after dosing; the radioactivity was primarily metabolites rather 

than parent compound. 

TnBP. Administration of a single intraperitoneal dose of 14 mg 14C-TnBP to male Wistar rats resulted in 

70% of the 14C recovered in the urine, 7% in exhaled air, and 4% in feces within 1 day (Suzuki et al. 

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PHOSPHATE ESTER FLAME RETARDANTS 161 

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1984a). The detection of radiolabel in the feces after an intraperitoneal injection suggested that some 

metabolites were excreted via the bile duct. 

SOCMA (1992) studied the excretion of 14C-TnBP-derived radioactivity in Sprague-Dawley rats over a 

168-hour period after a single intravenous injection of 5 mg TnBP/kg into the tail vein. The major 

portion of the recoverable dose was excreted in the urine and feces within 48 hours. Over the 168-hour 

period, approximately 69 and 80% of the injected dose was recovered in urine of males and females, 

respectively; in the same period, 17 and 7% was recovered in feces from males and females, respectively. 

Cumulative recovery of 14C in expired air accounted for 4–6% of the administered dose of TnBP. Only 

≤1% of the administered dose was recovered in tissues. In total, approximately 90% of the administered 

dose of radioactivity was recovered in excreta. 

SOCMA (1992) also studied the excretion of 14C-TnBP-derived radioactivity in Yucatan® minipigs by 

analyzing excreta collected for up to 168 hours after administration of a single intravenous dose of 5 mg 

TnBP/kg. About 82% of the administered dose was excreted in the urine and 2–3% in the feces. The 

majority of the urinary excretion occurred during the first 6 hours after dosing. There was no difference 

between males and females. 

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

Physiologically based pharmacokinetic (PBPK) models use mathematical descriptions of the uptake and 

disposition of chemical substances to quantitatively describe the relationships among critical biological 

processes (Krishnan et al. 1994). PBPK models are also called biologically based tissue dosimetry 

models. PBPK models are increasingly used in risk assessments, primarily to predict the concentration of 

potentially toxic moieties of a chemical that will be delivered to any given target tissue following various 

combinations of route, dose level, and test species (Clewell and Andersen 1985). Physiologically based 

pharmacodynamic (PBPD) models use mathematical descriptions of the dose-response function to 

quantitatively describe the relationship between target tissue dose and toxic end points. 

PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to 

delineate and characterize the relationships between: (1) the external/exposure concentration and target 

tissue dose of the toxic moiety, and (2) the target tissue dose and observed responses (Andersen and 

Krishnan 1994; Andersen et al. 1987). These models are biologically and mechanistically based and can 

be used to extrapolate the pharmacokinetic behavior of chemical substances from high to low dose, from 

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route to route, between species, and between subpopulations within a species. The biological basis of 

PBPK models results in more meaningful extrapolations than those generated with the more conventional 

use of uncertainty factors. 

The PBPK model for a chemical substance is developed in four interconnected steps: (1) model 

representation, (2) model parameterization, (3) model simulation, and (4) model validation (Krishnan and 

Andersen 1994). In the early 1990s, validated PBPK models were developed for a number of 

toxicologically important chemical substances, both volatile and nonvolatile (Krishnan and Andersen 

1994; Leung 1993). PBPK models for a particular substance require estimates of the chemical substancespecific physicochemical parameters, and species-specific physiological and biological parameters. The 

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

equations that describe the pharmacokinetic processes. Solving these differential and algebraic equations 

provides the predictions of tissue dose. Computers then provide process simulations based on these 

solutions. 

The structure and mathematical expressions used in PBPK models significantly simplify the true 

complexities of biological systems. If the uptake and disposition of the chemical substance(s) are 

adequately described, however, this simplification is desirable because data are often unavailable for 

many biological processes. A simplified scheme reduces the magnitude of cumulative uncertainty. The 

adequacy of the model is, therefore, of great importance, and model validation is essential to the use of 

PBPK models in risk assessment. 

PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the 

maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994). 

PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in 

humans who are exposed to environmental levels (for example, levels that might occur at hazardous waste 

sites) based on the results of studies where doses were higher or were administered in different species. 

Figure 3-11 shows a conceptualized representation of a PBPK model. 

If PBPK models for phosphate ester flame retardants exist, the overall results and individual models are 

discussed in this section in terms of their use in risk assessment, tissue dosimetry, and dose, route, and 

species extrapolations. 

No PBPK models have been developed for the phosphate ester flame retardants discussed in this profile. 

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Figure 3-11. Conceptual Representation of a Physiologically Based
 

Pharmacokinetic (PBPK) Model for a Hypothetical
 

Chemical Substance
 

Inhaled chemical Exhaled chemical 

Ingestion 

Lungs 

Liver 

Fat 

Slowly 

perfused 

tissues 

Richly 

perfused 

tissues 

Kidney 

Skin 

A 

R 

T 

E 

R 

I 

A 

L 

B 

L 

O 

O 

D 

Vmax 

Km GI 

Tract 

Feces 

Urine

 Chemicals 

contacting skin 

V 

E 

N 

O 

U 

S 

B 

L 

O 

O 

D 

Note: This is a conceptual representation of a physiologically based pharmacokinetic (PBPK) model for a 

hypothetical chemical substance. The chemical substance is shown to be absorbed via the skin, by inhalation, or by 

ingestion, metabolized in the liver, and excreted in the urine or by exhalation. 

Source: adapted from Krishnan and Andersen 1994 

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3.5 MECHANISMS OF ACTION 

3.5.1 Pharmacokinetic Mechanisms 

Absorption. Studies with TCEP, TDCP, and TnBP in animals showed that these substances are rapidly 

and extensively absorbed through the gastrointestinal tract (Herr et al. 1991; Nomeir et al. 1981; SOCMA 

1992). However, the mechanisms involved in the absorption of these compounds have not been studied. 

Given the fast absorption, it seems reasonable to assume that the process occurs through passive 

diffusion. TDCP was also rapidly absorbed through the skin of rats, but a rate of absorption was not 

estimated (Nomeir et al. 1981). A study with TnBP showed significant differences in dermal absorption 

between rats and minipigs; that rats absorbed about 10 times more of 14C-TnBP-derived radioactivity than 

did minipigs (SOCMA 1992). No mechanism for dermal absorption was proposed, but a study with 

isolated human skin showed that for a group of alkyl phosphate ester flame retardants, chain length was 

an important factor in dermal absorption; the shorter the alkyl chain length, the faster the compound was 

absorbed (Marzulli et al. 1965). It was also observed that substances with benzene/water partition ratios 

closest to 1 had the highest penetration rates, and compounds with the lower boiling points penetrated the 

skin better than those with the highest boiling points. 

Distribution. No specific mechanisms of distribution were apparent for the phosphate ester flame 

retardants for which there are distribution data (i.e., TCEP, TnBP, TDCP, TCPP). In general, oral studies 

with radiolabeled compounds showed no preferential accumulation in tissues. A study in which three 

dose levels of TDCP (0.086, 0.86, or 8.6 mg/kg) were administered to rats showed linear increases in 

distribution to tissues over the dose range tested 24 hours after dosing, indicating independence from dose 

size (Nomeir et al. 1981). That study also provided evidence of distribution independent from the route 

of exposure as tissue/blood ratios of radioactivity after dermal exposure to TDCP were similar to ratios 

calculated after intravenous administration of the compound. A study of distribution of 14C-TCEPderived radioactivity to various brain areas from rats also showed almost linear distribution of 

radioactivity over the dose range tested 2 hours after dosing (Herr et al. 1991). That study also showed 

that distribution to the areas monitored was sex-independent. 

Metabolism. The metabolism of TDCP, TCEP, and TnBP has been fairly well studied and involves 

both phase I and phase II reactions. In rats, metabolism was the main form of elimination of TDCP (Lynn 

et al. 1981). The role that metabolism may play in the toxicity and/or carcinogenicity of TDCP is 

unknown. 

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Studies in rats aimed at identifying the chemical entity responsible for the seizure activity and brain 

lesions in rats exposed to TCEP showed quantitative differences in metabolism between rats and mice and 

between female and male rats (Burka et al. 1991). Pretreatment of the rats with the mixed function 

oxidase inhibitor SK 525A, which should have led to accumulation of parent compound, did not result in 

increased neurotoxicity, which led Burka et al. (1991) to suggest that a metabolite rather than TCEP 

produces neurotoxicity. This, however, seems to be in conflict with the observation that at the time of 

seizure activity, only unmetabolized TCEP was detected in extractions of brain cortical tissues from 

individual rats. In addition, further experiments showed some evidence that in pooled tissues, the 

unmetabolized TCEP/metabolite ratio was greater for cortical tissues of female rats (the more sensitive 

gender) than male rats (Herr et al. 1991). In vitro studies with liver preparations from humans and rats 

also showed differences in the metabolism of TCEP between species and between male and female rats 

(Chapman et al. 1991). For example, both liver slices and microsomes from humans and male rats 

metabolized TCEP to bis(2-chloroethyl) hydrogen phosphate, 2-chloroethanol, and three unidentified 

metabolites. However, TCEP was metabolized by liver slices from female rats, but not by liver 

microsomes from female rats. In addition, TCEP was metabolized by rat plasma, without sex differences, 

but not by human plasma or whole blood. 

The metabolism of TnBP has been studied in rats and minipigs. SOCMA (1992, 1994) conducted studies 

in both species and reported that phase II metabolism appeared to be a much more significant 

biotransformation route in minipigs than in rats. In neither species did there appear to be significant 

differences in the metabolic profile between males and females. The role of metabolism of TnBP in the 

toxicity of this substance is not known. Intermediate- and chronic-duration toxicity studies with TnBP in 

rats showed the urinary bladder to be the most sensitive tissue, as it caused urinary bladder hyperplasia, 

which appeared to develop into urinary bladder tumors after chronic-duration exposure (Arnold et al. 

1997; Auletta et al. 1998a; FMC 1985a; Tyl et al. 1997). The mechanism by which this occurs is not 

known, but it has been suggested that it may involve one or more metabolites, particularly dibutyl 

phosphate (Arnold et al. 1997). 

Excretion. Studies of elimination of some of the selected phosphate ester flame retardants indicate that 

the urine is the main route of elimination and that, for some of them, there are differences between species 

and between male and female animals. For example, a comparative study of TDCP, TCPP, and TCEP 

reported that in rats, approximately 90% of the administered TCEP was excreted in the urine, whereas 

60% of TCPP and 40% of TDCP were excreted in the urine (Minegishi et al. (1988). It also appeared that 

enterohepatic circulation occurred for TCEP and TCPP, but not TDCP. A study with TCEP reported that 

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at high doses, female rats excreted less cumulative TCEP-derived radioactivity in urine and feces than 

males over a 24-hour period (Herr et al. 1991). It was also shown that male mice eliminated TCEPderived radioactivity significantly faster than male or female rats during an 8-hour period after a single 

gavage dose (Burka et al. 1991). Studies with TnBP in rats and minipigs applied the same doses of the 

chemical onto the skin showed that rats eliminated considerably more TnBP-derived radioactivity in the 

urine (up to 40% of the applied dose) than minipigs ( ≤4% of the applied dose) over the same period of 

time (SOCMA 1992). This reflected reduced absorption in minipigs compared to rats, since rats and 

minipigs excreted similar percentages of radioactivity in the urine following intravenous administration of 

the chemical. 

3.5.2 Mechanisms of Toxicity 

Few studies were located that explored possible mechanisms of action of the phosphate ester flame 

retardants flame retardants discussed in this profile. The rat kidney was a sensitive target for TCEP, as 

chronic treatment resulted in increased incidence of renal tubule hyperplasia (NTP 1991a). The 

mechanism by which this occurred is not known. However, a recent study suggested that TCEP might 

alter the levels of cell cycle regulatory proteins in the kidney (Ren et al. 2008). The investigators 

incubated primary cultured rabbit renal proximal tubule cells with TCEP and reported that TCEP 

decreased cell viability, inhibited the expression of some regulatory proteins (CDK4, cyclin D1, CDK2, 

cyclin E), increased the expression of others (p21WAF/Cip1, p27Kip1), and decreased DNA synthesis and cell 

numbers. Whether or not this also occurs in vivo in rats is not known, but further research in this area 

would be valuable. 

TCEP also induced brain lesions in rats in acute-, intermediate-, and chronic-duration studies; this was 

observed mostly in females (NTP 1991a, Tilson et al. 1990). The lesions occurred mostly in the 

hippocampus following acute- and intermediate-duration exposure and in the cerebral cortex and brain 

stem following chronic-duration exposure. In the acute study, the rats also exhibited seizure activity, and 

rats in the highest dose groups in the intermediate-duration study experienced occasional periods of 

hyperactivity after dosing; no clinical signs were reported in the chronic-duration study (NTP 1991a). 

Since in the acute study, the seizure activity and neurohistological damage were attenuated by 

pretreatment with atropine or chlordiazepoxide, Tilson et al. (1990) suggested that the morphological 

damage was related to the seizures produced by TCEP. What triggers the seizures is not known for 

certain, but a study of the effects of TCEP on ambulatory activity in mice suggested that TCEP may act as 

a GABA antagonist (Umezu et al. 1998). Through the use of various pharmacological manipulations with 

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cholinergic antagonists and GABA agonists, the investigators determined that the TCEP-induced 

increased ambulatory activity was not a result of inhibition of acetylcholinesterase, but of an action as 

GABA antagonist. It would be useful to try to replicate these results in rats. 

A characteristic effect of TnBP was the induction of urinary bladder hyperplasia in rats in intermediateand chronic-duration studies (Arnold et al. 1997; Auletta et al. 1998a; FMC 1985a; Tyl et al. 1991). The 

hyperplasia was the consequence of focal urothelial necrosis. In one of the intermediate-duration studies, 

it was shown that the effects were reversible upon cessation of treatment and that acidification of the 

urine with ammonium chloride did not prevent, but attenuated, the proliferative changes (Arnold et al. 

1997). The mechanism by which the urinary bladder changes occur is not known, but scanning electron 

microscopy showed that the epithelial necrosis was not due to the presence of urinary calculi, 

microcrystalluria, or precipitate formation. Since TnBP is extensively metabolized, Arnold et al. (1997) 

speculated that the cytotoxicity may be due to one or more metabolites, possibly dibutyl phosphate. 

TPP was one of several triaryl phosphates that were tested for effects on human nuclear receptors 

(Honkakoski et al. 2004). Nuclear receptors control a wide range of cellular processes and alterations in 

their functions can result in also a wide range of clinical manifestations. Experiments were conducted 

with HEK293 cells transfected with mouse or human nuclear constitutively active receptor (CAR) or 

pregnane X receptor (PXR) and their reported genes; the cells were incubated with vehicle, reference 

substances, or triaryl phosphates. The results showed TPP to be a weak activator of mouse CAR and 

PXR, but a greater activator of human CAR (5.5-fold) and PXR (3-fold). Additional experiments with 

COS-1 cells transfected with human glucocorticoid receptor (GR), progesterone receptor (PR), androgen 

receptor (AR), and estrogen receptor (ER) showed TPP to inhibit GR and AR in the absence of any added 

agonist and to inhibit testosterone-induced AR-activity by 30–40%. The significance of these findings to 

in vivo exposure situations remains to be determined. The few toxicity studies available with TPP in 

animals did not identify significant health effects. 

3.5.3 Animal-to-Human Extrapolations 

An animal model that can be used to predict health effects in humans resulting from exposure to any of 

the selected phosphate ester flame retardants has not been identified largely because there is very limited 

information regarding health effects of these substances in humans. Trying to predict what would happen 

to humans exposed to any of these chemicals based on the results from the available animal studies may 

be inappropriate at this time given that several studies identified significant differences in susceptibility 

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between species for some toxic effects. For example, treatment of rats and mice with TCEP resulted in 

brain lesions only in rats, even though mice received higher doses of TCEP (NTP 1991a). Also, rats were 

significantly more sensitive to the effects of TnBP on the urinary bladder than mice (Arnold et al. 1997; 

Auletta 1991; Auletta et al. 1998a, 1998b; FMC 1985a; Tyl et al. 1997). The mechanisms of these 

differential susceptibilities have not been elucidated, but may be related to differences in 

pharmacokinetics between species. Some evidence for this was presented by Chapman et al. (1991) in 

studies of the metabolism of TCEP by liver slices and microsomes, and plasma from male and female rats 

and humans. 

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS 

Recently, attention has focused on the potential hazardous effects of certain chemicals on the endocrine 

system because of the ability of these chemicals to mimic or block endogenous hormones. Chemicals 

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

terminology to describe such effects remains controversial. The terminology endocrine disruptors, 

initially used by Thomas and Colborn (1992), was also used in 1996 when Congress mandated the EPA to 

develop a screening program for “...certain substances [which] may have an effect produced by a 

naturally occurring estrogen, or other such endocrine effect[s]...”. To meet this mandate, EPA convened a 

panel called the Endocrine Disruptors Screening and Testing Advisory Committee (EDSTAC), and in 

1998, the EDSTAC completed its deliberations and made recommendations to EPA concerning endocrine 

disruptors. In 1999, the National Academy of Sciences released a report that referred to these same types 

of chemicals as hormonally active agents. The terminology endocrine modulators has also been used to 

convey the fact that effects caused by such chemicals may not necessarily be adverse. Many scientists 

agree that chemicals with the ability to disrupt or modulate the endocrine system are a potential threat to 

the health of humans, aquatic animals, and wildlife. However, others think that endocrine-active 

chemicals do not pose a significant health risk, particularly in view of the fact that hormone mimics exist 

in the natural environment. Examples of natural hormone mimics are the isoflavinoid phytoestrogens 

(Adlercreutz 1995; Livingston 1978; Mayr et al. 1992). These chemicals are derived from plants and are 

similar in structure and action to endogenous estrogen. Although the public health significance and 

descriptive terminology of substances capable of affecting the endocrine system remains controversial, 

scientists agree that these chemicals may affect the synthesis, secretion, transport, binding, action, or 

elimination of natural hormones in the body responsible for maintaining homeostasis, reproduction, 

development, and/or behavior (EPA 1997). Stated differently, such compounds may cause toxicities that 

are mediated through the neuroendocrine axis. As a result, these chemicals may play a role in altering, 

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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). 

No studies were located regarding endocrine disruption in humans after exposure to the phosphate ester 

flame retardants subject of this profile. 

The information available from studies in animals does not suggest that these substances have endocrine 

disrupting properties. Toxicity studies summarized in Section 3.2.2.2, Systemic Effects, did not find 

alterations in gross or microscopic appearance of endocrine glands. It should be noted, however, that 

none of the studies available examined endocrine gland function as judged, for example, by levels of 

hormones in serum (i.e., thyroid hormones, sex hormones). 

TCEP decreased fertility in mice in a continuous breeding protocol study following exposure of the 

parental generation to ≥350 mg/kg/day by gavage for approximately 14 weeks (NTP 1991b). Reduced 

fertility appeared to have been due primarily to alterations in sperm parameters such as concentration, 

motility, and abnormal forms, but a specific mechanism was not apparent. A study by Laham et al. 

(1984b) reported that administration of 411 mg TnBP/kg/day to rats by gavage for 14 days induced 

degenerative changes in the seminiferous tubules in the testes. However, this was based on the 

examination of only 4 male rats out of 10, and only one presented the lesions. A study of TDCP in which 

rabbits were administered up to 200 mg TDCP/kg/day by gavage for 12 weeks and then mated with 

untreated females showed no effect on fertility when the females were sacrificed at mid-gestation and 

their uteri were examined (Anonymous 1977). Examination of sperm from the rabbits showed no 

significant alterations in quantity or quality. 

Little information is available regarding tests that evaluate potential endocrine disrupting properties in 

vitro. TCEP, TnBP, and TBEP tested negative for estrogenic activity in a reporter gene expression assay 

using yeast cells (Nishihara et al. 2000). A substance was considered positive when its activity was >10% 

of the activity of 10-7 M 17β-estradiol. TPP was inactive (nonbinder) in a binding assay to the estrogen 

receptor from uteri from ovariectomized Sprague-Dawley rats (Blair et al. 2000). TPP was characterized 

as a moderate binder to the androgen receptor (AR) in a competitive binding assay that used a 

commercially obtained recombinant rat protein expressed in E. coli (Fang et al. 2003). The relative 

binding affinity of TPP was four orders of magnitude lower than that of the standard AR ligand used in 

the assay. TPP was also shown to inhibit the AR in COS-1 cells transfected with human AR in the 

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absence of any added agonist to the incubation medium and also to inhibit testosterone-induced ARactivity by 30–40% (Honkakoski et al. 2004). Föllman and Wober (2006) examined the estrogenic or 

anti-estrogenic effects of TCEP and TCPP with the recombinant yeast reporter gene assay and in human 

endometrial cancer cells and reported that neither compound showed hormonal activity. No information 

was located for the remaining phosphate ester flame retardants discussed in this profile. 

3.7 CHILDREN’S SUSCEPTIBILITY 

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

maturity at 18 years of age in humans, when all biological systems will have fully developed. Potential 

effects on offspring resulting from exposures of parental germ cells are considered, as well as any indirect 

effects on the fetus and neonate resulting from maternal exposure during gestation and lactation. 

Relevant animal and in vitro models are also discussed. 

Children are not small adults. They differ from adults in their exposures and may differ in their 

susceptibility to hazardous chemicals. Children’s unique physiology and behavior can influence the 

extent of their exposure. Exposures of children are discussed in Section 6.6, Exposures of Children. 

Children sometimes differ from adults in their susceptibility to hazardous chemicals, but whether there is 

a difference depends on the chemical (Guzelian et al. 1992; NRC 1993). Children may be more or less 

susceptible than adults to health effects, and the relationship may change with developmental age 

(Guzelian et al. 1992; NRC 1993). Vulnerability often depends on developmental stage. There are 

critical periods of structural and functional development during both prenatal and postnatal life, and a 

particular structure or function will be most sensitive to disruption during its critical period(s). Damage 

may not be evident until a later stage of development. There are often differences in pharmacokinetics 

and metabolism between children and adults. For example, absorption may be different in neonates 

because of the immaturity of their gastrointestinal tract and their larger skin surface area in proportion to 

body weight (Morselli et al. 1980; NRC 1993); the gastrointestinal absorption of lead is greatest in infants 

and young children (Ziegler et al. 1978). Distribution of xenobiotics may be different; for example, 

infants have a larger proportion of their bodies as extracellular water, and their brains and livers are 

proportionately larger (Altman and Dittmer 1974; Fomon 1966; Fomon et al. 1982; Owen and Brozek 

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 

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and development, levels of particular enzymes may be higher or lower than those of adults, and 

sometimes unique enzymes may exist at particular developmental stages (Komori et al. 1990; Leeder and 

Kearns 1997; NRC 1993; Vieira et al. 1996). Whether differences in xenobiotic metabolism make the 

child more or less susceptible also depends on whether the relevant enzymes are involved in activation of 

the parent compound to its toxic form or in detoxification. There may also be differences in excretion, 

particularly in newborns who all have a low glomerular filtration rate and have not developed efficient 

tubular secretion and resorption capacities (Altman and Dittmer 1974; NRC 1993; West et al. 1948). 

Children and adults may differ in their capacity to repair damage from chemical insults. Children also 

have a longer remaining lifetime in which to express damage from chemicals; this potential is particularly 

relevant to cancer. 

Certain characteristics of the developing human may increase exposure or susceptibility, whereas others 

may decrease susceptibility to the same chemical. For example, although infants breathe more air per 

kilogram of body weight than adults breathe, this difference might be somewhat counterbalanced by their 

alveoli being less developed, which results in a disproportionately smaller surface area for alveolar 

absorption (NRC 1993). 

No studies were located that described health effects in children following exposure to the phosphate ester 

flame retardants discussed in this profile. Also, no studies were located that compared the health effects 

of these compounds in young and adult animals to ascertain potential age-related differences in 

susceptibility. 

A limited number of studies in animals suggest that developmental indices, especially in studies of 

gestational exposure alone, are not particularly sensitive to exposure to these compounds. For example, 

rats exposed to 200 mg TCEP/kg/day on Gd 7–15 showed piloerection, general weakness, and reduced 

food consumption, and 7 out of 30 died (Kawashima et al. 1983a). However, fetal parameters recorded in 

survivors on Gd 20 were not affected and gestational exposure did not affect neonatal viability monitored 

up to week 10. Pregnant mice dosed with 940 mg TCEP/kg/day on Gd 6–13 suffered a significant 

reduction in body weight gain, yet at delivery, there were no significant effects on the number of viable 

litters, number of live pups born per litter, percent survival of pups, pup birth weight, or pup weight gain 

(Hardin et al. 1987). Similar results were reported with TBEP (Monsanto 1985b) and TnBP (Noda et al. 

1994) in rats. Doses of TBEP that induced frank signs of toxicity in the dams such as ataxia and lethargy, 

and reduced weight gain did not induce embryotoxicity or teratogenicity. Doses of TnBP that induced a 

significant reduction in adjusted weight gain on Gd 0–20 did not produce a significant difference between 

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groups in the number of corpora lutea, implants or living fetuses, incidence of dead or resorbed fetuses, 

sex ratio, or body weight of the living fetuses. In a study with TDCP, doses that significantly decreased 

weight gain in pregnant rats did not significantly affect fetal viability or mean fetal weight or length 

(Stauffer Chemical Co. 1981b). No developmental effects were reported in a gestational exposure study 

with TCPP (Kawasaki et al. 1982) or in a study with TPP administered to male and female rats in doses of 

up to approximately 690 mg/kg/day for 91 days before mating and continuing during gestation (Welsh et 

al. 1987). 

In a continuous breeding protocol study conducted by NTP (1991b), treatment of the F0 generation with 

≥350 mg TCEP/kg/day significantly reduced the number of live pups per litter. In addition, the number 

of F2 male pups per litter born to the treated F1 generation was significantly lower than in controls in the 

groups dosed with ≥175 mg TCEP/kg/day, the lowest dose level tested; a developmental NOAEL was not 

identified in the study. In the absence of clear signs of parental toxicity, the mechanism of action for 

these effects is unknown. In a 2-generation reproduction study, the only significant developmental effect 

was a significant reduction in F1 and F2 pup weight per litter measured 5 times from postnatal days 0 to 

21 at maternal doses of approximately 217 mg/kg/day; the number of pups per litter was comparable 

among groups (Tyl et al. 1997). Significant reductions in maternal body weight also occurred at this 

level, which may have contributed to the decrease in pup weight. 

No information was located regarding the pharmacokinetics of these compounds in children or regarding 

biomarkers of exposure or effect for these compounds 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). 

A biomarker of exposure is a xenobiotic substance or its metabolite(s) or the product of an interaction 

between a xenobiotic agent and some target molecule(s) or cell(s) that is measured within a compartment 

of an organism (NAS/NRC 1989). The preferred biomarkers of exposure are generally the substance 

itself, substance-specific metabolites in readily obtainable body fluid(s), or excreta. However, several 

factors can confound the use and interpretation of biomarkers of exposure. The body burden of a 

substance may be the result of exposures from more than one source. The substance being measured may 

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be a metabolite of another xenobiotic substance (e.g., high urinary levels of phenol can result from 

exposure to several different aromatic compounds). Depending on the properties of the substance (e.g., 

biologic half-life) and environmental conditions (e.g., duration and route of exposure), the substance and 

all of its metabolites may have left the body by the time samples can be taken. It may be difficult to 

identify individuals exposed to hazardous substances that are commonly found in body tissues and fluids 

(e.g., essential mineral nutrients such as copper, zinc, and selenium). Biomarkers of exposure to 

phosphate ester flame retardants are discussed in Section 3.8.1. 

Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an 

organism that, depending on magnitude, can be recognized as an established or potential health 

impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of 

tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial 

cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung 

capacity. Note that these markers are not often substance specific. They also may not be directly 

adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effects caused 

by phosphate ester flame retardants 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 Phosphate Ester Flame 

Retardants 

There are no specific biomarkers that can be used to identify exposure to the subject phosphate ester 

flame retardants flame retardants of this profile other than the chemical themselves. TDCP was detected 

in adipose tissue from members of the general Canadian population (LeBel and Williams 1986) and also 

in seminal fluid from the U.S. general population (Hudec et al. 1981), indicating that exposure to this 

substance had occurred or was ongoing. 

TPP was found to inhibit human blood monocyte carboxylesterase (Saboori et al. 1991), but so did a 

variety of organophosphorous compounds. Thus, reductions in the activity of this enzyme are not specific 

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for TPP. No studies were located of the metabolism of these substances in humans that could have 

provided information regarding metabolic products in urine. 

3.8.2	 Biomarkers Used to Characterize Effects Caused by Phosphate Ester Flame 

Retardants 

The few studies available of workers exposed to the phosphate ester flame retardants discussed in this 

profile did not identify any specific medical condition related to exposure (Stouffer Chemical Company 

1983a). Sutton et al. (1960) reported that red blood cell cholinesterase activity was significantly reduced 

(18%) in a small group of regular operators in a TPP production plant compared to unexposed subjects. 

However, exposure to other chemicals, particularly organophosphate pesticides, can also reduce the 

activity of red blood cell cholinesterase; therefore, a reduction in red blood cell cholinesterase activity 

may be used as biomarker for a class of chemicals, but not for any one of the chemicals discussed in this 

profile. 

3.9 INTERACTIONS WITH OTHER CHEMICALS 

No studies were located regarding interactions of the phosphate ester flame retardants discussed in this 

profile with other unrelated chemicals or with other phosphate esters. The mechanisms of action for some 

of the most sensitive effects of the selected phosphate ester flame retardants have not been elucidated. 

For example, the mechanisms by which TCEP induces brain damage in rats or TnBP induces urinary 

bladder hyperplasia in rats are not known; therefore, it is difficult to anticipate the type of response that 

might occur following simultaneous exposure to any of these chemicals and other substances. In addition 

to chemical-specific effects that occurred at low doses, such as those mentioned above, phosphate esters 

have also shown common effects. For instance, TCEP, TnBP, and TDCP induced increases in liver 

weight in rodents in long-term studies, but in the absence of information on a possible mechanism of 

action, any prediction of what the response would be to exposure to a mixture would be pure speculation. 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 

A susceptible population will exhibit a different or enhanced response to phosphate ester flame retardants 

than will most persons exposed to the same level of phosphate ester flame retardants in the environment. 

Reasons may include genetic makeup, age, health and nutritional status, and exposure to other toxic 

substances (e.g., cigarette smoke). These parameters result in reduced detoxification or excretion of 

phosphate ester flame retardants, or compromised function of organs affected by phosphate ester flame 

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PHOSPHATE ESTER FLAME RETARDANTS 175 

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retardants. Populations that are at greater risk due to their unusually high exposure to phosphate ester 

flame retardants are discussed in Section 6.7, Populations with Potentially High Exposures. 

There is no adequate information from studies in humans to determine whether there are populations 

unusually susceptible to the selected phosphate ester flame retardants discussed in this profile. Studies in 

animals have described species and gender differences in susceptibility to some of these chemicals. For 

example, male rats were more susceptible than females to the liver effects of TBEP (Reyna and Thacke 

1987a); female rats were more susceptible to brain lesions produced by exposure to TCEP than males, 

and rats were more susceptible than mice (NTP 1991a). However, making inferences into potential 

differences in humans based on what has been reported in studies in animals would be purely speculative 

at this time. 

3.11 METHODS FOR REDUCING TOXIC EFFECTS 

This section will describe clinical practice and research concerning methods for reducing toxic effects of 

exposure to phosphate ester flame retardants. 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 

phosphate ester flame retardants. When specific exposures have occurred, poison control centers and 

medical toxicologists should be consulted for medical advice. No texts were located that provide specific 

information about treatment following exposures to the subject phosphate ester flame retardants flame 

retardants of this profile. 

3.11.1 Reducing Peak Absorption Following Exposure 

There have been no reports of health effects in humans induced by exposure to phosphate ester flame 

retardants other than reports of skin irritation and contact dermatitis in subjects exposed to TnBP, TBEP, 

and TPP (ACGIH 2001; Camarasa and Serra-Baldrich 1992; Carlsen et al. 1986; IPCS 1991a, 1991b). 

Skin irritation can be relieved by applying general measures such as removing the contaminated clothing 

and washing the exposed area thoroughly with soap and water (HSDB 2009). If contact with the eyes 

occurs, irrigation with copious amounts water at room temperature for at least 15 minutes is 

recommended (HSDB 2009). In case of ingestion, emesis is not recommended because of the potential 

for gastrointestinal irritation. The use of activated charcoal is of unproven value in patients ingesting 

irritant chemicals where it may obscure the endoscopic findings when the procedure is justified (HSDB 

2009). If used, it is recommended that it be administered as slurry (240 mL water per 30 g of charcoal). 

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The usual dose is 25–100 g in adults and adolescents, 25–50 g in children (1–12 years), and 1 g/kg in 

infants <1 year old (HSDB 2009). 

3.11.2 Reducing Body Burden 

No information was located regarding reducing body burden following exposure to phosphate ester flame 

retardants. 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects 

The phosphate ester flame retardants discussed in this profile are not potent anticholinesterase agents, but 

cases of accidental or intentional acute exposure to high amounts may occur. If cholinergic signs and 

symptoms develop, appropriate treatment may be warranted. The following information has been 

extracted from HSDB (2009). Suction of oral secretions is recommended until atropine can be 

administered. Atropine should be administered intravenously until atropinization is achieved. Adults 

should receive 2–5 mg every 5–10 minutes, and children should receive 0.05 mg/kg every 10–15 minutes. 

This may be necessary for hours or days depending on the severity of the intoxication. Patients with 

moderate to severe poisoning should be treated with 2-PAM (Pralidoxime) in addition to atropine; 

2-PAM is most effective if given within 48 hours for 24 hours after cholinergic manifestations have 

ceased. The initial recommended dose is 30 mg/kg followed by an infusion of >8 mg/kg/hour. 

Alternatively, adults may receive 1–2 g 2-PAM in 100 mL of 0.9% saline over 15–30 minutes follow by 

infusion of 500–1,000 mg/hour as a 2.5% solution. The initial dose may be repeated 1 hour and then 

every 3–8 hours if muscle weakness or fasciculations persist. Children may be treated with 20– 

50 mg/2-PAM/kg infused over a 2-hour period (maximum 2 g) as a 5% solution in 0.9% saline followed 

by a continuous infusion of 10–20 mg/kg/hour. Alternatively, the initial dose may be repeated in 1 hour 

and then every 3–6 hours if muscle weakness or fasciculations persist. 

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 phosphate ester flame retardants 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 

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PHOSPHATE ESTER FLAME RETARDANTS 177 

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effects (and techniques for developing methods to determine such health effects) of phosphate ester flame 

retardants. 

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 Phosphate Ester Flame Retardants 

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to 

phosphate ester flame retardants are summarized in Figure 3-12. The purpose of this figure is to illustrate 

the existing information concerning the health effects of phosphate ester flame retardants. The presence 

of the acronym in a square indicates that one or more studies provide information associated with that 

particular effect for that particular phosphate ester. The presence of the acronym in the square does not 

necessarily imply anything about the quality of the study or studies, nor should missing information in 

this figure be interpreted as a “data need”. A data need, as defined in ATSDR’s Decision Guide for 

Identifying Substance-Specific Data Needs Related to Toxicological Profiles (Agency for Toxic 

Substances and Disease Registry 1989), is substance-specific information necessary to conduct 

comprehensive public health assessments. Generally, ATSDR defines a data gap more broadly as any 

substance-specific information missing from the scientific literature. 

As shown in Figure 3-12, there was very limited information on the effects in humans of the phosphate 

ester flame retardants discussed in this profile. The available information was derived from only a few 

occupational studies in which exposure was assumed to have been primarily by inhalation of vapor mists 

and dust. These studies provided information on morbidity and mortality of workers exposed to TDCP 

and TPP. A few studies were also available that provide information on dermal effects of TPP on 

members of the general population. 

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PHOSPHATE ESTER FLAME RETARDANTS 178 

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Figure 3-12. Existing Information on Health Effects of Phosphate Ester Flame 

Retardants 

TDCP 

TPP TDCP 

Death

Acute 

Intermediate

Chronic

Immunologic/Lymphoretic

Neurologic

Reproductive

Developmental

Genotoxic

Cancer 

Systemic 

TPP 

Inhalation TDCP

Oral 

Dermal 

Human 

All but 

TCPP 

All but 

TCPP 

Death

Acute 

Intermediate

Chronic

Immunologic/Lymphoretic

Neurologic

Reproductive

Developmental

Genotoxic

Cancer 

Systemic 

All 

All but 

TiBP 

All but 

TCPP 

TCEP 

TnBP 

TDCP 

All but 

TCPP 

All but 

TCPP 

All but 

TCPP 

All but 

TiBP 

TCEP 

TDCP 

TiBP 

TnBP 

TCEP 

TnBP 

TDCP 

TCEP 

Inhalation 

Oral 

Dermal 

Animal 

TCEP = tris-(2-chloroethyl)-phosphate; TCPP = tri-(2-chloroisopropyl) phosphate; TDCP = tris(1,3-dichloro-2-propyl) 

phosphate; TiBP = triisobutyl phosphate; TnBP = tributyl phosphate 

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Most of the studies available in animals were conducted by the oral route of exposure, although 

information on lethality due to acute high inhalation and dermal exposures was also available. Sufficient 

information on health effects of oral exposure to TCEP, TnBP, TBEP, and TDCP was available to derive 

oral MRLs for these substances, although not for all exposure durations. In general, information was 

available for systemic, neurological, reproductive, developmental effects, genotoxicity, and cancer; less 

data were located for immunological effects. Limited information was available for TPP and even less 

information was available for TiBP and TCPP. 

The information available from animal studies was insufficient to conclusively determine whether or not 

the effects of the selected phosphate ester flame retardants are route-dependent; however, the 

toxicokinetics data for a few of these chemicals suggested that, other than portal-of-entry effects such as 

skin or gastrointestinal irritation, the toxicity of these substances is probably not route-dependent. In 

addition, the environmental monitoring data available suggested that the levels of some of these 

substances to which the general population might be exposed through contact or use of consumer 

products (including food and water), or that are commonly found in environmental media are generally 

orders of magnitude lower than those used in studies with experimental animals. 

3.12.2 Identification of Data Needs 

Acute-Duration Exposure. No data were located regarding health effects in humans following acute 

exposure by any route to the phosphate ester flame retardants discussed in this profile. The acute 

inhalation studies in animals provide information mostly on lethal doses and are not adequate for 

derivation of acute-duration inhalation MRLs. The dermal studies available in animals were also 

designed to estimate lethal doses. However, it would be useful to determine whether dermal exposure to 

these substances results in sufficient material being absorbed to be of concern. The selection of an 

appropriate animal model for human dermal exposure is important; limited data with TnBP indicate that 

Yucatan® minipigs absorbed 10 times less TnBP through the skin than rats (SOCMA 1992). Sufficient 

data were available to derive acute-duration oral MRLs for TnBP and TBEP; both studies were 

gestational exposure studies in rats (Monsanto Co. 1985b; Noda et al. 1994). No MRLs were derived for 

TCEP, TDCP, TCPP, TiBP, or TPP due to either lack of studies or the studies available did not identify 

clear adverse effects. In general, and this applies also to the subsequent sections, the decision to 

recommend additional studies by any route for any one of phosphate ester flame retardants selected for 

this profile should take into account information regarding environmental monitoring, potential routes of 

exposure for the population, and information on levels of these substances in biological fluids from a 

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PHOSPHATE ESTER FLAME RETARDANTS 180 

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representative sample of the population. While recognizing that it would be useful for health assessors to 

have MRLs for all of these chemicals, this information should help prioritize the need for additional 

studies. 

Intermediate-Duration Exposure. No specific information was located regarding health effects in 

humans following intermediate-duration exposure to the selected phosphate ester flame retardants, 

although some workers exposed to TDCP or TPP in the studies conducted by Stauffer Chemical Co. 

(1983a) and Sutton et al. (1960) may have been exposed for <1 year. No intermediate-duration inhalation 

studies in animals were located. Intermediate-duration dermal studies in rabbits were available for TPP 

(Monsanto Co. 1979) and TBEP (Monsanto Co. 1985d). These studies evaluated systemic toxicity end 

points as well as effects at the application site. The only effects reported were dermal effects in rabbits 

treated with ≥10 mg TBEP/kg/day. Intermediate-duration oral studies, adequate for use as the basis for 

MRL derivation, were available for TCEP, TnBP, TBEP, and TDCP. The MRL for TCEP was based on 

necrosis of hippocampal neurons in female rats in a 16-week gavage study (NTP 1991a). That study also 

provided information on a wide range of systemic end points. In addition, a continuous breeding protocol 

study in mice was available (NTP 1991b). Several intermediate-duration studies in rats exposed to TnBP 

in the diet were available (Arnold et al. 1997; FMC 1985a; Laham et al. 1985a; Tyl et al. 1997). These 

studies identified the urinary bladder of rats as a sensitive target for TnBP and the intermediate-duration 

oral MRL for this chemical was based on this end point (Arnold et al. 1997). Information on reproductive 

and neurological effects of TnBP was also available (Arnold et al. 1997; Healy et al. 1995). The 

intermediate-duration oral MRL for TBEP was based on hepatic effects in rats exposed to TBEP in the 

diet in the only wide scope study available for this chemical (Reyna and Thacke 1987a). An 

intermediate-duration oral study that evaluated reproductive parameters in male rabbits was available for 

TDCP (Anonymous 1977). The limited scope of this study precluded its use for MRL derivation. 

However, data from the interim assessement of rats after 12 months of treatment in the 24-month bioassay 

conducted by Stauffer Chemical Co (1981a) were used to derive an intermediate-duration oral MRL for 

TDCP. Intermediate-duration oral studies with TPP provided information regarding organ weights in rats 

(Sutton et al. 1960), neurobehavioral effects in rats (Sobotka et al. 1986), reproductive and developmental 

effects in rats (Welsch et al. 1987), and immunological effects in rats (Hinton et al. 1996). However, no 

MRL was derived for TPP based on no clear evidence of toxicity provided in these studies. Only one 

intermediate-duration study that reported effects of unknown toxicological significance in rats was 

located for TiBP (Naylor and Ribelin 199). No intermediate-duration oral studies were available for 

TCPP. As indicated above, monitoring data as well as potential for exposure should be considered in the 

decision to recommend conducting studies to fill the data gaps for individual triphosphate ester flame 

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retardants. Since these chemicals are usually found as mixtures at hazardous waste sites and in 

environmental media, there is a need to conduct toxicity studies for mixtures to determine how these 

chemicals interact with each other and how this affects their toxicity. 

Chronic-Duration Exposure and Cancer. Studies by Stauffer Chemical Co. (1983a) and Sutton et 

al. (1960) provide data on workers exposed chronically to TDCP and TPP, respectively. Neither study 

found significant associations between exposure to these substances and adverse health effects. In both 

cases, the primary route of exposure is assumed to have been inhalation, but dermal exposure probably 

also occurred. No information was located regarding health effects in humans following chronic 

exposure to the other phosphate ester flame retardants discussed in this profile. No chronic inhalation or 

dermal studies were identified for any of the phosphate ester flame retardants discussed in this profile. 

Chronic data were available for TCEP in an NTP (1991a) bioassay that examined a wide range of end 

points in rats and mice treated with the chemical by gavage. The most sensitive effects identified in that 

study were brain lesions in female rats and renal tubule lesions in male and female rats. A chronicduration oral MRL was derived for TCEP based on the renal lesions in female rats; additional chronic 

studies for this chemical do not seem necessary. Long-term studies were also available for TnBP in rats 

and mice (Auletta et al. 1998a, 1998b). The urinary bladder from rats was the target for TnBP toxicity; 

treated rats showed an increased incidence of urinary bladder hyperplasia. Because the incidences were 

lower than those seen in intermediate-duration studies at comparable doses, the intermediate-duration oral 

MRL was also adopted as the chronic-duration MRL (a detailed explanation can be found in Section 2.3). 

A chronic-duration study in rats treated with TDCP in the diet was available (Stauffer Chemical Co. 

1981a). Liver and kidneys effects occurred at the lowest dose tested and the latter served as the basis for 

derivation of a chronic-duration oral MRL for TDCP. Additional studies for TDCP do not seem 

necessary. No chronic-duration oral studies were identified for TBEP, TPP, TiBP, or TCPP. It seems 

reasonable that before conducting chronic-duration studies with these chemicals, a more or less complete 

intermediate-duration database be available in which the most sensitive end points have been identified in 

well-conducted studies. As previously mentioned, studies of the toxicity of mixtures of phosphate esters 

flame retardants would be valuable since these substances are generally found as mixtures at hazardous 

waste sites and other environmental media. 

No associations between exposure to TDCP and cancer were reported in a retrospective cohort study that 

examined the mortality experience of workers employed in the manufacture of TDCP (Stauffer Chemical 

Co. 1983a). No further information was located regarding exposure to the selected phosphate ester flame 

retardants and cancer in humans. TCEP, TnBP, and TDCP have been tested for carcinogenicity in long-

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term oral bioassays. Treatment of rats with TCEP by gavage increased the incidence of renal tubule 

adenoma or carcinoma in males and renal tubule adenomas in females (NTP 1991a). TCEP also induced 

a nonsignificant increase in the incidence of a rare renal tubule neoplasm in male B6C3F1 mice. TCEP 

increased, although not significantly, the incidence of tumors of the Harderian gland in female B6C3F1 

mice. In another study, dietary treatment of mice with TCEP increased the incidences of renal and liver 

tumors in male mice and forestomach tumors and leukemia in female mice (Takada et al. 1989). In 

dermal assays, TCEP showed no significant carcinogenic, initiating, or promoting activity on the skin of 

female mice (Sala et al. 1982). TnBP increased the incidence of urinary bladder cancer in male rats 

(Auletta et al. 1998a) and hepatocellular adenomas in male mice (Auletta et al. 1998b). TDCP increased 

the incidence of neoplastic nodules in the liver of male and female rats and the incidence of hepatocellular 

carcinomas in male rats (Stauffer Chemical Co. 1981a). TDCP also increased the incidence of renal 

cortical tumors in male and female rats, interstitial cell tumors in the testes in male rats, and 

adrenocortical adenomas in female rats. Additional standard cancer studies for these chemicals seem 

unnecessary, but mechanistic studies are lacking. For example, further research is needed to elucidate the 

mechanism by which TnBP induces urinary bladder cancer in rats, which does not seem to be related to 

changes in urine pH and composition or to physical agents such as calculi, microcrystals, or precipitate 

(Auletta et al. 1998a). It would be valuable to determine also whether or not urinary bladder hyperplasia 

is a precursor of bladder cancer. The mechanisms of carcinogenicity for TCEP or TDCP also are not 

known. Studies of subcellular distribution of radioactivity derived from phosphate ester flame retardants, 

such as those conducted by Morales and Matthews (1980) with TDCP can provide information on the 

possible formation of adducts with cellular macromolecules that may be involved in carcinogenicity. No 

information was located regarding cancer effects in animals exposed to TBEP, TPP, TiBP, or TCPP. 

Knowing the extent of exposure of the general population to these substances may be a factor to consider 

in deciding whether or not to conduct cancer studies with these chemicals. 

Genotoxicity. No information was located regarding genotoxic effects of the selected phosphate ester 

flame retardants in humans. All of the selected phosphate ester flame retardants have been tested for 

genotoxic effects in in vitro assays in various strains of S. typhimurium. With a few exceptions, the 

results have been mostly negative. Positive results were reported for TDCP in the presence of metabolic 

activation in two studies (Gold et al. 1978; NTP 1983) and in one study both in the presence and absence 

of metabolic activation (Mortelmans et al. 1986). It is unclear what the value would be of conducting 

additional mutagenicity studies in prokaryotic organisms. In vitro assays in mammalian cells yielded 

negative results for TBEP (Mobil Oil Corp 1991; Monsanto Co. 1985c) and TnBP (Batt et al. 1992). 

Mixed results were reported for TCEP (Föllmann and Wober 2006; Galloway et al. 1987; NTP 1991a; 

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Sala et al. 1982), TCPP (Föllmann and Wober 2006), and TDCP (Brusick et al. 1979; Dybing et al. 1983; 

Søderlund et al. 1985; Stauffer Chemical Co. 1981b); no studies were located for TPP or TiBP. It is 

difficult to determine whether the different results with a specific test among the phosphate ester flame 

retardants represent true mechanistic differences or reflect methodological differences. Additional tests 

will probably not resolve the issue. However, as mentioned above, additional studies of the potential 

binding of phosphate ester flame retardants or their metabolites, particularly of those that have shown to 

induce cancer in animals, to cellular macromolecules could provide valuable information regarding 

mechanisms of carcinogenicity. TDCP, TCEP, TiBP, and TnBP yielded negative results in tests for 

clastogenicity in vivo (Batt et al. 1992; Brusick et al. 1979; Flowers and Garrett 1992; Sala et al. 1982; 

Stauffer Chemical Co. 1981b; Vogel and Nivard 1993). In vivo studies with TCPP, TBEP, and TPP 

would be valuable. 

Reproductive Toxicity. No information was located regarding reproductive effects in human exposed 

to the selected phosphate ester flame retardants. TCEP, TnBP, TPP, and TDCP have been tested for 

effects on fertility in oral studies. TCEP reduced fertility in mice in a continuous breeding protocol study 

(NTP 1991b). Both sexes were adversely affected, but the males appeared to be more sensitive than 

females, as all sperm end points examined (concentration, motility, and percent abnormal) were affected. 

In a 2-generation reproductive toxicity study in rats, TnBP had no significant effect on mating and 

fertility rates, or on gross and microscopic appearance of the reproductive organs in the F0 or 

F1 generations (Tyl et al. 1997). TDCP did not affect fertility in male rabbits treated by gavage for 

12 weeks and then mated with untreated females (Anonymous 1977). Fertility indices (number pregnant, 

corpora lutea, implantations, implantation efficiency, resorptions) were not affected in male or female rats 

dosed with TPP for 91 days before mating (Welsh et al. 1987). TBEP has not been tested for effects on 

fertility, but acute- and intermediate-duration studies in rats reported no gross or microscopic alterations 

in the reproductive organs of males and females (Komsta et al. 1989; Reyna and Thacke 1987a). 

Exposure of rats to TiBP in the diet for 13 weeks also did not result in gross or microscopic alterations in 

the reproductive organs (Naylor and Ribelin 1990). In the absence of any evidence indicating that the 

reproductive organs are sensitive targets for TBEP or TiBP, fertility testing does not appear necessary at 

this time. No relevant data were located for TCPP; acute and intermediate oral studies that might be 

conducted with this chemical should include examination of the reproductive organs to determine 

potential reproductive effects. 

Developmental Toxicity. No information was located regarding developmental effects in humans 

exposed to the phosphate ester flame retardants discussed in this profile. The developmental effects of 

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TCEP (Hardin et al. 1987; Kawashima et al. 1983a), TnBP (Noda et al. 1994), TBEP (Monsanto 1985b), 

TDCP (Stauffer Chemical Co. 1981b), TPP (Welsch et al. 1987), and TCPP (Kawasaki et al. 1982) have 

been examined in oral studies that included exposure during gestation. In general, these studies did not 

report fetotoxicity or teratogenicity even at doses that produced maternal toxicity. However, in a 

continuous breeding protocol study in mice exposed to TCEP, there was a decrease in the number of live 

male F2 pups per litter (NTP 1991b). Also, in a 2-generation reproductive study in mice exposed to 

TnBP, there was reduction in F1 and F2 pup weight per litter during postnatal days 0–21 (Tyl et al. 1997). 

Additional developmental studies for these six phosphate ester flame retardants do not seem necessary at 

this time. However, since no relevant information was located for TiBP, conducting a preliminary test in 

mice, as done for TCEP by Hardin et al. (1987), may be appropriate. 

Immunotoxicity. No studies were located that examined immunological effects in humans following 

exposure to the selected phosphate ester flame retardants discussed in this document. However, there 

have been reports of allergic dermal reactions to products containing TPP (Camarasa and Serra-Baldrich 

1992; Carlsen et al. 1986). Oral toxicity studies conducted with the selected phosphate ester flame 

retardants, except TCPP, did not report significant alterations in the gross or microscopic appearance of 

lymphoreticular tissues. However, immunocompetence was examined only in one study in rats exposed 

to TPP (Hinton et al. 1996). No significant alterations in the humoral response to immunization with 

SRBC were reported. Since very limited information is available regarding the immunotoxicity of the 

remaining phosphate ester flame retardants, studies performing a Tier I battery of tests would help 

evaluate the possibility that exposure to these chemicals might cause subtle alterations in immune 

parameters. 

Neurotoxicity. No relevant information was located regarding neurological effects in humans exposed 

to the selected phosphate ester flame retardants. Studies in animals have provided information regarding 

the effects of TCEP, TnBP, TBEP, TDCP, TiBP, and TPP on the nervous system. No relevant data were 

located for TCPP, but before conducting neurotoxicity studies for this chemical, it may be desirable first 

to determine whether there is any indication of neurotoxicity in a general toxicity study. The nervous 

system did not seem to be a particularly sensitive target for this group of chemicals except for TCEP. 

While effects were reported in some studies, they tended to occur at the highest dose levels. Some of the 

data available were limited to reports of lack of clinical signs and histopathological effects in the brain 

and spinal cord of rats in a 24-month study with TDCP (Stauffer Chemical Co. 1981a) or of similar 

observations in rats dosed with TiBP for 13 weeks (Naylor and Ribelin 1990). TPP was evaluated for 

neurobehavioral effects in rats in a 4-month dietary study; no significant effects were reported (Sobotka et 

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al. 1986). TnBP reduced nerve conduction velocity and altered the morphology of the nerve in rats 

(Laham et al. 1983), but did not significantly alter parameters of a functional observation battery in acuteor intermediate-duration studies (Healy et al. 1995). TBEP was also reported to cause a reduction in 

nerve conduction velocity in rats in an intermediate-duration study (Reyna and Thacke 1987b). TCEP 

affected the nervous system in acute-, intermediate-, and chronic-duration studies. Treatment with TCEP 

caused morphological damage to the hippocampus of rats in acute- (Tilson et al. 1990) and intermediateduration (NTP 1991a) studies and to the cortex and brain stem in a chronic-duration study (NTP 1991a); 

rats were considerably more sensitive than mice, and female rats appeared more sensitive than males. In 

the acute study, rats suffered seizures 60–90 minutes after dosing and showed mildly impaired learning 

behavior 3 weeks after dosing (Tilson et al. 1990). Pharmacokinetics studies have been conducted that 

tried to identify the chemical entity responsible for the physiological and morphological effects of TCEP 

as well as provide an explanation for the differential susceptibility between rats and mice and between 

female and male rats (Burka et al. 1991; Herr et al. 1991). These issues have not been resolved and 

continued research seems necessary. The mechanism by which TCEP or a metabolite induces seizures in 

rats has not been elucidated, although there is some evidence indicating that it acts as a GABA antagonist 

(Umezu et al. 1998). Further research on this specific issue would also be valuable. 

Epidemiological and Human Dosimetry Studies. Information on health effects in humans 

exposed specifically to the selected phosphate ester flame retardants (not to mixtures) was derived from a 

study of workers employed in the manufacture of TDCP (Stauffer Chemical Co. 1983a) and a study of 

operators in a TPP production plant (Sutton et al. 1960). In neither case were there associations found 

between exposure to the phosphate ester flame retardants and any health conditions. In addition, there are 

some reports of allergic dermal reactions to products containing TPP (Camarasa and Serra-Baldrich 1992; 

Carlsen et al. 1986). Follow-up evaluations of individuals who may have been occupationally exposed to 

any of these substances would provide valuable information. No specific group from the general 

population that may have been subjected to unusually high concentrations of these chemicals was 

identified. Studies in animals have identified sensitive targets for some of the phosphate ester flame 

retardants discussed in this profile (i.e., brain areas for TCEP, urinary bladder for TnBP, liver for TBEP). 

Studies have also shown differences in susceptibility between species. Therefore, there is no basis to 

speculate, based on studies in animals, what health effects might be observed (or what health effects one 

should look for) in subjects who might experience repeated exposure to these compounds. 

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PHOSPHATE ESTER FLAME RETARDANTS 186 

3. HEALTH EFFECTS 

Biomarkers of Exposure and Effect. 

Exposure. There are no specific biomarkers that can be used to identify exposure to the phosphate ester 

flame retardants flame retardants subject of this profile other than the chemicals themselves. Studies of 

levels of phosphate ester flame retardants in blood and urine of workers who are exposed to higher levels 

of these substances than the general population would be helpful to characterize potential biomarkers, 

which could be the parent compound and/or metabolites. These biomarkers could then be looked for in 

biological fluids of members of the general population, particularly children, to ascertain the prevalence 

and magnitude of exposure to these chemicals, if the existing analytical methods are sensitive enough to 

do so. 

Effect. There are no biomarkers of effect specific for the selected phosphate ester flame retardants. 

Exposure to high amounts of some of these chemicals, particularly TPP, may reduce the activity of 

plasma and red blood cell cholinesterase, but this can also occur following exposure to a variety of 

chemicals. Research to identify reliable biomarkers for exposure to these chemicals would be useful. 

Absorption, Distribution, Metabolism, and Excretion. There were no data regarding the 

toxicokinetics of the selected phosphate ester flame retardants in humans except for a study that 

investigated the metabolism of TCEP in human liver preparations in vitro (Chapman et al. 1991) and a 

study that investigated the pulmonary retention of TPP in volunteers exposed to an aerosol of this 

chemical (Landahl et al. 1951, 1952). There are no data regarding the toxicokinetics of these chemicals in 

animals following inhalation exposure, but this information would likely do little to further our 

understanding of the pharmacokinetics processes of these substances. There are studies in animals that 

provide information regarding the oral absorption of TCEP (Herr et al. 1991), TDCP (Nomeir et al. 1981), 

and TnBP (SOCMA 1992), and dermal absorption of TDCP (Nomeir et al. 1981) and TnBP (SOCMA 

1992). Tissue distribution data are available for TCPP, TCEP, TDCP, and TnBP following oral exposure 

(Herr et al. 1991; Minegishi et al. 1988; SOCMA 1992), for TDCP and TnBP following dermal exposure 

(Nomeir et al. 1981; SOCMA 1992), and for TDCP following intravenous administration (Lynn et al. 

1981). The metabolism of TCEP, TDCP, and TnBP has been well studied (Burka et al. 1991; Chapman 

et al. 1991; Lynn et al. 1981; Nomeir et al. 1981; SOCMA 1992, 1994; Suzuki et al. 1984a, 1984b). 

These studies were able to identify and quantify metabolites in excreta and propose metabolic pathways 

for these phosphate ester flame retardants. The excretion routes for TDCP, TCPP, TCEP, and TnBP 

(Burka et al. 1991; Herr et al. 1991; Minegishi et al. 1988; Suzuki et al. 1984a) have been studied in 

animals following oral exposure and for TnBP following dermal exposure (SOCMA 1992). It would be 

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PHOSPHATE ESTER FLAME RETARDANTS 187 

3. HEALTH EFFECTS 

useful to have information on the toxicokinetics of TBEP, TPP, and TiBP. Since phosphate ester flame 

retardants are usually found as mixtures in the environment, it would be valuable to have information on 

toxicokinetic interactions among these chemicals and how these interactions can potentially affect their 

toxicity. 

Comparative Toxicokinetics. Relevant information is available for TCEP and TnBP. Herr et al. 

(1991) studied the distribution of radioactivity in the brain of male and female rats following oral 

administration of 14C-TCEP and reported no significant differences between the sexes, although there was 

suggestive evidence that the parent compound/metabolite ratio in cortical tissues was greater in females 

than in males 2 hours after a single dose of TCEP. Herr et al. (1991) also reported slower excretion of 

metabolic products in females than in males. Burka et al. (1991) investigated the metabolism and 

excretion of TCEP-derived radioactivity in female and male rats and in male mice. The results showed 

quantitative differences in metabolic products between rats and mice and between male and female rats 

and slower elimination of radioactivity in the urine in rats than in mice. A study of the metabolism of 

TCEP by in vitro liver preparations and plasma from humans and male and female rats also showed 

differences between the rat sexes and between rats and humans (Chapman et al. 1991). Studies with 

TnBP showed that rats absorb about 10 times less TnBP through the skin than minipigs and that there are 

also differences in the metabolic disposition of TnBP between rats and minipigs (SOCMA 1992, 1994). 

No comparative data were located for other phosphate ester flame retardants. If the metabolism of any of 

the selected phosphate ester flame retardants can be elucidated in humans, for example, through the 

analysis of blood and urine samples from workers exposed to these compounds, it would be valuable to 

have data in more than one animal species to identify the best possible animal model for human risk 

assessment. 

Methods for Reducing Toxic Effects. Acute exposure to high amounts of phosphate ester flame 

retardants may inhibit cholinesterase activity to the extent that clinical signs and symptoms indicative of 

cholinergic stimulation may occur. If such situation arises, there are well-established treatment 

procedures. Since no population has been identified as having been subjected or currently undergoing 

exposure to excessive amounts of phosphate ester flame retardants, attempts to propose studies of specific 

methods to reduce possible adverse effects do not appear warranted at this time. 

Children’s Susceptibility. Data needs relating to both prenatal and childhood exposures, and 

developmental effects expressed either prenatally or during childhood, are discussed in detail in the 

Developmental Toxicity subsection above. 

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PHOSPHATE ESTER FLAME RETARDANTS 188 

3. HEALTH EFFECTS 

There are no studies that specifically address exposure to phosphate ester flame retardants in children. 

There have been some case reports of allergic dermatitis in subjects exposed to products containing TPP 

(Camarasa and Serra-Baldrich 1992; Carlsen et al. 1986). It is reasonable to assume that this may also 

occur in children. There is no information on whether exposure to phosphate ester flame retardants alters 

the developmental process in humans. Gestational exposure studies have been conducted with six out of 

the seven selected phosphate ester flame retardants discussed in this profile, the exception being TiBP. In 

general, these studies showed that developmental end points are not particularly sensitive. The possibility 

that phosphate ester flame retardants may have endocrine-disrupting ability in mammals has not been 

systematically studied. 

There are no data to evaluate whether pharmacokinetics of phosphate ester flame retardants in children 

are different from adults. There is no information on whether these substances can cross the placenta and 

there are no studies on whether they can be transferred from mother to offspring through maternal milk. 

Cross-fostering studies can provide important information regarding the role of in utero vs. lactation 

exposure to phosphate ester flame retardants in normal development. 

Research into the development of sensitive and specific biomarkers of exposures and effects for 

phosphate ester flame retardants would be valuable for both adults and children. There are no data on the 

interactions of phosphate ester flame retardants with other chemicals in children. There are no pediatricspecific methods to reduce peak absorption, reduce body burdens, or to interfere with the mechanisms of 

action of these compounds. Based on the information available, it is reasonable to assume that the 

supportive methods recommended for maintaining vital functions in adults will also be applicable to 

children. 

Child health data needs relating to exposure are discussed in Section 6.8.1, Identification of Data Needs: 

Exposures of Children. 

3.12.3 Ongoing Studies 

No ongoing studies pertaining to the phosphate ester flame retardants subject of this profile were 

identified in the Federal Research in Progress (FEDRIP 2009) database. 

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PHOSPHATE ESTER FLAME RETARDANTS 189 

4. CHEMICAL AND PHYSICAL INFORMATION 

4.1 CHEMICAL IDENTITY 

Phosphate esters are considered derivatives of the tri protic acid, phosphoric acid O=P(OH) 3, with the 

general formula of RxH3-xPO4 where x=1 for mono, x=2 for di, and x=3 for triesters. Phosphorus has a 

high affinity for oxygen due to the difference in electronegativity (1.4), and consequently, the P=O bond 

possesses more  character than  character. Therefore, the P=O bond, which dominates phosphate 

chemistry, can be more accurately depicted as a coordinate bond, PO, or as P+

–O-. These phosphoric 

acid esters are often referred to as organophosphates. Trialkyl, triaryl, and trihaloalkyl/aryl, and mixed 

phosphate esters possess a central phosphorus atom with an oxidation state of +5 and an approximate 

tetrahedral geometry (Fee 2005; Gard 2005). 

A wide array of substituents can occur as esters of phosphates. In many cases, all of the substituents are 

identical, as is the case for this profile; however, variable, mono-, di-, or tri-substituted as well as mixed 

substituents are common. The selected compounds, shown above, are trisubstituted, contain identical 

substituents, and fall into the following categories: alkyl (TnBP, TiBP), alkyl ether (TBEP), chloroalkyl 

(TCEP, TCPP, TDCP), and aryl (TPP) phosphate esters. Although the selected compounds are discrete 

chemicals, commercial formulations of TCPP may contain minor amounts of structural isomers (NAS 

2000). Table 4-1 lists common synonyms, trade names, and other pertinent information to identify the 

selected phosphate esters for this profile. 

4.2 PHYSICAL AND CHEMICAL PROPERTIES 

Table 4-2 lists important chemical and physical properties of the selected phosphate esters. 

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P 

O O O 

 

 

PHOSPHATE ESTER FLAME RETARDANTS 190 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of Selected Phosphate Ester Flame Retardantsa 

Tributoxyethyl 

Characteristic Tributyl phosphate Triisobutyl phosphate phosphate 

Synonym(s) TnBP; butyl phosphate; TiBP; isobutyl phosphate; TBEP; tri(2-butoxyethyl) 

phosphoric acid tributyl phosphoric acid; phosphate; tris(2-butoxyester; tri-n-butyl tris(2-methylpropyl) ester ethyl) phosphate; 

phosphate; 2-butoxyethanol, phostributoxyphosphine oxide phate; ethanol, 2-butoxy-, 

phosphate (3:1); phosphoric acid, tributoxyethyl 

ester; tributyl cellosolve 

phosphate 

Registered trade Disflamoll TB; Celluphos No data Kronitex KP-140; KP 140; 

name(s) 4; Phosflex 4b

; Skydrol Phosflex T-bep 

LD-4b 

Chemical formula C12H27O4P C12H27O4P C18H39O7P 

Chemical structure O 

O P O O O 

O O O 

Identification numbers: 

CAS registry 126-73-8 126-71-6 78-51-3 

RTECSc

 TC7700000 No data KJ9800000 

EPA hazardous waste No data No data No data 

EPA/OPP pesticide No data No data No data 

Code 

OHM/TADS No data No data No data 

DOT/UN/NA/IMDG No data No data No data 

shipping 

HSDB 1678 No data 2564 

EINECS 204-800-2 204-798-3 201-122-9 

NCI No data No data No data 

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PHOSPHATE ESTER FLAME RETARDANTS 191 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of Selected Phosphate Ester Flame Retardantsa 

Characteristic Triphenyl phosphate Tri-(2-chloroisopropyl) phosphate 

Synonym(s) TPP; phosphoric acid, triphenyl ester; TCPP; tris(1-chloro-2-propyl) 

triphenoxyphosphine oxide phosphate; tris(2-chloroisopropyl) 

phosphated

; phosphoric acid, 

tris(2-chloro-1-methyl) ethere 

Registered trade 

name(s) 

Celluflex TPP; Disflamoll TP; Phosflex 

TPP 

Hostaflam OP 820; Amgard TMCP; 

Fyrol PFCd

; Antiblaze 80f 

Chemical formula C18H15O4P C9H18Cl3O4P 

Chemical structure O 

P OO O 

Identification numbers: 

CAS registry 115-86-6 13674-84-5 

RTECSc

 TC8400000 TC9000000 

EPA hazardous waste No data No data 

EPA/OPP Pesticide No data No data 

Code 

OHM/TADS No data No data 

DOT/UN/NA/IMDG IMO 9.0 No data 

shipping 

HSDB 2536 No data 

EINECS 204-112-2 237-158-7 

NCI No data No data 

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PHOSPHATE ESTER FLAME RETARDANTS 192 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of Selected Phosphate Ester Flame Retardantsa 

Tris(1,3-dichloro-2-propyl) 

Characteristic phosphate Tris-(2-chloroethyl)-phosphate 

Synonym(s) TDCP; tris(1,3-dichloroisopropyl) TCEP; trichlorethyl phosphate; phosphosphate; tris(1-chloromethyl- phoric acid; tris(2-chloroethyl)ester; 

2-chloroethyl)phosphate; 2-propanol, tri(2-chloroethyl) phosphate; ethanol, 

1,3-dichloro-, phosphate (3:1) 2-chloro-, phosphate (3:1); tris(2-

chloroethyl) orthophosphate 

Registered trade Fyrol FR-2; Antiblaze 195f Antiblaze 100; Celluflex CEF; Disflamoll 

name(s) TCA; Fyrol CEF; Niax 3CF, Tolgard 

TCEP; Genomoll P; Hostaflam UP810; 

Levagard EP 

Chemical formula C9H15Cl6O4P C6H12Cl3O4P 

Chemical structure 

Identification numbers: 

CAS registry 13674-87-8 115-96-8 

RTECSc

 No data KK2450000 

EPA hazardous waste No data No data 

EPA/OPP Pesticide No data No data 

Code 

OHM/TADS No data No data 

DOT/UN/NA/IMDG No data UN: 3082g 

shipping 

HSDB 4364 2577 

EINECS 237-159-2 204-118-5 

NCI No data C60128 

a

All information obtained from HSDB 2009 and ChemIDplus 2009, except where noted. b

IPCS 1991a, 2000b 

c

RTECS 2009 

d

Ashford 1994 

e

Lewis 2000 

f

Weil 2001 

g

NIOSH 2007 

CAS = Chemical Abstracts Service; DOT/UN/NA/IMDG = Department of Transportation/United Nations/North 

America/Intergovernmental Maritime Dangerous Goods Code; EINECS = European Inventory of Existing Chemical 

Substances; EPA = Environmental Protection Agency; HSDB = Hazardous Substances Data Bank; NCI = National 

Cancer Institute; NIOSH = National Institute for Occupational Safety and Health; OHM/TADS = Oil and Hazardous 

Materials/Technical Assistance Data System; RTECS = Registry of Toxic Effects of Chemical Substances 

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PHOSPHATE ESTER FLAME RETARDANTS 193 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of Selected Phosphate Ester Flame 

Retardantsa
 

Property 

Tributyl phosphate 

(TnBP) 

Triisobutyl phosphate 

(TiBP) 

Tributoxyethyl phosphate 

(TBEP) 

Molecular weight 266.31 266.31d 398.48 

Physical 

description 

Colorless to pale-yellow 

liquid 

Clear, colorless, low 

viscosity liquidd 

Slightly yellow, oily liquid 

Melting point 

Boiling point 

Density 

Odor 

-80 °C 

289 °C; decomposesb 

0.9727 g/cm3 at 25 °C 

Odorless 

No data 

264 °Cc 

0.9681 g/cm3 at 20 °Cc 

Specific odord 

-70 °C 

215–228 °C at 4 mm Hg 

1.020 g/cm3 at 20 °C 

Sweetish, butyl-like 

Solubility: 

Water 0.28 g/L at 25 °C Very soluble in waterd; 

0.05% in waterd and 6.3% 

water in TnBPd 

1.1 g/L at 25 °C 

Organic 

solvent(s) 

Soluble in diethyl ether, 

benzene, carbon disulfide; 

miscible with ethanol 

Very soluble in benzene, 

ether, and ethanolc 

Soluble in most organic 

liquids; soluble in mineral 

oil; insoluble or limited 

solubility in glycerol, glycols, 

certain amines 

Other Miscible with most solvents No data No data 

and diluents 

Log Kow 

Vapor pressure 

Autoignition 

temperature 

Flashpoint 

4.00 

1.13x10-3 mm Hg at 25 °C 

>482 °Cb 

146 °C 

3.60 (estimated)

e 

0.0128 mm Hg at 25 °C 

(estimated)

e 

No data 

175 °C (Cleveland)d 

3.75 

0.03 mm Hg at 150 °C 

No data 

223 °C 

Flammability 

limits in air 

Combustible No data Combustible 

Conversion 

factors 

1 ppm=10.89 mg/m3b No data No data 

Explosive limits No data No data No data 

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PHOSPHATE ESTER FLAME RETARDANTS 194 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of Selected Phosphate Ester Flame 

Retardantsa
 

Tri-(2-chloroisopropyl) phosphate 

Property Triphenyl phosphate (TPP) (TCPP) 

Molecular weight 326.28 327.57 

Physical Colorless, crystalline powder; white Colorless liquidf 

Description platelets, crystals from absolute alcoholligroin, prisms from alcohol, needles from 

ether-ligroin 

Melting point 49–50 °C -40 °C 

Boiling point 245 °C at 11 mm Hg >270 °C; gradually decomposes when 

heated over 200°Cf 

Density 1.2055 g/cm3 at 50 °C 1.29 g/cm3 at 25 °Cf 

Odor Slightly aromatic odor resembling phenol Mild odorf 

Solubility: 

Water 0.0019 g/L at 25 °C 1.2 g/L at 25 °C 

Organic 

solvents 

Very soluble in carbon tetrachloride; 

soluble in alcohol, benzene, ether, 

Soluble in most organic solvents; insoluble 

in waterf 

chloroform and acetone; insoluble in 

petroleum 

Other Soluble in most lacquers, solvents No data 

thinners, and oils 

Log Kow 4.59 2.59 

Vapor pressure 6.28x10-6 mm Hg at 25 °C 2.02x10-5 mm Hg at 25 °C 

Autoignition No data No data 

temperature 

Flashpoint 220 °C No data 

Flammability Noncombustible No data 

limits in air 

Conversion 1 ppm=13.32 mg/m3 No data 

factors 

Explosive limits No data No data 

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PHOSPHATE ESTER FLAME RETARDANTS 195 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of Selected Phosphate Ester Flame 

Retardantsa

Tris(1,3-dichloro-2-propyl) phosphate 

Property (TDCP) Tris-(2-chloroethyl)-phosphate (TCEP)

Molecular weight 430.88 285.50 

Physical Viscous, clear liquid Clear, transparent, Low viscosity liquid 

Description 

Melting point 27 °C -55 °C 

Boiling point 236–237 °C at 5 mm Hg 330 °C at 1 atm 

Density 1.48 g/cm3

 at 25 °C 1.425 g/cm3 at 20 °C 

Odor Mild odor Slight odor 

Solubility: 

 Water 7 mg/L at 24 °C 7.0 g/L (temperature not specified) 

Organic Soluble in most organic solvents Soluble in most organic solvents; soluble 

solvents in carbon tetrachloride, alcohols, esters, 

ketones, and aromatic hydrocarbons; very 

slightly soluble in aliphatic hydrocarbons; 

insoluble in benzene 

 Other No data No data 

Log Kow 3.65 1.44 

Vapor pressure 5.2 x10-2 mm Hg at 25 °C (estimated)e

 6.125x10-2 mm Hg at 25 °C 

Autoignition No data 1,115 °C 

temperature 

Flashpoint 252 °C 216 °C 

Flammability No data Combustible 

limits in air 

Conversion No data 1 ppm=11.65 mg/m3

factors 

Explosive limits No data No data 

a

All information from HSDB 2009 and ChemIDplus 2009, except where noted. 

b

NIOSH 2005a 

c

Lide 2008 

d

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LANXESS 2005 

e

EPA 2009h 

f

Ashford 1994 
PHOSPHATE ESTER FLAME RETARDANTS 196 

4. CHEMICAL AND PHYSICAL INFORMATION 

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PHOSPHATE ESTER FLAME RETARDANTS 197 

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

5.1 PRODUCTION 

Phosphate esters are a class of anthropogenic organic compounds found in the environment as a result of 

release from commercial and industrial products (Watts and Linden 2009). Phosphate esters, TnBP, 

TiBP, TBEP, and TCEP are produced by chemical synthesis via condensation of phosphorus oxychloride 

and an alkyl or aryl alcohol (Davis and Richardson 1980; HSDB 2009; Kelly 2006; Muir 1984) at low 

temperatures and pressures to avoid formation of alkyl chlorides (Muir 1984). TPP is made from either 

phosphorus pentachloride or phosphorus oxychloride and phenol (HSDB 2009). TDCP is produced via 

the epoxide opening of epichlorohydrin in the presence of phosphorus oxychloride (Weil 2001), and 

TCPP is similarly produced with propylene oxide and sometimes TCEP with ethylene oxide (Muir 1984). 

Worldwide production of flame retardants in 1992 was estimated at 600,000 metric tons with 

102,000 metric tons representing phosphate ester-derived flame retardants. In 2001, estimates increased 

to 1,217,000 and 186,000 metric tons, respectively (Hartmann et al. 2004). Use of flame retardants in the 

United States totaled an estimated 622,000 metric tons in 2007 (Fink et al. 2008). This represents an 

increase of 58 thousand metric tons, or 10% over the 2004 level. The value of these products rose from 

$844 million in 2004 to $1,126 million in 2007, a 33% increase, (Fink et al. 2008) and U.S. flame 

retardant demand is expected to grow at a 2–3% average annual rate through 2012 (Fink et al. 2008) due 

to an increase in restrictions for competing polybrominated diphenyl ethers (PDBE) (Hartmann et al. 

2004; Quintana and Reemtsma 2006). 

TnBP production in 1975 was > 908 kg (1 metric ton) (HSDB 2009) and is currently estimated by the 

2006 Inventory Update Reporting (IUR) to be in the range of 1–10 million pounds (EPA 2006c). 

TiBP production is not listed with the EPA or other agencies as it appears that this chemical is produced 

predominantly outside of the United States. 

TBEP production is estimated by the 2006 IUR in the range of 1–10 million pounds (EPA 2006c). 

TPP production in 1975 was > 908 kg (1 metric ton) (HSDB 2009) and is currently estimated by the 

2006 IUR to be in the range of 10–50 million pounds (EPA 2006c). 

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PHOSPHATE ESTER FLAME RETARDANTS 198 

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

TCEP production in 1975 was estimated to be > 908 kg (1 metric ton) (HSDB 2009) and is currently 

estimated by the 2006 IUR to be in the range of 500,000–1 million pounds (EPA 2006c). 

TCPP annual worldwide demand exceeded 40,000 metric tons in 1997 (IPCS 1998) and currently is 

estimated by the 2006 IUR to be produced in the range of 10–50 million pounds (EPA 2006c). 

TDCP annual worldwide demand was 8,000 metric tons in 1997 (IPCS 1998) and is currently estimated 

by the 2006 IUR to be produced in the range of 10–50 million pounds (EPA 2006c). 

No information is available in the TRI database on facilities that manufacture or process phosphate ester 

flame retardants because this chemical is not required to be reported under Section 313 of the Emergency 

Planning and Community Right-to-Know Act (Title III of the Superfund Amendments and 

Reauthorization Act of 1986) (EPA 1998). 

5.2 IMPORT/EXPORT 

Imports of TBEP and TCEP were reported to be negligible in 1972, while all other selected phosphate 

esters were not listed as being imported (HSDB 2009). No export data were available for the selected 

phosphate ester compounds discussed in this profile. 

5.3 USE 

Trialkyl, triaryl, and trihaloalkyl/aryl, and mixed phosphate esters have been used since the 1940s in 

industrial consumer products (Muir 1984). Phosphate esters represent an important class of commercial 

additives used as flame retardants, plasticizers, hydraulic fluids, solvents, extraction agents, antifoam 

agents, adhesives, and coatings for electronic devices (Andresen and Bester 2006; Ashford 1994; Lewis 

2007; Lide 2008; Owens et al. 2007; Watts and Linden 2009; Weil 2001; Wolf and Kaul 2005). A 

summary of applications of the selected phosphate ester flame retardants is shown in Table 5-1. 

Flame retardants generally function in the vapor phase, where the enthalpy-generating combustion occurs, 

and serve to slow or hinder the ignition or growth of a fire (Gann and Gilman 2003). There are five 

specific mechanisms by which flame retardancy may occur: physical dilution, chemical interaction, inert 

gas dilution, thermal quenching, or protective coatings (Mack 2004). Phosphate ester flame retardation 

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PHOSPHATE ESTER FLAME RETARDANTS 199 

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

Table 5-1. Applications of Phosphate Ester Flame Retardants 

Floor Lacquer, 

Compound Flame Hydraulic finish, paint, Anti-foam Industrial 

Name retardant Plasticizer fluid wax glue agent processes 

Tributyl X X X X X X 

phosphate 

(TnBP) 

Triisobutyl 

phosphatea 

X X X 

(TiBP) 

Tributoxyethyl X X X X X 

phosphate 

(TBEP) 

Triphenyl X X X X 

phosphate 

(TPP) 

Tri-(2-chloro- X X 

isopropyl) 

phosphate 

(TCPP) 

Tris(1,3-di- X X X 

chloro-2-propyl) 

phosphate 

(TDCP) 

Tris- X X X X 

(2-chloroethyl)­

phosphate 

(TCEP) 

a

TiBP Datasheet, Anderson et al. 2004, 2006 

Source: Marklund et al. 2003 

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PHOSPHATE ESTER FLAME RETARDANTS 200 

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

mechanisms vary based on structure and properties, but generally function by suppressing flammability of 

pyrolysis products (vapor-phase mechanism) or by chemical interaction through changing the nature of 

the decomposition products (Weil 2001). In general, the effectiveness of a particular phosphorus 

compound depends strongly on the nature of the matrix polymer but, for chemically similar compounds, 

the flame-retardant effectiveness often increases with increasing phosphorus content (Granzow 1978). 

Halogens play an important part in contributing to flame retardancy, although this contribution is offset 

by the lower phosphorus content. The halogens reduce vapor pressure and water solubility, thus aiding 

retention of these additives (Weil 2001). 

Due to an increased demand for fire safety in commercial products, flame retardant use substantially 

increased during the 1960s and 1970s (Muir 1984). In particular, products made from synthetic polymers 

are treated with phosphate esters (Weil 2001). The chlorinated haloalkyl phosphates, TCPP, TDCP, and 

TCEP, are most commonly used as flame retardants in both rigid and flexible polyurethane foam, and 

some textiles (Anderson et al. 2004). 

The nonderivatized alkyl and aryl phosphates, TnBP, TiBP, TBEP, and TPP, all function predominantly 

as industrial plasticizers in polymers, rubbers, plastics, and vinyl resins, as well as flame retardants 

(Anderson et al. 2004, 2006). Phosphate esters are added to flexible plastics such as polyvinyl chloride 

(PVC) and polyurethane foams in low part per hundred concentrations (Muir 1984). Addition of 

phosphate esters often effects the flammability of rigid plastics such as PVC by dilution of the highly 

flammable chlorinated plasticizers (Green 1992). Phosphate esters can, however, change polymer 

decomposition chemistry when combusted (Gann and Gilman 2003). Advantages of phosphate esters 

over traditional plasticizers include low corrosivity of the combustion gases, lack of effect on polymer 

transparency, and suppression of afterglow. Disadvantages include volatility, sensitivity to hydrolysis, 

and negative effects on the heat distortion temperatures of plastics (Wolf and Kaul 2005). When used as 

flame retardants in polymers, phosphate esters typically represent 1–30% of the composition of the 

polymer with an average of 5–15% (Hartmann et al. 2004). 

TnBP and TPP are used as hydraulic fluids with flame retardant properties predominantly present as 

mixtures of various alkyl- and aryl-substituted phosphate esters (Anderson et al. 2004; Batt et al. 1992). 

They are recognized as replacements to polychlorinated biphenyls (PCBs) (Gomez-Belinchon et al. 1988; 

Muir 1984). Phosphate esters generally have better fire resistance than mineral oils and are less 

hazardous than PCBs. The lubricating properties are generally good; however, the high temperature 

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PHOSPHATE ESTER FLAME RETARDANTS 201 

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

stability is fair. Decomposition products, such as phosphoric acid, can be corrosive, deteriorate paints and 

finishes, and cause swelling of many seal materials in hydraulic systems (Denniston 1995). 

TnBP is used as a solvent for cellulose esters, lacquers, natural gums, herbicide solutions, and carbonless 

copying systems and as an extractant in the nuclear fuel reprocessing and other metals (Anderson et al. 

2004; Thomas and Macaskie 1996). Some trialkyl phosphates, O=P(OR)3, are outstanding solvents for 

nitrates, especially (UO2)(NO3)2, and are therefore important in uranium processing (Fee 2005). TnBP 

forms weak complexes with the neutral metal nitrates, affecting the solubilizing of the actinides in the 

organic phase (Godfrey et al. 1996). TnBP is the most frequently used solvent in liquid-liquid extraction 

for fuel reprocessing via a process known as the PUREX process (Plutonium Uranium Refining by 

EXtraction) (Dodi and Verda 2001; Godfrey et al. 1996; Stevens et al. 2007). This method enables 

recycling of extracted uranium and plutonium from an aqueous nitric acid phase (Dodi and Verda 2001) 

and is considered the most convenient method to retreat spent fuel (Lamouroux et al. 2000). Due to the 

acidic nature of the process, some decomposition of TnBP to dibutyl phosphate (DBP) and monobutyl 

phosphate (MBP) occurs via dealkylation of one or two butoxy groups, respectively (Dodi and Verda 

2001). 

TiBP is used as a pore size regulator for concrete, while TnBP shows excellent antifoam properties in 

concrete (Anderson et al. 2004; Andresen and Bester 2006). TBEP is also found in some floor polishes. 

TCEP was phased out due to toxicity issues (EPA 2006c). Electronic equipment can contain various 

phosphate esters (Carlsson et al. 2000; Marklund et al. 2003). 

5.4 DISPOSAL 

No data are available on the disposal of specific phosphate ester flame retardants; however, hydraulic 

fluids containing phosphate esters do have recommended disposal methods. Used phosphate ester 

hydraulic fluids are not listed as hazardous wastes and can be recycled or burned for energy recovery. In 

general, the newer phosphate ester hydraulic fluids do not contain known chemicals or other materials 

that are listed in 40 CFR 261 (Resource Conservation and Recovery Act [RCRA]). Recycling of some 

flame retardant-containing products, including some plastics, has been found possible (Lorenz and 

Bahadir 1993; Mayer et al. 1993). 

With the exception of TnBP, the selected phosphate ester flame retardants are regulated under the Toxic 

Substances Control Act (TSCA) of 1976, requiring the reporting of record-keeping, testing, and 

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PHOSPHATE ESTER FLAME RETARDANTS 202 

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

restrictions to the EPA. The High Production Volume Challenge (HPV) program, administered by the 

EPA, challenges companies to report health and environmental effects data publicly for chemicals 

produced or imported in the United States in quantities of 1 million pounds or more per year. All of the 

selected chemicals except TiBP appear on this list. 

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PHOSPHATE ESTER FLAME RETARDANTS 203 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.1 OVERVIEW 

Phosphate ester flame retardants have been identified in at least 8 of the 1,699 hazardous waste sites that 

have been proposed for inclusion on the EPA National Priorities List (NPL) (HazDat 2007). However, 

the number of sites evaluated for phosphate ester flame retardants is not known. The frequency of these 

sites can be seen in Figure 6-1. 

Phosphate ester flame retardants are released to the environment through their use in industrial and 

consumer products. Since their introduction in the 1940s and popularization in the 1970s, these 

anthropogenic compounds have been frequently detected in water, soil, and air (Muir 1984). Trialkyl, 

triaryl and trihaloalkyl/aryl, and mixed phosphate esters represent an important class of commercial 

additives used as flame retardants, plasticizers, hydraulic fluids, solvents, extraction agents, antifoam 

agents, adhesives, and coatings for electronic devices (Ashford 1994; Andresen and Bester 2006; Lide 

2008; Lewis 2007; Owens et al. 2007; Watts and Linden 2009; Weil 2001; Wolf and Kaul 2005). 

Water is the most common medium in which phosphate ester flame retardants are detected in the 

environment. Phosphate ester flame retardant presence is widespread in surface water and groundwater 

of the United States and other foreign countries, primarily due to landfill leaching of PVC plastics and 

polyurethane foams, effluent from industrial sources, and spills of hydraulic fluids. Many hydraulic 

fluids are composed of mixtures of phosphate esters and are consequently released into the environment 

as a mixture as indicated, for example, in the Toxicological Profile for Hydraulic Fliuds (ATSDR 1997). 

Ultimately, these primary contaminated waters are transported to secondary sources, such as drinking 

water, by treated sewage, agricultural runoff, and deposition from snow and rain (Andresen et al. 2004; 

Fries and Puttmann 2001; Gomez-Belinchon et al. 1988; Ishikawa et al. 1985; Lee and Rasmussen 2006; 

Meyer and Bester 2004; Muir 1984; Peterman et al. 1980; Reemtsma et al. 2006; Watts and Liden 2008, 

2009). Hydrolysis, although slow due to poor solubility and pH dependence, is the most important abiotic 

fate process for phosphate esters (Boethling and Cooper 1985). Biodegradation via hydrolysis from 

microbial esterases in river water, lake water, sewage, and sludge takes place in <10 days (Howard and 

Deo 1979; Mayer et al. 1981; Muir et al. 1980; Saeger et al. 1979). 

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Figure 6-1. Frequency of NPL Sites with Phosphate Flame Retardants 

PHOSPHATE ESTER FLAME RETARDANTS 204 

6. POTENTIAL FOR HUMAN EXPOSURE 

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PHOSPHATE ESTER FLAME RETARDANTS 205 

6. POTENTIAL FOR HUMAN EXPOSURE 

In soil and sediment, phosphate ester flame retardants are considered persistent as they have a tendency to 

adsorb strongly, thus limiting the availability of these substances to microorganisms (Boethling and 

Cooper 1985; Muir 1984). Phosphate esters generally have a low water solubility and relatively high 

octanol/water partition coefficient (Kow), which results in high soil adsorption coefficients (Koc). Muir 

(1984) reported Koc values ranging from 151 to 7,850 for several of the selected phosphate esters. 

Reports from soil analyses at military bases and airports have confirmed the presence of some phosphate 

esters, particularly TnBP, as it represents a major component in hydraulic fluid Skydrol 500B, Skydrol 

LD, and Hyjet IV (Monsanto Co. 1980). In addition, sediments of rivers and lakes have been shown to 

contain these compounds (Ishikawa et al. 1985; Muir et al. 1989). Volatilization and biodegradation are 

potential fate processes for phosphate esters adsorbed to soils (Anderson 1993; Muir 1984, 1989). 

Diffusion into air from plastics, textiles, adhesives, and electronics accounts for numerous reports of 

phosphate esters in indoor air (Carlsson et al. 2000; Garcia et al. 2007; Hutter et al. 2006; Ingerowski et 

al. 2001, 2003; Otake et al. 2004, 2001; Owens et al. 2007; Sjodin et al. 2001). Outdoor air sampled near 

places where hydraulic fluids are used, such as at airports and outside of newly constructed homes and 

buildings, have indicated the presence of these phosphate esters (Haraguchi et al. 1985; Monsanto Co. 

1980; Saito et al. 2007). 

Ingestion of food or water is the primary exposure pathway that humans have to the phosphate ester flame 

retardants discussed in this profile. Exposure to phosphate esters via direct or indirect dermal adsorption 

from treated matricies is also possible, but unlikely due to the chemical and physical properties that make 

flame retardants useful. Young children are at an increased exposure risk due to the potential for oral 

exposure via dissolution of phosphate esters from repeated sucking on treated materials (NRC 2000). 

Inhalation is also a potential route of exposure primarily in indoor air from PVC plasticizers, floor 

polishes, electronics, and textiles. 

Average daily intakes (ADIs) have been estimated for the U.S. population for TnBP, TPP, TBEP, TCPP, 

and TCEP (Gunderson 1988, 1995a, 1995b). The estimated ADI values are generally in the ng/kg body 

weight/day range. Additional sources of exposure for the general population include inhalation of air and 

ingestion of drinking water containing these phosphate esters. Occupational exposure may be greater 

than exposure to the general population for employees in industries where significant quantities of 

phosphate esters are manufactured or used. 

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PHOSPHATE ESTER FLAME RETARDANTS 206 

6. POTENTIAL FOR HUMAN EXPOSURE 

The selected phosphate esters indicated in Table 4-1 have been frequently detected in the environment 

due to their commercial production, use, and disposal. However, other compounds that were not selected 

are also reported in the environmental monitoring literature. Mixtures of several phosphate esters present 

in a single monitoring sample are commonplace. According to the surveyed literature, the most prevalent 

phosphate esters in all environmental and dietary samples appear to be TnBP and TPP. Consequently, a 

significant portion of the noted studies pertain to these compounds. TBEP is also quite prevalent due to 

its presence in floor polishes, while the chlorinated phosphate esters, TCEP, TCPP, and TDCP, all appear 

much less frequently in the literature. TiBP appears the most infrequently in published monitoring 

studies of the environment or food. 

6.2 RELEASES TO THE ENVIRONMENT 

The Toxics Release Inventory (TRI) data should be used with caution because only certain types of 

facilities are required to report (EPA 2005). This is not an exhaustive list. Manufacturing and processing 

facilities are required to report information to the TRI only if they employ 10 or more full-time 

employees; if their facility is included in Standard Industrial Classification (SIC) Codes 10 (except 1011, 

1081, and 1094), 12 (except 1241), 20–39, 4911 (limited to facilities that combust coal and/or oil for the 

purpose of generating electricity for distribution in commerce), 4931 (limited to facilities that combust 

coal and/or oil for the purpose of generating electricity for distribution in commerce), 4939 (limited to 

facilities that combust coal and/or oil for the purpose of generating electricity for distribution in 

commerce), 4953 (limited to facilities regulated under RCRA Subtitle C, 42 U.S.C. section 6921 et seq.), 

5169, 5171, and 7389 (limited S.C. section 6921 et seq.), 5169, 5171, and 7389 (limited to facilities 

primarily engaged in solvents recovery services on a contract or fee basis); and if their facility produces, 

imports, or processes ≥25,000 pounds of any TRI chemical or otherwise uses >10,000 pounds of a TRI 

chemical in a calendar year (EPA 2005). 

6.2.1 Air 

There is no information on releases of phosphate ester flame retardants to the atmosphere from 

manufacturing and processing facilities because these releases are not required to be reported (EPA 

1997). 

Phosphate ester flame retardants are generally liquids in their pure form at 25 °C and have moderate 

Henry’s Law constants (10-4–10-8 atm-m3

/mol) and vapor pressures (10-2–10-7 mm Hg); therefore, if 

aerosolized, they should exist in the vapor phase or vapor phase and particulate phase (Muir 1984). 

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PHOSPHATE ESTER FLAME RETARDANTS 207 

6. POTENTIAL FOR HUMAN EXPOSURE 

Halogenated phosphate esters have a reduced vapor pressure and solubility, which generally aid in 

retention of these compounds as additives. Releases to the air likely occur from industrial sources, such 

as the manufacture, production, and transportation of pure phosphate esters, as well as diffusion from 

products containing phosphate esters. 

Semi-volatile flame retardant hydraulic fluids could account for aerosolized phosphate esters lost from 

seal leakage, plastics, or vinyl car seats (EPA 1979). Skydrol 500B, a hydraulic fluid, contains 65–75% 

TnBP. In 1979, TnBP was detected in airport air over Vancouver, British Colombia at concentrations of 

0.01–0.3 mg/m3 (Monsanto Co. 1980). 

6.2.2 Water 

There is no information on releases of phosphate ester flame retardants to the water from manufacturing 

and processing facilities because these releases are not required to be reported (EPA 1997). 

Phosphate ester flame retardants are released to environmental surface water and groundwater primarily 

from leaching of hydraulic fluid spills and discarded or landfilled PVC, polyurethane foam, electronic 

wall coverings, and other flame retardant materials (Muir 1984). 

6.2.3 Soil 

There is no information on releases of phosphate ester flame retardants to the soil from manufacturing and 

processing facilities because these releases are not required to be reported (EPA 1997). 

Phosphate ester flame retardants are released to soil from the use of waste water for irrigation, the 

disposal of flame retardant plastics in landfills, the leakage of hydraulic fluids, or the deposition of 

aerosolized phosphate esters (Muir 1984). 

6.3 ENVIRONMENTAL FATE 

6.3.1 Transport and Partitioning 

Phosphate esters are synthetic compounds that are present in the air, water, and soil due to their use 

primarily as flame retardants, hydraulic fluids, and plasticizers. The ability of phosphate esters to enter 

the atmosphere as vapors depends greatly upon the vapor pressure of the individual compound. 

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PHOSPHATE ESTER FLAME RETARDANTS 208 

6. POTENTIAL FOR HUMAN EXPOSURE 

Therefore, phosphate esters can be present in the vapor phase or particulate phase (EPA 1979; Muir 

1984). 

Phosphate esters generally have low water solubilities and relatively high Kow values, which result in high 

Koc values. Muir (1984) reported the Koc values for TPP, TnBP, TBEP, TCEP, and TDCP as 7,850, 

3,592, 2,311, 151, and 2,591, respectively, using data from Kenaga and Goring (1980). TCEP, as 

apparent from the Koc values, is particularly mobile in soil and has the greatest potential to leach into 

groundwater. Relative to pesticides, the high Koc of the other phosphate esters indicate relatively low 

leaching potential. The fate and distribution of several phosphate esters were studied in laboratory 

experiments using river water, pond water, and sediment mesocosms (Muir et al. 1989). Following 

addition of each compound to the water column, rapid partitioning into the sediment was observed in each 

case. Volatilization of phosphate esters from dry soils is unlikely given the vapor pressures and 

adsorption coefficients; however, volatilization from moist soil is possible given the range of Henry’s 

Law constants (10-4–10-8 atm-m3

/mol) and vapor pressures (10-2–10-7 mm Hg) (Muir 1984). 

TnBP, TPP, TCEP, and TDCP have been reported to have a moderate potential to bioaccumulate in 

aquatic organisms based on their Kow values (Sasaki et al. 1981). Bioconcentration of phosphate esters 

requires assessment by using not only the Kow or water solubility, but also the capacity of absorption and 

metabolic behavior (Sasaki et al. 1981, 1982). Bioaccumulation ratios in fish (rainbow trout) are reported 

to range from 133 to 2,807 (Muir et al. 1981). Phosphate esters have been detected in fish, sediment, and 

water at or near the site of hydraulic fluid use (Mayer et al. 1981). 

Uptake or degradation of TCEP in water was nearly nonexistent, resulting in very low bioaccumulation 

for this compound as analyzed for bioconcentration in kilifish and goldfish using both a static water 

system and a continuous flow test system. Muir et al. (1983a) calculated the bioconcentration factors 

(BCFs) for TPP as 573 and 561 for rainbow trout and fathead minnows, respectively, using 14C-labeled 

TPP. It was found that, in general, the hydrolysis rate of the phosphate ester had a greater effect on 

bioconcentration than the hydrophobicity of the compound (Muir et al. 1983a). 

6.3.2 Transformation and Degradation 

6.3.2.1 Air 

These compounds are capable of degrading through reaction with hydroxyl radicals, which is the main 

route of atmospheric degradation for most organic substances. Predicted hydroxyl radical rate constants 

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PHOSPHATE ESTER FLAME RETARDANTS 209 

6. POTENTIAL FOR HUMAN EXPOSURE 

range from 10-12 to 10-11 cm3/molecule-second and corresponding atmospheric half-lives are on the order 

of 1–12 hours for the selected phosphate esters assuming a constant atmospheric hydroxyl radical 

concentration of 1.5x106 hydroxyl radicals per cm3 (Meylan and Howard 1993). Particulate-phase 

phosphate esters are subject to wet and dry deposition, while semi-volatile phosphate esters have the 

potential to hydrolyze to diesters, monoesters, and phosphoric acid (Ishikawa et al. 1992). Phosphate 

esters maintain oxidative stability at isothermal or room temperature conditions; however, thermal 

decomposition of these substances predominates at high temperature in the presence of air (Shankwalkar 

and Placek 1992). 

6.3.2.2 Water 

Hydrolysis is the most important abiotic fate process for phosphate esters proceeding stepwise to release 

alkyl and aryl alcohols (Boethling and Cooper 1985). The rate of hydrolysis is highly dependent on pH, 

temperature, presence of catalytic reagents, and stability of the conjugate acid or base, as well as the 

dielectric constant of the solvent (Katagi 2002). Phosphate esters are highly pH-dependent and generally 

are resistant to hydrolysis in neutral or acidic water (pH 5.0–7.0), but readily degrade in more alkaline 

conditions (pH 9.0–9.5) (Howard and Deo 1979; Mayer et al. 1981; Muir 1984). Half-lives of TPP at pH 

8.2, 9.0, and 9.5 were 7.5, 3.0, and 1.3 days, respectively, indicating much faster hydrolysis as alkalinity 

increases. TPP hydrolysis was measured in distilled, lake, and river water. The results showed that the 

pseudo first-order rate constants for distilled water, Lake Ontario water, and Seneca River water were 

0.93, 0.64, and 0.34 days-1, corresponding to half-lives of 0.75, 1.0, and 2.0 days, respectively (Howard 

and Deo 1979). 

Comparatively, dialkyl and diaryl phosphate esters have been found to be far less susceptible to 

hydrolysis than the corresponding triesters, likely due to the primary species being an anion. 

Dichloroalkyl phosphate esters such as TDCP are more labile than monochloroalkyl phosphate esters 

such as TCEP and TCPP (Hartley 1959; Muir 1984). Therefore, once the first ester substituent is 

hydrolyzed, removal of the second and third ester become much more difficult. 

Aqueous base-catalyzed hydrolysis occurs via an SN2-like nucleophilic attack on the phosphorus atom by 

OHon one of the tetrahedral faces, forming a transient tetracoordinate trigonal bipyramidal intermediate, 

followed by departure of the leaving group to form a phosphate diester. This mechanism and structure are 

evidenced by 18O labeling and crystallographic data, respectively (Davis and Richardson 1980; Katagi 

2002; Vernon 1959). Given this mechanism, electron-withdrawing substituents, such as halogens, 

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PHOSPHATE ESTER FLAME RETARDANTS 210 

6. POTENTIAL FOR HUMAN EXPOSURE 

increase the electrophilicity of the phosphorus, whereas electron-donating substituents are stabilizing 

(Davis and Richardson 1980). Through coordination, certain metal ions such as Ir, Rh, Co, Cu, Zn, and 

Mn have shown to facilitate phosphate ester hydrolysis. Low environmental concentrations of dissolved 

transition metals in the aquatic environment do, however, make this an unlikely mechanism. 

Heterogeneous reactions with suspended or sedimentary mineral phases have been shown to hydrolyze 

some phosphate esters (Baldwin et al. 1995). 

Nonhalogenated phosphate esters are degraded by microorganisms in activated sludge; however, the 

halogenated phosphate esters are resistant to biodegradation. Standard biodegradation tests indicated that 

both TnBP and TPP are readily biodegradable, but TCPP is not. TPP achieved 83–94% of its theoretical 

biochemical oxygen demand (BOD) and TnBP achieved 89–91% of its theoretical BOD in 28 days using 

an activated sludge as inoculum and the modified MITI (OECD 301C) test (IPCS 2004, 2006). TCPP 

achieved 0% of its theoretical BOD in 28 days using the same test (IPCS 2000a) and showed no decrease 

in concentration in landfill leachate after 80 days under aerobic conditions (Kawagoshi et al. 2002). 

Biodegradation is generally initiated by hydrolysis of the ester bond by microbial esterases (Yamada 

1987). The hydrolysis product of TnBP, butanol, can be used as a carbon source (Thomas and Macaskie 

1996, 1998). Consequently, several naturally isolated Pseudomonas cultures were found to substantially 

degrade TnBP by metabolizing and growing on minimal TnBP media as the feedstock (Thomas et al. 

1997). Ninety-six percent of both TnBP and TPP was degraded upon addition of activated sludge (Saeger 

et al. 1979). Takahashi et al. (2008) isolated a mixed bacterial culture capable of degrading previously 

nonbiodegradable chlorinated phosphate esters TCEP and TCPP. A mixed culture primarily composed of 

Acidovorax spp., Aquabacterium spp., and Sphingomonas spp. degraded TCEP, while a mixed culture of 

Acidovorax spp. and Sphingomonas spp. was found to degrade TCPP. 

Efforts to enhance the degradation of halogenated phosphate esters such as TCPP at water treatment 

facilities have been investigated (Watts and Linden 2008, 2009). The addition of ozone and hydrogen 

peroxide to produce photochemically generated hydroxyl radicals in aqueous solution was shown to be an 

effective method of increasing the oxidation of TCEP and TCPP in bench scale experiments. High initial 

levels of hydrogen peroxide are used in conjunction with a powerful ultraviolet light source to initiate the 

formation of hydroxyl radicals (Watts and Linden 2009). 

Removal of phosphate esters from waste water can require additional processing. Halogenated phosphate 

esters, including TCEP, are particularly biorecalcitrant and are emerging as significant contaminants from 

waste water pollution into freshwater resources (Watts and Linden 2008). Ishikawa and Baba (1988) 

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PHOSPHATE ESTER FLAME RETARDANTS 211 

6. POTENTIAL FOR HUMAN EXPOSURE 

recognized the pH dependence of hydrolysis while attempting to hydrolyze phosphate esters with aqueous 

chlorine. Chlorination had little effect on TCEP and TCPP at all pHs and only achieved 50% degradation 

at pH 7 for TnBP and TPP. 

6.3.2.3 Sediment and Soil 

Muir et al. (1989) studied the fate and degradation of four phosphate esters, including TPP, in 

sediment/water systems and observed rapid degradation of these substances. The average half-lives of 

TPP in river sediments were 2.8 days at 25 °C, 2.8 days at 10 °C, and 11.9 days at 2 °C; the overall 

average half-life was 7.0 days. Under anaerobic soil conditions, TPP had a half-life of 32 days (Anderson 

1993), while sterile soil produced nearly quantitative recovery of TPP after 101 days. TCEP soil 

attenuation was <33% from waste waters passed through soil columns for 1 month (Watts and Linden 

2008). 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 

Reliable evaluation of the potential for human exposure to phosphate ester flame retardants depends in 

part on the reliability of supporting analytical data from environmental samples and biological specimens. 

Concentrations of phosphate ester flame retardants in unpolluted atmospheres and in pristine surface 

waters are often so low as to be near the limits of current analytical methods. In reviewing data on 

phosphate ester flame retardants levels monitored or estimated in the environment, it should also be noted 

that the amount of chemical identified analytically is not necessarily equivalent to the amount that is 

bioavailable. The analytical methods available for monitoring phosphate ester flame retardants in a 

variety of environmental media are detailed in Chapter 7. 

6.4.1 Air 

Several phosphate esters were detected in the ambient air of Kitakyushu, Japan and measured by gas 

chromatography-mass spectrometry (GC-MS) at concentrations (μg/m3

) of 0.0023 (TnBP), 

0.0053 (TCPP), 0.0047 (TDCP), and 0.0022 (TPP) in 1983 (Haraguchi et al. 1985). Several phosphate 

esters were detected in outdoor air from eight sites in Tokyo, Japan including TnBP (0–1.7 ng/m3

), TCPP 

(0–3.1 ng/m3

), and TBEP (0–1.1 ng/m3) (Saito et al. 2007). 

TnBP is a component of two formulations of hydraulic fluid, Skydrol 500B and Skydrol LD. 

Consequently, TnBP was detected in the air at the CP air test facility at Vancouver International Airport 

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PHOSPHATE ESTER FLAME RETARDANTS 212 

6. POTENTIAL FOR HUMAN EXPOSURE 

at a concentration of 0.04–0.3 mg/m3 (Monsanto Co. 1980), indicating that phosphate ester hydraulic 

fluids may be released during aircraft maintenance operations from equipment using phosphate ester 

hydraulic fluids. 

The use of phosphate esters as an additive to flexible plastics, such as PVC and polyurethane foams, and 

their ability to leach from the polymer matrix often leads to their detection in indoor air at low levels. 

Phosphate esters have been found in indoor air from both homes and offices (Carlsson et al. 2000; Garcia 

et al. 2007; Hutter et al. 2006; Ingerowski et al. 2001, 2003; Otake et al. 2004, 2001; Owens et al. 2007; 

Sjodin et al. 2001). PVC plasticizers, floor polishes, and flame retardants for electronics and textiles are 

the primary contributors of phosphate esters to indoor air. PVC-containing plasticizer is a stiff resin but 

softens and expands upon heating and remains this way when cooled due to the molecular changes that 

take place (Otake et al. 2001, 2004). Phosphate esters are not chemically bound to host materials and 

consequently, can be emitted to the surrounding air as vapor or particulates depending on the vapor 

pressure of the compound (Carlsson et al. 2000; Garcia et al. 2007). 

Recognition that phosphate esters, particularly TCEP and TCPP, were impacting indoor air took place in 

1993 in Japan. TCEP was used in wall coverings and television sets in Japan until its carcinogenic 

properties were suspected and it was replaced with TCPP (Saito et al. 2007). In Tokyo, Japan, several 

phosphate esters were detected in indoor air environments. In 18 houses sampled, concentration ranges 

(ng/m3

) were 0–30.6 (TnBP), 0–1,260 (TCPP), 0–136 (TCEP), 0–13.7 (TBEP), and 0–0.60 (TDCP). In 

addition, 14 office buildings had concentration ranges (ng/m3

) of 0.46–21.7 (TnBP), 0–0.86 (TPP), 0– 

57.6 (TCPP), 0–42.1 (TCEP), 0–118 (TBEP), and 0–8.7 (TDCP) (Saito et al. 2007). In a newly 

constructed home in Tokyo, Japan, indoor air concentrations (ng/m3

) were 36.6 (TnBP), 5.5 (TCPP), 

1.2 (TCEP), 71.0 (TBEP), and 1.3 (TDCP). TBEP was determined to originate from the floor polishing 

agent, while TnBP originated from the polyolefin wall and ceiling coverings (Saito et al. 2007). 

Migration rates of TDCP and TCP were measured as 0.28 and 5.9 μg/m2

-hour, respectively, from 

computer monitors, and migration rates of TCPP and TCEP were measured as 1.7 and 13.0 μg/m2

-hour, 

respectively, from TV sets using an interior surface to solid extraction disk (Saito et al. 2007). This 

indicates that migration from electronic devices to air is occurring at ambient temperatures. 

6.4.2 Water 

Phosphate esters are commonly detected in surface water, groundwater, sewage, waste water, and 

drinking water due to their presence in many commercial products and the ability to leach or diffuse from 

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PHOSPHATE ESTER FLAME RETARDANTS 213 

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their anthropogenic source (Watts and Linden 2009). These contaminants are widely distributed in the 

aquatic environment (Ishikawa et al. 1985; Muir 1984). In the United States, the presence of phosphate 

esters has been reported in waters from the Delaware River, the Great Lakes region, and several Midwest 

rivers; phosphate esters have also been detected in water at foreign locations such as Japan, the 

Netherlands, Germany, and Canada (Muir 1984). Conventional treatment of drinking water in the United 

States showed that removal of TnBP, TBEP, TCEP, and TDCP was incomplete (Andresen and Bester 

2006). In particular, TCEP is resistant to conventional potable water and waste water treatments (Meyer 

and Bester, 2004; Reemtsma et al. 2006; Watts and Liden 2008, 2009). Several studies have measured 

phosphate esters in surface waters from Wisconsin (Peterman et al. 1980), Kansas (Lee and Rasmussen 

2006), and Germany (Andresen et al. 2004; Fries and Puttmann 2001). Phosphate esters have also been 

detected in coastal waters from Spain (Gomez-Belinchon et al. 1988) and Japan (Ishikawa et al. 1985). 

Pedersen et al. (2005) detected TCEP, TCPP, TBEP, and TDCP flame retardants in agricultural runoff 

from fields irrigated with treated effluent in Ventura County, California. 

Waters from waste water treatment facilities (WWTF) discharged into lakes, rivers, streams, and 

tributaries of various watersheds are known to contain phosphate esters. A number of studies indicate 

influent and effluent of WWTF testing positive for phosphate esters (Jackson and Sutton 2008; Marklund 

2005b; Pedersen et al. 2005; Reemtsma et al. 2006; Thruston et al. 1991). Therefore, introduction of 

these anthropogenic compounds into the environment is augmented if an effective purification is not 

performed to remove or degrade phosphate esters at the WWTF. 

Analysis of several streams in Johnson County, Kansas in 2002–2003 revealed the presence of phosphate 

ester flame retardants. On average, concentrations of 0.5 μg/L of TnBP, TPP, TBEP, TCEP, and TDCP 

were reported in these streams. In addition, several water samples collected and analyzed near a WWTF 

in the same area contained TBEP and TDCP. The mean concentrations of TBEP and TCDP in the 

effluent were 4.4 and 0.4 μg/L, respectively, and 2.0 and 0.4 μg/L <500 m downstream from the treatment 

plant. Maximum concentrations of 15 and 0.6 μg/L for TBEP and TDCP, respectively, were measured in 

the immediate effluent, and maximum levels of 6.2 and 0.6 μg/L, respectively, were measured <500 m 

downstream (Lee and Rasmussen 2006). A comprehensive study conducted by the U.S. Geological 

Survey from 1999 to 2000 analyzed surface water samples from 139 streams obtained in 30 states across 

the continental United States (Kolpin et al. 2002). TCEP, TDCP, and TPP were detected in 57.6, 12.9, 

and 14.1% of the surface water samples tested over this 2-year period, respectively. The maximum 

concentrations of TCEP, TDCP, and TPP were reported as 0.54, 0.16, and 0.22 μg/L, respectively, with 

median levels of 0.1, 0.1, and 0.04 μg/L, respectively (Kolpin et al. 2002). 

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Municipal waste water effluent collected from a treatment plant leading to the Oder River, Germany, 

contained mean levels of 622, 352, and 2,955 ng/L of TnBP, TCEP, and TBEP, respectively, in 

specimens obtained during a 2002–2003 sampling period (Fries and Puttmann 2003). Mean levels of 

TnBP, TCEP, and TBEP measured in the influent to the plant were 15,404, 986, and 12,835 ng/L, 

respectively. The concentration of TnBP, TCEP, and TBEP in river water at various sampling points in 

the river downstream from the plant ranged from 69 to 1,044 ng/L (TnBP), from not detected to 

1,036 ng/L (TCEP), and from 121 to 952 ng/L (TBEP). Groundwater samples obtained from areas 

adjacent to the river contained TnBP, TCEP, and TBEP at ranges from not detected to 1,120, from not 

detected to 312, and from 154 to 410 ng/L, respectively. 

Phosphate esters are widely used as incombustible plasticizers in Japan and, as a consequence, have been 

detected in the environment. Samples collected and analyzed in 1989–1990 from the Yodo River, Osaka 

City Rivers, Osaka Bay, and Yamato River in Japan indicated the presence of phosphate ester flame 

retardants. The most prevalent phosphate ester detected was TCPP at 13.1 μg/L in the Yamato River; 

however, TCEP, TnBP, TDCP, and TPP were also detected at lower concentrations (Fukushima et al. 

1992). 

Three volcanic lakes located in Central Italy were examined for the presence of phosphate esters 

(Bacaloni et al. 2008). Due to their location, the lakes lack emissaries and tributaries and sewage 

treatment plant inputs. Therefore, contamination can occur only via local anthropogenic activities or 

long-range transport and deposition from rainfall or runoff processes. The results of this study indicated 

the presence of TCEP, TCPP, TDCP, TPP, TiBP, TnBP, and TBEP in all three of these lakes at the parts 

per trillion (ng/L) level, with a noticeable seasonal variation for several of the compounds. For each of 

the three lakes, maximum concentrations of the phosphate esters tended to occur during the late summer 

to autumn months, which coincide with heavy tourist activity and increased vehicular traffic at all three 

locations. The mean monthly range of concentrations at all three lakes were as follows: TCEP, not 

detected to 64 ng/L; TCPP, 2–62 ng/L; TDCP, 2–60 ng/L; TPP 2–21 ng/L; TiBP, 1–380 ng/L; TnBP, 3– 

784 ng/L; and TBEP, 8–127 ng/L. 

Aerosolized phosphate esters are subject to wet deposition. TPP and TnBP were identified, but not 

quantified, in rainwater samples obtained from Los Angeles, California (Kawamura and Kaplan 1983), 

and snowfall samples from various areas of Northern Sweden (Marklund 2005a). TnBP was detected in 

the snowfall at an airport in Sweden at levels as high as 23,000 ng/kg, likely as a consequence of its use in 

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aircraft hydraulic fluids. TnBP, TCEP, and TBEP were detected in rainwater samples collected in 

Bahnbrucke, Germany at levels of 911, 121, and 394 ng/L, respectively (Fries and Puttmann 2003). 

TnBP is frequently used as a solvent in liquid-liquid extraction for uranium and plutonium fuel 

reprocessing. Consequently, it has been detected in storage ponds and waste streams at nuclear fuel 

reprocessing sites. TnBP and uranium concentrations in a typical fuel rod storage pond were 300 and 

142 μM, respectively (Thomas and Macaskie 1996). 

TCEP, TDCP, and TPP were analyzed in groundwater samples from 47 sites in 18 different states as part 

of a national reconnaissance program of water quality in the United States (Barnes et al. 2008). TCEP 

was detected in 29.8% of the samples tested at a maximum concentration of 0.737 μg/L. TDCP and TPP 

were detected in 2.1 and 4.3% of the groundwater samples tested, respectively; however, all detections 

were below the reporting level. Focazio et al. (2008) studied the frequency of detection of phosphate 

esters and 96 other compounds in 25 ground- and 49 surface-water sources used for public drinking water 

systems from 25 different states and Puerto Rico. TCEP, TDCP, TnBP, and TPP were detected in 20.3, 

12.2, 8.1, and 1.35% of the samples tested, respectively. The maximum concentration of TnBP was 

0.74 μg/L; however, all of the other compounds were detected below the reporting limit of 0.5 μg/L. 

TPP was identified, but not quantified, in water samples collected from groundwater and treated water 

obtained from 31 wells in the Piedmont and Highlands regions of Northern New Jersey (Stiles et al. 

2008). In a 1979 survey of treated potable drinking water from 29 municipalities across Canada, the 

presence of TnBP, TCEP, TDCP, TPP, and TBEP was frequently observed. TBEP was the most 

commonly detected phosphate ester with levels as high as 560 ng/L (Williams et al. 1981). Phosphate 

esters were detected in untreated surface water from the Ruhr River in Germany; reported concentrations 

of TCPP, TCEP, and TDCP were 50–150, 10–130, and 10–40 ng/L, respectively (Andresen and Bester 

2006). Following treatment of the water, the concentrations were all reduced to 0.3–3 ng/L (Andresen 

and Bester 2006). 

6.4.3 Sediment and Soil 

Available literature suggests that halogenated phosphate esters are somewhat persistent organic 

compounds when adsorbed to soils and sediments (Boethling and Cooper 1985; Muir 1984). However, 

Muir et al. (1989) found that nonhalogenated phosphate esters, particularly TPP, are degraded in <3 days. 

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In general, partitioning of phosphate esters provides potential for contact with sediments in lakes, rivers, 

and sea floors. 

A national survey conducted in 1977–1978 in Japan resulted in the detection of TnBP at concentrations of 

8–130 ng/g in rivers sediments, 3–24 ng/g in estuary sediments, and 2–240 ng/g in sea sediments 

(Ishikawa et al. 1985). Phosphate ester levels of 0.1–1 μg/g have been detected in river sediments of 

industrial areas contaminated with triaryl-based hydraulic fluids (Ishikawa et al. 1985; Muir et al. 1989). 

Commercial and military use of phosphate ester hydraulic fluid is estimated to result in up to 80% of the 

consumption of these to be lost to unrecovered leakage. Consequently, air force bases have reported 

detection of several phosphate esters, including TPP, in soils (David and Seiber 1999b; Monsanto Co. 

1980). In Glil-Yam, Israel, Muszkat et al. (1993) reported the presence of TnBP at 25 ppb in effluent 

used for crop irrigation. A national survey in 1977–1978 resulted in the detection of TCEP in sea 

sediments at a concentration of 90 ng/g (Ishikawa et al. 1985). 

6.4.4 Other Environmental Media 

In 1982, the Food and Drug Administration (FDA) found detectable levels of phosphate esters present in 

food samples during a portion of the annual Pesticide Screening program. The presence of these 

phosphate esters in foodstuffs presumably arose from the diffusion of these substances through the 

wrapping material used to package the food (Daft 1982). Since 1982, phosphate ester flame retardants are 

regularly tested for in various foods by the FDA’s Total Diet Study. The results obtained are summarized 

in Table 6-1. No data were available for TiBP or TDCP from this study (FDA 2006). The most 

frequently identified phosphate ester flame retardant was TPP, which also had the highest reported 

content. TPP was found in caramels and margarine at approximately 0.04 ppm. In baby foods, turkey 

and vegetables contained the highest level of TPP at approximately 0.02 ppm. TnBP was the second most 

frequently detected phosphate ester, but most levels measured were below 0.004 ppm, with baby cereal 

(prepared with water) and applesauce being the highest (FDA 2006). 

In a study based in the United Kingdom, similar to the U.S. based FDA Total Diet Study, the most 

prevalent of the selected phosphate esters were TnBP and TPP, occurring in meats, cereals, nuts, and 

some vegetables (Gilbert et al. 1986). 

House dust has been found to contain phosphate esters such as TCEP and TCPP (Garcia et al. 2007; 

Hutter et al. 2006; Ingerowski et al. 2001; Marklund 2003). TBEP was measured at levels of 4,300– 

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Table 6-1. Phosphate Ester Flame Retardant Levels in Food 

Food item Level (ppm) 

Tributyl phosphate (TnBP) 

Rice, white, enriched, cooked 0.00011 

Oatmeal, plain, cooked 0.00014 

Cream of wheat (farina), enriched, cooked 0.00200 

Corn flakes cereal 0.00314 

Fruit-flavored cereal, presweetened 0.00018 

Shredded wheat cereal 0.00123 

Raisin bran cereal 0.00018 

Crisped rice cereal 0.00086 

Oat ring cereal 0.00034 

Apple (red), raw (with peel) 0.00043 

Applesauce, bottled 0.00430 

Orange juice, frozen concentrate, reconstituted 0.00045 

Grapefruit juice, frozen concentrate, reconstituted 0.00091 

Prune juice, bottled 0.00089 

Dill cucumber pickles 0.00023 

Sugar, white, granulated 0.00045 

Peach, canned in light/medium syrup 0.00045 

Tomato juice, bottled 0.00018 

Baby food, cereal, mixed, dry, prepared with water 0.00432 

Tributoxyethyl phosphate (TBEP) 

Oatmeal, plain, cooked 0.00368 

Bread, whole wheat 0.00114 

Candy, caramels 0.00075 

BF, juice, apple 0.00018 

Peach, canned in light/medium syrup 0.00039 

Popsicle, fruit-flavored 0.00225 

Tri-(2-chloroisopropyl) phosphate (TCPP) 

Apple (red), raw (with peel) 0.00082 

Pear, raw (with peel) 0.00009 

Prunes, dried, uncooked 0.00015 

Apple juice, bottled 0.00005 

Tomato catsup 0.00030 

Tomato juice, bottled 0.00032 

Baby food, arrowroot cookies 0.00018 

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Table 6-1. Phosphate Ester Flame Retardant Levels in Food 

Food item Level (ppm) 

Triphenyl phosphate (TPP) 

Peas, green, frozen, boiled 0.00023 

Rolls, white, soft, enriched 0.00075 

Bread, whole wheat 0.00036 

Tortilla, flour 0.00050 

Bread, rye 0.00039 

Strawberries, raw/frozen 0.00028 

Lemonade, frozen concentrate, reconstituted 0.00041 

Sauerkraut, canned 0.00025 

Broccoli, fresh/frozen, boiled 0.00023 

Asparagus, fresh/frozen, boiled 0.00023 

Tomato, raw 0.00341 

Mashed potatoes with margarine and milk, prepared from instant 0.0025 

Scalloped potatoes, homemade 0.00023 

Soup, vegetable beef, canned, condensed prepared with water 0.00068 

White sauce homemade 0.00285 

Margarine, regular (salted) 0.04068 

Butter, regular (salted) 0.00175 

Cream substitute, non-dairy, liquid/frozen 0.00102 

Candy, caramels 0.04503 

Fruit drink, from powder 0.00023 

Wine, dry table, red/ white 0.00068 

Bread, cracked wheat 0.00057 

Crackers, graham 0.00045 

Sweet cucumber pickles 0.00025 

Beef and vegetable stew, canned 0.00975 

Baby food, juice, apple-banana 0.00295 

Baby food, zwieback toast 0.00400 

Baby food, vegetables and turkey 0.02175 

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Table 6-1. Phosphate Ester Flame Retardant Levels in Food 

Food item Level (ppm) 

Tris-(2-chloroethyl)-phosphate (TCEP) 

Peas, green, frozen, boiled 0.00182 

Oatmeal, plain, cooked 0.00002 

Cream of wheat (farina), enriched, cooked 0.00259 

Rolls, white, soft, enriched 0.00008 

Broccoli, fresh/frozen, boiled 0.00014 

Green beans, fresh/frozen, boiled 0.00159 

Baby food, turkey and rice 0.00048 

Baby food, peas 0.00002 

Bread, cracked wheat 0.00002 

Eggplant, fresh, peeled, boiled 0.00175 

Candy, hard, any flavor 0.00002 

Sweet cucumber pickles 0.00005 

Baby food, teething biscuits 0.00006 

Soup, Oriental noodles (ramen noodles), prepared with water 0.00725 

Baby food, pears and pineapple 0.00002 

Source: FDA Total Diet Study Market Baskets 1991–2003 (FDA 2006) 

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7,800 mg/kg in house dust prior to removal of the cleaning polish on the floor. Once a wet cleaning was 

performed, the level of TBEP dropped to 410 mg/kg after 3 months and to 90 mg/kg after 6 months 

(Hutter et al. 2006). Dust samples obtained from different private residences (houses) located in the 

northwest of Spain were found to contain levels of TBEP as high as 18.5 μg/g. Other phosphate esters 

were also detected in the dust samples at average concentrations (μg/g) of 0.21 (TiBP), 0.25 (TnBP), 

1.7 (TCEP), 3.9 (TCPP), 0.35 (TDCP), 2.6 (TPP), and 9.9 (TBEP) (Garcia et al. 2007). 

Phosphate esters were detected in soft polyurethane foam samples at levels of 0.4–0.7 μg/g for TnBP, 

0.8–3.1 μg/g for TCEP, 0.9–3.1 μg/g for TCPP, 4.5–10.2 μg/g for TDCP, 4.7–23.3 μg/g for TPP, and 

1.6 μg/g for TBEP (Nagase et al. 2003). 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 

Exposure to phosphate esters can occur through ingestion of food and water containing phosphate esters 

or inhalation of vapors or particulates released from flame retardant materials. Dermal exposure can 

occur through direct contact with flame-retarded textiles occurs; however, these substances are not highly 

absorbed through dermal routes. As fabrics and foams treated with phosphate ester flame retardants wear, 

they can shed small fibers and produce particles that could be injested or inhaled if ≤10 μm (NRC 2000). 

The most significant route of exposure to the general population is via ingestion of food or water 

contaminated with phosphate ester flame retardants (Fiserova-Bergerova and Pierce 1990; Hartmann et al. 

2004; Hughes et al. 2001; IPCS 1997). 

Data regarding dietary intake of phosphate ester flame retardants in children and adults in the United 

States are available only for select compounds and years. In 1980 and 1981–1982, ADI values of TCEP 

for adults were 0.041 and 0.055 μg/kg, respectively. In 1981–1982, the ADI for TnBP was found to be 

0.025 μg/kg. This value was determined by measuring of TnBP in meats and fruits, and TCEP in cereals 

(Gantrell 1986). The ADI was calculated by Gunderson (1988, 1995a, 1995b) from the reported FDA 

Total Diet Study and these data are summarized in Table 6-2. Mean daily intakes for male and female 

teenagers aged 14–16 were highest for TPP ranging from 1.6 to 18.2 ng/kg/day. For male and female 

adults aged 25–30, TPP also had the highest mean daily intakes, ranging from 0.8–18.4 ng/kg/day. Both 

male and female adults aged 60–65 showed the highest mean daily intake for TBEP, ranging from 0.2 to 

16.8 ng/kg/day. TPP was also quite prevalent for this age group. No data were reported for TiBP or 

TDCP (Gunderson 1988, 1995a, 1995b). 

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Table 6-2. Dietary Phosphate Ester Flame Retardant Intake 

Mean (ng/kg body weight/day) 

Age group 1982–1984a 1984–1986b 1986–1991c 

Tributyl phosphate (TnBP) 

6–11 months 38.9 42.5 3.0 

2 years 27.7 33.1 2.5 

14–16 years, females 3.5 4.5 0.5 

14–16 years, males 5.0 6.6 0.7 

25–30 years, females 3.3 4.0 0.3 

25–30 years, males 2.7 3.1 0.3 

60–65 years, males 5.4 6.2 0.4 

60–65 years, females 6.2 7.1 0.4 

Triphenyl phosphate (TPP) 

6–11 months 0.3 1.8 15.7 

2 years 4.4 16.0 34.8 

14–16 years, females 1.6 5.8 16.3 

14–16 years, males 1.2 5.0 18.2 

25–30 years, females 0.8 3.3 12.8 

25–30 years, males 1.6 5.5 18.4 

60–65 years, males 0.5 2.4 11.4 

60–65 years, females 0.5 2.4 15.8 

Tributoxyethyl phosphate (TBEP) 

6–11 months 2.9 0.2 5.2 

2 years 14.4 1.5 3.7 

14–16 years, females 8.4 0.7 1.2 

14–16 years, males 7.7 1.1 1.1 

25–30 years, females 12.9 0.4 2.0 

25–30 years, males 10.7 0.8 0.9 

60–65 years, males 16.8 0.2 3.4 

60–65 years, females 13.7 0.2 2.8 

Tri-(2-chloroisopropyl) phosphate (TCPP) 

6–11 months No data No data 0.1 

2 years No data No data 0.2 

14–16 years, females No data No data 0.1 

14–16 years, males No data No data 0.1 

25–30 years, females No data No data 0.1 

25–30 years, males No data No data 0.1 

60–65 years, males No data No data 0.1 

60–65 years, females No data No data 

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Table 6-2. Dietary Phosphate Ester Flame Retardant Intake 

Mean (ng/kg body weight/day) 

Age group 1982–1984a 1984–1986b 1986–1991c 

Tris-(2-chloroethyl)-phosphate (TCEP) 

6–11 months No data 4.9 No data 

2 years No data 6.5 No data 

14–16 years, females No data 2.1 No data 

14–16 years, males No data 1.1 No data 

25–30 years, females No data 1.8 No data 

25–30 years, males No data 1.3 No data 

60–65 years, males No data 3.1 No data 

60–65 years, females No data 2.6 No data 

a

Gunderson 1988 (ADI 1982–1984) b

Gunderson 1995a (ADI 1984–1986); expressed as μg/kg body weight/day in source.
 c

Gunderson 1995b (ADI 1986–1991); expressed as μg/kg body weight/day in source.
 

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In the United Kingdom, a diet study modeled after the U.S. Total Diet Study determined a total daily 

intake of 0.075–0.105 mg/day for trialkyl/aryl phosphates. The most prevalent of the selected phosphate 

esters were TnBP and TPP, found in meats, cereals, nuts, and some vegetables (Gilbert et al. 1986). 

In Canada, TDCP was detected in human adipose tissue by LeBel and Williams (1983, 1986) in 

concentrations that ranged from not detectable (<0.001 μg/kg) to 257 μg/kg. In later studies, samples 

from four out of six cities showed no detectable TDCP; however, two concentrations ranged up to 

32 μg/kg. (LeBel and Williams, 1983, 1986; LeBel et al. 1989). Using negative chemical ionization mass 

spectrometry (LC-MS-NCI) with a limit of detection of 0.01 μg, Hudec et al. (1981) found concentrations 

of TDCP in the seminal fluid of 34 out of 123 student donors ranging from 5 to 50 μg/L. 

Morgan and Hughes (1981) tested workers manufacturing triaryl phosphate esters, including TPP, for 

cholinesterase activity to determine its efficacy as a biomarker for absorption. The results showed that it 

is not adequately sensitive to be used as a biomarker for phosphate ester absorption. 

Three primary uses that account for the greatest potential worker exposure include aircraft manufacturing, 

hydraulic system component manufacturing, and commercial airline operations (Batt et al. 1992). In 

addition, workers in industries that manufacture plastics, floor polishes, wall coverings, and electronics 

may have a greater-than-average potential for exposure. 

A survey conducted by NIOSH (National Institute for Occupational Safety and Health) from 1981–1983 

collected data on potential occupational exposures to chemical agents. These data provided estimates that 

indicated the number of workers potentially exposed to TPP, TnBP, TBEP, TCEP, and TCPP were 

91,754, 109,402, 257,421, 5,073, and 120 respectively (NIOSH 1990). 

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 

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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). 

Exposure of children to phosphate ester flame retardants is likely to occur primarily through diet, indoor 

air, or by contact with flame retardant-treated plastics or fabrics. Young children are likely to have an 

increased oral exposure risk. Children may repeatedly suck on furnishing fabrics, plastics, or polished 

surfaces, presenting potential dissolution of leachable flame retardants. Effective phosphate ester flame 

retardants are dependant upon retention in the applied matrix, and are therefore likely chosen based upon 

their ability to resist extraction from the matrix (NRC 2000). Children and infants may be exposed to 

phosphate ester flame retardants through ingestion of dust in homes where plastics, foams, floor polishes, 

or wall covering products containing phosphate esters are used (Hutter et al. 2006). 

In 1980, the ADIs of TnBP for infants and toddlers were 0.051 and 0.132 μg/kg, respectively. In 

1979 and 1980, TCEP was found to have an ADI of 0.016 and 0.004 μg/kg, respectively, in infants and 

0.009 μg/kg and none detected, respectively, in toddlers. These were determined by measuring TnBP in 

cereals and TCEP in fruits (Gantrell 1985). Mean daily intakes for 6–11-month-old children were highest 

for TnBP between 1982 and 1986, ranging from 38.9 to 42.5 ng/kg//day. This number dropped 

significantly to 0.3 ng/kg/day in the last study published in 1986–1991. The next greatest exposure of 6– 

11-month-old children via diet appears to be TPP, with an ADI of 15.7 ng/kg/day in 1986–1991. The 

exposure data indicated that 2-year-old children could have exposures >30 ng/kg/day of TnBP and TPP 

(Gunderson 1988, 1995a, 1995b). 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 

Phosphate esters do not occur naturally in the environment; therefore, potential high exposures are limited 

to occupational or indoor environments. Occupational exposure to phosphate ester flame retardants may 

occur during the manufacture, use, transport, processing, or disposal/recycling of flame retardants. 

Routes of exposure could include inhalation, dermal contact, or ingestion. Living or working in an 

environment where there is an excess of flame retardant-treated products such as wall coverings, plastics, 

or electronics could contribute to a higher-than-average exposure. Additionally, living in an area where 

phosphate ester-contaminated effluent is used for drinking water or crop irrigation could contribute to a 

higher-than-average exposure (Fiserova-Bergerova and Pierce 1990; IPCS 1997). 

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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 phosphate ester flame retardants is available. Where 

adequate information is not available, ATSDR, in conjunction with NTP, is required to assure the 

initiation of a program of research designed to determine the health effects (and techniques for developing 

methods to determine such health effects) of phosphate ester flame retardants. 

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. Table 4-2 summarizes many of the relevant physical and 

chemical properties of the selected phosphate ester flame retardants. The only data need is for measured 

Log Kow and vapor pressures for TiBP. 

Production, Import/Export, Use, Release, and Disposal. According to the Emergency Planning 

and Community Right-to-Know Act of 1986, 42 U.S.C. Section 11023, industries are required to submit 

substance release and off-site transfer information to the EPA. The TRI, which contains this information 

for 2006, became available in February of 2008. This database is updated yearly and should provide a list 

of industrial production facilities and emissions. 

Current data on the use of each selected phosphate ester flame retardants are available and displayed in 

Table 5-1. Production, import, and export data are scarce and difficult to find, but estimates are provided 

by the EPA High Production Volume (HPV) Challenge Program or the Hazardous Substance Data Bank 

(HSDB) for all selected phosphate ester flame retardants. No data were available for manufacturers for 

TCPP and TiBP as indicated in Table 5-1 (EPA 2006; HSDB 2009). A data need exists for release and 

disposal of phosphate ester flame retardants. 

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Environmental Fate. The environmental entry mechanism of phosphate esters, as well as transport 

and partitioning, is highly dependent on the specific compound. The environmental fate mechanisms of 

groups within the selected compounds (e.g., halogenated, alkyl, and aryl phosphate esters) are well 

understood (Muir 1984). Hydrolysis and adsorption are the primary forces that influence phosphate ester 

environmental fate and are well documented (Howard and Deo 1979; Kenaga and Goring 1980; Mayer et 

al. 1981; Muir 1984). No data needs are identified. 

Bioavailability from Environmental Media. A data need exists for bioavailability of phosphate 

ester flame retardants from various media. Minimal data exist in the form of human monitoring, but 

several studies suggest that absorption of phosphate esters can occur via ingestion of foods and water 

contaminated with effluent or landfill leachate, inhalation of indoor and some outdoor air near airports 

and military installations, or dermal contact with contaminated soils or water (Fiserova-Bergerova and 

Pierce 1990; IPCS 1997; Monsanto Co. 1980; Saito et al. 2007). 

Food Chain Bioaccumulation. Sufficient bioaccumulation data are available for TnBP, TPP, TCEP, 

and TDCP (Muir 1980, 1983a; Sasaki et al. 1981, 1982); however, a data need exists for bioaccumulation 

of TiBP, TBEP, and TCPP. 

Exposure Levels in Environmental Media. Reliable monitoring data for the levels of phosphate 

ester flame retardants in contaminated media at hazardous waste sites are needed so that the information 

obtained on levels of phosphate ester flame retardants in the environment can be used in combination with 

the known body burden of phosphate ester flame retardants to assess the potential risk of adverse health 

effects in populations living in the vicinity of hazardous waste sites. 

Extensive reports are available regarding quantifiable levels of phosphate ester flame retardants detected 

in the environment. More specifically, extensive monitoring data exist on phosphate ester flame 

retardants in water (Andresen et al. 2004; Fries and Puttmann 2001; Gomez-Belinchon et al. 1988; 

Ishikawa et al. 1985; Lee and Rasmussen 2006; Meyer and Bester 2004; Muir 1984; Peterman et a 1980; 

Reemtsma et al. 2006; Watts and Liden 2008, 2009) and indoor air (Carlsson et al. 2000; Garcia et al. 

2007; Hutter et al. 2006; Ingerowski 2001, 2003; Otake et al. 2004, 2001; Owens et al. 2007; Sjodin et al. 

2001). Studies detecting phosphate ester flame retardants in outdoor air are more sparse (Haraguchi et al. 

1985; Monsanto Co. 1980; Saito et al. 2007). Additional data of phosphate ester flame retardants in soil 

and in food, as well as more recent average daily intake data, would be useful for estimating human 

exposure. In particular, there is a data need for environmental concentrations of TiBP. 

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PHOSPHATE ESTER FLAME RETARDANTS 227 

6. POTENTIAL FOR HUMAN EXPOSURE 

Exposure Levels in Humans. Given that these compounds are considered emerging pollutants in 

some of the literature, there are relatively little data concerning levels of phosphate ester flame retardants 

in humans. There are, however, studies that reported levels of TDCP in human adipose tissue (Lebel and 

Williams 1983, 1986) and in the seminal fluid of student donors (Hudec et al. 1981). A data need exists 

for additional information regarding levels of these substances in blood, and urine from individuals with 

potentially high exposures such as children and infants. A data need exists for studies adressing 

biomarkers as a method for determining exposure to mixtures of phosphate esters. 

This information is necessary for assessing the need to conduct health studies on these populations. 

Exposures of Children. Children are exposed to phosphate ester flame retardants by the same routes 

as adults. In addition, oral exposure can occur from dissolution of phosphate ester treated materials since 

children are more likely to repeadtedly suck on these materials (NRC 2000). A data need exists for levels 

of phosphate esters in blood and urine from children with known environmental exposure, as well as 

concentrations present in breast milk or infant formula to better estimate total exposure. Gantrell (1985) 

and Gunderson (1988, 1995a, 1995b) addressed only TnBP, TPP, TCEP, TCPP, and TBEP over a limited 

number of years (1982–1991). A data need exists for updated exposure in the form of ADI for children 

with the aforementioned compounds as well as new data regarding of TiBP and TDCP exposures. 

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 phosphate ester flame retardants were located. This 

substance is not currently one of the compounds for which a sub-registry has been established in the 

National Exposure Registry. The substance will be considered in the future when chemical selection is 

made for sub-registries to be established. The information that is amassed in the National Exposure 

Registry facilitates the epidemiological research needed to assess adverse health outcomes that may be 

related to exposure to this substance. 

6.8.2 Ongoing Studies 

No ongoing studies pertaining to the environmental fate of phosphate ester flame retardants were 

identified in a search of the Federal Research in Progress database (FEDRIP 2009) 

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PHOSPHATE ESTER FLAME RETARDANTS 228 

6. POTENTIAL FOR HUMAN EXPOSURE 

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PHOSPHATE ESTER FLAME RETARDANTS 229 

7. ANALYTICAL METHODS 

The purpose of this chapter is to describe the analytical methods that are available for detecting, 

measuring, and/or monitoring phosphate ester flame retardants, their metabolites, and other biomarkers of 

exposure and effect to phosphate ester flame retardants. 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 NIOSH. Other methods 

presented in this chapter are those that are approved by groups such as the Association of Official 

Analytical Chemists (AOAC) and the American Public Health Association (APHA). Additionally, 

analytical methods are included that modify previously used methods to obtain lower detection limits 

and/or to improve accuracy and precision. 

7.1 BIOLOGICAL MATERIALS 

Methods for the determination of phosphate ester flame retardants in biological materials are summarized 

in Table 7-1. There is virtually no information regarding the toxicokinetics of these chemicals in humans, 

including information on possible metabolites; consequently, there are no methods for determining 

metabolites. Thus far, detection of the parent compound is the only method available for detecting 

exposure to phosphate ester flame retardants. 

There are very few published articles regarding bioanalytical methods for phosphate ester flame 

retardants, but interest in these compounds as emerging pollutants has stimulated development of a select 

few (Shah et al. 2006). The bioanalytical methods presented are preliminary and are not accepted 

methods of accurately determining phosphate ester flame retardants in biological materials. 

Alkyl and aryl phosphate ester flame retardants were measured in blood using a method developed by 

Jonsson and Nilsson (2003). The sample preparation from blood plasma consisted of a hollow fibrebased XT-tube extractor to perform the liquid-liquid microextraction in hexane/methyl tert-butyl ether 

2:1 (v/v). A top gas chromatograph equipped with a TS-2 nitrogen-phosphorus detector (NPD) was 

employed to analyze the phosphate esters. The detection limits were 0.3 ng/mL for TPP and 36 ng/mL 

for TBEP. Recoveries varied between 40 and 80% with a relative standard deviation (RSD) around 4% 

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PHOSPHATE ESTER FLAME RETARDANTS 230 

7. ANALYTICAL METHODS 

Table 7-1. Analytical Methods for Determining Phosphate Ester Flame
 

Retardants in Biological Materials
 

Sample 

matrix 

Preparation 

method 

Analytical 

method 

Sample 

detection limit Analyte 

Percent 

recovery Reference 

Urine MISPE >80% 

recovery 

LC-ESI-MS 0.025 ng/μL TPP 72–75 

RSD: 11–12% 

Moller et al. 

2004 

No data TnBP No data 

Blood 

plasma 

Liquid-liquid 

microextraction 

GC-MSNPD 0.3 ng/mL TPP 40–80 

RSD: 4% 

Jonsson and 

Nilsson 2003 

36 ng/mL TnBP 40–80 

RSD: 4% 

No data TBEP, 

TCEP, 

TCPP 

40–80 

RSD: 4% 

Blood 

Plasma 

Methanol 

extraction, 

acetonitrile 

precipitation, then 

SPME 

GC-ICP-MS 17 ng/L 

240 ng/L 

24 ng/L 

TnBP 

TCEP 

TPP 

43 

RSD 11% 

49 

RSD 7% 

66 

RSD 14% 

Shah et al. 

2006 

Tissue Extract with 

benzene or 

acetone/hexane; 

fractionation by 

GPC 

GC-MSNPD No data TPP, 

TnBP, 

TBEP, 

TDCP, 

TCEP 

2.5 ng: 78–96 

10 ng: 52–100 

25 ng: 88–105 

LeBel and 

Williams 1983 

Seminal 

fluid 

Steam distillation; 

continuous liquidliquid extraction 

LC-MS-NCI 0.01 μg TDCP No data Hudec et al. 

1981 

ESI = electronspray; GC = gas chromatography; GPC = gel permeation chromatography; ICP = inductively coupled 

plasma; LC = liquid chromatography; MISPE = molecularly imprinted polymer solid-phase extraction; MS = mass 

spectrometry; NCI = negative chemical ionization; NPD = nitrogen-phosphorus detection; RSD = relative standard 

deviation; SPME = solid phase microextraction; TBEP = tributoxyethyl phosphate; TCEP = tris-(2-chloroethyl)­

phosphate; TCPP = tri-(2-chloroisopropyl) phosphate ; TiBP = triisobutyl phosphate; TnBP = tributyl phosphate; 

TOF = time of flight; TPP = triphenyl phosphate 

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PHOSPHATE ESTER FLAME RETARDANTS 231 

7. ANALYTICAL METHODS 

for most compounds. The method was also able to detect and quantify other phosphate ester flame 

retardants such as TnBP, TCEP, and TCPP, although the detection limit was not sufficiently low. 

Another analytical method to determine phosphorus-specific compounds in human plasma was published 

by Shah et al. (2006). This technique uses solid-phase microextraction (SPME) followed by gas 

chromatography (GC) inductively coupled plasma (ICP) mass spectrometry (MS) and high resolution GC 

time of flight (TOF) MS. The detection limits from blood plasma were 17 ng/L for TnBP, 240 ng/L for 

TCEP, and 24 ng/L for TPP. 

In urine, Moller et al. (2004) detected and quantified TnBP and TPP hydrolysis products. The method is 

capable of extracting the corresponding diesters of TnBP and TPP via molecularly imprinted polymer 

solid-phase extraction (MISPE) and liquid chromatography (LC) electrospray (ESI) MS method using a 

Hypercarb LC column with a graphitized carbon stationary phase. The detection limit was 0.025 ng/μL 

for diphenyl phosphate, the hydrolysis product of TPP. 

In Canada, TDCP was detected in human adipose tissue by LeBel and Williams (1983, 1986) in 

concentrations that ranged from not detectable (<0.001 μg/kg) to 257 μg/kg. In later studies, samples 

from four out of six cities showed no detectable TDCP; however, two concentrations ranged up to 

32 μg/kg (LeBel and Williams 1983, 1986; LeBel et al. 1989). Using LC negative chemical ionization 

(NCI) MS with a limit of detection of 0.01 μg, Hudec et al. (1981) found TDCP in the seminal fluid of 

34 out of 123 student donors. The TDCP concentrations ranged from 5 to 50 μg/L. 

7.2 ENVIRONMENTAL SAMPLES 

Methods for the determination of phosphate ester flame retardants in environmental samples are 

summarized in Table 7-2. 

Standard environmental analysis methods are available for several of the selected phosphate ester flame 

retardants from the U.S. Geological Survey (USGS) and NIOSH (NIOSH 1994a, 1994b; USGS 2001). 

All standardized methods, as well as literature methods available, utilize either liquid- or gas-based 

chromatography with predominantly GC flame photometric detection (FPD) being employed. Methods 

for analyzing phosphate ester flame retardants in air, water, soil, and other environmental media are 

prevalent throughout the literature. 

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PHOSPHATE ESTER FLAME RETARDANTS 232 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Phosphate Ester Flame Retardants in
 

Environmental Samples
 

Sample 

matrix 

Preparation 

method 

Analytical 

method 

Sample 

detection limit 

Percent 

recovery Analyte(s) Reference 

Air (indoor) Collection on filter, 

extract with ethyl 

ether, filter 

NIOSH 5034 

GC-FPD 

2 μg/sample No data TnBP NIOSH 

1994a 

Air (indoor) Absorbed on a 

filter, extracted 

with 

GC-MS 3 ng/mL or 

13 ng/m3 

92–109 TnBP, TiBP, 

TPP 

Solbu et al. 

2007 

dichloromethane 

Air (outdoor) Trap with glycerolFlorisil column, 

elute with 

GC-FPD 1 ng/m3 No data Trialkyl/aryl 

phosphates 

ICPS 1991b 

(EHC-111) 

MeOH/water, 

extract with 

hexane 

Water, 

sediments, 

solid wastes, 

sludges 

Collection on filter, 

extract with ethyl 

ether, filter 

NIOSH 5038 

GC-FPD 

10 μg/sample No data TPP NIOSH 

1994b 

Filtered 

waste water 

and water 

Filtered, extracted 

with an SPE 

cartridge 

containing a 

polystyrene 

divinylbenzene 

phase, dried, 

rinsed with 

DCM/ether, and 

concentrated 

USGSNWQL 

O-1433-01 

GC-MS 

TnBP 0.1 μg/L TnBP: 110a 

, 

5.97% RSD 

TBEP 0.2 μg/L TBEP: 103.4a , 

12.52% RSD 

TPP 0.06 μg/L TPP: 90a , 

4.5% RSD 

TDCP: 0.08 μg/L TDCP: 96.4a , 

5.29% RSD 

TCEP: 0.08 μg/L TCEP: 100a , 

5.04% RSD 

TnBP, 

TBEP, TPP, 

TDCP, 

TCEP 

USGS 2001 

Water 

(drinking) 

Adsorb resin, 

elute 

GC-NPD 1 ng/L No data Trialkyl/aryl 

phosphates 

LeBel et al. 

1979 

Sediments 

(sea or river) 

Extract with MeCN 

or acetone, Florisil 

column 

GC-FPD TnBP: 2 ng/g 

TCPP: 5 ng/g 

TCEP: 5 ng/g 

TPP: 5 ng/g 

83–98 TnBP, 

TCEP, TPP, 

TCPP 

Ishikawa et 

al. 1985 

a

Percent recovery and relative standard deviation were reported by NEMI (2009). 

DCM = dichloromethane; FPD = flame photometric detection; GC = gas chromatography; MS = mass spectrometry; 

NIOSH = National Institute for Occupational Safety and Health; NPD = nitrogen-phosphorus detection; RSD = relative 

standard deviation; SPE = solid phase extraction; TBEP = tributoxyethyl phosphate; TCEP = tris-(2-chloroethyl)­

phosphate; TCPP = tri-(2-chloroisopropyl) phosphate; TiBP = triisobutyl phosphate; TnBP = tributyl phosphate; 

TPP = triphenyl phosphate; USGS = U.S. Geological Survey 

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PHOSPHATE ESTER FLAME RETARDANTS 233 

7. ANALYTICAL METHODS 

Drinking water has been analyzed for TPP using a modified version of EPA method 525.5 using 

C-18 bonded solid phase extraction columns (Stiles et al. 2008) and also using GC-MS with NPD (LeBel 

et al. 1979). TPP adsorbed to sediments and soils can also be analyzed using a method developed by 

Degeus et al. (1994) using thermionic detection (TID) with supercritical fluid chromatography (SFC). 

An alternative method for testing for phosphate ester flame retardants was developed by Lombardo and 

Egry (1979) based on an AOAC method developed for analysis of pesticide residues in fatty foods. The 

method extracted the hydraulic fluid from contaminated fish samples and analyzed them by gas-liquid 

chromatography (GLC) with phosphorus selective detection. The analysis yielded concentrations of TPP 

concentrations of 0.06 and 0.12 ppm in carp and 0.15 ppm in goldfish collected from Waukegan Harbor, 

Illinois. 

Several other methods were developed for detection of phosphate esters in various types of media. 

Lamouroux et al. (2000) report an LC-MS method for determining degradation products of TnBP used in 

nuclear fuel processing. The TnBP content affects the performance of the extracting solvent; therefore, 

determining the diester and monoester content is desired. 

Nagase et al. (2003) used GC-FPD to detect phosphate ester flame retardants in polyurethane foam 

cushions. The detection limits were 0.3–0.9 μg/g. The recoveries from a 0.05 g sample of soft 

polyurethane foam were 80–90%, when the spiked amounts were 0.25–1 μg. The compounds were 

detected from soft polyurethane foam at the level of 0.4–23.3 μg/g. 

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 phosphate ester flame retardants is available. Where 

adequate information is not available, ATSDR, in conjunction with NTP, is required to assure the 

initiation of a program of research designed to determine the health effects (and techniques for developing 

methods to determine such health effects) of phosphate ester flame retardants. 

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 

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PHOSPHATE ESTER FLAME RETARDANTS 234 

7. ANALYTICAL METHODS 

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. In vitro analytical methods have shown to detect TnBP, TPP, TCEP, TCPP, and TBEP in 

bodily fluids using GC-MS (Moller et al. 2004; Jonsson and Nilsson 2003). It is not documented whether 

these methods could be applied to analysis of TiBP or TDCP in bodily fluids. TDCP is the only analyte 

of the selected phosphate esters reported to be analyzed in human tissue and seminal fluid (Hudec et al. 

1981; Lebel and Williams 1983, 1986). There are no specific biomarkers of exposure other than the 

phosphate esters themselves. A data need exists for additional bioanalytical methods for TiBP and 

TDCP. As information becomes available regarding the metabolism of these chemicals in humans, 

appropriate methods need to be developed for the detection and quantification of metabolites in tissues 

and biological fluids. 

Effect. No significant health effects have been reported in humans exposed to the phosphate ester flame 

retardants discussed in this profile in the limited studies available of workers exposed to TDCP or TPP 

(Stauffer Chem Co. 1983; Sutton et al. 1960). Consequently, no associations have been established 

between body burdens of phosphate esters and health effects. More information is needed regarding the 

toxicity and toxicokinetics of these substances to determine whether the existing analytical methods 

reported in Table 7-1 are adequate in selectivity and sensitivity to measure phosphate esters in biological 

materials at levels associated with adverse health effects. 

Methods for Determining Parent Compounds and Degradation Products in Environmental 

Media. GC coupled with various detection methods (MS, FPD, or NPD) provide sufficiently accurate, 

precise, and repeatable methods for determining phosphate ester concentrations in the environment 

(Ishikawa et al. 1985; LeBel et al. 1979; NIOSH 1994a, 1994b; Solbu et al. 2007; USGS 2001; IPCS 

1991a, 1991b). These analytical methods can adequately measure phosphate esters in air, water, soil, and 

sediments at concentrations in the ng/L or ng/m3 range. 

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PHOSPHATE ESTER FLAME RETARDANTS 235 

7. ANALYTICAL METHODS 

7.3.2 Ongoing Studies 

No ongoing studies pertaining to analytical methods for phosphate ester flame retardants were identified 

in a search of the Federal Research Progress database (FEDRIP 2009). 

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PHOSPHATE ESTER FLAME RETARDANTS 237 

8. REGULATIONS, ADVISORIES, AND GUIDELINES
 

MRLs are substance specific estimates, which are intended to serve as screening levels, are used by 

ATSDR health assessors and other responders to identify contaminants and potential health effects that 

may be of concern at hazardous waste sites. 

The international and national regulations, advisories, and guidelines regarding phosphate ester flame 

retardants in air, water, and other media are summarized in Table 8-1. 

ATSDR has derived an intermediate-duration oral MRL of 0.6 mg/kg/day for TCEP based on an 

increased incidence of brain lesions in female Fischer-344 rats dosed by gavage 5 days/week for 16 weeks 

(NTP 1991a). The MRL was derived using benchmark modeling of incidence data for brain lesions in 

female rats. The predicted dose associated with a 10% extra risk (BMD10) for brain lesions was 

143.41 mg/kg/day; the lower 95% confidence limit on this dose (BMDL10) was 85.07 mg/kg/day. An 

uncertainty factor of 100 was used (10 for animal to human extrapolation and 10 for human variability). 

ATSDR has derived a chronic-duration oral MRL of 0.3 mg/kg/day for TCEP based on an increased 

incidence of renal tubule epithelial hyperplasia in female Fischer-344 rats dosed by gavage 5 days/week 

for 2 years (NTP 1991a). The MRL was derived using benchmark modeling of incidence data for renal 

lesions in female rats. The BMD10 for renal lesions was 53.09 mg/kg/day; the BMDL10 was 

36.09 mg/kg/day. An uncertainty factor of 100 was used (10 for animal to human extrapolation and 

10 for human variability). 

ATSDR has derived an acute-duration oral MRL of 1.1 mg/kg/day for TnBP based on decreased body 

weight gain in Wistar rats during pregnancy (Noda et al. 1994). The MRL was derived using benchmark 

modeling of the decrease in body weight gain. The BMD1SD was 130.32 mg/kg/day; the corresponding 

BMDL1SD was 111.47 mg/kg/day. An uncertainty factor of 100 was used (10 for animal to human 

extrapolation and 10 for human variability). 

ATSDR has derived an intermediate-duration oral MRL of 0.02 mg/kg/day for TnBP based on an 

increased incidence of urinary bladder hyperplasia in male Sprague-Dawley rats dosed via the diet for 

10 weeks (Arnold et al. 1997). The MRL was derived using benchmark modeling of incidence data for 

urinary bladder lesions in male rats. The BMD10 for urinary bladder lesions was 3.30 mg/kg/day; the 

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PHOSPHATE ESTER FLAME RETARDANTS 238 

8. REGULATIONS, ADVISORIES, AND GUIDELINES 

Table 8-1. Regulations and Guidelines Applicable to Phosphate Ester Flame 

Retardants
 

Agency Description Information Reference 

INTERNATIONAL 

Guidelines: 

IARC Carcinogenicity classification Group 3a IARC 2009 

Tris-(2-chloroethyl)-phosphate 

WHO Air quality guidelines No WHO 2000 

Drinking water quality guidelines No WHO 2006 

NATIONAL 

Regulations and 

Guidelines: 

a. Air 

ACGIH TLV (8-hour TWA) 

Tributyl phosphate 

Triphenyl phosphate 

2.5 mg/m3 (0.19 ppm) 

3.0 mg/m3 (0.22 ppm) 

ACGIH 2008 

TLV Basis 

Tributyl phosphate Nausea, headache, 

eye and upper 

respiratory irritation 

Triphenyl phosphate Cholinesterase 

inhibitor 

AIHA ERPG values No AIHA 2008 

EPA AEGL values No EPA 2009a 

Hazardous air pollutant No EPA 2009b 

42 USC 7412 

NIOSH REL (10-hour TWA) 

Tributyl phosphate 

Triphenyl phosphate 

2.5 mg/m3 (0.19 ppm) 

3.0 mg/m3 (0.22 ppm) 

NIOSH 2005b 

IDLH 

Tributyl phosphate 

Triphenyl phosphate 

327 mg/m3 (30 ppm) 

1,000 mg/m3 (75 ppm) 

Target organs 

Tributyl phosphate Eyes, skin, and 

respiratory system 

Triphenyl phosphate Blood and peripheral 

nervous system 

OSHA PEL (8-hour TWA) for general industry 

Tributyl phosphate 

Triphenyl phosphate 

5.0 mg/m3 (0.46 ppm) 

3.0 mg/m3 (0.22 ppm) 

OSHA 2009 

29 CFR 1910.1000, 

Table Z-1 

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PHOSPHATE ESTER FLAME RETARDANTS 239 

8. REGULATIONS, ADVISORIES, AND GUIDELINES 

Table 8-1. Regulations and Guidelines Applicable to Phosphate Ester Flame 

Retardants
 

Agency Description Information Reference 

NATIONAL (cont.) 

b. Water 

EPA Drinking water standards and health 

advisories 

No EPA 2006a 

National primary drinking water 

standards 

No EPA 2003 

National recommended water quality 

criteria 

No EPA 2006b 

c. Food 

FDA EAFUSb No FDA 2008 

d. Other 

ACGIH Carcinogenicity classification ACGIH 2008 

Tributyl phosphate No 

Triphenyl phosphate A4c 

EPA Inert ingredients are permitted for use in 

nonfood use pesticide products 

EPA 2009c 

Tributyl phosphate, tributoxyethyl 

phosphate, and triphenyl phosphate 

Yes 

Carcinogenicity classification No IRIS 2009 

RfC No 

RfD No 

Superfund, emergency planning, and 

community right-to-know 

Designated CERCLA hazardous 

substance 

No EPA 2009d 

40 CFR 302.4 

Effective date of toxic chemical 

release reporting 

No EPA 2009e 

40 CFR 372.65 

TSCA chemical lists and reporting 

periods 

Tributyl phosphate, triisobutyl 

phosphate, and tributoxyethyl 

phosphate 

EPA 2009f 

40 CFR 712.30 

Effective date 10/29/1990 

Reporting date 12/27/1990 

TSCA health and safety data reporting 

Tributyl phosphate 

EPA 2009g 

40 CFR 716.120 

Effective date 06/18/1986 

Sunset date 06/18/1996 

Triisobutyl phosphate 

Effective date 10/29/1990 

Sunset date 11/09/1993 

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PHOSPHATE ESTER FLAME RETARDANTS 240 

8. REGULATIONS, ADVISORIES, AND GUIDELINES 

Table 8-1. Regulations and Guidelines Applicable to Phosphate Ester Flame 

Retardants
 

Agency Description Information Reference 

NATIONAL (cont.) 

EPA Tributoxyethyl phosphate 

Effective date 10/29/1990 

Sunset date 12/19/1995 

Triphenyl phosphate 

Effective date 10/04/1982 

Sunset date 10/04/1992 

TSCA chemical lists and reporting EPA 2009f 

periods 40 CFR 712.30 

Tri-(2-chloroisopropyl) phosphate 

and tris-(2-chloroethyl)-phosphate 

Effective date 12/16/1988 

Sunset date 11/09/1993 

Tris(1,3-dichloro-2-propyl) phosphate 

Effective date 12/16/1988 

Sunset date 12/19/1995 

NTP Carcinogenicity classification No data NTP 2005 

a

Group 3: not classifiable as to carcinogenicity to humans

b

The EAFUS list of substances contains ingredients added directly to food that FDA has either approved as food 

additives or listed or affirmed as GRAS.
 c

A4: not classifiable as a human carcinogen
 

ACGIH = American Conference of Governmental Industrial Hygienists; AEGL = acute exposure guideline levels;
 

AIHA = American Industrial Hygiene Association; CERCLA = Comprehensive Environmental Response,
 

Compensation, and Liability Act; CFR = Code of Federal Regulations; EAFUS = Everything Added to Food in the 

United States; EPA = Environmental Protection Agency; ERPG = emergency response planning guidelines;
 

FDA = Food and Drug Administration; GRAS = Generally Recognized As Safe; IARC = International Agency for
 

Research on Cancer; IDLH = immediately dangerous to life or health; IRIS = Integrated Risk Information System;
 

NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicology Program;
 

OSHA = Occupational Safety and Health Administration; PEL = permissible exposure limit; REL = recommended 

exposure limit; RfC = inhalation reference concentration; RfD = oral reference dose; TLV = threshold limit values;
 

TSCA = Toxic Substances Control Act; TWA = time-weighted average; USC = United States Code; WHO = World
 

Health Organization
 

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PHOSPHATE ESTER FLAME RETARDANTS 241 

8. REGULATIONS, ADVISORIES, AND GUIDELINES 

BMDL10 was 1.96 mg/kg/day. An uncertainty factor of 100 was used (10 for animal to human 

extrapolation and 10 for human variability). 

ATSDR has adopted the intermediate-duration oral MRL of 0.02 mg/kg/day for TnBP also as the chronicduration oral MRL for TnBP. A detailed explanation can be found in Section 2.3. 

ATSDR has derived an acute-duration oral MRL of 4.8 mg/kg/day for TBEP based on decreased body 

weight gain in CD rats during gestation days 6–15 (Monsanto Co. 1985b). The MRL was derived using 

benchmark modeling of the decrease in body weight gain. The BMD1SD was 824.97 mg/kg/day; the 

corresponding BMDL1SD was 477.25 mg/kg/day. An uncertainty factor of 100 was used (10 for animal to 

human extrapolation and 10 for human variability). 

ATSDR has derived an intermediate-duration oral MRL of 0.2 mg/kg/day for TBEP based on an 

increased incidence of periportal hepatocyte hypertrophy in male Sprague-Dawley rats dosed via the diet 

for 18 weeks (Reyna and Thacke 1987a). The MRL was derived using benchmark modeling of incidence 

data for hepatocyte vacuolation in male rats. The BMD10 for hepatocyte hypertrophy was 

80.62 mg/kg/day; the BMDL10 was 21.92 mg/kg/day. An uncertainty factor of 100 was used (10 for 

animal to human extrapolation and 10 for human variability). 

ATSDR has derived an intermediate-duration oral MRL of 0.05 mg/kg/day for TDCP based on increased 

absolute kidney weight in male Sprague-Dawley rats dosed via the diet for 12 months (Stauffer Chemical 

Co. 1981a). The MRL was derived using benchmark modeling of the increase in kidney weight. The 

BMD1SD was 13.36 mg/kg/day; the corresponding BMDL1SD was 4.69 mg/kg/day. An uncertainty factor 

of 100 was used (10 for animal to human extrapolation and 10 for human variability). 

ATSDR has derived a chronic-duration oral MRL of 0.02 mg/kg/day for TDCP based on an increased 

incidence of renal tubular epithelial hyperplasia in male Sprague-Dawley rats dosed via the diet for 

2 years (Stauffer Chemical Co. 1981a). The MRL was derived using benchmark modeling of incidence 

data for renal lesions in male rats. The BMD10 for renal tubular hyperplasia was 2.60 mg/kg/day; the 

lower 95% confidence limit on this dose (BMDL10) was 1.94 mg/kg/day. An uncertainty factor of 

100 was used (10 for animal to human extrapolation and 10 for human variability). 

EPA (IRIS 2009) has not established an oral reference dose (RfD) or inhalation reference concentration 

(RfC) for phosphate ester flame retardants. 

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PHOSPHATE ESTER FLAME RETARDANTS 242 

8. REGULATIONS, ADVISORIES, AND GUIDELINES 

The International Agency for Research on Cancer (IARC) has classified TCEP as a Group 3 carcinogen 

(not classifiable as to carcinogenicity to humans) (IARC 2009). The American Conference of 

Governmental Industrial Hygienists (ACGIH) has classified TPP as an A4 carcinogen (not classifiable as 

a human carcinogen) (ACGIH 2008). Neither the National Toxicology Program (NTP) nor the EPA has 

classified the phosphate ester flame retardants discussed in this profile for human carcinogenicity (IRIS 

2009; NTP 2005). 

OSHA has required employers of workers who are occupationally exposed to TnBP and TPP to institute 

engineering controls and work practices to reduce and maintain employee exposure at or below 

permissible exposure limits (PELs) (OSHA 2009). The employer must use engineering and work practice 

controls to reduce exposures to not exceed 5 and 3 mg/m3 at any time for TnBP and TPP, respectively 

(OSHA 2009). 

Under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), TnBP, TBPE, and TPP are 

permitted for use in nonfood pesticide products (EPA 2009c). 

All of the phosphate ester flame retardants subject of this profile are required under Section 4(a) of the 

Toxic Substances Control Act (TSCA) to submit copies of health and safety studies (EPA 2009f). TnBP, 

TiBP, and TBEP are required to report production, use, and exposure-related information on chemical 

substances listed under TSCA (EPA 2009g). 

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PHOSPHATE ESTER FLAME RETARDANTS 243 

9. REFERENCES 

*Abe A, Urano K. 1994. Influence of chemicals commonly found in a water environment on the 

Salmonella mutagenicity test. Sci Total Environ 153(1-2):169-175. 

*ACGIH. 2001. Tributyl phosphate. In: Documentation of the threshold limit values and biological 

exposure indices. Cincinnati, OH: American Conference of Governmental Industrial Hygienists. 

*ACGIH. 2008. Triphenyl phosphate. Threshold limit values for chemical substances and physical 

agents and biological exposure indices. Cincinnati, OH: American Conference of Governmental 

Industrial Hygienists. 

*Adinolfi M. 1985. The development of the human blood-CSF-brain barrier. Dev Med Child Neurol 

27(4):532-537. 

*Adlercreutz H. 1995. Phytoestrogens: Epidemiology and a possible role in cancer protection. Environ 

Health Perspect Suppl 103(7):103-112. 

*Agency for Toxic Substances and Disease Registry. 1989. Decision guide for identifying substancespecific data needs related to toxicological profiles; Notice. Agency for Toxic Substances and Disease 

Registry. Fed Regist 54(174):37618-37634. 

Agency for Toxic Substances and Disease Registry. 1990. Biomarkers of organ damage or dysfunction 

for the renal, hepatobiliary, and immune systems. Subcommittee on Biomarkers of Organ Damage and 

Dysfunction. Atlanta, GA: Agency for Toxic Substances and Disease Registry. 

*Agency for Toxic Substances and Disease Registry. 1997. Toxicological profile for hydraulic fluids. 

Atlanta, GA: Agency for Toxic Substances and Disease Registry. 

http://www.atsdr.cdc.gov/toxprofiles/tp99.pdf. September 09, 2009. 

Ahrens VD, Henion JD, Maylin GA, et al. 1978. A water extractable toxic compound in vinyl upholstery 

fabric. Bull Environ Contam Toxicol 20(3):418-422. 

*AIHA. 2008. Emergency response planning guidelines (ERPG). American Industrial Hygiene 

Association. Fairfax, VA. http://www.aiha.org/1documents/Committees/ERP-erpglevels.pdf. May 19, 

2009. 

+*Akzo Chemicals Inc. 1991. Summary of the meeting between Akzo Chem Inc and US EPA 

concerning the pharmacokinetics tests on tributyl phosphate. Submitted to the U.S. Environmental 

Protection Agency under TSCA Section 4. OTS0534064. EPA 40-9121301. 

Al-Saleh I, Al-Doush I, Echeverria-Quevedo A. 1999. Residues of pesticides in grains locally grown in 

Saudi Arabia. Bull Environ Contam Toxicol 63(4):451-459. 

*Cited in text 

+Cited in supplemental document 

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PHOSPHATE ESTER FLAME RETARDANTS 244 

9. REFERENCES 

*Altman PL, Dittmer DS. 1974. In: Biological handbooks: Biology data book. Vol. III. 2nd ed. 

Bethesda, MD: Federation of American Societies of Experimental Biology. 

*Andersen ME, Clewell HJ, Gargas ML, et al. 1987. Physiologically based pharmacokinetics and the 

risk assessment process for methylene chloride. Toxicol Appl Pharmacol 87(2):185-205. 

*Andersen ME, Krishnan K. 1994. Relating in vitro to in vivo exposures with physiologically based 

tissue dosimetry and tissue response models. In: Salem H, ed. Animal test alternatives: Refinement, 

reduction, and replacement. New York, NY: Marcel Dekker, Inc., 9-25. 

*Anderson C, Wischer D, Schmieder A, et al. 1993. Fate of triphenyl phosphate in soil. Chemosphere 

27(5):869-879. 

*Anderson JA, Grundmann A, Bester K. 2004. Organophosphorus flame retardants and plasticisers in 

surface waters. Sci Total Environ 332:155-166. 

*Andresen J, Bester K. 2006. Elimination of organophosphate ester flame retardants and plasticizers in 

drinking water purification. Water Res 40(3):621-629. 

*Andresen JA, Grundmann A, Bester K. 2004. Organophosphorus flame retardants and plasticisers in 

surface waters. Sci Total Environ 332(1-3):155-166. 

+*Anonymous. 1977. Health and safety data for 4 chemicals with cover letter dated 021089 (sanitized). 

Submitted to the U.S. Environmental Protection Agency under TSCA Section 8D. EPA86-8900001189. 

OTS0516689, p 1-Slide 10-14; p 4-Slide 214, 222, 223; p 5-Slide 271; p 13; Slide814-815 p 15; Slide 

954-984 p 20; Slide 1227, 1253, 1278; p 25. 

+*Arnold LL, Christenson WR, Cano M, et al. 1997. Tributyl phosphate effects on urine and bladder 

epithelium in male Sprague-Dawley rats. Fundam Appl Toxicol 40(2):247-255. 

*Ashford RD. 1994. Ashford's dictionary of industrial chemicals. Properties, production, uses. London, 

England: Wavelength Publications, Ltd., 925-926. 

+*Auletta CS. 1991. A 90-day dietary study of tributyl phosphate in the mouse. Synthetic Organic 

Chemical Manufacturers Association, Inc. Submitted to the U.S. Environmental Protection Agency under 

TSCA Section 4. OTS0534083. 

+*Auletta CS, Kotkoskie LA, Saulog T, et al. 1998b. A dietary oncogenicity study of tributyl phosphate 

in the CD-1 mouse. Toxicology 128(2):135-141. 

+*Auletta CS, Weiner ML, Richter WR. 1998a. A dietary toxicity/oncogenicity study of tributyl 

phosphate in the rat. Toxicology 128(2):125-134. 

*Bacaloni A, Cucci F, Guarino C, et al. 2008. Occurrence of organophosphorus flame retardant and 

plasticizers in three volcanic lakes of central Italy. Environ Sci Technol 42(6):1898-1903. 

*Baldwin DS, Beattie JK, Coleman LM. 1995. Phosphate ester hydrolysis facilitated by mineral phases. 

Environ Sci Technol 29(6):1706-1709. 

*Barnes DG, Dourson M. 1988. Reference dose (RfD): Description and use in health risk assessments. 

Regul Toxicol Pharmacol 8(4):471-486. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

PHOSPHATE ESTER FLAME RETARDANTS 245 

9. REFERENCES 

Barnes KK, Christenson SC, Kolpin DW, et al. 2004. Pharmaceuticals and other organic waste water 

contaminants within a leachate plume downgradient of a municipal landfill. Ground Water Monit Remed 

24:119-126. 

*Barnes KK, Kolpin DW, Furlong ET, et al. 2008. A national reconnaissance of pharmaceuticals and 

other organic wastewater contaminants in the United States 1 groundwater. Sci Total Environ 402(2-

3):192-200. 

*Batt KJ, Healy CE, Kneiss JJ, et al. 1992. Genotoxicity testing of tributyl phosphate. Environ Mol 

Mutagen 19(20):5. 

Bengtsson BE, Tarkpea M, Sletten T, et al. 1986. Bioaccumulation and effects of some technical triaryl 

phosphate products in fish and Nitocra-spinipes. Environ Toxicol Chem 5(9):853-861. 

Benigni R. 1991. QSAR prediction of rodent carcinogenicity for a set of chemicals currently bioassayed 

by the USA National Toxicology Program. Mutagenesis 6(5):423-425. 

Benigni R. 1997. The first US National toxicology program exercise on the prediction of rodent 

carcinogenicity: Definitive results. Mutat Res 387(1):35-45. 

Berdasco N, McCready DI. 2006. Triethyl phosphate, tripropyl phosphate, and tributyl phosphate: Oral 

risk assessment and class based evaluation level. Toxicol Sci 90(1-S):79. 

*Berger GS, ed. 1994. Epidemiology of endometriosis. In: Endometriosis: Modern surgical 

management of endometriosis. New York, NY: Springer-Verlag, 3-7. 

Berne C, Allainmat B, Garcia D. 2005. Tributyl phosphate degradation by Rhodopseudomonas palustris 

and other photosynthetic bacteria. Biotechnol Lett 27(8):561-566. 

Berne C, Montjarret B, Guountti Y, et al. 2004. Tributyl phosphate degradation by Serratia odorifera. 

Biotechnol Lett 26(8):681-686. 

Berne C, Pignol D, Lavergne J, et al. 2007. CYP201A2, a cytochrome P450 from Rhodopseudomonas 

palustris, plays a key role in the biodegradation of tributyl phosphate. Appl Microbiol Biotechnol 

77(1):135-144. 

Bernstein ME. 1984. Agents affecting the male reproductive system: Effects of structure on activity. 

Drug Metab Rev 15:941-996. 

*Blair RM, Fang H, Branham WS, et al. 2000. The estrogen receptor relative binding affinities of 188 

natural and xenochemicals: Structural diversity of ligands. Toxicol Sci 54:138-153. 

*Boethling RS, Cooper JC. 1985. Environmental fate and effects of triaryl and tri-alkyl/aryl phosphate 

esters. Res Rev 94:49-99. 

Bogan BW, Lahner LM, Trbovic V, et al. 2001. Effects of alkylphosphates and nitrous oxide on 

microbial degradation of polycyclic aromatic hydrocarbons. Appl Environ Microbiol 67(5):2139-2144. 

Bondy HF, Field EJ, Worden AN, et al. 1960. A study on the acute toxicity of the tri-aryl phosphates 

used as plasticizers. Br J Ind Med 17:190-200. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

PHOSPHATE ESTER FLAME RETARDANTS 246 

9. REFERENCES 

Brodsky J, Brodesser J, Bauer C, et al. 1997. The environmental fate of six existing chemicals in 

laboratory tests. Chemosphere 34(3):515-538. 

Brooks AL, McDonald KE, Mitchell C, et al. 1996. The combined genotoxic effects of radiation and 

occupational pollutants. Appl Occup Environ Hyg 11(4):410-416. 

*Brusick D, Matheson D, Jagannath DR, et al. 1979. A comparison of the genotoxic properties of 

tris(2,3-dibromopropyl)phosphate and tris(1,3-dichloro-2-propyl)phosphate in a battery of short-term 

bioassays. J Environ Pathol Toxicol 3(1-2):207-226. 

*Burka LT, Sanders JM, Herr DW, et al. 1991. Metabolism of tris(2-chloroethyl) phosphate in rats and 

mice. Drug Metab Dispos 19(2):443-447. 

*Camarasa JG, Serra-Baldrich E. 1992. Allergic contact dermatitis from triphenyl phosphate. Contact 

Dermatitis 26(4):264-265. 

*Carlsen L, Andersen KE, Egsgaard H. 1986. Triphenyl phosphate allergy from spectacle frames. 

Contact Dermatitis 15(5):274-277. 

Carlsson H, Nilsson U, Becker G, et al. 1997. Organophosphate ester flame retardants and plasticizers in 

the indoor environment: Analytical methodology and occurrence. Environ Sci Technol 31(10):2931-

2936. 

*Carlsson H, Nilsson U, Ostman C. 2000. Video display units: An emission source of the contact 

allergenic flame retardant triphenyl phosphate in the indoor environment. Environ Sci Technol 34:3885-

3889. 

*Carrington CD, Lapadula DM, Othman M, et al. 1996. Assessment of the delayed neurotoxicity of 

tributylphosphate, tributoxyethyl phosphate, and dibutylphenyl phosphate. Int J Occup Med Immunol 

Toxicol 5(1):61-68. 

Chambers HW, Casida JE. 1967. Protective activity of nicotinic acid derivatives and their 1-alkyl- 2-

and 1-alkyl-6-pyridones against selected neurotoxic agents. Toxicol Appl Pharmacol 10(1):105-118. 

Chambers JEH. 1969. Protective activity of 1,3-disubstituted 2- and 6-pyridones against selected 

neurotoxic agents. Toxicol Appl Pharmacol 14(2):249-258. 

Chapin RE, Sloane RA. 1997. Reproductive assessment by continuous breeding: Evolving study design 

and summaries of ninety studies. Environ Health Perspect 105(Suppl 1):199-205. 

Chapin RE, Sloane RA, Haseman JK. 1998. Reproductive endpoints in general toxicity studies: Are 

they predictive? Reprod Toxicol 12(4):489-494. 

*Chapman DE, Michener SR, Powis G. 1991. Metabolism of the flame retardant plasticizer tris(2-

chloroethyl)phosphate by human and rat liver preparations. Fundam Appl Toxicol 17(2):215-224. 

*ChemIDplus. 2009. Phosphate flame retardants. ChemIDplus. Bethesda, MD: U.S. National Library 

of Medicine. http://sis.nlm.nih.gov/chemical.html. July 8, 2009. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

PHOSPHATE ESTER FLAME RETARDANTS 247 

9. REFERENCES 

*Clewell HJ, Andersen ME. 1985. Risk assessment extrapolations and physiological modeling. Toxicol 

Ind Health 1(4):111-131. 

*Daft JL. 1982. Identification of aryl alkyl phosphate residues in foods. Bull Environ Contam Toxicol 

29(2):221-227. 

David MD, Seiber JN. 1999a. Accelerated hydrolysis of industrial organophosphates in water and soil 

using sodium perborate. Environ Pollut 105(1):121-128. 

*David MD, Seiber JN. 1999b. Analysis of organophosphate hydraulic fluids in U.S. Air Force base 

soils. Arch Environ Contam Toxicol 36(3):235-241. 

*Davis CS, Richardson RJ. 1980. Organophosphorus compounds. In: Spencer PS, Schaumburg HH, 

eds. Experimental and clinical neurotoxicology. New York, NY: Oxford University Press, 527-544. 

*Degeus H, Zegers BN, Lingeman H, et al. 1994. Determination of trialkyl and triaryl phosphates in 

sediment using microwave extraction and packed-capillary supercritical fluid chromatography. Int J 

Environ Anal Chem 56:119-132. 

*Denniston AD. 1995. Hydraulic Fluids. In: Kirk-Othmer encylcopedia of chemical technology. John 

Wiley & Sons, 1-22. 

http://mrw.interscience.wiley.com/emrw/9780471238966/kirk/article/hydrdenn.a01/current/pdf. June 03, 

2009. 

Dix K, Deterding LJ, Burka LT, et al. 1994. Tris(2-chloroethyl) phosphate pharmacokinetics in the 

Fischer 344 rat: A comparison of conventional methods and in vivo microdialysis coupled with tandem 

mass spectrometry. J Pharm Sci 83(11):1622-1629. 

Dobry A, Keller R. 1957. Vapor pressures of some phosphate and phosphonate esters. J Phys Chem 

61:1448-1449. 

*Dodi A, Verda G. 2001. Improved determination of tributyl phosphate degradation products (monoand dibutyl phosphates) by ion chromatography. J Chromatogr A 920(1-2):275-281. 

Dollahite JW, Pierce KR. 1969. Neurologic disturbances due to triaryl phosphate toxicity. Am J Vet 

Res 30(8):1461-1468. 

+Dow Chemical Co.. 1956. Results of range finding toxicological tests on tributyl phosphate with cover 

letter and attachments (sanitized). Submitted to the U.S. Environmental Protection Agency under TSCA 

Section 8D. OTS0530109. 

*Dybing E, Soederlund E, Holme J, et al. 1983. Comparative genotoxicity studies of the flame 

retardants tris-bp and tris-cp. [Abstract]. Toxicol Lett 18(Suppl 1):58. 

+*Eastman Kodak Co. 1968. Toxicity and health hazard study for tri-n-butyl phosphate with cover letter 

dated 081186. Eastman Kodak Company. Submitted to the U.S. Environmental Protection Agency under 

TSCA Section 8D. OTS0510265. EPA86860000118. 

+Eastman Kodak Co. 1987. Letter dated 03/11/87 from Eastman Kodak Co. Regarding toxicity report 

of tributyl phosphate. Eastman Kodak Company. Submitted to the U.S. Environmental Protection 

Agency under TSCA Section 4. OTS0523050. EPA40-8721015. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

 

 

 

 

PHOSPHATE ESTER FLAME RETARDANTS 248 

9. REFERENCES 

+*Eastman Kodak Co. 1990. Letter from Eastman Kodak Company to US EPA submitting enclosed 

health and safety studies on triiosbutyl phosphate with attachments. Eastman Kodak Company. 

Submitted to the U.S. Environmental Protection Agency under TSCA Section 8D. OTS0528335. 

EPA86-910000041. 

+EF Houghton & Co. 1996. Product data sheet from EF Houghton & Co. containing acute toxicity 

values for four triaryl phosphate esters. EF Houghton & Company. Submitted to the U.S. Environmental 

Protection Agency under TSCA Section 4. OTS0519194. 

+*EI Dupont Denemours. 1953a. Toxicity of tributyl phosphate, "Alkaterge" c, and "Foamex" with 

cover letter dated 070286. Submitted to the U.S. Environmental Protection Agency under TSCA Section 

8D. OTS0510228. EPA868600078. 

+EI Dupont Denemours. 1953b. Toxicity of tributyl phosphate, Alkaterge C, and Foamex with cover 

letter (sanitized). Submitted to the U.S. Environmental Protection Agency under TSCA Section 8D. 

OTS0530140. 

+*Eldefrawi AT, Mansour NA, Brattsten LB, et al. 1977. Further toxicologic studies with commercial 

and candidate flame retardant chemicals part 2. Bull Environ Contam Toxicol 17(6):720-726. 

*EPA. 1979. Assessment of the need for limitation on triaryl and trialkyl/aryl phosphates. Draft final 

report. Washington, DC: Environmental Protection Agency. 

*EPA. 1990. Interim methods for development of inhalation reference concentrations. Washington, DC: 

U.S. Environmental Protection Agency, Office of Health and Environmental Assessment, Office of 

Research and Development. EPA600890066A. PB90238890. 

*EPA. 1997. Special report on environmental endocrine disruption: An effects assessment and analysis. 

Washington, DC: U.S. Environmental Protection Agency, Risk Assessment Forum. 

*EPA. 1998. Automated Form R for Windows: User’s guide (RY97). Washington, DC: U.S. 

Environmental Protection Agency, Office of Pollution Prevention and Toxics. 

*EPA. 2000. Benchmark dose technical guidance document. Washington, DC: U. S. Environmental 

Protection Agency, Risk Assessment Forum. EPA630R00001. 

*EPA. 2003. National primary drinking water regulations. Washington, DC: Office of Ground Water and 

Drinking Water, U.S. Environmental Protection Agency. EPA816F03016. 

http://www.epa.gov/safewater/contaminants/index.html. May 19, 2009. 

*EPA. 2005. Toxic chemical release inventory reporting forms and instructions: Revised 2004 version. 

Section 313 of the Emergency Planning and Community Right-to-Know Act (Title III of the Superfund 

Amendments and Reauthorization Act of 1986). U.S. Environmental Protection Agency, Office of 

Environmental Information. EPA260B05001. 

*EPA. 2006a. Drinking water standards and health advisories. Washington, DC: Office of Water, U.S. 

Environmental Protection Agency. EPA822R04005. http://epa.gov/waterscience/criteria/drinking/. May 

19, 2009. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

PHOSPHATE ESTER FLAME RETARDANTS 249 

9. REFERENCES 

*EPA. 2006b. National recommended water quality criteria. Washington, DC: Office of Water, Office 

of Science and Technology, U.S. Environmental Protection Agency. 

http://www.epa.gov/waterscience/criteria/wqcriteria.html. May 11, 2009. 

*EPA. 2006c. Inventory update reporting. Non-confidential 2006 IUR records by company. U.S. 

Environmental Protection Agency. http://cfpub.epa.gov/iursearch/index.cfm?s=comp. June 4, 2009. 

*EPA. 2009a. Acute exposure guideline levels (AEGLs). Washington, DC: Office of Pollution 

Prevention and Toxics, U.S. Environmental Protection Agency. http://www.epa.gov/oppt/aegl/. May 19, 

2009. 

*EPA. 2009b. Hazardous air pollutants. Clean Air Act. Washington, DC: U.S. Environmental 

Protection Agency. United States Code. 42 USC 7412. http://www.epa.gov/ttn/atw/orig189.html. May 

19, 2009. 

*EPA. 2009c. Inert pesticide ingredients in pesticide products. Washington, DC: U.S. Environmental 

Protection Agency. http://www.epa.gov/opprd001/inerts/lists.html. May 19, 2009. 

*EPA. 2009d. Superfund, emergency planning, and community right-to-know programs. Designation, 

reportable quantities, and notifications. U.S. Environmental Protection Agency. Code of Federal 

Regulations. 40 CFR 302.4. http://www.epa.gov/lawsregs/search/40cfr.html. May 20, 2009. 

*EPA. 2009e. Superfund, emergency planning, and community right-to-know programs. Toxic 

chemical release reporting. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 

CFR 372.65. http://www.epa.gov/lawsregs/search/40cfr.html. May 11, 2009. 

*EPA. 2009f. Toxic substances control act. Chemical lists and reporting periods. U.S. Environmental 

Protection Agency. Code of Federal Regulations. 40 CFR 712.30. 

http://www.epa.gov/lawsregs/search/40cfr.html. May 20, 2009. 

*EPA. 2009g. Toxic substances control act. Health and safety data reporting. U.S. Environmental 

Protection Agency. Code of Federal Regulations. 40 CFR 716.120. 

http://www.epa.gov/lawsregs/search/40cfr.html. May 20, 2009. 

*EPA. 2009h. Estimation program interface (EPI) suite. U.S. Environmental Protection Agency. 

http://www.epa.gov/oppt/exposure/pubs/episuite.htm. July 21, 2009. 

Eriksson P, Johansson N, Viberg H, et al. 2004. Comparative developmental neurotoxicity of flame 

retardants, polybrominated flame retardants and organophosphorus compounds in mice. Organohalogen 

Compounds 66:3119-3121. 

*Fang H, Tong W, Branham WS, et al. 2003. Study of 202 natural, synthetic, and environmental 

chemicals for binding to the androgen receptor. Chem Res Toxicol 16(10):1338-1358. 

Fautz R, Miltenburger HG. 1994. Influence of organophosphorus compounds on different cellular 

immune functions in vitro. Toxicol In Vitro 8(5):1027-1031. 

*FDA. 2006. Total diet study: Market baskets 1991-3 through 2003-4. U.S. Food and Drug 

Administration. Center for Food Safety & Applied Nutrition. 

http://vm.cfsan.fda.gov/~acrobat/TDS1byfd.pdf. June 24, 2009. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

 

 

PHOSPHATE ESTER FLAME RETARDANTS 250 

9. REFERENCES 

*FDA. 2008. Everything added to food in the United States (EAFUS). Washington, DC: U.S. Food and 

Drug Administration. http://vm.cfsan.fda.gov/~dms.eafus.html. May 19, 2009. 

*FEDRIP. 2009. Federal Research in Progress database. Springfield, VA: National Technical 

Information Service. 

*Fee DC, Gard DR, Yang CD. 2006. Phosphorus compounds. In: Kirk-Othmer encyclopedia of 

chemical technology. John Wiley & Sons, 1-73. 

http://mrw.interscience.wiley.com/emrw/9780471238966/kirk/article/phosfee.a01/current/pdf. June 03, 

2009. 

*Fink U, Hajduk R, Mori H, et al. 2008. Flame retardants. SRI Consulting SCUP Report Flame 

Retardants. http://www.novapdf.com/. April 27, 2009. 

*Fiserova-Bergerova V, Pierce JT, Droz PO. 1990. Dermal absorption potential of industrial chemicals: 

Criteria for skin notation. Am J Ind Med 17(5):617-636. 

*Flowers LJ, Garrett SL. 1992. Mouse micronucleus study of MCS-2518 (final report) with cover letter 

dated 030493. Monsanto Company. Submitted to the U.S. Environmental Protection Agency under 

TSCA Section 8D. EPA86-930000153. OTS0538147. 

+*FMC. 1976. Acute inhalation study in rats with kronitex TBP with cover letter dated 0080886. 

Submitted to the U.S. Environmental Protection Agency under TSCA Section 8D. OTS0510262. 

EPA86860000114. 

+*FMC. 1979. Dermal corrosion in rabbits with TBP with cover letter dated 080886. Submitted to the 

U.S. Environmental Protection Agency under TSCA Section 8D. OTS0510257. EPA868600000109. 

+*FMC. 1981. Rabbit skin irritation testing on tributyl phosphate with cover letter 080886. Submitted 

to the U.S. Environmental Protection Agency under TSCA Section 8D. OTS0510255. 

EPA868600000107. 

+*FMC. 1982. Acute toxicity screening tests triphenyl phosphate (commercial non-FMC product) with 

cover letter. Submitted to the U.S. Environmental Protection Agency under TSCA Section 8D. 

OTS206297. EPA878213753. 

+*FMC. 1985a. Thirteen week feeding study of tributyl phosphate in rats. FMC Toxicology Laboratory. 

Submitted to the U.S. Environmental Protection Agency under TSCA Section 4. OTS0523056. 

FMC. 1985b. Thirteen week feeding study of tributyl phosphate in rats final report. Volume 2. 

Submitted to the U.S. Environmental Protection Agency under TSCA Section FYI. OTS02850380. 

*Focazio MJ, Kolpin DW, Barnes KK, et al. 2008. A national reconnaissance for pharmaceuticals and 

other organic wastewater contaminants in the United States. II. Untreated drinking water sources. Sci 

Total Environ 402(2-3):201-216. 

*Föllmann W, Wober J. 2006. Investigation of cytotoxic, genotoxic, mutagenic, and estrogenic effects 

of the flame retardants tris-(2-chloroethyl)-phosphate (TCEP) and tris-(2-chloropropyl)-phosphate 

(TCPP) in vitro. Toxicol Lett 161:124-134. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

PHOSPHATE ESTER FLAME RETARDANTS 251 

9. REFERENCES 

*Fomon SJ. 1966. Body composition of the infant: Part 1: The male reference infant. In: Faulkner F, 

ed. Human development. Philadelphia, PA: WB Saunders, 239-246. 

*Fomon SJ, Haschke F, Ziegler EE, et al. 1982. Body composition of reference children from birth to 

age 10 years. Am J Clin Nutr 35(Suppl 5):1169-1175. 

Freudenthal RI, Henrich RT. 1999. A subchronic toxicity study of Fyrol PCF in Sprague-Dawley rats. 

Int J Toxicol 18(3):173-176. 

Freudenthal RI, Henrich RT. 2000. Chronic toxicity and carcinogenic potential of tris-(1,3-dichloro-2-

propyl) phosphate in Sprague-Dawley rat. Int J Toxicol 19(2):119-125. 

*Fries E, Puttmann W. 2001. Occurrence of organophosphate esters in surface water and ground water 

in Germany. J Environ Monit 3(6):621-626. 

*Fries E, Puttmann W. 2003. Monitoring of the three organophosphate esters TBP, TCEP and TBEP in 

river water and ground water (Oder, Germany). J Environ Monit 5(2):346-352. 

*Fukushima M, Kawai S, Yamaguchi Y. 1992. Behavior of organophosphoric acid triesters in Japanese 

riverine and coastal environment. Water Sci Technol 25(11):271-278. 

*Galloway SM, Armstrong MJ, Reuben C, et al. 1987. Chromosome aberrations and sister chromatid 

exchanges in Chinese hamster ovary cells: Evaluations of 108 chemicals. Environ Mol Mutagen 

10(Suppl 10):1-175. 

*Gann RG, Gilman JW. 2003. Flame retardants: an overview. In: Kirk-Othmer encyclopedia of 

chemical technology. John Wiley & Sons, 447-454. 

http://mrw.interscience.wiley.com/emrw/9780471238966/kirk/article/overgann.a01/current/pdf. June 03, 

2009. 

Gant DB, Eldefrawi ME, Eldefrawi AT. 1987. Action of organophosphates on GABAA receptor and 

voltage-dependent chloride channels. Fundam Appl Toxicol 9(4):698-704. 

*Garcia M, Rodriguez I, Cela R. 2007. Microwave-assisted extraction of organophosphate flame 

retardants and plasticizers from indoor dust samples. J Chromatogr A 1152(1-2):280-286. 

*Gard DR. 2005. Phosphate acids and phosphates. In: Kirk-Other encyclopedia of chemical 

technology. John Wiley & Sons, 1-56. 

http://mrw.interscience.wiley.com/emrw/9780471238966/kirk/article/phosgard.a01/current/pdf. June 03, 

2009. 

*Gartrell MJ, Craun JC, Podrebarac DS, et al. 1985. Pesticides, selected elements, and other chemicals 

in infant and toddler diet samples, October 1979-September 1980. J Assoc Off Anal Chem 68:1163-

1183. 

Gartrell MJ, Craun JC, Podrebarac DS, et al. 1986. Pesticides, selected elements, and other chemicals in 

adult total diet samples, October 1980-March 1982. J Assoc Off Anal Chem 69:146-161. 

General Electric Co. 1985. A clinical study of industrial workers exposed to organophosphate esters and 

a comparison group including cover letter dated 3/21/85. General Electric Company. Submitted to the 

U.S. Environmental Protection Agency under TSCA Section 4. EPA40-8542544. OTS0518443. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

PHOSPHATE ESTER FLAME RETARDANTS 252 

9. REFERENCES 

General Electric Co. 1988. Morbidity study of workers in a resin production processing plant with cover 

letter dated 020388. General Electric Company. Submitted to the U.S. Environmental Protection Agency 

under TSCA Section 8D. 86-880000129. OTS0514019. 

Gerhart JM, Tyl RW, Myers CB, et al. 1993. Two generation study of dietary tributyl phosphate (TBP) 

in CD rats. Toxicologist 13(1):76. 

*Gilbert J, Shepherd MJ, Wallwork MA, et al. 1986. A survey of trialkyl and triaryl phosphates in 

United Kingdom total diet samples. Food Addit Contam 3(2):113-122. 

*Giwercman A, Carlsen E, Keiding N, et al. 1993. Evidence for increasing incidence of abnormalities of 

the human testis: A review. Environ Health Perspect 101(Supp 2):65-71. 

*Gold MD, Blum A, Ames BN. 1978. Another flame retardant, tris-(1,3-dichloro-2-propyl)phosphate, 

and its expected metabolites are mutagens. Science 200:785-787. 

*Gomez-Belinchon JI, Grimalt JO, Albaiges J. 1988. Analysis and persistence of tributyl phosphates in 

riverine and marine coastal waters. Chemosphere 17(11):2189-2198. 

Granzow A. 1978. Flame retardation by phosphorus compounds. Acc Chem Res 11(5):177-183. 

*Green J. 1992. A review of phosphorus-containing flame retardants. J Fire Sci 10(6):470-487. 

*Gunderson EL. 1988. FDA total diet study, April 1982-April 1984, dietary intakes of pesticides, 

selected elements and other chemicals. J AOAC Int 71:1200-1209. 

*Gunderson EL. 1995a. FDA total diet study, July 1986-April 1991, dietary intakes of pesticides, 

selected elements, and other chemicals. J AOAC Int 78(6):1353-1363. 

*Gunderson EL. 1995b. Dietary intake of pesticides, selected elements, and other chemicals: FDA total 

diet study, June 1984-April 1986. J AOAC Int 78(4):910-921. 

*Guzelian PS, Henry CJ, Olin SS. 1992. In: Similarities and differences between children and adults: 

Implications for risk assessment. Washington, DC: International Life Sciences and Press Institute Press. 

*Haraguchi K, Yamashita T, Shigemori N. 1985. Sampling and analysis of phosphoric acid triesters in 

ambient air. Taiki Osen Gakkaishi 20:407-415. 

+*Hardin BD, Schuler RL, Burg JR, et al. 1987. Evaluation of 60 chemicals in a preliminary 

developmental toxicity test. Teratog Carcinog Mutagen 7:29-48. 

*Hartley GS. 1959. Hydrolysis and phosphoric esters and related compounds. Chemical Society 

(London) Special Publication 8:33-45. 

*Hartmann PC, Burgi D, Giger W. 2004. Organophosphate flame retardants and plasticizers in indoor 

air. Chemosphere 57(8):781-787. 

*Haworth S, Lawlor T, Mortelmans K, et al. 1983. Salmonella mutagenicity test results for 250 

chemicals. Environ Mutagen 5(Suppl 1):3-142. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

PHOSPHATE ESTER FLAME RETARDANTS 253 

9. REFERENCES 

*HazDat. 2007. Phosphate ester flame retardants. HazDat Database. ATSDR’s Hazardous Substance 

Release and Health Effects Database. Atlanta, GA: Agency for Toxic substances and Disease Registry. 

+*Healy CE, Beyrouty PC, Broxup BR. 1995. Acute and subchronic neurotoxicity studies with tri-Nbutyl phosphate in adult Sprague-Dawley rats. Am Ind Hyg Assoc J 56(4):349-355. 

Henschler D, Schmuck G, Van Aerssen M, et al. 1992. The inhibitory effect of neuropathic 

organophosphate esters on neurite outgrowth in cell cultures: A basis for screening for delayed 

neurotoxicity. Toxicol In Vitro 6(4):327-335. 

*Herr DW, Sanders JM, Matthews HB. 1991. Brain distribution and fate of tris(2-chloroethyl) phosphate 

in Fischer 344 rats. Drug Metab Dispos 19(2):436-442. 

Hicke K, Thiemann W. 1987. The decomposition of selected phosphoric acid esters by UV radiation. 

Vom Wasser 69:85-93. 

Hinton DM, Jessop JJ, Arnold A, et al. 1987. Evaluation of immunotoxicity in a subchronic feeding 

study of triphenyl phosphate. Toxicol Ind Health 3(1):71-90. 

+*Hinton DM, Jessop JJ, Arnold A, et al. 1996. Evaluation of immunotoxicity in a subchronic feeding 

study of triphenyl phosphate. Int J Occup Med Immunol Toxicol 5(1):43-60. 

*Hoel DG, Davis DL, Miller AB, et al. 1992. Trends in cancer mortality in 15 industrialized countries, 

1969-1986. J Natl Cancer Inst 84(5):313-320. 

*Honkakoski P, Palvimo JJ, Penttila L, et al. 2004. Effects of triaryl phosphates on mouse and human 

nuclear receptors. Biochem Pharmacol 67(1):97-106. 

*Howard PH, Deo PG. 1979. Degradation of aryl phosphates in aquatic environments. Bull Environ 

Contam Toxicol 22(3):337-344. 

*HSDB. 2009. Phosphate ester flame retardants. Hazardous Substances Data Bank. National Library of 

Medicine. http://toxnet.nlm.nih.gov. 

*Hudec T, Thean J, Kuehl D, et al. 1981. Tris(dichloropropyl)phosphate, a mutagenic flame retardant: 

Frequent occurrence in human seminal plasma. Science 211(4485):951-952. 

*Hughes MF, Edwards BC, Mitchell CT, et al. 2001. In vitro dermal absorption of flame retardant 

chemicals. Food Chem Toxicol 39(12):1263-1270. 

*Hutter HP, Moshammer H, Wallner P, et al. 2006. Health complaints and annoyances after moving into 

a new office building: A multidisciplinary approach including analysis of questionnaires, air and house 

dust samples. Int J Hyg Environ Health 209(1):65-68. 

IARC. 1990. Tris(2-chloroethyl) phosphate. In: IARC monographs on the evaluation of carcinogenic 

risks to humans. Vol. 48. Lyon, France: International Agency for Research on Cancer, 109-120. 

*IARC. 1999. Tris(2-chloroethyl) phosphate. In: IARC monographs on the evaluation of carcinogenic 

risks to humans. Vol. 71 1999/09/07 ed. Lyon, France: International Agency for Research on Cancer, 

1543-1548. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

PHOSPHATE ESTER FLAME RETARDANTS 254 

9. REFERENCES 

*IARC. 2009. Agents reviewed by the IARC monographs. Volumes 1-99. Lyon, France: International 

Agency for Research on Cancer. http://monographs .iarc.fr/ENG/Classification/index.php. May 11, 

2009. 

*Ingerowski G, Friedle A, Thumulla J. 2001. Chlorinated ethyl and isopropyl phosphoric acid triesters 

in the indoor environment--an inter-laboratory exposure study. Indoor Air 11(3):145-149. 

*IPCS. 1991a. Tri-n-butyl phosphate. Environmental Health Criteria 112. International Programme on 

Chemical Safety. http://www.inchem.org/documents/ehc/ehc/ehc112.htm. April 23, 2009. 

*IPCS. 1991b. Triphenyl phosphate. Environmental Health Criteria 111. International Programme on 

Chemical Safety. http://www.inchem.org/documents/ehc/ehc/ehc111.htm. April 13, 2009. 

*IPCS. 1997. Flame retardants: A general introduction. Environmental Health Criteria 1997. 

International Programme on Chemical Safety. http://www.inchem.org/documents/ehc/ehc/ehc192.htm. 

June 4, 2009. 

*IPCS. 1998. Flame retardants: Tris(Chloropropyl) phosphate and tris(2-chloreothyl) phosphate. 

Environmental Health Criteria 209. International Programme on Chemical Safety. 

http://www.inchem.org/documents/ehc/ehc/ehc209.htm. April 13, 2009. 

*IPCS. 2000a. Tris(1-chloro-2-propyl)phosphate. Screening Information Data Set (SIDS) for high 

production volume chemicals. International Programme on Chemical Safety. 

http://www.inchem.org/documents/sids/sids/13674845.pdf. April 28, 2009. 

*IPCS. 2000b. Flame retardants: Tris(2-butoxyethyl) phosphate, tris (2-ethylehexyl) phosphate and 

tetrakis (hydroxymethyl) phosphonium salts. Environmental Health Criteria 218. International 

Programme on Chemical Safety. http://www.inchem.org/documents/ehc/ehc/ehc218.htm. April 13, 

2009. 

*IPCS. 2004. Tributyl phosphate. Screening Information Data Set (SIDS) for high production volume 

chemicals. International Programme on Chemical Safety. 

http://www.inchem.org/documents/sids/sids/126-73-8.pdf. April 28, 2009. 

IPCS. 2005. Trimethyl phosphate. Screening Information Data Set (SIDS) for high production volume 

chemicals. International Programme on Chemical Safety. 

http://www.inchem.org/documents/sids/sids/512561.pdf. April 28, 2009. 

*IPCS. 2006. Triphenyl phosphate. Screening Information Data Set (SIDS) for high production volume 

chemicals. International Programme on Chemical Safety. 

http://www.inchem.org/documents/sids/sids/115866.pdf. June 3, 2009. 

*IRIS. 2009. Integrated Risk Information System. Washington, DC: U.S. Environmental Protection 

Agency. http://www.epa.gov/iris/subst/index.html. May 11, 2009. 

*Ishikawa S, Baba K. 1988. Reaction of organic phosphate esters with chlorine in aqueous solution. 

Bull Environ Contam Toxicol 41(1):143-150. 

*Ishikawa S, Taketomi M, Shinohara R. 1985. Determination of trialkyl and triaryl phosphates in 

environmental samples. Water Res 19(1):119-125. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

PHOSPHATE ESTER FLAME RETARDANTS 255 

9. REFERENCES 

*Ishikawa S, Uchimura Y, Baba K, et al. 1992. Photochemical behavior of organic phosphate esters in 

aqueous solution irradiated with a mercury lamp. Bull Environ Contam Toxicol 49:368-374. 

*Jackson J, Sutton R. 2008. Sources of endocrine-disrupting chemicals in urban wastewater, Oakland, 

CA. Sci Total Environ 405(1-3):153-160. 

+*Johannsen FR, Wright PL, Gordon DE, et al. 1977. Evaluation of delayed neurotoxicity and doseresponse relationships of phosphate esters in the adult hen. Toxicol Appl Pharmacol 41(2):291-304. 

*Johanson CE. 1980. Permeability and vascularity of the developing brain: Cerebellum vs. cerebral 

cortex. Brain Res 190(1):3-16. 

*Jonsson OB, Nilsson UL. 2003. Miniaturized dynamic liquid-liquid extraction of organophosphate 

triesters from blood plasma using the hollow fibre-based XT-tube extractor. Anal Bioanal Chem 

377(1):182-188. 

*Katagi T. 2002. Abiotic hydrolysis of pesticides in the aquatic environment. Rev Environ Contam 

Toxicol 175:79-261. 

*Kawagoshi Y, Nakamura S, Fukunaga I. 2002. Degradation of organophosphoric esters in leachate 

from a sea-based solid waste disposal site. Chemosphere 48(2):219-225. 

Kawamura K, Kaplan IR. 1983. Organic compounds in the rainwater of Los Angeles. Environ Sci 

Technol 17:497-501. 

+*Kawasaki H, et al. 1982. Studies on the toxicity of insecticides and food additives in pregnant rats-(5) 

foetal toxicity of tris-(chloropropyl) phosphate. Chemical Manufacturers Association. Submitted to the 

U.S. Environmental Protection Agency under TSCA Section 8D. EPA86-950000008. OTS0557521. 

*+Kawashima K, Tanaka S, Nakaura S, et al. 1983a. Effect of oral administration of tris(2-

chloroethyl)phosphate to pregnant rats on prenatal and postnatal developments. Eisei Shikenjo Hokoku 

101:55-61. 

Kawashima K, Tanaka S, Nakaura S, et al. 1983b. Effect of phosphoric acid tri-esters flame retardants 

on the prenatal and postnatal development of rats. J Toxicol Sci 8:339. 

*Kelly PF. 2006. Phosphorus: Inorganic chemistry. In: Encyclopedia of inorganic chemistry. John 

Wiley & Sons, 1-21. 

http://mrw.interscience.wiley.com/emrw/9780470862100/eic/article/ia185/current/pdf. June 4, 2009. 

*Kenaga EE, Goring CAI. 1980. Relationship between water solubility, soil, sorption, octanol-water 

partitioning, and concentration of chemicals in biota. In: Aquatic toxicology. Philadelphia, PA: 

American Society for Testing and Materials, 78-115. 

Ketelaar JAA, Gersmann HR. 1958. Chemical studies on insecticides VI: The rate of hydrolysis of 

some phosphorous acid esters. Recueil 77:973-981. 

Kim SD, Cho J, Kim IS, et al. 2007. Occurrence and removal of pharmaceuticals and endocrine 

disruptors in South Korean surface, drinking, and waste waters. Water Res 41(5):1013-1021. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

 

PHOSPHATE ESTER FLAME RETARDANTS 256 

9. REFERENCES 

Kitos PA, Suntornwat O. 1992. Teratogenic effects of organophosphorus compounds. In: Chambers JE, 

Levi PE, eds. Organophosphates: Chemistry, fate, and effects. San Diego, CA: Academic Press, 387-

417. 

*Kolpin DW, Furlong ET, Meyer MT, et al. 2002. Pharmaceuticals, hormones, and other organic 

wastewater contaminants in U.S. streams, 1999-2000: A national reconnaissance. Environ Sci Technol 

36:1202-1211. 

*Komori M, Nishio K, Kitada M, et al. 1990. Fetus-specific expression of a form of cytochrome P-450 

in human livers. Biochemistry 29(18):4430-4433. 

+*Komsta E, Secours VE, Chu I, et al. 1989. Short-term toxicity of nine industrial chemicals. Bull 

Environ Contam Toxicol 43(1):87-94. 

Krishnan K, Andersen ME. 1994. Physiologically based pharmacokinetic modeling in toxicology. In: 

Hayes AW, ed. Principles and methods of toxicology. 3rd ed. New York, NY: Raven Press, Ltd., 149-

-188. 

*Krishnan K, Anderson ME, Clewell HJ, et al. 1994. Physiologically based pharmacokinetic modeling 

of chemical mixtures. In: Yang RSH, ed. Toxicology of chemical mixtures. Case studies, mechanisms, 

and novel approaches. San Diego, CA: Academic Press, 399-437. 

+*Laham S, Broxup B, Long G. 1985a. Induction of urinary bladder hyperplasia in Sprague-Dawley rats 

orally administered tri-n-butyl phosphate. Arch Environ Health 40(6):301-306. 

Laham S, Broxup BR, Long GW. 1985c. Subchronic oral toxicity of tributoxyethyl phosphate in the 

Sprague-Dawley rat. Arch Environ Health 40(1):12-17. 

+*Laham S, Long G, Broxup B. 1984b. Subacute oral toxicity of tri-n-butyl phosphate in the SpragueDawley rat. J Appl Toxicol 4(3):150-154. 

+*Laham S, Szabo J, Long G. 1983. Effects of tri-n-butyl phosphate on the peripheral nervous system of 

the Sprague-Dawley rat. Drug Chem Toxicol 6(4):363-377. 

Laham S, Szabo J, Long G. 1984a. Short-term neurotoxicity studies on tributoxyethyl phosphate orally 

administered to Sprague-Dawley rats. Chemosphere 13(7):801-812. 

+*Laham S, Szabo J, Long G, et al. 1985b. Dose-response toxicity studies on tributoxyethyl phosphate 

orally administered to Sprague-Dawley rats. Am Ind Hyg Assoc J 46(8):442-448. 

*Lamouroux C, Virelizier H, Moulin C, et al. 2000. Direct determination of dibutyl and monobutyl 

phosphate in a tributyl phosphate/nitric aqueous-phase system by electrospray mass spectrometry. Anal 

Chem 72(6):1186-1191. 

*Landahl HD, Tracewell TN, Lassen WH. 1951. On the retention of air-borne particulates in the human 

lung: II. Arch Ind Hyg Occup Med 3(4):359-366. 

*Landahl HD, Tracewell TN, Lassen WH. 1952. Retention of air-borne particulates in the human lung: 

III. Arch Ind Hyg Occup Med 6(6):508-511. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

PHOSPHATE ESTER FLAME RETARDANTS 257 

9. REFERENCES 

*LANXESS. 2005. Technical datasheets. Triisobutyl phosphate. LANXESS Corporation. 

http://www.phosphorous-chemicals.com/P/download/Phosphorchemikalien_e/TiBP_e.pdf. June 23, 

2009. 

*Lebel G. L, Williams DT. 1983. Determination of organic phosphate triesters in human adipose tissue. 

Journal of the Association of Official Analytical Chemists 66(3):691-699. 

*LeBel GL, Williams DT. 1986. Levels of triaryl phosphates in human adipose tissue from eastern 

Ontario. Bull Environ Contam Toxicol 37(1):41-46. 

*LeBel GL, Williams DT, Berard D. 1989. Triarylalkyl phosphate residues in human adipose autopsy 

samples from six Ontario municipalities. Bull Environ Contam Toxicol 43(2):225-230. 

*LeBel GL, Williams DT, Griffith G, et al. 1979. Isolation and concentration of organophosphorus 

pesticides from drinking water at the ng/L level, using macroreticular resin. J Assoc Off Anal Chem 

62(2):241-249. 

*Lee CJ, Rasmussen TJ. 2006. Occurrence of organic wastewater compounds in effluent-dominated 

streams in northeastern Kansas. Sci Total Environ 371(1-3):258-269. 

Leeder JS, Kearns GL. 1997. Pharmacogenetics in pediatrics: Implications for practice. Pediatr Clin 

North Am 44(1):55-77. 

*Leung H. 1993. Physiologically-based pharmacokinetic modelling. In: Ballantyne B, Marrs T, Turner 

P, eds. General and applied toxicology. Vol. 1. New York, NY: Stockton Press, 153-164. 

*Lewis RJ. 2000. Sax's dangerous properties of industrial materials. 10th ed. New York, NY: John 

Wiley & Sons, Inc., 2131, 3622. 

*Lewis, RJ. 2007. Hawley’s condensed chemical dictionary. 15th ed. New York, NY: John Wiley & 

Sons, 1261, 1262, 1286, 1288. 

*Lide, DR. 2008. CRC handbook of chemistry and physics. 88th ed. Boca Raton, FL: CRC Press, 3-

502. 

*Livingston AL. 1978. Forage plant estrogens. J Toxicol Environ Health 4(2-3):301-324. 

Lombardo P, Egry IJ. 1979. Identification and gas-liquid chromatographic determination of aryl 

phosphate residues in environmental samples. J Assoc Off Anal Chem 62:47-51. 

*Lorenz W, Bahadir M. 1993. Recycling of flame retardants containing printed circuits: A study of the 

possible formation of polyhalogenated dibenzodioxins/-furans. Chemosphere 26:2221-2229. 

Lynn RK, Wong K, Dickinson RG, et al. 1980. Diester metabolites of the flame retardant chemicals, 

tris(1,3-dichloro-2-propyl)phosphate and tris(2,3-dibromopropyl) phosphate in the rat: Identification and 

quantification. Res Commun Chem Pathol Pharmacol 28(2):351-360. 

*Lynn RK, Wong K, Garve-Gould C, et al. 1981. Disposition of the flame retardant, tris(1,3-dichloro-2-

propyl) phosphate, in the rat. Drug Metab Dispos 9(5):434-441. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

 

PHOSPHATE ESTER FLAME RETARDANTS 258 

9. REFERENCES 

*Mack AG. 2004. Flame retardants, halogenated. In: Kirk-Othmer encyclopedia of chemical 

technology. John Wiley & Sons, 454-483. 

http://mrw.interscience.wiley.com/emrw/9780471238966/kirk/article/halopett.a01/current/pdf. June 03, 

2009. 

+*MacKellar DG. 1976. Acute toxicity screening tests for Kronitex TBP with cover letter dated 080886. 

Submitted to the U.S. Environmental Protection Agency under TSCA Section 8D. OTS0510263. 

EPA868600000116. 

Majeska JB, Matheson DW. 1983. Quantitative estimate of mutagenicity of tris-(1,3-dichloro-2-

propyl)phosphate (TCPP) and its possible metabolites in Salmonella. [Abstract]. Environ Mutagen 

5:478-479. 

Mandel JS, Berlinger NT, Kay N, et al. 1989. Organophosphate exposure inhibits non-specific esterase 

staining in human blood monocytes. Am J Ind Med 15(2):207-212. 

*Marklund A, Andersson B, Haglund P. 2003. Screening of organophosphorus compounds and their 

distribution in various indoor environments. Chemosphere 53:1137-1146. 

*Marklund A, Andersson B, Haglund P. 2005a. Traffic as a source of organophosphorus flame 

retardants and plasticizers in snow. Environ Sci Technol 39(10):3555-3562. 

*Marklund A, Andersson B, Haglund P. 2005b. Organophosphorus flame retardants and plasticizers in 

Swedish sewage treatment plants. Environ Sci Technol 39(19):7423-7429. 

*Marzulli FN, Callahan JF, Brown DWC. 1965. Chemical structure and skin penetrating capacity of a 

short series of organic phosphates and phosphoric acid. J Invest Dermatol 44:339-344. 

Matthews HB, Dixon D, Herr DW, et al. 1990. Subchronic toxicity studies indicate that tris(2-

chloroethyl)phosphate administration results in lesions in the rat hippocampus. Toxicol Ind Health 

6(1):1-15. 

Matthews HB, Eustis SL, Haseman J. 1993. Toxicity and carcinogenicity of chronic exposure to tris(2-

chloroethyl)phosphate. Fundam Appl Toxicol 20(4):477-485. 

*Mayer FL, Adams WJ, Finley MT, et al. 1981. Phosphate ester hydraulic fluids: An aquatic 

environmental assessment of Pydrauls 50E and 115E. In: Branson DR, Dickson KL, eds. Aquatic 

toxicology and hazard assessment. American Society for Testing Materials (ASTM). Vol. STP 737. 

Philadelphia, PA, 103-123. 

*Mayr U, Butsch A, Schneider S. 1992. Validation of two in vitro test systems for estrogenic activities 

with zearalenone, phytoestrogens and cereal extracts. Toxicology 74(2-3):135-149. 

*Meylan WM, Howard PH. 1993. Computer estimation of the atmospheric gas-phase reaction rate of 

organic compounds with hydroxyl radicals and ozone. Chemosphere 26(12):2293-2299. 

Miles Inc. 1993. Tris-chloroisopropylphosphate, vorversuch zur dosisfindung fur eine subakute 

toxikologische studie an mannlichen Wistar-ratten (in German) with cover letter dated 111593. 

Submitted to the U.S. Environmental Protection Agency under TSCA Section 8D. OTS0556628. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

PHOSPHATE ESTER FLAME RETARDANTS 259 

9. REFERENCES 

*Minegishi K, Kurebayashi H, Nambaru, et al. 1988. Comparative studies on absorption, distribution, 

and excretion of flame retardants halogenated alkyl phosphate in rats. Eisei Kagaku 2:102-114. 

+Mobil Oil Co. 1979a. Initial submission: Acute oral toxicity study with trisbutoxyethyl phosphate in 

rats (final report) with cover letter dated 063092. Mobil Oil Corporation. Submitted to the U.S. 

Environmental Protection Agency under TSCA Section 8E. OTS0540432. EPA88-920004084. 

+Mobil Oil Co. 1979b. Dermal corrosion assay (D.O.T.) in rabbits with tributyl phosphate with cover 

letter dated 071586. Mobil Oil Corporation. Submitted to the U.S. Environmental Protection Agency 

under TSCA Section 8D. OTS0510232. EPA86860000082. 

+*Mobil Oil Co. 1981. Four hour acute inhalation toxicity study in Sprague-Dawley rats with 2263-80 

with cover letter and attachment (sanitized). Mobil Oil Corporation. Submitted to the U.S. 

Environmental Protection Agency under TSCA Section 8D. OTS0530431. 

*Mobil Oil Co. 1991. Evaluation of test article tributoxyethyl phosphate for mutagenic potential 

employing the L5178Y TK+/- mutageneisis assay with cover letter dated 052091 (sanitized). Mobil Oil 

Corporation. Submitted to the U.S. Environmental Protection Agency under TSCA Section 8D. 

OTS0530432. 

*Moller K, Crescenzi C, Nilsson U. 2004. Determination of a flame retardant hydrolysis product in 

human urine by SPE and LC-MS. Comparison of molecularly imprinted solid-phase extraction with a 

mixed-mode anion exchanger. Anal Bioanal Chem 378(1):197-204. 

+*Monsanto Co. 1979. A three-week dermal toxicity study of santicizer-154 and triphenyl phosphate in 

rabbits. Monsanto Company. Submitted to the U.S. Environmental Protection Agency under TSCA 

Section 8D. EPA878211874. OTS206227. 

*Monsanto Co. 1980. Evaluation of health hazards associated with occupational exposure to skydrol 

hydraulic fluids with attachments, cover sheet and letter dated 020190. Monsanto Company. Submitted 

to the U.S. Environmental Protection Agency under TSCA Section 8D. EPA86-900000073. 

OTS0522305. 

*+Monsanto Co. 1985d. A 21-day dermal toxicity study in rabbits with tributoxyethyl phosphate (final 

report) with attachments and cover letter dated 062785. Monsanto Company. Submitted to the U.S. 

Environmental Protection Agency under TSCA Section 8D. EPA86-910000306. OTS0526536. 

*Monsanto Co. 1985a. Tributoxyethyl phosphate: Range-finding teratology study in rats (final report) 

with cover letter dated 060485. Monsanto Company. Submitted to the U.S. Environmental Protection 

Agency under TSCA Section 8D. EPA86-910000305. OTS0528535. 

+*Monsanto Co. 1985b. Tributoxyethyl phosphate: Teratology study in rats with attachments and cover 

letter dated 083085. Monsanto Company. Submitted to the U.S. Environmental Protection Agency under 

TSCA Section 8D. EPA96-910000298. OTS0528528. 

*Monsanto Co. 1985c. Tributoxyethyl phosphate: CHO/HGPRT mammalian cell forward gene 

mutation assay with attachments, cover sheets and letter dated 121285. Monsanto Company. Submitted 

to the U.S. Environmental Protection Agency under TSCA Section 8D. EPA86-910000299. 

OTS0528529. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

 

 

PHOSPHATE ESTER FLAME RETARDANTS 260 

9. REFERENCES 

*Monsanto Co. 1985e. In vitro microbiological mutagenicity assays with tributoxyethyl phosphate (final 

report) with cover letter dated 010884. Monsanto Company. Submitted to the U.S. Environmental 

Protection Agency under TSCA Section 8D. EPA86-910000304. OTS0528534. 

+Monsanto Co. 1986. Studies on the delayed neurotoxicity of tributyl phosphate. Monsanto Company. 

Submitted to the U.S. Environmental Protection Agency under TSCA Section 4. OTS0523069. EPA40-

8621033. 

+*Monsanto Co. 1989a. Acute oral toxicity study in rats with tri-isobutyl phosphate (final report) with 

cover letter dated 072189. Monsanto Company. Submitted to the U.S. Environmental Protection Agency 

under TSCA Section 8D. OTS0528540. EPA86-910000310. 

+*Monsanto Co. 1989b. Primary dermal irritation study in rabbits (4-hour exposure/semi-occlusive 

covering) with tri-isobutyl phosphate (final report) with cover sheets and letter dated 121890. Monsanto 

Company. Submitted to the U.S. Environmental Protection Agency under TSCA Section 8D. 

OTS0528542. EPA86-910000312. 

*Monsanto Co. 1992. Evaluation of the skin irritating and sensitizing propensities of MCS 2495 in 

humans (final report) with attachments and cover letter dated 022692 (sanitized). Monsanto Company. 

Submitted to the U.S. Environmental Protection Agency under TSCA Section 8D. OTS0535407. 

*Morales NM, Matthews HB. 1980. In-vivo binding of the flame retardants tris-2 3 di bromopropyl 

phosphate and tris-1 3 di chloro-2-propyl phosphate to macro molecules of mouse liver kidney and 

muscle. Bull Environ Contam Toxicol 25(1):34-38. 

*Morgan AA, Hughes JP. 1981. An investigation into the value of cholinesterase estimations of workers 

in a plant manufacturing tri-aryl phosphate plasticizers. J Soc Occup Med 31(2):69-75. 

Morrissey RE, Schwetz BA, Lamb J. C IV, et al. 1988. Evaluation of rodent sperm, vaginal cytology, 

and reproductive organ weight data from National Toxicology Program 13-week studies. Fundam Appl 

Toxicol 11:343-358. 

*Morselli PL, Franco-Morselli R, Bossi L. 1980. Clinical pharmacokinetics in newborns and infants: 

Age-related differences and therapeutic implications. Clin Pharmacokinet 5(6):485-527. 

*Mortelmans K, Haworth S, Lawlor T, et al. 1986. Salmonella mutagenicity tests. 2. Results from the 

testing of 270 chemicals. Environ Mutagen 8(Suppl 7):1-119. 

*Muir DCG. 1984. Phosphate esters. In: Hutzinger O, ed. The Handbook of environmental chemistry. 

Vol. 3. Part C. Anthropogenic compounds. New York, NY: Springer-Verlag, 41-66. 

*Muir DC, Grift NP, Blouw AP, et al. 1980. Environmental dynamics of phosphate esters: 1. Uptake 

and bioaccumulation of triphenyl phosphate by rainbow trout (Salmo gairdneri). Chemosphere 

9(9):525-532. 

Muir DC, Yarechewski AL, Grift NP. 1983a. Environmental dynamics of phosphate esters: 3. 

Comparison of the bioconcentration of 4 triaryl phosphates by fish. Chemosphere 12(2):155-166. 

*Muir DCG, Grift NP, Lockhart WL. 1981. Comparison of laboratory and field results for prediction of 

the environmental behavior of phosphate esters. Environ Toxicol Chem 1:113-119. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

 

PHOSPHATE ESTER FLAME RETARDANTS 261 

9. REFERENCES 

Muir DCG, Townsend BE, Lockhart WL. 1983b. Bioavailability of 6 organic chemicals to Chironomus 

tentans larvae in sediment and water. Environ Toxicol Chem 2:269-281. 

*Muir DCG, Yarechewski AL, Grift NP. 1989. Biodegradation of four triaryl/alkyl phosphate esters in 

sediment under various temperature and redox conditions. Toxicol Environ Chem 18:269-286. 

*Muszkat L, Lahav D, Ronen D, et al. 1993. Penetration of pesticides and industrial organics deep into 

soil and into groundwater. Arch Insect Biochem Physiol 22(3-4):487-499. 

*Nagase M, Toba M, Kondo H, et al. 2003. Estimation of organophosphoric acid triesters in soft 

polyurethane foam using a concentrated sulfuric acid dissolution technique and gas chromatography with 

flame photometric detection. Anal Sci 19(12):1617-1620. 

*Nakamura A, Tateno N, Kojima S, et al. 1979. Mutagenicity of halogenated alkanols and their 

phosphoric acid esters for Salmonella typhimurium. Mutat Res 66:373-380. 

*NAS. 2000. Toxicological risks of selected flame-retardant chemicals. Washington, DC: National 

Academy Press. http://www.nap.edu/catalog.php?record_id=9841#orgs. June 23, 2009. 

*NAS/NRC. 1989. Report of the oversight committee. Washington, DC: National Academy of 

Sciences, National Research Council, National Academy Press. Biologic markers in reproductive 

toxicology. 

Nayak NC, Sathar SA, Mughal S, et al. 1996. The nature and significance of liver cell vacolation 

following hepatocellular injury-an analysis based on observations on rats rendered tolerant to hepatotoxic 

damage. Virchows Arch 428:353-365. 

+*Naylor MW, Ribelin WR. 1990. 90-Day study of triisobutyl phosphate (TIBP) administered in feed to 

albino rats. Monsanto Company. Submitted to the U.S. Environmental Protection Agency under TSCA 

Section 8D. EPA86-920000201. OTS0534406. 

*NIOSH. 1990. Tributoxyethyl phosphate; tributyl phosphate; triphenyl phosphate; tris(2-chloroisopropyl) phosphate (TCPP; Tris-(2-chloroethyl)-phosphate. Estimated numbers of employees 

potentially exposed to specific agents by 2-digit Standard Industrial Classification (SIC). National 

Occupational Exposure Survey conducted from 1981-1983. Centers for Disease Control. National 

Institute for Occupational Safety and Health. http://www.cdc.gov/noes/ September 10, 2009. 

*NIOSH. 1994a. Tributyl phosphate. Method 5034. NIOSH manual of analytical methods. National 

Institute of Occupational Safety and Health. http://www.cdc.gov/niosh/nmam/pdfs/5034.pdf. June 4, 

2009. 

*NIOSH. 1994b. Triphenyl phosphate. Method 5038. National Institute of Occupational Safety and 

Health. http://www.cdc.gov/niosh/nmam/pdfs/5038.pdf. June 4, 2009. 

*NIOSH. 2005a. Tributyl phosphate. ICSC: 0584. International Chemical Safety Cards. National 

Institute for Occupational Safety and Health. http://www.cdc.gov/niosh/ipcsneng/neng0584.html. June 

23, 2009. 

*NIOSH. 2005b. Tributyl phosphate and triphenyl phosphate. NIOSH pocket guide to chemical 

hazards. Atlanta, GA: National Institute for Occupational Safety and Health, Centers for Disease Control 

and Prevention. http://www.cdc.gov/niosh/npg/. May 19, 2009. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

PHOSPHATE ESTER FLAME RETARDANTS 262 

9. REFERENCES 

*NIOSH. 2007. Tris(2-chloroethyl) phosphate. ICSC: 1677. International Chemical Safety Cards. 

National Institute for Occupational Safety and Health. 

http://www.cdc.gov/niosh/ipcsneng/neng1677.html. June 23, 2009. 

*Nishihara T, Nishikawa J, Kanayama T, et al. 2000. Estrogenic activities of 517 chemicals by yeast 

two-hybrid assay. J Health Sci 46(4):282-298. 

+*Noda T, Yamano T, Shimizu M, et al. 1994. Effects of tri-n-butyl phosphate on pregnancy in rats. 

Food Chem Toxicol 32(11):1031-1036. 

*Nomeir AA, Kato S, Matthews HB. 1981. The metabolism and disposition of tris(1,3-dichloro-2-

propyl) phosphate (Fyrol FR-2) in the rat. Toxicol Appl Pharmacol 57(3):401-413. 

*NRC. 1993. Pesticides in the diets of infants and children. Washington, DC: National Research 

Council. National Academy Press. 

*NRC. 2000. Exposure assessment methodology. In: Toxicological risks of selected flame-retardant 

chemicals. National Research Council. Washington, DC: National Academy Press, 35-52. 

*NTP. 1982. Mutagenesis testing results. National Toxicology Program. NTP Tech Bull 7:5-9. 

*NTP. 1983. Salmonella mutagenesis test results. National Toxicology Program. NTP Tech Bull 9:5-6. 

+*NTP. 1991b. Final report on the reproductive toxicity of tris(2-chloroethyl)phosphate reproduction 

and fertility assessment in Swiss CD-1 mice when administered via gavage. 

+*NTP. 1991a. NTP toxicology and carcinogenesis studies of tris(2-chloroethyl) phosphate (CAS No. 

115-96-8) in F344/N rats and B6C3F1 mice (gavage studies). Program NT. TR 391. 

http://ntp.niehs.nih.gov/ntp/htdocs/LT_rpts/tr391.pdf. May 6, 2009. 

*NTP. 2005. Report on carcinogens. 11th ed. Research Triangle Park, NC: U.S. Department of Health 

and Human Services, Public Health Service, National Toxicology Program. http://ntpserver.niehs.nih.gov/ntp.roc/toc11.html. May 11, 2009. 

NTP/NIEHS. 1997. Reproductive toxicology. Tris(2-chloroethyl)phosphate. Environ Health Perspect 

105 Suppl 1:365-366. 

Obersteiner EJ, Sharma RP. 1978. Evaluation of cytotoxic responses caused by selected 

organophosphorus esters in chick sympathetic ganglia cultures. Can J Comp Med 42(1):80-88. 

+Oishi H, Oishi S, Hiraga K. 1980. Toxicity of tri-n-butyl phosphate, with special reference to organ 

weights, serum components and cholinesterase activity in male rats. Toxicol Lett 6(2):81-85. 

+*Oishi H, Oishi S, Hiraga K. 1982. Toxicity of several phosphoric acid esters in rats. Toxicol Lett 

13:29-34. 

OSHA. 1992. Chemical sampling information (CSI). Tributyl phosphate. Occupational Safety and 

Health Administration. http://www.osha.gov/dts/chemicalsampling/data/CH_272700.html. June 23, 

2009. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

PHOSPHATE ESTER FLAME RETARDANTS 263 

9. REFERENCES 

OSHA. 1999. Chemical sampling information (CSI). Triphenyl phosphate. Occupational Safety and 

Health Administration. http://www.osha.gov/dts/chemicalsampling/data/CH_274400.html. June 23, 

2009. 

*OSHA. 2009. Toxic and hazardous substances. Occupational safety and health standards. 

Occupational Safety and Health Administration. Code of Federal Regulations. 29 CFR 1910.1000, Table 

Z1. http://www.osha.gov/comp-links.html. May 19, 2009. 

*Otake T, Yoshinaga J, Yanagisawa Y. 2001. Analysis of organic esters of plasticizer in indoor air by 

GC-MS and GC-FPD. Environ Sci Technol 35(15):3099-3102. 

*Otake T, Yoshinaga J, Yanagisawa Y. 2004. Exposure to phthalate esters from indoor environment. J 

Expo Anal Environ Epidemiol 14(7):524-528. 

*Owen GM, Brozek J. 1966. Influence of age, sex and nutrition on body composition during childhood 

and adolescence. In: Falkner F, ed. Human development. Philadelphia, PA: WB Saunders, 222-238. 

*Owens CV, Jr., Lambright C, Bobseine K, et al. 2007. Identification of estrogenic compounds emitted 

from the combustion of computer printed circuit boards in electronic waste. Environ Sci Technol 

41(24):8506-8511. 

Parker GB. 1980. Continuous quantitative analysis of low concentrations of tributyl phosphate vapors in 

flowing air streams. Am Ind Hyg Assoc J 41(3):220-222. 

*Pedersen JA, Soliman M, Suffet IH. 2005. Human pharmaceuticals, hormones, and personal care 

product ingredients in runoff from agricultural fields irrigated with treated wastewater. J Agric Food 

Chem 53:1625-1632. 

*Peterman PH, Delfino JJ, Dube DJ, et al. 1980. Chloro-organic compounds in the lower Fox River, 

Wisconsin. In: Afghan BK, Mackay D, eds. Hydrocarbons and halogenated hydrocarbons in the aquatic 

environment. New York, NY: Plenum Press, 145-160. 

*Quintana JB, Reemtsma T. 2006. Potential of membrane-assisted solvent extraction for the 

determination of phosphoric acid triesters in wastewater samples by liquid chromatography-tandem mass 

spectrometry. J Chromatogr A 1124(1-2):22-28. 

*Reemtsma T, Weiss S, Mueller J, et al. 2006. Polar pollutants entry into the water cycle by municipal 

wastewater: A European perspective. Environ Sci Technol 40(17):5451-5458. 

*Ren X, Lee YJ, Han HJ, et al. 2008. Effect of tris-(2-chloroethyl)-phosphate (TCEP) at environmental 

concentration on the levels of cell cycle regulatory protein expression in primary cultured rabbit renal 

proximal tubule cells. Chemosphere 74:84-88. 

+*Reyna MS, Thake DG. 1987a. Eighteen week feeding study of tributoxyethyl phosphate (TBEP) 

administered to Sprague-Dawley rats. Monsanto Agricultural Company. Submitted to the U.S. 

Environmental Protection Agency under TSCA Section 8D. OTS0530087. 

+*Reyna MS, Thake DG. 1987b. Evaluation of the peripheral nervous system of Sprague-Dawley rats 

after 19 weeks of feeding tributoxyethyl phosphate (TBEP). Monsanto Agricultural Company. 

Submitted to the U.S. Environmental Protection Agency under TSCA Section 8D. OTS0530086. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

PHOSPHATE ESTER FLAME RETARDANTS 264 

9. REFERENCES 

*RTECS. 2009. Phosphate ester flame retardants. Registry of Toxic Effects on Chemical Substances. 

National Institute of Occupational Safety and Health. MDL Information Systems, Inc. 

Ruckman SA, Green OP, Palmer AK, et al. 1999. Tri-isobutylphosphate: A prenatal toxicity study in 

rats. Toxicol Lett 105(3):231-237. 

*Saboori AM, Lang DM, Newcombe DS. 1991. Structural requirements for the inhibition of human 

monocyte carboxylesterase by organophosphorus compounds. Chem Biol Interact 80(3):327-338. 

*Saeger VW, Hicks O, Kaley RG, et al. 1979. Environmental fate of selected phosphate esters. Environ 

Sci Technol 13(7):840-844. 

Saito I, Onuki A, Seto H. 2001. Determination of organic phosphate triesters in indoor and outdoor air. 

[Abstract]. Earozoru Kenkyu 16:209-216. 

*Saito I, Onuki A, Seto H. 2007. Indoor organophosphate and polybrominated flame retardants in 

Tokyo. Indoor Air 17(1):28-36. 

*Sala M, Gu ZG, Moens G, et al. 1982. In vivo and in vitro biological effects of the flame retardants 

tris(2,3-dibromopropyl) phosphate and tris(2-chlorethyl)orthophosphate. Eur J Cancer Clin Oncol 

18(12):1337-1344. 

Salovsky P, Shopova V, Dancheva V. 1998. Antioxidant defense mechanisms in the lung toxicity of trin-butyl phosphate. Am J Ind Med 33(1):11-15. 

*Sasaki K, Suzuki T, Takeda M, et al. 1982. Bioconcentration and excretion of phosphoric-acid triesters 

by killifish Oryzias-latipes. Bull Environ Contam Toxicol 28(6):752-759. 

*Sasaki K, Suzuki T, Takeda M, et al. 1984. Metabolism of phosphoric acid triesters by rat liver 

homogenate. Bull Environ Contam Toxicol 33(3):281-288. 

*Sasaki K, Takeda M, Uchiyama M. 1981. Toxicity, absorption, and elimination of phosphoric acid 

triesters by killifish and goldfish. Bull Environ Contam Toxicol 27:775-782. 

Sato K, Kadokami K. 1995. Determination of organophosphoric acid triester in aquatic environmental 

samples by GC/MS. Kankyo Kagaku 5:821-827. 

Schroeder RE, Gerhart JM, Kneiss J. 1991. Developmental toxicity studies of tributyl phosphate (TBP) 

in the rat and rabbit. [Abstract]. Teratology 43(5):455. 

Sellstrom U, Jansson B. 1987. Mass spectrometric determination of tris(1,3-dichloro-2-propyl)-

phosphate (TDCP) using NCI-technique. Int J Environ Anal Chem 29(4):277-287. 

*Setchell BP, Waites GMH. 1975. The blood testis barrier. In: Creep RO, Astwood EB, Geiger SR, 

eds. Handbook of physiology: Endocrinology V. Washington, DC: American Physiological Society, 

143-172. 

*Shah M, Meija J, Cabovska B, et al. 2006. Determination of phosphoric acid triesters in human plasma 

using solid-phase microextraction and gas chromatography coupled to inductively coupled plasma mass 

spectrometry. J Chromatogr A 1103(2):329-336. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

PHOSPHATE ESTER FLAME RETARDANTS 265 

9. REFERENCES 

*Shankwalker SG, Placek DG. 1992. Oxidation and weight loss characteristics of commercial phosphate 

esters. Ind Eng Chem Res 31(7):1810-1813. 

Shepel'skaia NR, Dyshginevich NE. 1981. [Experimental study of the gonadotoxic effect of tri-

(chloroethyl)-phosphate] (Russian). Gig Sanit (6):20-21. 

*Sjodin A, Carlsson H, Thuresson K, et al. 2001. Flame retardants in indoor air at an electronics 

recycling plant and at other work environments. Environ Sci Technol 35(3):448-454. 

+*Smyth HF, Carpenter CP, Weil CS. 1951. Range-finding toxicity data: List IV. AMA Arch Ind Hyg 

Occup Med 4:119-122. 

+*Sobotka TJ, Brodie RE, Arnold A, et al. 1986. Neuromotor function in rats during subchronic dietary 

exposure to triphenyl phosphate. Neurobehav Toxicol Teratol 8(1):7-10. 

+SOCMA. 1990. Tributyl phosphate: Skin sensitization study in guinea pigs (final report) with cover 

letter dated 032690. Submitted to the U.S. Environmental Protection Agency under TSCA Section 4. 

OTS0528314. EPA40-9021192. 

*SOCMA. 1992. Letter from SOCMA to USEPA regarding oral/dermal pharmacokinetic testing of 

tributyl phosphate (TBP) with attachments, dated 12/23/92. Synthetic Organic Chemical Manufacturers 

Association, Inc. Submitted to the U.S. Environmental Protection Agency under TSCA Section 4. 

OTS0572980. 

*SOCMA. 1994. Metabolism of tributyl phosphate in Yucatan minipigs following intravenous and 

dermal exposure (part II), with cover letter dated 05/16/94. Synthetic Organic Chemical Manufacturers 

Association, Inc. Submitted to the U.S. Environmental Protection Agency under TSCA Section 8D. 

EPA86-940000966. OTS0557376. 

*Søderlund EJ, Dybing E, Holme JA, et al. 1985. Comparative genotoxicity and nephrotoxicity studies 

of the two halogenated flame retardants tris(1,3-dichloro-2-propyl)phosphate and tris(2,3-

dibromopropyl)phosphate. Acta Pharmacol Toxicol (Copenh) 56(1):20-29. 

*Solbu K, Thorud S, Hersson M, et al. 2007. Determination of airborne trialkyl and triaryl 

organophosphates originating from hydraulic fluids by gas chromatography-mass spectrometry. 

Development of methodology for combined aerosol and vapor sampling. J Chromatogr A 1161(1-2):275-

283. 

Sprague GL, Sandvik LL, Brookins-Hendricks MJ. 1981. Neurotoxicity of 2 organophosphorus ester 

flame retardants in hens. J Toxicol Environ Health 8(3):507-518. 

*SRI. 2000. Directory of chemical producers. United States: Menlo Park, CA: SRI Consulting, 956. 

*SRI. 2008. Directory of chemical producers: United States. Menlo Park, CA: SRI Consulting, 781-

782. 

Stanley JKJ, Bryne RH. 1990. Inorganic complexation of zinc(II) in seawater. Geochim Cosmochim 

Acta 54(3):753-760. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

 

PHOSPHATE ESTER FLAME RETARDANTS 266 

9. REFERENCES 

+*Stauffer Chemical Co. 1973. Toxicology laboratory report-phosflex 4 with cover letter dated 081286. 

Submitted to the U.S. Environmental Protection Agency under TSCA Section 8D. OTS0510245. 

EPA86860000097. 

+*Stauffer Chemical Co. 1981a. A two year oral toxicity/carcinogenicity study of Fyrol FR-2 in rats. In: 

A two-year oral toxicity/carcinogenicity study of fyrol FR-2 in rats (volume I-IV) (final reports) with 

attachments, cover sheets and letter dated 093081. Submitted to the U.S. Environmental Protection 

Agency under TSCA Section 8E. EPA88-8100282. OTS0204911. 

+*Stauffer Chemical Co. 1981b. Toxicology reports on FYROL FR-2 (volume I-II) with attachments 

and cover letters dated 020381. Submitted to the U.S. Environmental Protection Agency under TSCA 

Section 8E. EPA88-8100271. OTS0204911. 

*Stauffer Chemical Co. 1983. A mortality study of workers employed at a Fyrol FR-2 manufacturing 

plant with attachment and cover letter dated 040384. Submitted to the U.S. Environmental Protection 

Agency under TSCA Section 8E. EPA88-8400615. OTS0204911. 

*Stegeman SD, Costello JG, Garrett SL. 1992. Ames/Salmonella mutagenicity assay of MCS-2518 

(final report) with cover letter dated 030493. Monsanto Company. Submitted to the U.S. Environmental 

Protection Agency under TSCA Section 8D. EPA86-930000154. OTS0538148. 

*Stevens GW, Lo TC, Baird MHI. 2007. Extraction, liquid-liquid. In: Kirk-Othmer encyclopedia of 

chemical technology. John Wiley & Sons, 1-62. 

http://mrw.interscience.wiley.com/emrw/9780471238966/kirk/article/liqulo.a01/current/pdf. June 02, 

2009. 

*Stiles R, Yang I, Lippincott RL, et al. 2008. Measurement of drinking water contaminants by solid 

phase microextraction initially quantified in source water samples by the USGS. Environ Sci Technol 

42(8):2976-2981. 

+Stropp G. 1996. Tris (2-chloroisopropyl) phosphat-acute oral toxicity study in male and female Wistar 

rats, with TSCA health and safety study cover letter dated 08/23/96. Submitted to the U.S. 

Environmental Protection Agency under TSCA Section 8D. OTS0558767. EPA86960000566. 

+*Sutton WL, Terhaar CJ, Miller FA, et al. 1960. Studies on the industrial hygiene and toxicology of 

triphenyl phosphate. Arch Environ Health 1:33-46. 

*Suzuki T, Sasaki K, Takeda M, et al. 1984a. Metabolism of tributyl phosphate in male rats. J Agric 

Food Chem 32(3):603-610. 

*Suzuki T, Sasaki K, Takeda M, et al. 1984b. Some S-containing metabolites of tributyl phosphate in 

the rat. J Agric Food Chem 32(6):1278-1283. 

Suzuki Y, Kikuchi H, Kato C, et al. 1977. Effect of alkyl phosphates on beta-glucuronidase in rats: 

Release of beta-glucuronidase from liver microsomes into serum. Biochem Pharmacol 26(9):881-885. 

*Takada K, Yasuhara K, Nakaji Y, et al. 1989. Carcinogenicity study of tris (2-chloroethyl) phosphate in 

ddY mice. J Toxicol Pathol 2:213-222. 

Takahashi S, Kawashima K, Kawasaki M, et al. 2008. Enrichment and characterization of chlorinated 

organophosphate ester-degrading mixed bacterial cultures. J Biosci Bioeng 106(1):27-32. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

PHOSPHATE ESTER FLAME RETARDANTS 267 

9. REFERENCES 

Tanaka D, Bursian SJ, Aulerich RJ. 1994. Age-related effects of triphenyl phosphite-induced delayed 

neuropathy on central visual pathways in the European ferret (Mustela putorius furo). Fundam Appl 

Toxicol 22(4):577-587. 

Tanaka D, Bursian SJ, Lehning EJ, et al. 1990. Exposure to triphenyl phosphite results in widespread 

degeneration in the mammalian central nervous system. Brain Res 531(1-2):294-298. 

*Tarvainen K. 1995. Analysis of patients with allergic patch test reactions to a plastics and glues series. 

Contact Dermatitis 32(6):346-351. 

*Tennant RW, Ashby J. 1991. Classification according to chemical structure, mutagenicity to 

Salmonella and level of carcinogenicity of a further 39 chemicals tested for carcinogenicity by the U.S. 

National Toxicology Program. Mutat Res 257(3):209-228. 

*Thomas K, Colborn T. 1992. Organochlorine endocrine disruptors in human tissue. In: Colborn T, 

Clement C, eds. Chemically induced alterations in sexual and functional development: The 

wildlife/human connection. Princeton, NJ: Princeton Scientific Publishing, 365-394. 

*Thomas RA, Macaskie LE. 1996. Biodegradation of tributyl phosphate by naturally occurring 

microbial isolates and coupling to the removal of uranium from aqueous solution. Environ Sci Technol 

30(7):2371-2375. 

*Thomas RA, Macaskie LE. 1998. The effect of growth conditions on the biodegradation of tributyl 

phosphate and potential for the remediation of acid mine drainage waters by a naturally-occurring mixed 

microbial culture. Appl Microbiol Biotechnol 49(2):202-209. 

*Thomas RA, Morby AP, Macaskie LE. 1997. The biodegradation of tributyl phosphate by naturally 

occurring microbial isolates. FEMS Microbiol Lett 155(2):155-159. 

*Thruston AD, Richardson SD, McGuire JM, et al. 1991. Multispectral identification of alkyl and 

chloroalkyl phosphates from an industrial effluent. J Am Soc Mass Spectrom 2:419-426. 

+*Tilson HA, Veronesi B, McLamb RL, et al. 1990. Acute exposure to tris(2-chloroethyl)phosphate 

produces hippocampal neuronal loss and impairs learning in rats. Toxicol Appl Pharmacol 

106(2):254-269. 

+*Tyl RW, Gerhart JM, Myers CB, et al. 1997. Two-generation reproductive toxicity study of dietary 

tributyl phosphate in CD rats. Fundam Appl Toxicol 40(1):90-100. 

*Umezu T, Yonemoto J, Soma Y, et al. 1998. Tris(2-chloroethyl)phosphate increases ambulatory 

activity in mice: Pharmacological analyses of its neurochemical mechanism. Toxicol Appl Pharmacol 

148(1):109-116. 

+*Union Carbide Corportation. 1943. Range finding tests on tributyl phosphate with cover letter dated 

081186. Submitted to the U.S. Environmental Protection Agency under TSCA Section 8D. 

OTS0510270. EPA86860000125. 

*USGS. 2001. Methods of analysis by the U. S. Geological Survey National Water Quality Laboratory. 

Determination of wastewater compounds by polystyrene-divinylbenzene solid-phase extraction and 

capillary-column gas chromatography/mass spectrometry. Denver, CO: U. S. Geological Survey. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

PHOSPHATE ESTER FLAME RETARDANTS 268 

9. REFERENCES 

*Vernon CA. 1959. The mechanisms of hydrolysis of organic phosphates. In: Phosphoric esters and 

related compounds. Special Publication. Vol. 8. London: Chemical Society, 17-32. 

*Vieira I, Sonnier M, Cresteil T. 1996. Developmental expression of CYP2E1 in the human liver: 

Hypermethylation control of gene expression during the neonatal period. Eur J Biochem 238(2):476-483. 

*Vogel EW, Nivard MJ. 1993. Performance of 181 chemicals in a Drosophila assay predominantly 

monitoring interchromosomal mitotic recombination. Mutagenesis 8(1):57-81. 

*Watanabe K, Sakamoto K, Sasaki T. 1996. Comparisons on chemically-induced mutagenicity among 

four bacterial strains, Salmonella typhimurium TA102 and TA2638, and Escherichia coli WP2/pKM101 

and WP2 uvrA/pKM101: Collaborative study I. Mutat Res 361(2-3):143-155. 

Watanabe K, Sasaki T, Kawakami K. 1998. Comparisons of chemically-induced mutation among four 

bacterial strains, Salmonella typhmiurium TA102 and TA2638, and Escherichia coli WP2/pKM101 and 

WP2 uvrA/pKM101: Collaborative study III and evaluation of the usefulness of these strains. Mutat Res 

416(3):169-181. 

*Watts MJ, Linden KG. 2008. Photooxidation and subsequent biodegradability of recalcitrant tri-alkyl 

phosphates TCEP and TBP in water. Water Res 42(20):4949-4954. 

*Watts MJ, Linden KG. 2009. Advanced oxidation kinetics of aqueous trialkyl phosphate flame 

retardants and plasticizers. Environ Sci Technol 43(8):2937-2942. 

*Weil ED. 2001. Flame retardants, phosphorus. In: Kirk-Othmer encyclopedia of chemical technology. 

New York, NY: Wiley & Sons, 484-510. 

http://mrw.interscience.wiley.com/emrw/9780471238966/kirk/article/phosweil.a01/current/pdf. June 02, 

2009. 

*Weiner ML, Jortner BS. 1999. Organophosphate-induced delayed neurotoxicity of triarylphosphates. 

Neurotoxicology 20(4):653-674. 

+*Welsh JJ, Collins TF, Whitby KE, et al. 1987. Teratogenic potential of triphenyl phosphate in 

Sprague-Dawley (Spartan) rats. Toxicol Ind Health 3(3):357-369. 

*West JR, Smith HW, Chasis H. 1948. Glomerular filtration rate, effective renal blood flow, and 

maximal tubular excretory capacity in infancy. J Pediatr 32:10-18. 

*WHO. 2000. Air quality guidelines. 2nd ed. Geneva, Switzerland: World Health Organization. 

http://www.euro.who.int/air/activities/20050223_4. May 11, 2009. 

*WHO. 2006. Guidelines for drinking-water quality. 3rd ed. Geneva, Switzerland: World Health 

Organization. http://www.who.int/water_sanitation_health/dwq/gdwq3/en/. May 11, 2009. 

*Widdowson EM, Dickerson JWT. 1964. Chemical composition of the body. In: Comar CL, Bronner 

F, eds. Mineral metabolism: An advance treatise. Volume II: The elements Part A. New York, NY: 

Academic Press, 1-247. 

Williams DT, Lebel GL. 1981. A national survey of tri haloalkyl phosphates tri alkyl phosphates and tri 

aryl phosphates in Canadian drinking water. Bull Environ Contam Toxicol 27(4):450-457. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

PHOSPHATE ESTER FLAME RETARDANTS 269 

9. REFERENCES 

*Williams DT, LeBel GL, Benoit FM. 1981. Identification of trialkyl and triaryl phosphates in distilled 

and Super-Q water. J Assoc Off Anal Chem 64(3):635-640. 

Williams GM, Mori H, McQueen CA. 1989. Structure-activity relationships in the rat hepatocyte DNArepair test for 300 chemicals. Mutat Res 221:263-286. 

Wolf R, Kaul BL. 2005. Plastics, adhesives. In: Ullmann's encyclopedia of industrial chemistry. John 

Wiley & Sons, 1-51. 

http://mrw.interscience.wiley.com/emrw/9783527306732/ueic/article/a20_459/current/pdf. June 4, 2009. 

Woo YT, Lai DY, Argus MF, et al. 1996. Carcinogenicity of organophosphorus pesticides-compounds. 

An analysis of their structure-activity relationships. J Environ Sci Health C Environ Carcinog Ecotoxicol 

Rev 14(1):1-42. 

*Yamada S. 1987. Water pollution by organophosphoric acid triesters and its effects of aquatic 

organisms- a review. Bull Tokai Reg Fish Res Lab 123:15-30. 

Yasuhara A. 1994. Determination of tris2-chloroethyl phosphate in leachates from landfills by capillary 

gas chromatography using flame photometric detection. J Chromatogr A 684(2):366-369. 

Yasuhara A, Nakasugi O. 1994. Leaching of tris(2-chloroethyl)phosphate from waste plastics into water. 

[Abstract]. Kankyo Kagaku 4:420-421. 

*Zeiger E, Anderson B, Haworth S, et al. 1987. Salmonella mutagenicity tests. III. Results from the 

testing of 255 chemicals. Environ Mutagen 9(Suppl 9):1-110. 

Zeiger E, Anderson B, Haworth S, et al. 1988. Salmonella mutagenicity tests. IV. Results from the 

testing of 300 chemicals. Environ Mol Mutagen 11(Suppl 12):1-158. 

*Zeiger E, Anderson B, Haworth S, et al. 1992. Salmonella mutagenicity tests: V. Results from the 

testing of 311 chemicals. Environ Mol Mutagen 19(Suppl 21):2-141. 

*Ziegler EE, Edwards BB, Jensen RL, et al. 1978. Absorption and retention of lead by infants. Pediatr 

Res 12(1):29-34. 

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PHOSPHATE ESTER FLAME RETARDANTS 270 

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PHOSPHATE ESTER FLAME RETARDANTS 271 

10. GLOSSARY
 

Absorption—The taking up of liquids by solids, or of gases by solids or liquids. 

Acute Exposure—Exposure to a chemical for a duration of 14 days or less, as specified in the 

Toxicological Profiles. 

Adsorption—The adhesion in an extremely thin layer of molecules (as of gases, solutes, or liquids) to the 

surfaces of solid bodies or liquids with which they are in contact. 

Adsorption Coefficient (Koc)—The ratio of the amount of a chemical adsorbed per unit weight of 

organic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium. 

Adsorption Ratio (Kd)—The amount of a chemical adsorbed by sediment or soil (i.e., the solid phase) 

divided by the amount of chemical in the solution phase, which is in equilibrium with the solid phase, at a 

fixed solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per gram of soil or 

sediment. 

Benchmark Dose (BMD)—Usually defined as the lower confidence limit on the dose that produces a 

specified magnitude of changes in a specified adverse response. For example, a BMD10 would be the 

dose at the 95% lower confidence limit on a 10% response, and the benchmark response (BMR) would be 

10%. The BMD is determined by modeling the dose response curve in the region of the dose response 

relationship where biologically observable data are feasible. 

Benchmark Dose Model—A statistical dose-response model applied to either experimental toxicological 

or epidemiological data to calculate a BMD. 

Bioconcentration Factor (BCF)—The quotient of the concentration of a chemical in aquatic organisms 

at a specific time or during a discrete time period of exposure divided by the concentration in the 

surrounding water at the same time or during the same period. 

Biomarkers—Broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as markers of exposure, markers of effect, and markers of susceptibility. 

Cancer Effect Level (CEL)—The lowest dose of chemical in a study, or group of studies, that produces 

significant increases in the incidence of cancer (or tumors) between the exposed population and its 

appropriate control. 

Carcinogen—A chemical capable of inducing cancer. 

Case-Control Study—A type of epidemiological study that examines the relationship between a 

particular outcome (disease or condition) and a variety of potential causative agents (such as toxic 

chemicals). In a case-controlled study, a group of people with a specified and well-defined outcome is 

identified and compared to a similar group of people without outcome. 

Case Report—Describes a single individual with a particular disease or exposure. These may suggest 

some potential topics for scientific research, but are not actual research studies. 

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PHOSPHATE ESTER FLAME RETARDANTS 272 

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 of people that examines 

the relationship between exposure and outcome to a chemical or to chemicals at one point in time. 

Data Needs—Substance-specific informational needs that if met would reduce the uncertainties of human 

health assessment. 

Developmental Toxicity—The occurrence of adverse effects on the developing organism that may result 

from exposure to a chemical prior to conception (either parent), during prenatal development, or 

postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point 

in the life span of the organism. 

Dose-Response Relationship—The quantitative relationship between the amount of exposure to a 

toxicant and the incidence of the adverse effects. 

Embryotoxicity and Fetotoxicity—Any toxic effect on the conceptus as a result of prenatal exposure to 

a chemical; the distinguishing feature between the two terms is the stage of development during which the 

insult occurs. The terms, as used here, include malformations and variations, altered growth, and in utero 

death. 

Environmental Protection Agency (EPA) Health Advisory—An estimate of acceptable drinking water 

levels for a chemical substance based on health effects information. A health advisory is not a legally 

enforceable federal standard, but serves as technical guidance to assist federal, state, and local officials. 

Epidemiology—Refers to the investigation of factors that determine the frequency and distribution of 

disease or other health-related conditions within a defined human population during a specified period. 

Genotoxicity—A specific adverse effect on the genome of living cells that, upon the duplication of 

affected cells, can be expressed as a mutagenic, clastogenic, or carcinogenic event because of specific 

alteration of the molecular structure of the genome. 

Half-life—A measure of rate for the time required to eliminate one half of a quantity of a chemical from 

the body or environmental media. 

Immediately Dangerous to Life or Health (IDLH)—The maximum environmental concentration of a 

contaminant from which one could escape within 30 minutes without any escape-impairing symptoms or 

irreversible health effects. 

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PHOSPHATE ESTER FLAME RETARDANTS 273 

10. GLOSSARY 

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. 

Incidence—The ratio of individuals in a population who develop a specified condition to the total 

number of individuals in that population who could have developed that condition in a specified time 

period. 

Intermediate Exposure—Exposure to a chemical for a duration of 15–364 days, as specified in the 

Toxicological Profiles. 

In Vitro—Isolated from the living organism and artificially maintained, as in a test tube. 

In Vivo—Occurring within the living organism. 

Lethal Concentration(LO) (LCLO)—The lowest concentration of a chemical in air that has been reported 

to have caused death in humans or animals. 

Lethal Concentration(50) (LC50)—A calculated concentration of a chemical in air to which exposure for 

a specific length of time is expected to cause death in 50% of a defined experimental animal population. 

Lethal Dose(LO) (LDLo)—The lowest dose of a chemical introduced by a route other than inhalation that 

has been reported to have caused death in humans or animals. 

Lethal Dose(50) (LD50)—The dose of a chemical that has been calculated to cause death in 50% of a 

defined experimental animal population. 

Lethal Time(50) (LT50)—A calculated period of time within which a specific concentration of a chemical 

is expected to cause death in 50% of a defined experimental animal population. 

Lowest-Observed-Adverse-Effect Level (LOAEL)—The lowest exposure level of chemical in a study, 

or group of studies, that produces statistically or biologically significant increases in frequency or severity 

of adverse effects between the exposed population and its appropriate control. 

Lymphoreticular Effects—Represent morphological effects involving lymphatic tissues such as the 

lymph nodes, spleen, and thymus. 

Malformations—Permanent structural changes that may adversely affect survival, development, or 

function. 

Minimal Risk Level (MRL)—An estimate of daily human exposure to a hazardous substance that is 

likely to be without an appreciable risk of adverse noncancer health effects over a specified route and 

duration of exposure. 

Modifying Factor (MF)—A value (greater than zero) that is applied to the derivation of a Minimal Risk 

Level (MRL) to reflect additional concerns about the database that are not covered by the uncertainty 

factors. The default value for a MF is 1. 

Morbidity—State of being diseased; morbidity rate is the incidence or prevalence of disease in a specific 

population. 

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PHOSPHATE ESTER FLAME RETARDANTS 274 

10. GLOSSARY 

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) that represents the best estimate of relative risk (risk as a ratio of the incidence 

among subjects exposed to a particular risk factor divided by the incidence among subjects who were not 

exposed to the risk factor). An OR of greater than 1 is considered to indicate greater risk of disease in the 

exposed group compared to the unexposed group. 

Organophosphate or Organophosphorus Compound—A phosphorus-containing organic compound 

and especially a pesticide that acts by inhibiting cholinesterase. 

Permissible Exposure Limit (PEL)—An Occupational Safety and Health Administration (OSHA) 

allowable exposure level in workplace air averaged over an 8-hour shift of a 40-hour workweek. 

Pesticide—General classification of chemicals specifically developed and produced for use in the control 

of agricultural and public health pests. 

Pharmacokinetics—The dynamic behavior of a material in the body, used to predict the fate 

(disposition) of an exogenous substance in an organism. Utilizing computational techniques, it provides 

the means of studying the absorption, distribution, metabolism, and excretion of chemicals by the body. 

Pharmacokinetic Model—A set of equations that can be used to describe the time course of a parent 

chemical or metabolite in an animal system. There are two types of pharmacokinetic models: data-based 

and physiologically-based. A data-based model divides the animal system into a series of compartments, 

which, in general, do not represent real, identifiable anatomic regions of the body, whereas the 

physiologically-based model compartments represent real anatomic regions of the body. 

Physiologically Based Pharmacodynamic (PBPD) Model—A type of physiologically based doseresponse model that quantitatively describes the relationship between target tissue dose and toxic end 

points. These models advance the importance of physiologically based models in that they clearly 

describe the biological effect (response) produced by the system following exposure to an exogenous 

substance. 

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PHOSPHATE ESTER FLAME RETARDANTS 275 

10. GLOSSARY 

Physiologically Based Pharmacokinetic (PBPK) Model—Comprised of a series of compartments 

representing organs or tissue groups with realistic weights and blood flows. These models require a 

variety of physiological information: tissue volumes, blood flow rates to tissues, cardiac output, alveolar 

ventilation rates, and possibly membrane permeabilities. The models also utilize biochemical 

information, such as air/blood partition coefficients, and metabolic parameters. PBPK models are also 

called biologically based tissue dosimetry models. 

Prevalence—The number of cases of a disease or condition in a population at one point in time. 

Prospective Study—A type of cohort study in which the pertinent observations are made on events 

occurring after the start of the study. A group is followed over time. 

q1*—The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the 

multistage procedure. The q1* can be used to calculate an estimate of carcinogenic potency, the 

incremental excess cancer risk per unit of exposure (usually μg/L for water, mg/kg/day for food, and 

μg/m3 for air). 

Recommended Exposure Limit (REL)—A National Institute for Occupational Safety and Health 

(NIOSH) time-weighted average (TWA) concentration for up to a 10-hour workday during a 40-hour 

workweek. 

Reference Concentration (RfC)—An estimate (with uncertainty spanning perhaps an order of 

magnitude) of a continuous inhalation exposure to the human population (including sensitive subgroups) 

that is likely to be without an appreciable risk of deleterious noncancer health effects during a lifetime. 

The inhalation reference concentration is for continuous inhalation exposures and is appropriately 

expressed in units of mg/m3 or ppm. 

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

daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious 

effects during a lifetime. The RfD is operationally derived from the no-observed-adverse-effect level 

(NOAEL, from animal and human studies) by a consistent application of uncertainty factors that reflect 

various types of data used to estimate RfDs and an additional modifying factor, which is based on a 

professional judgment of the entire database on the chemical. The RfDs are not applicable to 

nonthreshold effects such as cancer. 

Reportable Quantity (RQ)—The quantity of a hazardous substance that is considered reportable under 

the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA). Reportable 

quantities are (1) 1 pound or greater or (2) for selected substances, an amount established by regulation 

either under CERCLA or under Section 311 of the Clean Water Act. Quantities are measured over a 

24-hour period. 

Reproductive Toxicity—The occurrence of adverse effects on the reproductive system that may result 

from exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related 

endocrine system. The manifestation of such toxicity may be noted as alterations in sexual behavior, 

fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of 

this system. 

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PHOSPHATE ESTER FLAME RETARDANTS 276 

10. GLOSSARY 

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 group. 

Short-Term Exposure Limit (STEL)—The American Conference of Governmental Industrial 

Hygienists (ACGIH) maximum concentration to which workers can be exposed for up to 15 minutes 

continually. No more than four excursions are allowed per day, and there must be at least 60 minutes 

between exposure periods. The daily Threshold Limit Value-Time Weighted Average (TLV-TWA) may 

not be exceeded. 

Standardized Mortality Ratio (SMR)—A ratio of the observed number of deaths and the expected 

number of deaths in a specific standard population. 

Target Organ Toxicity—This term covers a broad range of adverse effects on target organs or 

physiological systems (e.g., renal, cardiovascular) extending from those arising through a single limited 

exposure to those assumed over a lifetime of exposure to a chemical. 

Teratogen—A chemical that causes structural defects that affect the development of an organism. 

Threshold Limit Value (TLV)—An American Conference of Governmental Industrial Hygienists 

(ACGIH) concentration of a substance to which most workers can be exposed without adverse effect. 

The TLV may be expressed as a Time Weighted Average (TWA), as a Short-Term Exposure Limit 

(STEL), or as a ceiling limit (CL). 

Time-Weighted Average (TWA)—An allowable exposure concentration averaged over a normal 8-hour 

workday or 40-hour workweek. 

Toxic Dose(50) (TD50)—A calculated dose of a chemical, introduced by a route other than inhalation, 

which is expected to cause a specific toxic effect in 50% of a defined experimental animal population. 

Toxicokinetic—The absorption, distribution, and elimination of toxic compounds in the living organism. 

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PHOSPHATE ESTER FLAME RETARDANTS 277 

10. GLOSSARY 

Uncertainty Factor (UF)—A factor used in operationally deriving the Minimal Risk Level (MRL) or 

Reference Dose (RfD) or Reference Concentration (RfC) from experimental data. UFs are intended to 

account for (1) the variation in sensitivity among the members of the human population, (2) the 

uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating from 

data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using lowestobserved-adverse-effect level (LOAEL) data rather than no-observed-adverse-effect level (NOAEL) data. 

A default for each individual UF is 10; if complete certainty in data exists, a value of 1 can be used; 

however, a reduced UF of 3 may be used on a case-by-case basis, 3 being the approximate logarithmic 

average of 10 and 1. 

Xenobiotic—Any chemical that is foreign to the biological system. 

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PHOSPHATE ESTER FLAME RETARDANTS 278 

10. GLOSSARY 

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PHOSPHATE ESTER FLAME RETARDANTS A-1 

APPENDIX A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS 

The Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) [42 U.S.C. 

9601 et seq.], as amended by the Superfund Amendments and Reauthorization Act (SARA) [Pub. L. 99– 

499], requires that the Agency for Toxic Substances and Disease Registry (ATSDR) develop jointly with 

the U.S. Environmental Protection Agency (EPA), in order of priority, a list of hazardous substances most 

commonly found at facilities on the CERCLA National Priorities List (NPL); prepare toxicological 

profiles for each substance included on the priority list of hazardous substances; and assure the initiation 

of a research program to fill identified data needs associated with the substances. 

The toxicological profiles include an examination, summary, and interpretation of available toxicological 

information and epidemiologic evaluations of a hazardous substance. During the development of 

toxicological profiles, Minimal Risk Levels (MRLs) are derived when reliable and sufficient data exist to 

identify the target organ(s) of effect or the most sensitive health effect(s) for a specific duration for a 

given route of exposure. An MRL is an estimate of the daily human exposure to a hazardous substance 

that is likely to be without appreciable risk of adverse noncancer health effects over a specified duration 

of exposure. MRLs are based on noncancer health effects only and are not based on a consideration of 

cancer effects. These substance-specific estimates, which are intended to serve as screening levels, are 

used by ATSDR health assessors to identify contaminants and potential health effects that may be of 

concern at hazardous waste sites. It is important to note that MRLs are not intended to define clean-up or 

action levels. 

MRLs are derived for hazardous substances using the no-observed-adverse-effect level/uncertainty factor 

approach. They are below levels that might cause adverse health effects in the people most sensitive to 

such chemical-induced effects. MRLs are derived for acute (1–14 days), intermediate (15–364 days), and 

chronic (365 days and longer) durations and for the oral and inhalation routes of exposure. Currently, 

MRLs for the dermal route of exposure are not derived because ATSDR has not yet identified a method 

suitable for this route of exposure. MRLs are generally based on the most sensitive chemical-induced end 

point considered to be of relevance to humans. Serious health effects (such as irreparable damage to the 

liver or kidneys, or birth defects) are not used as a basis for establishing MRLs. Exposure to a level 

above the MRL does not mean that adverse health effects will occur. 

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PHOSPHATE ESTER FLAME RETARDANTS 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 100-fold below levels that 

have been shown to be nontoxic in laboratory animals. 

Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the 

Division of Toxicology and Environmental Medicine, expert panel peer reviews, and agency-wide MRL 

Workgroup reviews, with participation from other federal agencies and comments from the public. They 

are subject to change as new information becomes available concomitant with updating the toxicological 

profiles. Thus, MRLs in the most recent toxicological profiles supersede previously published levels. 

For additional information regarding MRLs, please contact the Division of Toxicology and 

Environmental Medicine, Agency for Toxic Substances and Disease Registry, 1600 Clifton Road NE, 

Mailstop F-62, Atlanta, Georgia 30333. 

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PHOSPHATE ESTER FLAME RETARDANTS A-3 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Tris(2-chloroethyl) phosphate (TCEP) 

CAS Numbers: 115-96-8 

Date: September 2009 

Profile Status: Draft 3, Pre-public 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [X] Intermediate [ ] Chronic 

Graph Key: 23 

Species: Rat 

Minimal Risk Level: 0.6 [X] mg/kg/day [ ] ppm 

Reference: NTP. 1991a. NTP toxicology and carcinogenesis studies of tris(2-chloroethyl) phosphate 

(CAS No. 115-96-8) in F344/N rats and B6C3F1 mice (gavage studies). Program NT. TR 391. 

http://ntp.niehs.nih.gov/ntp/htdocs/LT_rpts/tr391.pdf. May 6, 2009. 

Experimental design: Groups of Fischer-344 rats (10/sex/dose) were administered 0, 22, 44, 88, 175, or 

350 mg TCEP by gavage in corn oil 5 days/week for 16 weeks (females) or 18 weeks (males). End points 

examined included clinical signs, body weight, serum cholinesterase activity, organ weight, gross 

necropsy, and histopathology of tissues and organs (control and highest dose group). The brain and 

kidneys of mid-dose (88 mg/kg/day) females were also examined microscopically. 

Effect noted in study and corresponding doses: Two females in each the 175 and 350 mg/kg/day groups 

died on week 4 due to overdosing that week; others in these groups showed ataxia, convulsions, excessive 

salivation, and gasping. Females receiving 175 and 350 mg/kg/day experienced occasional periods of 

hyperactivity after dosing. High-dose females showed periodic convulsions during week 12. At 

termination, serum cholinesterase was reduced by 25 and 41% in females treated with 175 and 

350 mg/kg/day, respectively; serum cholinesterase activity in males was comparable among groups. 

Final absolute and relative (to body weight or brain weight) weight of the liver and kidney of treated 

males and females were increased relative to controls (>10% at 175 mg/kg/day). At termination, serum 

cholinesterase was reduced by 25 and 41% in females treated with 175 and 350 mg/kg/day, respectively; 

cholinesterase in males was comparable among groups. There were no gross lesions due to treatment. 

However, necrosis of neurons of the hippocampus was seen in 10/10 females and in 2/10 males treated 

with 350 mg/kg/day, and in 8/10 females treated with 175 mg/kg/day. The affected neurons were mainly 

in the dorsomedial portion of the pyramidal row of the hippocampus. The more severe lesions showed 

mineral deposits in the affected areas. High-dose females also showed neuronal necrosis in the thalamus. 

The dose of 88 mg TCEP/kg/day is a NOAEL for brain lesions in female rats. 

Dose and end point used for MRL derivation: BMDL10 of 85.07 mg/kg/day for brain lesions in female 

rats. 

[ ] NOAEL [ ] LOAEL [X] BMDL10 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL 

[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. 

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PHOSPHATE ESTER FLAME RETARDANTS A-4 

APPENDIX A 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not 

applicable. 

Was a conversion used from intermittent to continuous exposure? Yes, the test chemical was 

administered 5 days/week; therefore, the BMDL10 of 85.07 mg/kg/day was adjusted for continuous 

exposure by multiplying by 5 and dividing by 7 yielding a duration-adjusted BMDL10 of 

60.76 mg/kg/day. 

Other additional studies or pertinent information that lend support to this MRL: Only three studies were 

available for review. NTP (1991a) also conducted studies in B6C3F1 mice and reported that no brain 

lesions were observed in mice treated with up to 700 mg TCEP/kg/day for 16 weeks. Similar doses were 

tested in CD-1 mice in a reproductive study that used a continuous breeding protocol, and no brain lesions 

were reported in that study (NTP 1991b). In the reproductive study, the lowest dose tested, 175 mg 

TCEP/kg/day, caused a significant reduction in the number of live F2 male pups per litter. In a 90-day 

study in male and female Sprague-Dawley rats administered up to 586 mg TCEP/kg/day via the diet, no 

brain lesions were reported (Anonymous 1977). However, it is unclear in the report available whether the 

brain was examined microscopically. No adverse effects were reported in that study, including 

hematology and clinical chemistry parameters, and histopathology of organs and tissues. 

Modeling of the changes in absolute kidney weight in female rats proved unsuccessful as an adequate fit 

could not be obtained with any model. However, if the changes in absolute kidney weight in female rats 

in the NTP (1991a) study had been used as basis for MRL derivation using a NOAEL/LOAEL approach, 

the NOAEL would have been 88 mg TCEP/kg/day (<10% increase in kidney weight). The next highest 

dose, 175 mg/kg/day induced a 16% increase in absolute kidney weight. Applying an uncertainty factor 

of 100 (10 for animal to human extrapolation and 10 for human variability) to the duration-adjusted 

NOAEL of 62.86 mg/kg/day (88 mg/kg/day x 5/7) would have resulted in an MRL of 0.6 mg/kg/day for 

TCEP, which supports the MRL derived using the BMD approach using the data set for brain lesions. 

Agency Contacts (Chemical Managers): G. Daniel Todd, Ph.D. 

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PHOSPHATE ESTER FLAME RETARDANTS A-5 

APPENDIX A 

BENCHMARK MODELING OF BRAIN LESIONS IN FEMALE RATS 

Incidence data for brain lesions in female rats exposed to TCEP (NTP 1991a) were analyzed using the 

BMD approach for MRL derivation (Table A-1). Models in the EPA Benchmark Dose Software (BMDS 

version 2.1) (gamma, logistic, log-logistic, multi-stage, probit, log-probit, quantal linear, Weibull models) 

were fit to the brain lesions data to determine a potential point of departure for the MRL. Adequate 

model fit is judged by three criteria: goodness-of-fit (p>0.1), visual inspection of the dose-response curve, 

and scaled residual at the data point (except the control) closest to the predefined BMR. Among all the 

models providing adequate fit to the data, the lowest BMDL is selected as the point of departure when 

differences between the BMDLs estimated from these models are more than 3-fold; otherwise, the BMDL 

from the model with the lowest AIC is chosen. In accordance with EPA (2000) guidance, BMDs and 

BMDLs associated with an extra risk of 10% are calculated for all models. Based on these criteria, a 

Log-logistic model provided the best fit to the data (Table A-2). 

Table A-1. Incidence of Hippocampal Necrosis in Female Rats Exposed to
 

Tris(2-chloroethyl) Phosphate for 16 Weeks
 

Dose (mg/kg/day) Total number of rats Number of rats with lesions 

0 10 0 

22 10 0 

44 10 0 

88 10 0 

175 10 8 

350 10 10 

Source: NTP 1991a 

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PHOSPHATE ESTER FLAME RETARDANTS A-6 

APPENDIX A 

Table A-2. Model Predictions for Necrosis of Hippocampal Neurons in Female
 

Rats
 

Model 

Gammab 

χ2 Goodness of 

fit p-valuea 

1.00 

AIC 

12.52 

BMD10 

(mg/kg/day) 

106.78 

BMDL10 

(mg/kg/day) 

80.41 

Logistic 1.00 14.01 160.02 88.23 

LogLogistic 1.00 12.01 143.41 85.07 

LogProbit 

Multistagec (2-degree 

polynomial) 

1.00 

0.41 

14.01 

20.35 

140.11 

56.58 

84.26 

41.38 

Probit 1.00 14.01 147.06 85.11 

Weibullb 1.00 14.01 149.30 84.03 

Quantal-Linear 0.02 33.31 22.12 14.85 

a

Values <0.10 fail to meet conventional goodness-of-fit criteria b

Power restricted to ≥1 c

Betas restricted to ≥0; 1-degree polynomial 

AIC = Akaike Information Criterion; BMD/BMC = maximum likelihood estimate of the dose/concentration associated 

with the selected benchmark response; BMDL/BMCL = 95% lower confidence limit on the BMD/BMC; SD = standard 

deviation 

Source: NTP 1991a 

From this model, the predicted doses associated with a 10% extra risk (BMD10) for brain lesions in female 

rats was 143.41 mg/kg/day; the lower 95% confidence limit on this dose (BMDL10) was 85.07 mg/kg/day 

(Figure A-1). Modeling the decrease in the number of live F2 male pups per litter reported in the NTP 

(1991b) study resulted in the Linear (constant variance) model providing the best fit with a BMD10 and 

BMDL10 of 242.19 and 167.83 mg/kg/day, respectively, considerably higher than the values obtained in 

the analysis of the brain lesions in female rats. 

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PHOSPHATE ESTER FLAME RETARDANTS A-7 

APPENDIX A 

Figure A-1. Predicted and Observed Incidence of Brain Lesions in Female Rats 

Exposed to Tris(2-chloroethyl) Phosphate for 16 Weeks 

Log-Logistic Model with 0.95 Confidence Level 

0 

0.2 

0.4 

0.6 

0.8 

1 

Fraction Affected 

BMDL BMD 

Log-Logistic 

0 50 100 150 200 250 300 350 

dose 

10:04 05/18 2009 

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PHOSPHATE ESTER FLAME RETARDANTS A-8 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Tris(2-chloroethyl) phosphate (TCEP) 

CAS Numbers: 115-96-8 

Date: September 2009 

Profile Status: Draft 3, Pre-public 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [ ] Intermediate [X] Chronic 

Graph Key: 34 

Species: Rat 

Minimal Risk Level: 0.3 [X] mg/kg/day [ ] ppm 

Reference: NTP. 1991a. NTP toxicology and carcinogenesis studies of tris(2-chloroethyl) phosphate 

(CAS No. 115-96-8) in F344/N rats and B6C3F1 mice (gavage studies). Program NT. TR 391. 

http://ntp.niehs.nih.gov/ntp/htdocs/LT_rpts/tr391.pdf. May 6, 2009. 

Experimental design: Groups of Fischer-344 rats (60 rats/sex/dose) were administered 0, 44, or 88 mg 

TCEP/kg/day by gavage in corn oil 5 days/week for 104 weeks. End points examined included clinical 

signs, body weight, organ weight, gross necropsy, and histopathology of all major tissues and organs at 

interim sacrifice (week 66, 10 rats/sex/group) and at termination. Hematology and clinical chemistry tests 

were conducted at interim sacrifice. 

Effect noted in study and corresponding doses: There were no clinical signs attributable to administration 

of TCEP or effects on body weight. Survival was reduced in high-dose males and females. Females that 

died early frequently had brain lesions, males did not. There were no chemical-related alterations in 

clinical chemistry and hematology parameters at week 66. Interim necropsy revealed a significant 

increase in absolute and relative liver and kidney weights in high-dose males. At termination, one of the 

principal nonneoplastic alterations attributed to administration of TCEP was a significant increase in renal 

tubule epithelial hyperplasia in the convoluted tubules of the cortex in high-dose males and females. The 

lesions were focal or multifocal and were characterized by stratification of the epithelial cells with partial 

to complete obliteration of the tubule lumens. In addition to the kidneys lesions, high-dose female rats 

showed degenerative lesions in the brain. The degenerative lesions were located in the cerebral cortex 

and brain stem, involved both the gray and white matter, and were focally distributed. Specifically, the 

lesions were in the thalamus, hypothalamus, basal ganglia, and frontal and parietal cortex. Other affected 

structures included the cingulate cortex, olfactory cortex, superior colliculus, hippocampus, geniculate 

body, globus pallidus, ventral pallidum, and amygdaloid nuclear region. The lesions varied in severity 

from minimal to marked, and often involved extensive areas. Active lesions were characterized by 

degeneration and necrosis with hemorrhage, while resolving lesions exhibited loss of neurons and 

neuropil, proliferation of glial cells, capillary hyperplasia, hypertrophy of the tunica media of small 

vessels, and hemosiderin-laden macrophages. Brain lesions were already observed at the 66-month 

interim sacrifice. Incidences of lesions in specific areas ranged from 24 to 38%. However, the reporting 

of the data (no individual animal data) in the NTP (1991a) report does not allow the determination of 

whether individual animals had more than one lesion type. The lesion with the highest incidence was 

cerebrum gliosis with an incidence of 19/50 (38%); the incidences in the control and low-dose groups 

were 0/50 and 0/49, respectively. A NOAEL of 44 mg/kg/day was defined for renal tubule epithelial 

hyperplasia in male and female rats and for cerebrum gliosis in female rats. 

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PHOSPHATE ESTER FLAME RETARDANTS A-9 

APPENDIX A 

Dose and end point used for MRL derivation: BMDL10 of 36.09 mg/kg/day for renal tubule epithelial 

hyperplasia in female rats. 

[ ] NOAEL [ ] LOAEL [X] BMDL10 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL 

[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. 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not 

applicable. 

Was a conversion used from intermittent to continuous exposure? Yes, the test chemical was 

administered 5 days/week; therefore, the BMDL10 of 36.09 mg/kg/day was adjusted for continuous 

exposure by multiplying by 5 and dividing by 7 yielding a duration-adjusted BMDL10 of 

25.78 mg/kg/day. 

Other additional studies or pertinent information that lend support to this MRL: The NTP (1991a) study 

was the only chronic-duration oral study available for TCEP. The BMDL10 for cerebrum gliosis in female 

rats was somewhat higher (59.86 mg/kg/day) than that obtained for the renal tubular hyperplasia in both 

male and female rats; therefore, the MRL derived based on renal lesion is protective of brain lesions. 

Agency Contacts (Chemical Managers): G. Daniel Todd, Ph.D. 

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PHOSPHATE ESTER FLAME RETARDANTS A-10 

APPENDIX A 

BENCHMARK MODELING OF RENAL TUBULE HYPERPLASIA IN FEMALE RATS 

Incidence data for renal tubule epithelial hyperplasia in female rats exposed to TCEP (NTP 1991a) were 

analyzed using the BMD approach for MRL derivation (Table A-3). Models in the EPA BMDS 

(version 2.1) (gamma, logistic, log-logistic, multi-stage, probit, log-probit, quantal linear, Weibull 

models) were fit to the brain lesions data to determine a potential point of departure for the MRL. 

Adequate model fit is judged by three criteria: goodness-of-fit (p>0.1), visual inspection of the doseresponse curve, and scaled residual at the data point (except the control) closest to the predefined BMR. 

Among all the models providing adequate fit to the data, the lowest BMDL is selected as the point of 

departure when differences between the BMDLs estimated from these models are more than 3-fold; 

otherwise, the BMDL from the model with the lowest AIC is chosen. In accordance with EPA (2000) 

guidance, BMDs and BMDLs associated with an extra risk of 10% are calculated for all models. Based 

on these criteria, a Gamma model provided the best fit to the data (Table A-4). 

Table A-3. Incidence of Renal Tubule Epithelial Hyperplasia in Rats Exposed to 

Tris(2-chloroethyl) Phosphate for 2 Years 

Dose (mg/kg/day) Total number of rats Males with lesions Females with lesions 

0 50 0 0 

44 50 2 3 

88 50 24 16 

Source: NTP 1991a 

Table A-4. Model Predictions for Incidence of Renal Tubule Epithelial 

Hyperplasia in Female Rats 

Model 

Gammab 

χ2 Goodness of 

fit p-valuea 

1.00 

AIC 

89.38 

BMD10 

(mg/kg/day) 

53.09 

BMDL10 

(mg/kg/day) 

36.09 

Logistic 0.52 90.06 60.16 49.51 

LogLogistic 1.00 89.38 53.33 36.29 

LogProbit 

Multistagec (1-degree 

polynomial) 

Probit 

1.00 

0.16 

0.66 

89.38 

91.51 

89.71 

52.37 

32.13 

57.32 

37.59 

22.50 

46.59 

Weibullb 1.00 89.38 53.83 35.90 

Quantal-Linear 0.16 91.51 32.13 22.50 

a

Values <0.10 fail to meet conventional goodness-of-fit criteria b

Power restricted to ≥1 c

Betas restricted to ≥0; 1-degree polynomial 

AIC = Akaike Information Criterion; BMD/BMC = maximum likelihood estimate of the dose/concentration associated 

with the selected benchmark response; BMDL/BMCL = 95% lower confidence limit on the BMD/BMC; NA 

SD = standard deviation 

Source: NTP 1991a 

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PHOSPHATE ESTER FLAME RETARDANTS A-11 

APPENDIX A 

From this model, the predicted doses associated with a 10% extra risk (BMD10) for renal tubule 

hyperplasia in female rats was 53.09 mg/kg/day; the lower 95% confidence limit on this dose (BMDL10) 

was 36.09 mg/kg/day (Figure A-2). Modeling the data set for renal tubule hyperplasia in male rats 

resulted in the Log logistic model providing the best fit with a BMD10 and BMDL10 of 54.80 and 

43.58 mg/kg/day, respectively, only slightly higher than the values obtained in the analysis of the lesions 

in female rats. Modeling the data set for cerebrum gliosis in female rats resulted in the Log logistic model 

providing the best fit with a BMD10 and BMDL10 of 80.04 and 59.86 mg/kg/day, respectively. Therefore, 

the MRL based on renal lesions is protective of brain lesions. 

Figure A-2. Predicted and Observed Incidence of Renal Tubule Hyperplasia in 

Female Rats Exposed to Tris(2-chloroethyl) Phosphate for 2 Years
 

Gamma Multi-Hit Model with 0.95 Confidence Level 

0.5 

0.4 

0.3 

0.2 

0.1 

0 

0 10 20 30 40 50 60 70 80 90 

dose 

10:48 05/18 2009 

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BMDL BMD 

Gamma Multi-Hit 

Fraction Affected 
 

 

 

 

 

 

 

 

 

 

 

 

PHOSPHATE ESTER FLAME RETARDANTS A-12 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Tributyl phosphate (TnBP) 

CAS Numbers: 126-76-8 

Date: September 2009 

Profile Status: Draft 3, Pre-public 

Route: [ ] Inhalation [X] Oral 

Duration: [X] Acute [ ] Intermediate [ ] Chronic 

Graph Key: 13 

Species: Rat 

Minimal Risk Level: 1.1 [X] mg/kg/day [ ] ppm 

Reference: Noda T, Yamano T, Shimizu M, et al. 1994. Effects of TRI-n-butyl phosphate on pregnancy 

in rats. Food Chem Toxicol 32(11):1031-1036. 

Experimental design: Groups of Wistar rats (20 rats/sex/dose level) were administered 0, 62.5, 125, 250, 

or 500 mg TnBP/kg/day by gavage in corn oil on Gd 7–17. Clinical signs, body weight, and food 

consumption were monitored. Sacrifices were conducted on Gd 20. The gravid uterus, the position and 

number of living and dead fetuses in the uterus, including resorbed fetuses in the uterus, the number of 

corpora lutea, and maternal liver, kidneys, and spleen weights were recorded. The living fetuses were 

examined for their sex and external malformation, and then weighed. Skeletal abnormalities were 

evaluated in half of the fetuses, whereas the other half was evaluated for visceral abnormalities. 

Effect noted in study and corresponding doses: Rats exposed to 500 mg TnBP/kg/day showed 

piloerection, wetting of abdominal hair with urine, and salivation during treatment, but these signs 

disappeared after the last treatment. Final maternal weight was reduced 6–9% in the two highest dose 

groups. Adjusted body weight gain (weight gain from Gd 0 to 20 minus gravid uterus weight) was 

reduced 13% at 125 mg/kg/day, 39% at 250 mg/kg/day, and 63% at 500 mg/kg/day. Absolute liver and 

kidney weight in treated rats was not affected (<10% change relative to controls). Spleen weight was 

reduced 11% at 500 mg/kg/day. Gravid uterus weight was not affected by treatment. All pregnant rats 

had fetuses on Gd 20. There were no significant differences between the groups in any of the 

developmental parameters evaluated. There was only one malformation occurring in the 125 mg/kg/day 

dose group and consisted of conjoined twins. No visceral anomalies were reported. Based on a 

significant reduction in maternal body weight gain at ≥125 mg/kg/day, a maternal NOAEL and LOAEL 

of 62.5 and 125 mg/kg/day, respectively, were defined in this study; the highest dose tested, 

500 mg/kg/day was a developmental NOAEL. 

Dose and end point used for MRL derivation: BMDL of 111.47 mg/kg/day for decrease weight gain in 

pregnant rats on Gd 0–20. 

[ ] NOAEL [ ] LOAEL [X] BMDL 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL 

[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. 

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PHOSPHATE ESTER FLAME RETARDANTS A-13 

APPENDIX A 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not 

applicable. 

Was a conversion used from intermittent to continuous exposure? Not applicable. 

Other additional studies or pertinent information that lend support to this MRL: Only one additional 

study was a potential source of data for MRL derivation. In that study, groups of Sprague-Dawley rats 

(10/sex/group) were administered 0, 137, or 411 mg TnBP/kg/day by gavage on 14 consecutive days 

(Laham et al. 1984b). End points examined included clinical signs, body weight, hematological and 

clinical chemistry tests, and histological examinations of the brain, heart, kidneys, liver, lungs, spleen, 

ovaries, and testes. Significant findings in high-dose rats included decreased hemoglobin in females, 

increased absolute and relative liver weight in males and females, increased serum potassium in females, 

decreased absolute and relative spleen weight, and degenerative changes in the testes. A study of limited 

scope reported decreased nerve conduction velocity accompanied by morphological alterations in the 

sciatic nerve of rats dosed with 411 mg TnBP/kg/day for 14 days; the NOAEL was 274 mg TnBP/kg/day 

(Laham et al. 1983). 

Agency Contacts (Chemical Managers): G. Daniel Todd, Ph.D. 

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PHOSPHATE ESTER FLAME RETARDANTS A-14 

APPENDIX A 

BENCHMARK MODELING OF REDUCED WEIGHT GAIN IN PREGNANT RATS 

Data from Noda et al. (1994) were analyzed using the BMD approach for MRL derivation. BMD models 

in the EPA BMDS (version 2.1) (linear, polynomial, power, and Hill models) were fit to the maternal 

body weight gain data (Table A-5) to determine potential points of departure for the MRL. 

Table A-5. Data for the Change in Adjusted Body Weight Gain in Pregnant Rats 

on Gestation Days 0–20 

Dose (mg/kg/day) Number of animals tested Body weight gain (g) Standard deviation 

0 20 38.0 7.46 

62.5 20 37.2 8.27 

125 20 33.2 8.98 

250 20 23.0 6.51 

500 20 9.4 8.56 

Source: Noda et al. 1994 

Adequate model fit is judged by three criteria: goodness-of-fit (p>0.1), visual inspection of the doseresponse curve, and scaled residual at the data point (except the control) closest to the predefined BMR. 

Among all the models providing adequate fit to the data, the lowest BMDL is selected as the point of 

departure when differences between the BMDLs estimated from these models are more than 3-fold; 

otherwise, the BMDL from the model with the lowest AIC is chosen. In the absence of a clear criteria as 

to what level of change in weight gain during pregnancy should be considered adverse, the BMR was 

defined as a change in mean body weight gain equal to one standard deviation from the control mean 

(EPA 2000). Based on the criteria for model selection, the Linear model provided the best fit (Table A6 and Figure A-3). 

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PHOSPHATE ESTER FLAME RETARDANTS A-15 

APPENDIX A 

Table A-6. Model Predictions for Tributyl Phosphate, Change in Body Weight
 

Gain on Gestation Days 0–20
 

Model Variance Means BMD1SD BMDL1SD 

(constant variance) p-valuea p-valuea AIC (mg/kg/day) (mg/kg/day) 

Hill 0.65 0.86 520.89 162.91 113.67 

Linearb 0.65 0.46 519.44 130.32 111.47 

Polynomial (2-degree 

polynomial) c 0.65 0.28 521.43 133.85 111.53 

Polynomial (3-degree 

polynomial)c 0.65 0.28 521.43 133.85 111.53 

Power 0.65 0.31 521.19 145.15 112.27 

a

Values <0.10 fail to meet conventional goodness-of-fit criteria b

Coefficients restricted to be negative 

AIC = Akaike Information Criterion; BMD/BMC = maximum likelihood estimate of the dose/concentration associated 

with the selected benchmark response; BMDL/BMCL = 95% lower confidence limit on the BMD/BMC; SD = standard 

deviation 

Source: Noda et al. 1994 

Figure A-3. Fit of Linear Model (Constant Variance) to Data on Body Weight Gain 

on Gestation Days 0–20 

Linear Model with 0.95 Confidence Level 

45 

40 

35 

30 

25 

20 

15 

10 

5 

0 100 200 300 400 500 

dose 

14:13 05/26 2009 

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BMDL BMD 

Linear 

Mean Response 
 

 

 

 

 

 

 

 

 

 

 

 

PHOSPHATE ESTER FLAME RETARDANTS A-16 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Tributyl phosphate (TnBP) 

CAS Numbers: 126-76-8 

Date: September 2009 

Profile Status: Draft 3, Pre-public 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [X] Intermediate [ ] Chronic 

Graph Key: 22 

Species: Rat 

Minimal Risk Level: 0.02 [X] mg/kg/day [ ] ppm 

Reference: Arnold LL, Christenson WR, Cano M, et al. 1997. Tributyl phosphate effects on urine and 

bladder epithelium in male Sprague-Dawley rats. Fundam Appl Toxicol 40(2):247-255. 

Experimental design: Groups of male Sprague-Dawley rats (20 in the control and high-dose group, 10 in 

the low- and mid-dose groups) were fed a diet containing 0, 200, 700, or 3,000 ppm TnBP for 10 weeks. 

This corresponds to doses of approximately 0, 9, 33, or 143 mg TnBP/kg/day based on a similar study in 

male Sprague-Dawley rats exposed to the same dietary concentrations of TnBP (Auletta et al. 1998a). 

End points examined included clinical signs, body weight, food consumption, urinalysis, and histological 

examination (10 rats per group at termination) of the stomach, kidneys, and urinary bladder. To evaluate 

the effect of urine acidification, an additional group of rats received 3,000 ppm TnBP plus 12,300 ppm 

ammonium chloride. Yet another group received ammonium chloride alone. Reversibility of the effects 

of TnBP was examined in a group of 10 rats kept on a control diet for 10 weeks after the 10-week 

treatment period. 

Effect noted in study and corresponding doses: There were no clinical signs attributable to TnBP. Mean 

final weight of the high-dose group was reduced >10% relative to controls; food consumption was not 

significantly affected. During the recovery period, body weight of the high-dose recovered to control 

levels. Urinary parameters on week 11 among treated groups were comparable to controls except for 

osmolality and creatinine, which were significantly lower in the high-dose group than in controls, 

indicating a dilutional effect. Urinary pH in the groups receiving ammonium chloride was 6.0 compared 

to ≥ 7.5 in the other groups. There was no evidence of an amorphous precipitate, abnormal microcrystals, 

or calculi in the urine from individual rats. Crystals were present in the control and TnBP-treated rats. 

Treatment with TnBP caused urinary bladder hyperplasia in mid-and high-dose rats, with severity that 

was dose-related, reversible, and less severe in the rats dosed also with ammonium chloride. Incidences 

were 0/10, 0/10, 8/10, and 10/10 with increasing doses (see also Table A-7 below). There were no 

histological alterations in the stomach or kidneys. A NOAEL of 9 mg TnBP/kg/day for urothelial 

hyperplasia was defined in this study; the LOAEL was 33 mg/kg/day. 

Dose and end point used for MRL derivation: BMDL10 of 1.96 mg/kg/day for urinary bladder hyperplasia 

in male rats dosed in the diet for 10 weeks. 

[ ] NOAEL [ ] LOAEL [X] BMDL10 

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PHOSPHATE ESTER FLAME RETARDANTS A-17 

APPENDIX A 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL 

[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, doses were 

estimated based on a similar study in male Sprague-Dawley rats exposed to the same dietary 

concentrations of TnBP (Auletta et al. 1998a). 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not 

applicable. 

Was a conversion used from intermittent to continuous exposure? Not applicable. 

Other additional studies or pertinent information that lend support to this MRL: The urinary bladder was 

also the most sensitive tissue in two additional intermediate-duration studies. Increased incidence of 

urinary bladder hyperplasia was reported in male and female rats in a 3-month dietary study (FMC 

1985a); the NOAEL was 13.8 mg TnBP/kg/day and the LOAEL was 68.1 mg TnBP/kg/day. Tyl et al. 

(1997) reported similar results in F0 and F1 male and female rats dosed with approximately 51 mg 

TnBP/kg/day in a 2-generation reproductive study; the NOAEL was 15 mg TnBP/kg/day (see Table A-7, 

below). 

Agency Contacts (Chemical Managers): G. Daniel Todd, Ph.D. 

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PHOSPHATE ESTER FLAME RETARDANTS A-18 

APPENDIX A 

BENCHMARK MODELING OF URINARY BLADDER HYPERPLASIA IN RATS 

Incidence data for urothelial hyperplasia in male rats from the Arnold et al. (1997) study, for urothelial 

hyperplasia in F0 males and females from the Tyl et al. (1997) study, and for urothelial hyperplasia in 

males from the FMC 1985a) study were analyzed using the BMD approach for MRL derivation. 

Incidences are shown in Table A-7. The data set from Tyl et al. (1997) corresponds to incidences in the 

parental generation (F0). Incidences in F1 females were virtually the same as in F0 females, whereas 

incidences in mid-dose F1 males were slightly lower than in F0 males. Also included in Table A-6 is the 

data set from the 2-year study of Auletta et al. (1998a). 

Table A-7. Incidence of Urinary Bladder Hyperplasia Induced by Tributyl
 

Phosphate in Four Studies in Rats
 

NOAEL LOAEL BMDL10 

Arnold et al. (1997)–10 weeks 

Dose (mg/kg/day) 0 9 33 143 1.96 

Incidence 0/10 0/10 8/10 10/10 

FMC (1985a)–13 weeks 

Dose (mg/kg/day) 0.12 0.6 2.8 13.8 68.1 360 

Males 0/10 0/10 0/10 0/10 10/10 10/10 2.60 

Tyl et al. (1997)–10 weeks 

Dose (mg/kg/day) 0 15 51 217 

Males 0/30 1/29 22/29 30/30 13.77 

Females 0/30 2/29 21/30 30/30 4.16 

Auletta et al. (1998a)–2 years 

Dose (mg/kg/day) 0 9 33 143 

Males 3/50 3/50 12/49 17/49 23.51 

Females 1/50 1/50 5/49 29/49 19.85 

BMDL10 = The 95% lower confidence limit on the dose associated with a 10% extra risk; LOAEL = lowest-observedadverse-effect level; NOAEL = no-observed-adverse-effect level 

Models in the EPA BMDS (version 2.1) (gamma, logistic, log-logistic, multi-stage, probit, log-probit, 

quantal linear, Weibull models) were fit to urothelial hyperplasia data to determine potential points of 

departure for the MRL. Adequate model fit is judged by three criteria: goodness-of-fit (p>0.1), visual 

inspection of the dose-response curve, and scaled residual at the data point (except the control) closest to 

the predefined BMR. Among all the models providing adequate fit to the data, the lowest BMDL is 

selected as the point of departure when differences between the BMDLs estimated from these models are 

more than 3-fold; otherwise, the BMDL from the model with the lowest AIC is chosen. In accordance 

with EPA (2000) guidance, BMDs and BMDLs associated with an extra risk of 10% are calculated for all 

models. Using these criteria, the Multistage model fit of the Arnold et al. (1997) data set was selected for 

MRL derivation. Table A-8 shows model prediction for the data set from Arnold et al. (1997), as this 

data set was the one selected for MRL derivation. The fit of the data by the Multistage model is shown in 

Figure A-4. 

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PHOSPHATE ESTER FLAME RETARDANTS A-19 

APPENDIX A 

Table A-8. Model Predictions for Incidence of Urinary Bladder Hyperplasia in
 

Male Rats
 

χ2 Goodness of fit BMD10 BMDL10 

Model p-valuea AIC (mg/kg/day) (mg/kg/day) 

Gammab 1.00 12.01 19.74 8.03 

Logistic 1.00 14.01 28.80 10.49 

LogLogistic 1.00 14.01 26.21 8.27 

LogProbit 1.00 14.01 21.67 8.24 

Multistagec 0.22 19.03 3.30 1.96 

Probit 1.00 14.01 25.25 9.61 

Weibullb 1.00 14.01 23.96 7.89 

Quantal-Linear 0.22 19.03 3.30 1.96 

a

Values <0.10 fail to meet conventional goodness-of-fit criteria b

Power restricted to ≥1 c

Betas restricted to ≥0; 1-degree polynomial 

AIC = Akaike Information Criterion; BMD/BMC = maximum likelihood estimate of the dose/concentration associated 

with the selected benchmark response; BMDL/BMCL = 95% lower confidence limit on the BMD/BMC 

Source: Arnold et al. 1997 

A BMD10 and BMDL10 of 3.30 and 1.96 mg/kg/day, respectively, were derived for the incidence data 

reported by Arnold et al. (1997). Analysis of the urinary hyperplasia data in F0 males in the Tyl et al. 

(1997) study yielded a BMD10 and BMDL10 of 20.29 and 13.77 mg TnBP/kg/day, respectively; the 

corresponding values from the analysis of incidences in F0 female rats were 5.58 and 4.16 mg 

TnBP/kg/day. Analysis of the incidence in males in the FMC (1985a) study yielded a BMD10 and 

BMDL10 of 4.49 and 2.60 mg TnBP/kg/day, respectively. In order to be health protective, the lowest 

BMDL10 of 1.96 mg TnBP/kg/day from Arnold et al. (1997) is selected as the point of departure for the 

MRL. Applying an uncertainty factor of 100 (10 for animal to human extrapolation and 10 for human 

variability) to the BMDL10 of 1.96 mg TnBP/kg/day yields an intermediate-duration oral MRL of 

0.02 mg/kg/day for TnBP. 

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PHOSPHATE ESTER FLAME RETARDANTS A-20 

APPENDIX A 

Figure A-4. Fit of Multistage Model to Data on Incidence of Urinary Bladder
 

Hyperplasia in Male Sprague-Dawley Rats
 

Multistage Model with 0.95 Confidence Level 

0

 0.2

 0.4

 0.6

 0.8

 1

 0 20 40 60 80 100 120 140 

Fraction Affected 

BMDL BMD

Multistage 

dose 

15:42 05/17 2009 

Source: Arnold et al. 1997 

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PHOSPHATE ESTER FLAME RETARDANTS A-21 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Tributyl phosphate (TnBP) 

CAS Numbers: 126-76-8 

Date: September 2009 

Profile Status: Draft 3, Pre-public 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [ ] Intermediate [X] Chronic 

Species: Rat 

Minimal Risk Level: 0.02 [X] mg/kg/day [ ] ppm 

Reference: Arnold LL, Christenson WR, Cano M, et al. 1997. Tributyl phosphate effects on urine and 

bladder epithelium in male Sprague-Dawley rats. Fundam Appl Toxicol 40(2):247-255. 

It is recommended that the intermediate-duration oral MRL of 0.02 mg/kg/day for TnBP also be adopted 

as chronic-duration oral MRL, as explained below. 

Only two chronic-duration oral studies were located for TnBP, one in rats (Auletta et al. 1998a) and one 

in mice (Auletta et al. 1998b). As in the intermediate-duration studies, the urinary bladder from rats was 

the most sensitive target for TnBP toxicity. Rats were dosed via the diet for 2 years, whereas mice were 

treated for 18 months. Male rats received doses of 0, 9, 33, or 143 mg TnBP/kg/day, whereas females 

received doses of 0, 12, 42, or 182 mg TnBP/kg/day. The doses for male and female mice were 0, 28.9, 

169, or 585 mg/kg/day and 0, 24.1, 206, or 711 mg/kg/day, respectively. At termination, the incidences 

of trace to severe urinary bladder hyperplasia in male rats were 3/50, 3/50, 12/49, and 17/49 with 

increasing doses (see Table A-7 in the derivation of the intermediate-duration oral MRL). The 

corresponding incidences in female rats were 1/50, 1/50, 5/49, and 29/49. Urinary bladder hyperplasia 

was not observed in mice. Based on these findings, the increased incidence of urothelial hyperplasia in 

rats was used to determine a point of departure for derivation of a chronic-duration oral MRL for TnBP. 

Incidence data for urinary bladder hyperplasia in male and female rats exposed to TnBP (Auletta et al. 

1998a) were analyzed using the BMD approach for MRL derivation. Models in the EPA BMDS 

(version 2.1) (gamma, logistic, log-logistic, multi-stage, probit, log-probit, quantal linear, Weibull 

models) were fit to the urinary bladder lesion data to determine potential points of departure for the MRL. 

Adequate model fit is judged by three criteria: goodness-of-fit (p>0.1), visual inspection of the doseresponse curve, and scaled residual at the data point (except the control) closest to the predefined BMR. 

Among all the models providing adequate fit to the data, the lowest BMDL is selected as the point of 

departure when differences between the BMDLs estimated from these models are more than 3-fold; 

otherwise, the BMDL from the model with the lowest AIC is chosen. In accordance with EPA (2000) 

guidance, BMDs and BMDLs associated with an extra risk of 10% are calculated for all models. 

Comparing across models using these criteria showed that the Gamma model provided the best for the 

incidence data in male rats, whereas the Multistage 1-degree polynomial provided the best fit for the 

incidence data in female rats. This analysis yielded respective BMDL10 values of 23.51 and 19.85 mg 

TnBP/kg/day (Tables A-9 and A-10). 

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PHOSPHATE ESTER FLAME RETARDANTS A-22 

APPENDIX A 

Table A-9. Model Predictions for Tributyl Phosphate, Incidence of Urinary
 

Bladder Hyperplasia in Male Rats
 

χ2 Goodness of fit BMDL10 

Model p-valuea AIC BMD10 (mg/kg/day) (mg/kg/day) 

Gammab 0.13 171.02 35.41 23.51 

Logistic 0.03 173.60 64.45 50.10 

LogLogistic 0.00 190.72 2.17x1012 NA 

LogProbit 0.00 188.72 4.25x109 NA 

Multistagec 0.13 171.02 35.41 23.51 

Probit 0.04 173.30 60.52 46.60 

Weibullb 0.13 171.02 35.41 23.51 

Quantal-Linear 0.13 171.02 35.41 23.51 

a

Values <0.10 fail to meet conventional goodness-of-fit criteria b

Power restricted to ≥1 c

Betas restricted to ≥0; 1-degree polynomial 

AIC = Akaike Information Criterion; BMD/BMC = maximum likelihood estimate of the dose/concentration associated 

with the selected benchmark response; BMDL/BMCL = 95% lower confidence limit on the BMD/BMC; 

NA = Benchmark dose computation failed (lower limit includes zero) 

Source: Auletta et al. 1998a 

Table A-10. Model Predictions for Tributyl Phosphate, Incidence of Urinary
 

Bladder Hyperplasia in Female Ratsa
 

χ2 Goodness of Fit BMD10 

Model p-valueb AIC (mg/kg/day) BMDL10 (mg/kg/day) 

Gammac 0.74 124.28 47.67 28.56 

Logistic 0.49 123.59 73.30 59.41 

LogLogistic 0.76 124.27 47.03 28.66 

LogProbit 0.91 124.18 45.90 33.21 

Multistaged 0.14 126.67 26.26 19.85 

Probit 0.62 123.14 65.64 53.59 

Weibullc 0.68 124.34 48.48 28.42 

Quantal-Linear 0.14 126.67 26.26 19.85 

AIC = Akaike Information Criterion; BMD/BMC = maximum likelihood estimate of the dose/concentration associated 

with the selected benchmark response; BMDL/BMCL = 95% lower confidence limit on the BMD/BMC 

a

Auletta et al. 1998a 

b

Values <0.10 fail to meet conventional goodness-of-fit criteria c

Power restricted to ≥1 d

Betas restricted to ≥0; 1-degree polynomial 

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PHOSPHATE ESTER FLAME RETARDANTS A-23 

APPENDIX A 

As seen in Tables A-9 and A-10, and also in Table A-7, these values are higher than the BMDL10 values 

obtained in the analyses of the incidences of urinary bladder hyperplasia reported in the intermediateduration studies (Arnold et al. 1997; Tyl et al. 1997). As the data show, the incidences of urinary bladder 

hyperplasia at comparable high doses are higher in the intermediate-duration studies than in the chronicduration study. A likely explanation for this phenomenon is provided in the chronic study by the 

observation that rats with malignant bladder tumors usually did not have any remaining uninvolved 

epithelium to evaluate for the presence or absence of hyperplasia (Auletta et al. 1998a). Whether urinary 

bladder hyperplasia is a potential precursor of urinary bladder tumors is not known for certain, but the 

data are suggestive. The lower incidence of hyperplasia at the higher dose levels in the chronic-duration 

study may just be the result of the hyperplasia transforming into neoplasia. As shown in Table A-7, dose 

levels that did not increase the incidence of urothelial hyperplasia in the intermediate-duration studies 

(NOAELs ranged from 9 to 15 mg/kg/day) also did not increase the incidence of urinary bladder 

hyperplasia in the chronic-duration study (NOAEL was 9 mg/kg/day) and did not increase the incidence 

of neoplastic lesions; thus, the NOAEL from intermediate-duration studies would also be protective for 

chronic exposure. Therefore, the intermediate-duration oral MRL of 0.02 mg/kg/day based on a BMDL10 

of 1.96 mg/kg/day is adopted also as chronic-duration oral MRL for TnBP. 

Agency Contacts (Chemical Managers): G. Daniel Todd, Ph.D. 

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PHOSPHATE ESTER FLAME RETARDANTS A-24 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Tris(2-butoxyethyl) phosphate (TBEP) 

CAS Numbers: 78-51-3 

Date: September 2009 

Profile Status: Draft 3, Pre-public 

Route: [ ] Inhalation [X] Oral 

Duration: [X] Acute [ ] Intermediate [ ] Chronic 

Graph Key: 3 

Species: Rat 

Minimal Risk Level: 4.8 [X] mg/kg/day [ ] ppm 

Reference: Monsanto Co. 1985b. Tributoxyethyl phosphate: Teratology study in rats with attachments 

and cover letter dated 083085. Submitted to the U.S. Environmental Protection Agency under TSCA 

Section 8D. EPA96-910000298. OTS0528528. 

Experimental design: Groups of female Sprague-Dawley rats (25/dose group) were administered 0, 250, 

500, or 1500 mg TBEP/kg/day by gavage in corn oil on Gd 6–15. End points monitored included 

mortality, clinical signs, and body weight. Sacrifices were conducted on Gd 20. Immediately after 

sacrifice, the uterus and ovaries were exposed and the number and location of viable and nonviable 

fetuses, early and late resorptions, and number of total implantations and corpora lutea were recorded. 

Fetuses were weighed, sexed, and examined for external malformations and variations. Fetuses were then 

prepared for visceral and skeletal examinations. 

Effect noted in study and corresponding doses: There was one early death in the high-dose group, but the 

cause of death could not be determined. Chemical-related clinical signs included wet haircoat matting or 

staining with urine, brown material or blood on the face, neck, thorax, and/or anogenital area; this was 

observed in approximately half of the high-dose rats. Following dosing on Gd 6, two high-dose rats were 

ataxic, had reduced righting reflex, and/or were lethargic. Terminal body weight of the dams (unadjusted 

for uterine content) was significantly reduced, but only 6% relative to controls. Weight gain in high-dose 

rats was significantly reduced from Gd 6 on; during treatment (Gd 6–15), weight gain in this group was 

reduced 35%. Fetal body weight and sex ratios were not affected and neither were other developmental 

parameters. Treatment with TBEP did not affect the incidence of external, visceral, or skeletal anomalies. 

A maternal NOAEL and LOAEL of 500 and 1500 mg TBEP/kg/day, respectively, were defined in this 

study. The highest dose tested, 1500 mg/kg/day, was a developmental NOAEL based on no evidence of 

fetotoxicity or teratogenicity. 

Dose and end point used for MRL derivation: BMDL of 477.25 mg/kg/day for decrease weight gain in 

pregnant rats on Gd 6–15. 

[ ] NOAEL [ ] LOAEL [X] BMDL 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL 

[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. 

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PHOSPHATE ESTER FLAME RETARDANTS A-25 

APPENDIX A 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not 

applicable. 

Was a conversion used from intermittent to continuous exposure? Not applicable. 

Other additional studies or pertinent information that lend support to this MRL: Only one additional 

study was a potential source of data for MRL derivation. In that study, Sprague-Dawley rats (10/sex/dose 

level) were treated with up to 100 mg TBEP/kg/day by gavage in corn oil for 14 days (Komsta et al. 

1989). End points monitored included clinical signs, body weight, hematology and clinical chemistry at 

termination, organ weights (brain, heart, liver, kidney, and spleen), microsomal liver enzyme activities, 

and gross and microscopic morphology of all major tissues and organs. The results did not show any 

significant differences between the treated and control groups for any of the parameters evaluated. 

However, because no adverse effects were reported, the Komsta et al. (1989) study was not considered a 

suitable basis for an MRL. An additional study that used considerably higher doses reported that 1 week 

after administration of a single gavage dose of ≥1,750 mg TBEP/kg, female rats showed slight tremors 

and piloerection, whereas those treated with 3,200 mg/kg exhibited tremors and abnormal gait; males 

appeared to be somewhat less sensitive. Examination of the sciatic nerve showed nerve degeneration in 

females dosed with ≥2,000 mg/kg. The NOAEL for males and females was 3,200 and 1,500 mg/kg, 

respectively. 

Agency Contacts (Chemical Managers): G. Daniel Todd, Ph.D. 

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PHOSPHATE ESTER FLAME RETARDANTS A-26 

APPENDIX A 

BENCHMARK MODELING OF REDUCED WEIGHT GAIN IN PREGNANT RATS 

Data from Monsanto Co. (1985b) were analyzed using the BMD approach for MRL derivation. BMD 

models in the EPA BMDS (version 2.1) (linear, polynomial, power, and Hill models) were fit to the 

maternal body weight gain data to determine potential points of departure for the MRL (Table A-11). 

Adequate model fit is judged by three criteria: goodness-of-fit (p>0.1), visual inspection of the doseresponse curve, and scaled residual at the data point (except the control) closest to the predefined BMR. 

Among all the models providing adequate fit to the data, the lowest BMDL is selected as the point of 

departure when differences between the BMDLs estimated from these models are more than 3-fold; 

otherwise, the BMDL from the model with the lowest AIC is chosen. In the absence of a clear criteria as 

to what level of change in weight gain during pregnancy should be considered adverse, the BMR was 

defined as a change in mean body weight gain equal to one standard deviation from the control mean 

(EPA 2000). 

Table A-11. Data for the Change in Body Weight Gain in Pregnant Rats on 

Gestation Days 6–15
 

Dose (mg/kg/day) Number of animals tested Body weight gain (g) Standard deviation 

0 25 55 5.5 

250 25 53 8.4 

500 25 52 7.6 

1,500 25 36 11.1 

Source: Monsanto Co. 1985b 

As seen in Table A-12, using the criteria for model selection mentioned above, the Multistage 3-degree 

polynomial model provided the best fit. The corresponding BMD1SD was 824.97 mg/kg/day; the 

corresponding benchmark dose limit (BMDL1SD) was 477.25 mg/kg/day. Applying an uncertainty factor 

of 100 (10 for animal to human extrapolation and 10 for human variability) to the BMDL1SD of 

477.25 mg/kg/day results in an acute-duration oral MRL of 4.8 mg/kg/day for TBEP. The model fit is 

shown in Figure A-5. 

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PHOSPHATE ESTER FLAME RETARDANTS A-27 

APPENDIX A 

Table A-12. Model Predictions for Change in Maternal Body Weight Gain on 

Gestation Days 6–15
 

Variance Means BMD1SD BMDL1SD 

Model p-valuea p-valuea AIC (mg/kg/day) (mg/kg/day) 

Linear—constant 0.007 0.27 530.012 635.60 521.84 

Hill—nonconstant 0.18 NA 525.61 766.47 NA 

Linearb—nonconstant 0.18 0.27 523.40 533.99 418.71 

Polynomial (2-degree 

polynomial)b—nonconstant 

0.18 0.42 523.41 776.36 469.34 

Polynomial (3-degree 

polynomial)b—nonconstant 

0.18 0.50 523.23 824.97 477.25 

Power—nonconstant 0.18 0.36 523.60 766.71 461.90 

a

Values <0.10 fail to meet conventional goodness-of-fit criteria b

Coefficients restricted to be negative 

AIC = Akaike Information Criterion; BMD/BMC = maximum likelihood estimate of the dose/concentration associated 

with the selected benchmark response; BMDL/BMCL = 95% lower confidence limit on the BMD/BMC; NA = p-value 

not determined; SD = standard deviation 

Source: Monsanto Co. 1985b 

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PHOSPHATE ESTER FLAME RETARDANTS A-28 

APPENDIX A 

Figure A-5. Fit of Polynomial Model (Nonconstant Variance) to Data on Body
 

Weight Gain on Gestation Days 6–15
 

Polynomial Model with 0.95 Confidence Level 

30 

35 

40 

45 

50 

55 

Mean Response 

BMDL BMD

Polynomial 

0 200 400 600 800 1000 1200 1400 

dose 

17:54 05/17 2009 

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PHOSPHATE ESTER FLAME RETARDANTS A-29 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Tris(2-butoxyethyl) phosphate (TBEP) 

CAS Numbers: 78-51-3 

Date: September 2009 

Profile Status: Draft 3, Pre-public 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [X] Intermediate [ ] Chronic 

Graph Key: 9 

Species: Rat 

Minimal Risk Level: 0.2 [X] mg/kg/day [ ] ppm 

Reference: Reyna MS, Thake DG. 1987a. Eighteen week feeding study of tributoxyethyl phosphate 

(TBEP) administered to Sprague-Dawley rats. Monsanto Agricultural Company. Submitted to the U.S. 

Environmental Protection Agency under TSCA Section 8D. OTS0530087. 

Experimental design: Groups of Sprague-Dawley rats (20/sex/group) were fed a diet containing 0, 300, 

3,000, or 10,000 ppm TBEP for approximately 18 weeks (Reyna and Thacke 1987a). This corresponds to 

doses of approximately 0, 17.3, 173, or 578 mg/kg/day for males and 0, 21, 209, or 698 mg/kg/day for 

females using food intake and body weight data from the study. End points monitored included clinical 

signs, body weight, food consumption, clinical chemistry and hematology (weeks 9 and 18), organ 

weights (brain, liver, kidneys, testes with epididymides), and gross and microscopic examination of all 

the major organs and tissues of controls and high-dose rats plus target tissues defined by the high-dose 

group and gross lesions from all necropsied animals. 

Effect noted in study and corresponding doses: There were no treatment-related mortalities or adverse 

clinical signs. Body weight was not significantly affected by treatment with the test material. Food 

consumption was lower in high-dose males and females and mid-dose males during the first week of the 

study, but was comparable to controls the remainder of the study. Ophthalmological examinations at 

termination were unremarkable. Statistically significant hematological changes included decreased 

leukocyte (lymphocyte) in high-dose males on week 9, and increased platelet counts in high-dose males 

and females on week 9 and 18 and in mid-dose males on week 9. Significant clinical chemistry changes 

consisted of increased serum cholesterol in high-dose males on week 18 and on mid- and high-dose 

females on week 9, increased serum GGT activity in high-dose males on week 9 and 18 and in high-dose 

females on week 9, decreased serum cholinesterase in high-dose males and females on weeks 9 and 18, 

and decreased erythrocyte cholinesterase in all treated females only on week 9; brain cholinesterase 

activity was not affected. Absolute and relative liver weights were increased in high-dose males and 

females, but not significantly. Histopathology was restricted to the liver of males and consisted of 

increased incidence of periportal hepatocellular hypertrophy (0/10, 0/10, 3/10, 7/10) and periportal 

vacuolization (1/10, 2/10, 6/10, 7/10). 

Dose and end point used for MRL derivation: BMDL10 of 21.92 mg/kg/day for hepatocyte hypertrophy in 

male rats dosed in the diet for 18 weeks. 

[ ] NOAEL [ ] LOAEL [X] BMDL10 

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PHOSPHATE ESTER FLAME RETARDANTS A-30 

APPENDIX A 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL 

[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, ppm in food 

were converted to doses using mean food intake and body weight from the study. 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not 

applicable. 

Was a conversion used from intermittent to continuous exposure? Not applicable. 

Other additional studies or pertinent information that lend support to this MRL: The study by Reyna and 

Thacke (1987a) was the only intermediate-duration oral study that examined a wide range of end points 

available for review. In the same study, although presented separately, the investigators measured tail 

nerve conduction velocity at the end of the treatment period (Reyna and Thacke 1987b). Following these 

measurements, the sciatic, tibial, and plantar nerves were processed for light microscopy. A significant 

reduction in nerve conduction velocity was measured only in high-dose females. Since both the absolute 

and relative refractory periods were decreased (the opposite of what would be expected in the case of a 

reduction in conduction velocity), the effect was not seen in males, and morphology of the nerves was 

unremarkable, the decrease in conduction velocity in females appeared questionable. 

Agency Contacts (Chemical Managers): G. Daniel Todd, Ph.D. 

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PHOSPHATE ESTER FLAME RETARDANTS A-31 

APPENDIX A 

BENCHMARK MODELING OF HEPATOCYTE HYPERTROPHY AND VACUOLIZATION IN 

MALE RATS
 

Incidence data for periportal hepatocyte hypertrophy and vacuolization in male rats exposed to TBEP 

(Reyna and Thacke 1987a) were analyzed using the BMD approach for MRL derivation (Tables A-13 and 

A-14). 

Table A-13. Incidence of Periportal Hepatocyte Hypertrophy in Male Rats 

Exposed to Tris(2-butoxyethyl) Phosphate for 18 Weeks
 

Dose (mg/kg/day) Total number of rats Number of rats with lesions 

0 10 0 

17.3 10 0 

173 10 3 

578 10 7 

Source: Reyna and Thacke 1987a 

Table A-14. Incidence of Periportal Hepatocyte Vacuolization in Male Rats 

Exposed to Tris(2-butoxyethyl) Phosphate for 18 Weeks 

Dose (mg/kg/day) Total number of rats Number of rats with lesions 

0 10 1 

17.3 10 2 

173 10 6 

578 10 7 

Source: Reyna and Thacke 1987a 

Models in the EPA BMDS (version 2.1) (gamma, logistic, log-logistic, multi-stage, probit, log-probit, 

quantal linear, Weibull models) were fit to the hepatocyte hypertrophy and hepatocyte vacuolation 

reported in male rats to determine a point of departure for the MRL. Adequate model fit is judged by 

three criteria: goodness-of-fit (p>0.1), visual inspection of the dose-response curve, and scaled residual at 

the data point (except the control) closest to the predefined BMR. Among all the models providing 

adequate fit to the data, the lowest BMDL is selected as the point of departure when differences between 

the BMDLs estimated from these models are more than 3-fold; otherwise, the BMDL from the model 

with the lowest AIC is chosen. In accordance with EPA (2000) guidance, BMDs and BMDLs associated 

with an extra risk of 10% are calculated for all models. 

Based on the criteria for model selection, comparing across models (Tables A-15 and A-16), the best fit 

for the hepatocyte hypertrophy data was provided by the Log logistic model; the BMD10 and BMDL10 

were 80.62 and 21.92 mg TBEP/kg/day, respectively. The best fit for the incidence of hepatocyte 

vacuolization was provided by the Log logistic model, which estimated a BMD10 and BMDL10 of 22.02 

and 8.88 mg TBEP/kg/day, respectively. Since hypertrophy is a more valid physiological end point than 

vacuolization, the BMDL10 of 21.92 mg/kg/day is selected as the point of departure for the intermediateduration MRL. Applying an uncertainty factor of 100 (10 for animal to human extrapolation and 10 for 

human variability) to the BMDL10 results in an intermediate-duration oral MRL of 0.2 mg/kg/day for 

TBEP. The model fit for hepatocyte hypertrophy is shown in Figure A-6. 

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PHOSPHATE ESTER FLAME RETARDANTS A-32 

APPENDIX A 

Table A-15. Model Predictions for Incidence of Hepatocyte Hypertrophy in Male 

Rats
 

χ2 Goodness of fit 

Model p-valuea AIC BMD10 (mg/kg/day) BMDL10 (mg/kg/day) 

Gammab 0.87 28.85 78.52 32.71 

Logistic 0.22 32.18 168.20 104.90 

LogLogistic 0.93 28.68 80.62 21.92 

LogProbit 0.99 26.54 88.23 54.34 

Multistagec 0.95 27.14 52.73 31.87 

Probit 0.26 31.71 156.18 100.50 

Weibullb 0.86 28.92 74.28 32.50 

Quantal-Linear 0.95 27.14 52.73 31.87 

AIC = Akaike Information Criterion; BMD/BMC = maximum likelihood estimate of the dose/concentration associated 

with the selected benchmark response; BMDL/BMCL = 95% lower confidence limit on the BMD/BMC 

a

Values <0.10 fail to meet conventional goodness-of-fit criteria b

Power restricted to ≥1 c

Betas restricted to ≥0; 1-degree polynomial 

Source: Reyna and Thacke 1987a 

Table A-16. Model Predictions for Incidence of Hepatocyte Vacuolization in Male 

Rats 

χ2 Goodness of fit BMD10 BMDL10 

Model p-valuea AIC (mg/kg/day) (mg/kg/day) 

Gammab 0.42 47.89 43.84 24.80 

Logistic 0.18 49.64 95.80 60.25 

LogLogistic 0.76 46.73 22.02 8.88 

LogProbit 0.32 48.40 73.86 40.22 

Multistagec 0.42 47.89 43.84 24.80 

Probit 0.19 49.59 93.91 62.31 

Weibullb 0.42 47.89 43.84 24.80 

Quantal-Linear 0.42 47.89 43.84 24.80 

a

Values <0.10 fail to meet conventional goodness-of-fit criteria b

Power restricted to ≥1 c

Betas restricted to ≥0; 1-degree polynomial 

AIC = Akaike Information Criterion; BMD/BMC = maximum likelihood estimate of the dose/concentration associated 

with the selected benchmark response; BMDL/BMCL = 95% lower confidence limit on the BMD/BMC; NA = not 

applicable; SD = standard deviation 

Source: Reyna and Thacke 1987a 

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PHOSPHATE ESTER FLAME RETARDANTS A-33 

APPENDIX A 

Figure A-6. Fit of Log Logistic Model to Data on the Incidence of Periportal
 

Hepatocyte Hypertrophy in Male Rats
 

Log-Logistic Model with 0.95 Confidence Level 

0

 0.2

 0.4

 0.6

 0.8

 1

 0 100 200 300 400 500 600 

Fraction Affected 

BMDL BMD 

Log-Logistic 

dose 

17:31 05/17 2009 

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PHOSPHATE ESTER FLAME RETARDANTS A-34 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Tris(1,3-dichloro-2-propyl) phosphate (TDCP) 

CAS Numbers: 13674-87-8 

Date: September 2009 

Profile Status: Draft 3, Pre-public 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [X ] Intermediate [ ] Chronic 

Graph Key: 4 

Species: Rat 

Minimal Risk Level: 0.05 [X] mg/kg/day [ ] ppm 

Reference: Stauffer Chemical Co. 1981a. A two year oral toxicity/carcinogenicity study of fyrol FR-2 in 

rats. In: A two-year oral toxicity/carcinogenicity study of fyrol FR-2 in rats (volume I-IV) (final reports) 

with attachments, cover sheets and letter dated 093081. Stauffer Chemical Company. Submitted to the 

U.S. Environmental Protection Agency under TSCA Section 8E. EPA88-8100282. OTS0204911. 

Experimental design: Groups of Sprague-Dawley rats (60/sex/dose level) were fed a diet that provided 0, 

5, 20, or 80 mg/kg/day of TDCP for 24 months. End points monitored included lethality, clinical signs, 

body weight, food consumption, hematology, clinical chemistry and urinalysis (at 3, 6, 12, 18, and 

24 months, 9–10 rats/sex/sampling), gross necropsy, and histopathology at termination and at 12 months 

(10 rats/sex/dose). 

Effect noted in study and corresponding doses: Mortality was comparable among groups during the first 

year of the study. Clinical signs were comparable among groups. Body weights were reduced in males 

and females 5–7% relative to controls at the 3- and 6-month time points. At week 50, mean body weight 

of males was 12% lower than controls, whereas mean body weight of females was 8% lower than 

controls. Hematology tests showed significant reductions in hemoglobin and hematocrit in high-dose 

males both at 3 and 6 months and of hemoglobin in females at 6 months. High-dose males also showed a 

reduction in red blood cell count at 6 months. The differences in mean hematological parameters between 

treated and control rats seen at 3 and 6 months were ≤5%. At 12 months, there were significant 

reductions in hemoglobin in high-dose males (10.6%) and females (7.5%) and in red cell counts in highdose males (10.7%). None of these alterations were observed after 24 months of treatment with TDCP. 

Prothrombin times and partial thromboplastin times showed considerable variability from interval to 

interval and no consistent pattern of differences between treated and control rats were apparent during the 

study. Serum alkaline phosphatase levels were lower than controls in high-dose rats both at the 3- and 

6-month intervals. BUN values in treated rats were not significantly different than in controls. Other 

clinical chemistry tests showed no consistent dose-related differences between controls and treated rats 

that could be attributed to treatment with TDCP. The most significant observations at 12 months were 

dose-related increases in absolute kidney and liver weights which achieved significance at the highest 

dose level; these changes in organs weight were not accompanied by histological alterations. Changes in 

kidney weight were more marked than those in liver weight, 48% increase in high-dose males and 39% 

increase in high-dose females relative to controls. At the lowest dose, kidney weight was increased 12% 

in males relative to controls. In mid-dose males, absolute thyroid and liver weight were increased by 

14 and 12%, respectively; the corresponding increases in high-dose males were 25 and 26%. Since the 

kidney was the most sensitive end point in rats exposed to TDCP for 24 months in the same study, it 

would appear that the increase in kidney weight observed at 12 months is on the continuum of the same 

spectrum of health effects used to derive the chronic-duration MRL and may, in fact, be a precursor to the 

renal tubule hyperplasia seen in rats exposed to TDCP for 24 months. Since the hematological changes 

observed during the first year of the study are of questionable toxicological significance, it is appropriate 

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PHOSPHATE ESTER FLAME RETARDANTS A-35 

APPENDIX A 

to use the changes in absolute kidney weight at the 12-month time point as basis for derivation of an 

intermediate-duration oral MRL for TDCP. Changes in absolute kidney weight in male and female rats 

were analyzed using the BMD approach for MRL derivation as detailed below. 

Dose and end point used for MRL derivation: BMDL1SD of 4.49 mg/kg/day for increase absolute kidney 

weight in male rats. 

[ ] NOAEL [ ] LOAEL [X] BMDL1SD 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL 

[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. 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not 

applicable. 

Was a conversion used from intermittent to continuous exposure? Not applicable. 

Other additional studies or pertinent information that lend support to this MRL: Only one addition 

intermediate-duration study is available for TDCP (Anonymous 1977). In that study, male rabbits were 

administered doses of 0, 2, 20, or 200 mg TDC/kg/day by gavage for 12 weeks. During the last week of 

treatment, male fertility was tested by mating the males with untreated females. Fertility was assessed by 

sacrificing the females at mid-gestation and evaluating their uteri. After the mating period, the males 

were sacrificed and sperm from the cauda epididymides were analyzed for motility, morphology, and 

concentration. Blood was also collected for hematology and clinical chemistry tests. The pituitary, liver, 

kidneys, and reproductive tract were processed for microscopic examination. The treatment-related 

effects appeared to be a significant increase in relative liver weight (23%) and in absolute kidney weight 

(14%) at 200 mg/kg/day. Neither gross necropsy nor microscopic examinations revealed significant 

alterations in the organs examined. 

Agency Contacts (Chemical Managers): G. Daniel Todd, Ph.D. 

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PHOSPHATE ESTER FLAME RETARDANTS A-36 

APPENDIX A 

BENCHMARK MODELING OF CHANGES IN KIDNEY WEIGHT IN RATS 

Data from Stauffer Chem Co. (1981a) were analyzed using the BMD approach for MRL derivation. 

BMD models in the EPA BMDS (version 2.1) (linear, polynomial, power, and Hill models) were fit to the
	

absolute kidney weight male and female datasets (Tables A-17 and A-18) to determine potential points of
	

departure for the MRL. 

Table A-17. Data for the Change in Absolute Kidney Weight in Male rats 

Dose (mg/kg/day) Number of animals tested Kidney weight (g) Standard deviation 

0 9 3.185 0.488 

5 10 3.571 0.311 

20 10 3.736 0.654 

80 10 4.703 0.853 

Source: Stauffer Chem Co. 1981a 

Table A-18. Data for the Change in Absolute Kidney Weight in Female rats 

Dose (mg/kg/day) Number of animals tested Kidney weight (g) Standard deviation 

0 10 2.031 0.193 

5 10 2.179 0.198 

20 10 2.271 0.269 

80 10 2.836 0.443 

Source: Stauffer Chem Co. 1981a 

Adequate model fit is judged by three criteria: goodness-of-fit (p>0.1), visual inspection of the doseresponse curve, and scaled residual at the data point (except the control) closest to the predefined BMR. 

Among all the models providing adequate fit to the data, the lowest BMDL is selected as the point of 

departure when differences between the BMDLs estimated from these models are more than 3-fold; 

otherwise, the BMDL from the model with the lowest AIC is chosen. In the absence of a clear criteria as 

to what level of change in kidney weight should be considered adverse, the BMR was defined as a change 

in mean kidney weight equal to one standard deviation from the control mean (EPA 2000). Based on the 

criteria for model selection, the Hill model provided the best fit for the male data set, whereas the Linear 

model provided the best fit for the female data set (Tables A-19 and A-20). In order to be health 

protective, the male BMDL1SD of 4.69 mg/kg/day is preferred as point of departure over the female 

BMDL1SD of 13.49 mg/kg/day. The model fit of the male data set is shown in Figure A-7. 

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PHOSPHATE ESTER FLAME RETARDANTS A-37 

APPENDIX A 

Table A-19. Model predictions for TDCP, changes in absolute kidney weight in 

male rats 

Variance Means BMD1SD BMDL1SD 

Model p-valuea p-valuea AIC (mg/kg-day) (mg/kg-day) 

Constant variance 

Linearb 0.02 0.52 3.98 34.6 25.79 

Nonconstant variance 

Hill 0.11 0.48 1.70 13.36 4.69 

Linearb 0.11 0.48 0.67 24.86 16.31 

Polynomial (2-degree 

polynomial)b 0.11 0.48 0.67 24.86 16.31 

Polynomial (3-degree 

polynomial)b 0.11 0.48 0.67 24.86 16.31 

Power 0.11 0.48 0.67 24.86 16.31 

AIC = Akaike Information Criterion; BMD/BMC = maximum likelihood estimate of the dose/concentration associated 

with the selected benchmark response; BMDL/BMCL = 95% lower confidence limit on the BMD/BMC; SD = standard 

deviation 

a

Values <0.10 fail to meet conventional goodness-of-fit criteria b

Coefficients restricted to be positive 

Source: Stauffer Chem Co. 1981a 

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PHOSPHATE ESTER FLAME RETARDANTS A-38 

APPENDIX A 

Table A-20. Model predictions for TDCP, changes in absolute kidney weight in 

female rats 

Variance Means BMD1SD BMDL1SD 

Model p-valuea p-valuea AIC (mg/kg-day) (mg/kg-day) 

Constant variance 

Linearb 0.02 0.72 -55.58 29.59 22.67 

Nonconstant variance 

Hill 0.83 0.35 -60.81 14.80 5.79 

Linearb 0.83 0.56 -62.53 19.73 13.49 

Polynomial (2-degree 

polynomial)b 0.83 0.56 -62.53 19.73 13.49 

Polynomial (3-degree 

polynomial)b 0.83 0.56 -62.53 19.73 13.49 

Power 0.83 0.56 -62.53 19.73 13.49 

AIC = Akaike Information Criterion; BMD/BMC = maximum likelihood estimate of the dose/concentration associated 

with the selected benchmark response; BMDL/BMCL = 95% lower confidence limit on the BMD/BMC; SD = standard 

deviation 

a

Values <0.10 fail to meet conventional goodness-of-fit criteria b

Coefficients restricted to be positive 

Source: Stauffer Chem Co. 1981a 

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PHOSPHATE ESTER FLAME RETARDANTS A-39 

APPENDIX A 

Figure A-7. Fit of Hill model (non-constant variance) to data on TDCP, changes in 

absolute kidney weight in male rats 

Hill Model with 0.95 Confidence Level 

3

 3.5

 4

 4.5

 5

 5.5

 0 10 20 30 40 50 60 70 80 

Mean Response 

BMDL BMD

Hill 

dose 

09:03 08/17 2009 

Source: Stauffer Chemical Co. 1981a 

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PHOSPHATE ESTER FLAME RETARDANTS A-40 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Tris(1,3-dichloro-2-propyl) phosphate (TDCP) 

CAS Numbers: 13674-87-8 

Date: September 2009 

Profile Status: Draft 3, Pre-public 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [ ] Intermediate [X] Chronic 

Graph Key: 10 

Species: Rat 

Minimal Risk Level: 0.02 [X] mg/kg/day [ ] ppm 

Reference: Stauffer Chemical Co. 1981a. A two year oral toxicity/carcinogenicity study of fyrol FR-2 in 

rats. In: A two-year oral toxicity/carcinogenicity study of fyrol FR-2 in rats (volume I-IV) (final reports) 

with attachments, cover sheets and letter dated 093081. Stauffer Chemical Company. Submitted to the 

U.S. Environmental Protection Agency under TSCA Section 8E. EPA88-8100282. OTS0204911. 

Experimental design: Groups of Sprague-Dawley rats (60/sex/dose level) were fed a diet that provided 0, 

5, 20, or 80 mg/kg/day of TDCP for 24 months. End points monitored included lethality, clinical signs, 

body weight, food consumption, hematology, clinical chemistry and urinalysis (periodically throughout 

the study), gross necropsy, and histopathology at termination and at 12 months (10 rats/sex/dose). 

Effect noted in study and corresponding doses: Mortality was comparable among groups during the first 

year of the study, but increased in high-dose males during the second year and was significantly higher 

than controls at termination. Clinical signs were comparable among groups. Ophthalmological 

examinations at 18 and 24 months suggested that treatment with TDCP may have accelerated the 

development of sacculations along the course of the retinal arterioles in high-dose rats. In general, body 

weights of mid- and high-dose rats were lower than controls throughout the study. At termination, final 

body weights of high-dose males and females were 24 and 21% lower than controls, respectively. At 

week 50, body weights of mid-dose males and females were 12 and 8% lower than controls, respectively. 

There was no consistent pattern of differences among groups over time regarding food consumption. 

Hemoglobin, hematocrit, and total erythrocyte values were often significantly lower than controls in highdose rats and the differences were usually more pronounced in males. This was observed throughout the 

study. At 24 months, prothrombin times and partial thromboplastin times were significantly elevated in 

high-dose males. Serum alkaline phosphatase values were lower than controls in high-dose males 

throughout the study; the biological significance of this is unclear. BUN was markedly elevated in a few 

mid- and high-dose rats at 18 and 24 months, which was consistent with microscopic evidence of renal 

pathology. Other clinical chemistry parameters were not consistently altered by treatment. Plasma 

cholinesterase was lower in high-dose females at 18 months (34%, significant) and 24 months (30%, not 

significant); changes at other times or in red blood cell cholinesterase were inconsistent. Urinalyses were 

unremarkable. Significant changes in organ weight consisted of increase absolute and relative liver, 

kidney, and thyroid weights in high-dose males and females at 12 and 24 months. At termination, gross 

observations revealed masses, nodules, and raised areas in the liver of high-dose rats; enlargement of the 

kidney in mid- and high-dose males and high-dose females plus higher incidence of discolorations, 

surface irregularities, masses, nodules, and cysts in treated rats than in controls; higher incidence of small 

seminal vesicles and testicular enlargement, masses, nodules, flaccidity, and discolorations in mid- and 

high-dose males. Nonneoplastic lesions that were significantly increased in treated rats were foci/areas of 

hepatocellular alterations (high-dose males and females), dilation of liver sinusoids (high-dose males and 

females), hyperplasia of convoluted tubular epithelium of the kidney (high-dose males and females, middose males), and chronic nephropathy (high-dose males and females). None of these alterations were 

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PHOSPHATE ESTER FLAME RETARDANTS A-41 

APPENDIX A 

seen at the 12-month interim sacrifice. Hyperplasia of the renal convoluted tubular epithelium was the 

most sensitive effect and occurred with incidences of 2/45, 10/49, 28/48, and 24/46 in males as the doses 

increased; the corresponding incidences in females were 0/49, 1/48, 3/48, and 22/50. A NOAEL and 

LOAEL of 5 and 20 mg TDCP/kg/day, respectively, for renal epithelial hyperplasia in male rats was 

defined in this study. 

Dose and end point used for MRL derivation: BMDL10 of 1.94 mg/kg/day for renal tubular epithelial 

hyperplasia in male rats dosed in the diet for 2 years. 

[ ] NOAEL [ ] LOAEL [X] BMDL10 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL 

[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, ppm in food 

were converted to doses by the investigators. 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not 

applicable. 

Was a conversion used from intermittent to continuous exposure? Not applicable. 

Other additional studies or pertinent information that lend support to this MRL: The study by Stauffer 

Chemical Co. (1981a) was the only chronic-duration oral study available for review. 

Agency Contacts (Chemical Managers): G. Daniel Todd, Ph.D. 

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PHOSPHATE ESTER FLAME RETARDANTS A-42 

APPENDIX A 

BENCHMARK MODELING OF RENAL TUBULE HYPERPLASIA IN RATS 

Incidence data for renal tubule epithelial hyperplasia in male rats exposed to TDCP (Stauffer Chemical 

Co. 1981a) were analyzed using the BMD approach for MRL derivation (Table A-21). 

Table A-21. Incidence of Renal Tubule Epithelial Hyperplasia in Rats Exposed to 

Tris(1,3-dichloro-2-propyl) phosphate for 2 Years 

Dose Total number of Males with Total number of Females with 

(mg/kg/day) males lesions females lesions 

0 45 2 49 0 

5 49 10 48 1 

20 48 28 48 3 

80 46 24 50 22 

Source: Stauffer Chemical Co. 1981a 

A glance at these incidences shows that males were clearly more sensitive than females. Therefore, the 

data set for hyperplasia of the renal convoluted tubular epithelium in males served as the basis for 

determining a point of departure for MRL derivation. Models in the EPA BMDS (version 2.1) (gamma, 

logistic, log-logistic, multi-stage, probit, log-probit, quantal linear, Weibull models) were fit to the renal 

tubular epithelial hyperplasia data in male rats to determine potential points of departure for the MRL 

(Table A-22). 

Table A-22. Model Predictions Incidence of Renal Tubular Epithelial Hyperplasia 

in Male Rats (Highest Dose Dropped) 

χ2 Goodness of BMD10 BMDL10 

Model fit p-valuea AIC (mg/kg/day) (mg/kg/day) 

Gammab NA 137.16 3.04 1.95 

Logistic 0.18 137.11 6.07 4.86 

LogLogistic NA 137.16 3.22 1.46 

LogProbit 0.43 135.78 4.40 3.35 

Multistagec (1-degree 

polynomial) 

0.78 135.23 2.60 1.94 

Probit 0.22 136.74 5.59 4.53 

Weibullb NA 137.16 3.02 1.95 

Quantal-Linear 0.78 135.23 2.60 1.94 

a

Values <0.10 fail to meet conventional goodness-of-fit criteria b

Power restricted to ≥1 c

Betas restricted to ≥0; 1-degree polynomial 

AIC = Akaike Information Criterion; BMD/BMC = maximum likelihood estimate of the dose/concentration associated 

with the selected benchmark response; BMDL/BMCL = 95% lower confidence limit on the BMD/BMC; NA = not 

applicable 

Source: Stauffer Chemical Co. 1981a 

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PHOSPHATE ESTER FLAME RETARDANTS A-43 

APPENDIX A 

Adequate model fit is judged by three criteria: goodness-of-fit (p>0.1), visual inspection of the doseresponse curve, and scaled residual at the data point (except the control) closest to the predefined BMR. 

Among all the models providing adequate fit to the data, the lowest BMDL is selected as the point of 

departure when differences between the BMDLs estimated from these models are more than 3-fold; 

otherwise, the BMDL from the model with the lowest AIC is chosen. In accordance with EPA (2000) 

guidance, BMDs and BMDLs associated with an extra risk of 10% are calculated for all models. Since an 

adequate fit to the data set could not be obtained with any of the models, the high-dose was dropped, in 

accordance with EPA (2000) guidance. Comparing across models (Table A-22) using the selection 

criteria mentioned above shows that the Multistage (1-degree polynomial) model provided the best fit to 

the renal epithelial hyperplasia. From this model, the predicted dose associated with a 10% extra risk 

(BMD10) was 2.60 mg TDCP/kg/day; the lower 95% confidence limit on this dose was (BMDL10) was 

1.94 mg TDCP/kg/day. Applying an uncertainty factor of 100 (10 for animal to human extrapolation and 

10 for human variability) to the BMDL10 of 1.94 mg/kg/day yields a chronic-duration oral MRL of 

0.02 mg/kg/day for TDCP. The model fit is shown in Figure A-8. 

Figure A-8. Fit of Multistage (1-Degree Polynomial) Model to Data on 

TDCP, Incidence of Renal Tubular Epithelia Hyperplasia in Male Rats 

Multistage Model with 0.95 Confidence Level 

Fraction Affected 

0.7 

0.6 

0.5 

0.4 

0.3 

0.2 

0.1 

0 

BMDL BMD

Multistage 

0 5 10 15 20 

dose 

11:35 05/18 2009 

Source: Stauffer Chemical Co. 1981a 

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PHOSPHATE ESTER FLAME RETARDANTS A-44 

APPENDIX A 

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PHOSPHATE ESTER FLAME RETARDANTS B-1 

APPENDIX B. USER'S GUIDE 

Chapter 1 

Public Health Statement 

This chapter of the profile is a health effects summary written in nontechnical language. Its intended 

audience is the general public, especially people living in the vicinity of a hazardous waste site or 

chemical release. If the Public Health Statement were removed from the rest of the document, it would 

still communicate to the lay public essential information about the chemical. 

The major headings in the Public Health Statement are useful to find specific topics of concern. The 

topics are written in a question and answer format. The answer to each question includes a sentence that 

will direct the reader to chapters in the profile that will provide more information on the given topic. 

Chapter 2 

Relevance to Public Health 

This chapter provides a health effects summary based on evaluations of existing toxicologic, 

epidemiologic, and toxicokinetic information. This summary is designed to present interpretive, weightof-evidence discussions for human health end points by addressing the following questions: 

1.		 What effects are known to occur in humans? 

2.		 What effects observed in animals are likely to be of concern to humans? 

3.		 What exposure conditions are likely to be of concern to humans, especially around hazardous 

waste sites? 

The chapter covers end points in the same order that they appear within the Discussion of Health Effects 

by Route of Exposure section, by route (inhalation, oral, and dermal) and within route by effect. Human 

data are presented first, then animal data. Both are organized by duration (acute, intermediate, chronic). 

In vitro data and data from parenteral routes (intramuscular, intravenous, subcutaneous, etc.) are also 

considered in this chapter. 

The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using 

existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer 

potency or perform cancer risk assessments. Minimal Risk Levels (MRLs) for noncancer end points (if 

derived) and the end points from which they were derived are indicated and discussed. 

Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to public 

health are identified in the Chapter 3 Data Needs section. 

Interpretation of Minimal Risk Levels 

Where sufficient toxicologic information is available, ATSDR has derived MRLs for inhalation and oral 

routes of entry at each duration of exposure (acute, intermediate, and chronic). These MRLs are not 

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PHOSPHATE ESTER FLAME RETARDANTS B-2 

APPENDIX B 

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. 

MRLs should help physicians and public health officials determine the safety of a community living near 

a chemical emission, given the concentration of a contaminant in air or the estimated daily dose in water. 

MRLs are based largely on toxicological studies in animals and on reports of human occupational 

exposure. 

MRL users should be familiar with the toxicologic information on which the number is based. Chapter 2, 

"Relevance to Public Health," contains basic information known about the substance. Other sections such 

as Chapter 3 Section 3.9, "Interactions with Other Substances,” and Section 3.10, "Populations that are 

Unusually Susceptible" provide important supplemental information. 

MRL users should also understand the MRL derivation methodology. MRLs are derived using a 

modified version of the risk assessment methodology that the Environmental Protection Agency (EPA) 

provides (Barnes and Dourson 1988) to determine reference doses (RfDs) for lifetime exposure. 

To derive an MRL, ATSDR generally selects the most sensitive end point which, in its best judgment, 

represents the most sensitive human health effect for a given exposure route and duration. ATSDR 

cannot make this judgment or derive an MRL unless information (quantitative or qualitative) is available 

for all potential systemic, neurological, and developmental effects. If this information and reliable 

quantitative data on the chosen end point are available, ATSDR derives an MRL using the most sensitive 

species (when information from multiple species is available) with the highest no-observed-adverse-effect 

level (NOAEL) that does not exceed any adverse effect levels. When a NOAEL is not available, a 

lowest-observed-adverse-effect level (LOAEL) can be used to derive an MRL, and an uncertainty factor 

(UF) of 10 must be employed. Additional uncertainty factors of 10 must be used both for human 

variability to protect sensitive subpopulations (people who are most susceptible to the health effects 

caused by the substance) and for interspecies variability (extrapolation from animals to humans). In 

deriving an MRL, these individual uncertainty factors are multiplied together. The product is then 

divided into the inhalation concentration or oral dosage selected from the study. Uncertainty factors used 

in developing a substance-specific MRL are provided in the footnotes of the levels of significant exposure 

(LSE) tables. 

Chapter 3 

Health Effects 

Tables and Figures for Levels of Significant Exposure (LSE) 

Tables and figures are used to summarize health effects and illustrate graphically levels of exposure 

associated with those effects. These levels cover health effects observed at increasing dose 

concentrations and durations, differences in response by species, MRLs to humans for noncancer end 

points, and EPA's estimated range associated with an upper- bound individual lifetime cancer risk of 1 in 

10,000 to 1 in 10,000,000. Use the LSE tables and figures for a quick review of the health effects and to 

locate data for a specific exposure scenario. The LSE tables and figures should always be used in 

conjunction with the text. All entries in these tables and figures represent studies that provide reliable, 

quantitative estimates of NOAELs, LOAELs, or Cancer Effect Levels (CELs). 

The legends presented below demonstrate the application of these tables and figures. Representative 

examples of LSE Table 3-1 and Figure 3-1 are shown. The numbers in the left column of the legends 

correspond to the numbers in the example table and figure. 

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PHOSPHATE ESTER FLAME RETARDANTS B-3 

APPENDIX B 

LEGEND 

See Sample LSE Table 3-1 (page B-6) 

(1)		 Route of Exposure. One of the first considerations when reviewing the toxicity of a substance 

using these tables and figures should be the relevant and appropriate route of exposure. Typically 

when sufficient data exist, three LSE tables and two LSE figures are presented in the document. 

The three LSE tables present data on the three principal routes of exposure, i.e., inhalation, oral, 

and dermal (LSE Tables 3-1, 3-2, and 3-3, respectively). LSE figures are limited to the inhalation 

(LSE Figure 3-1) and oral (LSE Figure 3-2) routes. Not all substances will have data on each 

route of exposure and will not, therefore, have all five of the tables and figures. 

(2)		 Exposure Period. Three exposure periods—acute (less than 15 days), intermediate (15– 

364 days), and chronic (365 days or more)—are presented within each relevant route of exposure. 

In this example, an inhalation study of intermediate exposure duration is reported. For quick 

reference to health effects occurring from a known length of exposure, locate the applicable 

exposure period within the LSE table and figure. 

(3)		 Health Effect. The major categories of health effects included in LSE tables and figures are 

death, systemic, immunological, neurological, developmental, reproductive, and cancer. 

NOAELs and LOAELs can be reported in the tables and figures for all effects but cancer. 

Systemic effects are further defined in the "System" column of the LSE table (see key number 

18). 

(4)		 Key to Figure. Each key number in the LSE table links study information to one or more data 

points using the same key number in the corresponding LSE figure. In this example, the study 

represented by key number 18 has been used to derive a NOAEL and a Less Serious LOAEL 

(also see the two "18r" data points in sample Figure 3-1). 

(5)		 Species. The test species, whether animal or human, are identified in this column. Chapter 2, 

"Relevance to Public Health," covers the relevance of animal data to human toxicity and 

Section 3.4, "Toxicokinetics," contains any available information on comparative toxicokinetics. 

Although NOAELs and LOAELs are species specific, the levels are extrapolated to equivalent 

human doses to derive an MRL. 

(6)		 Exposure Frequency/Duration. The duration of the study and the weekly and daily exposure 

regimens are provided in this column. This permits comparison of NOAELs and LOAELs from 

different studies. In this case (key number 18), rats were exposed to “Chemical x” via inhalation 

for 6 hours/day, 5 days/week, for 13 weeks. For a more complete review of the dosing regimen, 

refer to the appropriate sections of the text or the original reference paper (i.e., Nitschke et al. 

1981). 

(7)		 System. This column further defines the systemic effects. These systems include respiratory, 

cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, and 

dermal/ocular. "Other" refers to any systemic effect (e.g., a decrease in body weight) not covered 

in these systems. In the example of key number 18, one systemic effect (respiratory) was 

investigated. 

(8)		 NOAEL. A NOAEL is the highest exposure level at which no harmful effects were seen in the 

organ system studied. Key number 18 reports a NOAEL of 3 ppm for the respiratory system, 

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PHOSPHATE ESTER FLAME RETARDANTS B-4 

APPENDIX B 

which was used to derive an intermediate exposure, inhalation MRL of 0.005 ppm (see 

footnote "b"). 

(9)		 LOAEL. A LOAEL is the lowest dose used in the study that caused a harmful health effect. 

LOAELs have been classified into "Less Serious" and "Serious" effects. These distinctions help 

readers identify the levels of exposure at which adverse health effects first appear and the 

gradation of effects with increasing dose. A brief description of the specific end point used to 

quantify the adverse effect accompanies the LOAEL. The respiratory effect reported in key 

number 18 (hyperplasia) is a Less Serious LOAEL of 10 ppm. MRLs are not derived from 

Serious LOAELs. 

(10)		 Reference. The complete reference citation is given in Chapter 9 of the profile. 

(11)		 CEL. A CEL is the lowest exposure level associated with the onset of carcinogenesis in 

experimental or epidemiologic studies. CELs are always considered serious effects. The LSE 

tables and figures do not contain NOAELs for cancer, but the text may report doses not causing 

measurable cancer increases. 

(12)		 Footnotes. Explanations of abbreviations or reference notes for data in the LSE tables are found 

in the footnotes. Footnote "b" indicates that the NOAEL of 3 ppm in key number 18 was used to 

derive an MRL of 0.005 ppm. 

LEGEND 

See Sample Figure 3-1 (page B-7) 

LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the 

reader quickly compare health effects according to exposure concentrations for particular exposure 

periods. 

(13)		 Exposure Period. The same exposure periods appear as in the LSE table. In this example, health 

effects observed within the acute and intermediate exposure periods are illustrated. 

(14)		 Health Effect. These are the categories of health effects for which reliable quantitative data 

exists. The same health effects appear in the LSE table. 

(15)		 Levels of Exposure. Concentrations or doses for each health effect in the LSE tables are 

graphically displayed in the LSE figures. Exposure concentration or dose is measured on the log 

scale "y" axis. Inhalation exposure is reported in mg/m3 or ppm and oral exposure is reported in 

mg/kg/day. 

(16)		 NOAEL. In this example, the open circle designated 18r identifies a NOAEL critical end point in 

the rat upon which an intermediate inhalation exposure MRL is based. The key number 

18 corresponds to the entry in the LSE table. The dashed descending arrow indicates the 

extrapolation from the exposure level of 3 ppm (see entry 18 in the table) to the MRL of 

0.005 ppm (see footnote "b" in the LSE table). 

(17)		 CEL. Key number 38m is one of three studies for which CELs were derived. The diamond 

symbol refers to a CEL for the test species-mouse. The number 38 corresponds to the entry in the 

LSE table. 

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PHOSPHATE ESTER FLAME RETARDANTS B-5 

APPENDIX B 

(18)		 Estimated Upper-Bound Human Cancer Risk Levels. This is the range associated with the upperbound for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are derived 

from the EPA's Human Health Assessment Group's upper-bound estimates of the slope of the 

cancer dose response curve at low dose levels (q1*). 

(19)		 Key to LSE Figure. The Key explains the abbreviations and symbols used in the figure. 

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1 2 3 4 

→

SAMPLE 

Table 3-1. Levels of Significant Exposure to [Chemical x] – Inhalat

→→

Exposure 

Key to frequency/ figurea Species duration 

INTERMEDIATE EXPOSURE 

5 6 

Systemic ↓ ↓

NOAEL 

System (ppm) 

7 8 ↓ ↓

LOAEL (effect) Less serious (ppm) 

9 

↓

Serious (ppm) 

→→

18 Rat 13 wk Resp 3b 10 (hyperplasia) 

5 d/wk 

6 hr/d 

CHRONIC EXPOSURE 

Cancer 11 

↓

38 Rat 18 mo 20 (CEL, multiple 

5 d/wk organs) 

7 hr/d 

39 Rat 89–104 wk 10 (CEL, lung tumors, 

5 d/wk nasal tumors) 

6 hr/d 

40 Mouse 79–103 wk 10 (CEL, lung tumors, 

5 d/wk hemangiosarcomas) 

6 hr/d 

a The number corresponds to entries in Figure 3-1. b Used to derive an intermediate inhalation Minimal Risk Level (MRL) of 5x10-3 ppm; dose adjusted for intermittent 

by an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability). 

12 
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PHOSPHATE ESTER FLAME RETARDANTS B-8 

APPENDIX B 

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PHOSPHATE ESTER FLAME RETARDANTS C-1 

APPENDIX C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS 

ACGIH American Conference of Governmental Industrial Hygienists 

ACOEM American College of Occupational and Environmental Medicine 

ADI acceptable daily intake 

ADME absorption, distribution, metabolism, and excretion 

AED atomic emission detection 

AFID alkali flame ionization detector 

AFOSH Air Force Office of Safety and Health 

ALT alanine aminotransferase 

AML acute myeloid leukemia 

AOAC Association of Official Analytical Chemists 

AOEC Association of Occupational and Environmental Clinics 

AP alkaline phosphatase 

APHA American Public Health Association 

AST aspartate aminotransferase 

atm atmosphere 

ATSDR Agency for Toxic Substances and Disease Registry 

AWQC Ambient Water Quality Criteria 

BAT best available technology 

BCF bioconcentration factor 

BEI Biological Exposure Index 

BMD/C benchmark dose or benchmark concentration 

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

BMDLX 95% lower confidence limit on the BMDX 

BMDS Benchmark Dose Software 

BMR benchmark response 

BSC Board of Scientific Counselors 

C centigrade 

CAA Clean Air Act 

CAG Cancer Assessment Group of the U.S. Environmental Protection Agency 

CAS Chemical Abstract Services 

CDC Centers for Disease Control and Prevention 

CEL cancer effect level 

CELDS Computer-Environmental Legislative Data System 

CERCLA Comprehensive Environmental Response, Compensation, and Liability Act 

CFR Code of Federal Regulations 

Ci curie 

CI confidence interval 

CL ceiling limit value 

CLP Contract Laboratory Program 

cm centimeter 

CML chronic myeloid leukemia 

CPSC Consumer Products Safety Commission 

CWA Clean Water Act 

DHEW Department of Health, Education, and Welfare 

DHHS Department of Health and Human Services 

DNA deoxyribonucleic acid 

DOD Department of Defense 

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PHOSPHATE ESTER FLAME RETARDANTS C-2 

APPENDIX C 

DOE 

DOL 

DOT 

DOT/UN/ 

NA/IMDG 

DWEL 

ECD 

ECG/EKG 

EEG 

EEGL 

EPA 

F 

F1 

FAO 

FDA 

FEMA 

FIFRA 

FPD 

fpm 

FR 

FSH 

g 

GC 

gd 

GLC 

GPC 

HPLC 

HRGC 

HSDB 

IARC 

IDLH 

ILO 

IRIS 

Kd 

kg 

kkg 

Koc 

Kow 

L 

LC 

LC50 

LCLo 

LD50 

LDLo 

LDH 

LH 

LOAEL 

LSE 

LT50 

m 

Department of Energy 

Department of Labor 

Department of Transportation 

Department of Transportation/United Nations/ 

North America/Intergovernmental Maritime Dangerous Goods Code 

drinking water exposure level 

electron capture detection 

electrocardiogram 

electroencephalogram 

Emergency Exposure Guidance Level 

Environmental Protection Agency 

Fahrenheit 

first-filial generation 

Food and Agricultural Organization of the United Nations 

Food and Drug Administration 

Federal Emergency Management Agency 

Federal Insecticide, Fungicide, and Rodenticide Act 

flame photometric detection 

feet per minute 

Federal Register 

follicle stimulating hormone 

gram 

gas chromatography 

gestational day 

gas liquid chromatography 

gel permeation chromatography 

high-performance liquid chromatography 

high resolution gas chromatography 

Hazardous Substance Data Bank 

International Agency for Research on Cancer 

immediately dangerous to life and health 

International Labor Organization 

Integrated Risk Information System 

adsorption ratio 

kilogram 

metric ton 

organic carbon partition coefficient 

octanol-water partition coefficient 

liter 

liquid chromatography 

lethal concentration, 50% kill 

lethal concentration, low 

lethal dose, 50% kill 

lethal dose, low 

lactic dehydrogenase 

luteinizing hormone 

lowest-observed-adverse-effect level 

Levels of Significant Exposure 

lethal time, 50% kill 

meter 

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PHOSPHATE ESTER FLAME RETARDANTS C-3 

APPENDIX C 

MA trans,trans-muconic acid 

MAL maximum allowable level 

mCi millicurie 

MCL maximum contaminant level 

MCLG maximum contaminant level goal 

MF modifying factor 

MFO mixed function oxidase 

mg milligram 

mL milliliter 

mm millimeter 

mmHg millimeters of mercury 

mmol millimole 

mppcf millions of particles per cubic foot 

MRL Minimal Risk Level 

MS mass spectrometry 

NAAQS National Ambient Air Quality Standard 

NAS National Academy of Science 

NATICH National Air Toxics Information Clearinghouse 

NATO North Atlantic Treaty Organization 

NCE normochromatic erythrocytes 

NCEH National Center for Environmental Health 

NCI National Cancer Institute 

ND not detected 

NFPA National Fire Protection Association 

ng nanogram 

NHANES National Health and Nutrition Examination Survey 

NIEHS National Institute of Environmental Health Sciences 

NIOSH National Institute for Occupational Safety and Health 

NIOSHTIC NIOSH's Computerized Information Retrieval System 

NLM National Library of Medicine 

nm nanometer 

nmol nanomole 

NOAEL no-observed-adverse-effect level 

NOES National Occupational Exposure Survey 

NOHS National Occupational Hazard Survey 

NPD nitrogen phosphorus detection 

NPDES National Pollutant Discharge Elimination System 

NPL National Priorities List 

NR not reported 

NRC National Research Council 

NS not specified 

NSPS New Source Performance Standards 

NTIS National Technical Information Service 

NTP National Toxicology Program 

ODW Office of Drinking Water, EPA 

OERR Office of Emergency and Remedial Response, EPA 

OHM/TADS Oil and Hazardous Materials/Technical Assistance Data System 

OPP Office of Pesticide Programs, EPA 

OPPT Office of Pollution Prevention and Toxics, EPA 

OPPTS Office of Prevention, Pesticides and Toxic Substances, EPA 

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PHOSPHATE ESTER FLAME RETARDANTS C-4 

APPENDIX C 

OR odds ratio 

OSHA Occupational Safety and Health Administration 

OSW Office of Solid Waste, EPA 

OTS Office of Toxic Substances 

OW Office of Water 

OWRS Office of Water Regulations and Standards, EPA 

PAH polycyclic aromatic hydrocarbon 

PBPD physiologically based pharmacodynamic 

PBPK physiologically based pharmacokinetic 

PCE polychromatic erythrocytes 

PEL permissible exposure limit 

pg picogram 

PHS Public Health Service 

PID photo ionization detector 

pmol picomole 

PMR proportionate mortality ratio 

ppb parts per billion 

ppm parts per million 

ppt parts per trillion 

PSNS pretreatment standards for new sources 

RBC red blood cell 

REL recommended exposure level/limit 

RfC reference concentration 

RfD reference dose 

RNA ribonucleic acid 

RQ reportable quantity 

RTECS Registry of Toxic Effects of Chemical Substances 

SARA Superfund Amendments and Reauthorization Act 

SCE sister chromatid exchange 

SGOT serum glutamic oxaloacetic transaminase 

SGPT serum glutamic pyruvic transaminase 

SIC standard industrial classification 

SIM selected ion monitoring 

SMCL secondary maximum contaminant level 

SMR standardized mortality ratio 

SNARL suggested no adverse response level 

SPEGL Short-Term Public Emergency Guidance Level 

STEL short term exposure limit 

STORET Storage and Retrieval 

TD50 toxic dose, 50% specific toxic effect 

TLV threshold limit value 

TOC total organic carbon 

TPQ threshold planning quantity 

TRI Toxics Release Inventory 

TSCA Toxic Substances Control Act 

TWA time-weighted average 

UF uncertainty factor 

U.S. United States 

USDA United States Department of Agriculture 

USGS United States Geological Survey 

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PHOSPHATE ESTER FLAME RETARDANTS C-5 

APPENDIX C 

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 

% 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 

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PHOSPHATE ESTER FLAME RETARDANTS C-6 

APPENDIX C 

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PHOSPHATE ESTER FLAME RETARDANTS D-1 

APPENDIX D. INDEX
 

absorbed dose............................................................................................................................................173
	

acetylcholinesterase .......................................................................................................................... 117, 167
	

adenocarcinoma ........................................................................................................................................124
	

adipose tissue ............................................................................................ 144, 147, 149, 173, 223, 227, 231
	

adrenal gland.................................................................................................................................................5
	

adrenals ............................................................................................................................................... 34, 111
	

adsorbed.................................................................................................................................... 205, 215, 233
	

adsorption.................................................................................................................................. 205, 208, 226
	

aerobic.......................................................................................................................................................210
	

alanine aminotransferase (see ALT) .........................................................................................................108
	

ALT (see alanine aminotransferase) .........................................................................................................108
	

ambient air ................................................................................................................................................211
	

anaerobic...................................................................................................................................................211
	

androgen receptor.............................................................................................................................. 167, 169
	

aspartate aminotransferase (see AST).........................................................................................................41
	

AST (see aspartate aminotransferase).........................................................................................................41
	

atropine ............................................................................................................................................. 166, 176
	

bioaccumulation........................................................................................................................ 147, 208, 226
	

bioavailability ...........................................................................................................................................226
	

bioconcentration factor .............................................................................................................................208
	

biodegradation............................................................................................................................... 2, 205, 210
	

biomarker .................................................................................. 172, 173, 174, 186, 188, 223, 227, 229, 234
	

blood cell count............................................................................................................................. 30, 41, 106
	

body weight effects........................................................................................................................... 112, 135
	

breast milk..................................................................................................................................... 6, 223, 227
	

cancer.................................................................................................. 5, 17, 37, 43, 170, 171, 179, 181, 183
	

carcinogen................................................................................................................................. 137, 240, 242
	

carcinogenic ................................................................................................ 5, 15, 16, 35, 123, 124, 182, 212
	

carcinogenicity.......................................................................... 5, 15, 16, 124, 137, 164, 181, 183, 240, 242
	

carcinoma............................................................................................................................ 15, 123, 124, 182
	

carcinomas .................................................................................................................. 15, 123, 124, 125, 182
	

cardiovascular ..................................................................................................................................... 17, 104
	

cardiovascular effects.................................................................................................................. 41, 104, 126
	

cholinesterase.......................................................................... 13, 17, 42, 117, 118, 136, 174, 186, 187, 223
	

chromosomal aberrations.................................................................................................................. 142, 143
	

clearance ...................................................................................................................................................149
	

death.................................................................................................................................... 12, 17, 18, 35, 37
	

delayed neurotoxicity.................................................................................................................................. 13
	

dermal effects.............................................................................................................. 42, 112, 134, 177, 180
	

developmental effects ............................................. 15, 18, 42, 121, 122, 123, 137, 172, 179, 180, 183, 187
	

elimination rate .........................................................................................................................................159
	

endocrine........................................................................................................................... 111, 168, 169, 188
	

endocrine effects ............................................................................................................................... 111, 134
	

erythema....................................................................................................................................................135
	

estrogen receptor............................................................................................................................... 167, 169
	

estrogenic ..................................................................................................................................................169
	

fetus....................................................................................................................................................... 6, 170
	

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PHOSPHATE ESTER FLAME RETARDANTS D-2 

APPENDIX D 

gastrointestinal effects ...................................................................................................................... 104, 126
	

general population..................................... 4, 6, 7, 11, 36, 144, 147, 173, 177, 179, 182, 185, 186, 205, 220
	

genotoxic..................................................................................................................................... 35, 142, 182
	

genotoxicity............................................................................................................................... 137, 143, 179
	

groundwater ........................................................................................................ 11, 203, 207, 208, 212, 215
	

half-life.............................................................................................................. 145, 146, 148, 149, 173, 211
	

hematological effects ............................................................................................................ 33, 41, 105, 134
	

hepatic effects ..................................................................................................................... 41, 107, 134, 180
	

hydrolysis.......................................................................... 152, 153, 155, 200, 203, 208, 209, 210, 211, 231
	

hydroxyl radical ................................................................................................................................ 208, 210
	

immune system ...........................................................................................................................................15
	

immunological ................................................................................ 12, 35, 42, 115, 116, 136, 179, 180, 184
	

immunological effects......................................................................................................... 12, 179, 180, 184
	

Kow .................................................................................................................... 193, 194, 195, 205, 208, 225
	

LD50..................................................................................................................... 18, 33, 34, 43, 44, 125, 126
	

leukemia.......................................................................................................................... 5, 15, 123, 124, 182
	

lymphoreticular........................................................................................................... 42, 115, 116, 136, 184
	

metabolic effects ............................................................................................................................... 113, 136
	

milk ................................................................................................................................................... 188, 218
	

musculoskeletal effects ..................................................................................................................... 107, 134
	

neonatal............................................................................................................................................. 119, 171
	

neoplasm ............................................................................................................................................. 15, 182
	

neoplastic .............................................................................................................. 15, 26, 123, 124, 125, 182
	

neurobehavioral................................................................................................................... 18, 169, 180, 184
	

neurological effects....................................................................................... 18, 42, 116, 119, 136, 180, 184
	

nuclear................................................................................................. 21, 110, 117, 151, 167, 201, 215, 233
	

ocular effects............................................................................................................................. 112, 126, 135
	

pharmacodynamic.....................................................................................................................................161
	

pharmacokinetic........................................................................ 144, 161, 168, 162, 163, 170, 172, 186, 188
	

placenta ................................................................................................................................................. 6, 188
	

rate constant ...................................................................................................................................... 208, 209
	

renal effects................................................................................................................................. 41, 109, 134
	

reproductive effects....................................................................................... 14, 42, 119, 120, 121, 137, 183
	

respiratory effects........................................................................................................................ 38, 104, 126
	

retention ............................................................................................................................ 186, 200, 207, 224
	

salivation..................................................................................................... 22, 24, 29, 43, 44, 117, 118, 121
	

solubility ........................................................................................................... 193, 200, 203, 205, 207, 208
	

systemic effects........................................................................................................... 38, 104, 114, 126, 169
	

thyroid......................................................................................................................... 31, 111, 123, 134, 169
	

toxicokinetic................................................................................................ 35, 143, 179, 186, 187, 229, 234
	

tremors .................................................................................................................................... 13, 27, 44, 118
	

tumors ........................................................................... 5, 13, 15, 16, 26, 115, 123, 124, 125, 137, 165, 182
	

vapor phase ............................................................................................................................... 198, 206, 208
	

vapor pressure ................................................................................................... 200, 206, 207, 208, 212, 225
	

volatility....................................................................................................................................................200
	

volatilization ....................................................................................................................................... 11, 208
	

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