United States
Environmental Protection
Agency
Office of Water
Regulations and Standards (WH-S53)
Washington DC 20460
May 1981
EPA-440/4-81-020
cvEPA
An Exposure
and Risk Assessment
for Phthalate Esters
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2-'01
PORT DOCUMENTATION 1- *EPOIT NO.
; 3. 4ecl0ienrs Accession Ho.
PAGE i ii'A.-<4'+U/4-cii-UZU {
Itle MM SuotKle
in Exposure and Risk Assessment for Phthalate Esters
)i(2-Ethylhexyl) Phthalate Di-n-Butyl Phthalate Dimethyl
'hthalate Diethyl Phthalate Di-n-Octyl Phthalate
iutyl Benzyl Phthalate
«rthort« Perwak, J.; Goyer, M. ; Schimke, G.; Eschenroeder , A.;
Fiksel, J.; Scow, K.: and Wallace, D.
•erforming Organization Nemo end Address
irthur D. Little, Inc.
10 Acorn Park
;amfaridge, MA 02140
Sponsoring Organization Name and Addreia
Monitoring and Data Support Division
Dffice of Water Regulations and Standards
U.S. Environmental Protection Agency
Washington, D.C. 20460
s. Report Date Final Revision
May 1981
6.
8. Performing Organization Rept, No.
10. Praiect/Taak/Worfc Unit No.
It, Contracted or &nnttQ} No.
(o C-68-01-3857
(G) C-68-01-5949
13. Type of Report & Period Covered
Final
14.
Supplementary Not**
Extensive Bibliographies
. Abttract (Umre 200 words)
This report assesses the risk of exposure to di(2-ethylhexyl) phthalate, di-n-butyl
phthalate, dimethyl phthalate, diethyl phthalate, di-n-octyl phthalate, and butyl
benzyl phthalate. This study is part of a program to identify the sources of and
evaluate exposure to 129 priority pollutants. The analysis is based on available
information from government, industry, and technical publications assembled in May of
1981.
The assessment includes an identification of releases to the environment during
production, use, or disposal of the substance. In addition, the fate of phthalate
esters in the environment is considered; ambient levels to which various populations
of humans and aquatic life are exposed are reported. Exposure levels are estimated
and available data on toxicity are presented and interpreted. Information concerning
all of these topics is combined in an assessment of the risks of exposure to phthalate
esters for various subpopulations.
7. Document AnalysM a. Descriptor*
Exposure
Risk
Water Pollution
Air Pollution
Effluents
Waste Disposal
Food Contamination
Toxic Diseases
Butyl Benzyl Phthalate
Phthalate Esters
Di(2-Ethylhexyl) Phthalate
Di-n-Butyl Phthalate
Dimethyl Phthalate
Diethyl Phthalate
Pollutant Pathways
Risk Assessment
U.S. EnvironK^n-al Protection Agency
P.O. £ lor. 5 , T •:' c ~>. r 7 ' 5 •"•' I, - .1:",)
230
Ltroot, Eocia 167G
e. COSATI neld/Qrouo
Availability Statement
Qfoicago, 1.L 60604
06T
Release to Public
19. Security Clau (Thi* fteoort)
Unclassified
21. No. yf ?*«•*
175
; a. Security CU*> (This ?*«e>
22. Price
316.00
• ANSI-Z39.18)
See irmructloni an ^evene
OPTIONAL FORM 272 (+-771
(Formerly NT1S-35)
Oeoartment of Commerce
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EPA-440/4-81-020
October 1980
(Revised May 1981)
AN EXPOSURE AND RISK ASSESSMENT
FOR PHTHALATE ESTERS
Di(2-Ethylhexyl) Phthalata
Di-n-Butyl Phthalate
Dimethyl Phthalate
Diethyl Phthalate
Di-n-Octyl Phthalate
Butyl Benzyl Phthalate
BY
Joanne Perwak.
Muriel Goyer, Gerald Schimke, Alan Eschenroeder
Joseph Fiksel, Kate Scow, and Douglas Wallace
Arthur D. Little, Inc.
Michael Slimak
Project Manager
U.S. Environmental Protection Agency
U.S. EPA Contract 68-01-3857
68-01-5949
Monitoring and Data Support Division (WH-553)
Office of Water Regulations and Standards
Washington, D.C. 20460
OFFICE OF WATER REGULATIONS AND STANDARDS
OFFICE OF WATER AND WASTE MANAGEMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
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FOREWORD
Effective regulatory action for toxic chemicals requires an
understanding of the human and environmental risks associated with the
manufacture, use, and disposal of the chemical. Assessment of risk
requires a scientific judgment about the probability of harm to the
environment resulting from known or potential environmental concentra-
tions. The risk assessment process integrates health effects data
(e.g., carcinogenicity, teratogenicity) with information on exposure.
The components of exposure include an evaluation of the sources of the
chemical, exposure pathways, ambient levels, and an identification of
exposed populations including humans and aquatic life.
This assessment was performed as part of a program to determine
the environmental risks associated with current use and disposal
patterns for 65 chemicals and classes of chemicals (expanded to 129
priority pollutants") named in the 1977 Clean Water Act. It includes
an assessment of risk for humans and aquatic life and is intended to
serve as a technical basis for developing the most appropriate and
effective strategy for mitigating these risks.
This document is a contractors' final report. It has been
extensively reviewed by the individual contractors ?nd by the EPA at
several stages of completion. Each chapter of the draft was reviewed
by members of the authoring contractor's senior technical staff (e.g.,
toxicologists, environmental scientists) who had not previously been
directly involved in the work. These individuals were selected by
management to be the technical peers of the chapter authors. The
chapters were comprehensively checked for uniformity in quality and
content by the contractor's editorial team, which also was responsible
for the production of the final report. The contractor's senior
project management subsequently reviewed the final report in its
entirety.
At EPA a senior staff member was responsible for guiding the
contractors, reviewing the manuscripts, and soliciting comments, where
appropriate, from related programs within EPA (e.g., Office of Toxic
Substances, Research and Development, Air Programs, Solid and
Hazardous Waste, etc.). A complete draft was summarized by the
assigned EPA staff member and reviewed for technical and policy
implications with the Office Director (formerly the Deputy Assistant
Administrator) of Water Regulations and Standards. Subsequent revi-
sions were included in the final report.
Michael W. Slimak, Chief
Exposure Assessment Section
Monitoring & Data Support Division fWH-553)
Office of Water Regulations and Standards
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TABLE OF CONTENTS
Page
List of Figures
List of Tables
Acknowledgments
1.0 TECHNICAL SUMMARY -^
2.0 INTRODUCTION . 2-1
3.0 MATERIALS BALANCE 3-1
3.1 Introduction and Methodology 3_i
3.2 Production ' - ,
3.2.1 Manufacturing Process 3_3
3.2.2 Producers and Production Volume of
Phthalate Esters -, -,
3.3 Uses ^Ig
3.3.1 General Uses 2_fi
3.3.2 Distributed Use of Phthalate Esters 3.3
3.4 Releases of Phthalate Esters 2-12
3.4.1 Manufacture 3_12
3.4.2 Transportation 3~14
3.4.3 Formulation and Product Fabrication 3-15
3.4.4 Products in Use -, ,<-
3.4.5 Disposal f^I
3.5 Summary I~^a
4.0 FATE AND DISTRIBUTION OF PHTHALATE ESTERS
IN THE ENVIRONMENT 4-1
4.1 Monitoring Data , ,
4.1.1 Levels in Water and Sediment 4 t
4.1.2 Levels in Soil 4_J
4.1.3 Levels in Air ~
4.1.4 Levels in Biota
^f Phchalata Esters in the Environment
.1 Methodology
.2 Physical and Chemical Properties
3 Face in Wacar " "
_
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TABLE OF CONTENTS (Continued)
4.2.4 Fate in Air
4.2.5 Fats in Biota
4.2.6 Fate in Soil
4.3 Summary 4-18
5.0 HUMAN EFFECTS AND EXPOSURE 5-1
5.1 Human Toxicity 5-1
5.1.1 Di(2-Ethylhexyl) Phthalate (DEEP) 5-1
5.1.2 Dimethyl Phthalate (DMP) 5-6
5.1.3 Diethyl Phthalate (DEP) 5-6
5.1.4' Di-n-Butyl Phthalate (DBP) 5.7
5.1.5 Butyl Benzyl Phthalate (BBP) 5-7
5.1.6 Di-n-Octyl Phthalate (DNOP) 5-8
5.1.7 Overview 5-8
5.2 Human Exposure 5-9
5.2.1 Food 5-9
5.2.2 Drinking Water - 5-15
5.2.3 Inhalation 5-15
5.2.3.1 Occupational 5-15
5.2.3.2 General Population 5-17
5.2.4 Dermal Absorption 5-17
5.2.5 Medical Exposures 5-18
5.3 Summary 5-19
6.0 BIOTIC EFFECTS AND EXPOSURE 6-1
6.1 Effects on Biota 6-1
6.1.1 Aquatic Organisms 6-1
6.1.1.1 Considerations in Phthalate
Toxicity Studies 6-1
6.1.1.2 Relative Toxicity of Phthalates 6-5
6.1.1.3 Metabolism 6-7
6.1.2 Terrestrial Organisms 6-8
6.2 Exposure to 3iota 6-8
7.0 RISK CONSIDERATIONS
7.1 Methodology
7.2 Human Exposure
7.3 The Carcinogenicity of DEEP
7.4 Human Risks Associatad tfita Other Effects
7.5 Risk to Sioca
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TABLE OF CONTENTS (Continued)
3.0 REFERENCES
APPENDIX A. Materials Balance Worksheet A-l
APPENDIX 3. Physical-Chemical Properties 3-1
APPENDIX C. Fate in Water - Modeling Results C-l
APPENDIX D. Fate in Air - Modeling Results D-l
APPENDIX E. Human Toxicity E-1
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" LIST OF FIGURES
Figure
No. Page
3-1 Este-rification of Di(2-Ethylhexyl) Phthalate 3-4
3-2 Total Phthalate Ester Production Supply/Demand
Relationship, 1977 (Thousand kkg) 3-10
3-3 Losses of Phthalates During Production and Use
(Thousand kkg) 3-13
4-1 Distribution of Ambient Levels of Di(2-£thylhexyl)
Phthalate (DEHP) 4-3
4-2 Distribution of Ambient Levels of Di-n-butyl
Phthalate (DBF) 4-4
4-3 Distribution of Ambient Levels of Di-n-octyl
Phthalate (DNOP)
4-4 Distribution of Ambient Levels of Dimethyl
Phthalate (DMP) 4-6
4-5 Distribution of Ambient Levels of Dieth'yl
Phthalate (DEP) " 4-7
4-6 Summary of Fate Analyses for Di(2-Ethylhexyl)
Phthalate (DEHP) 4-20
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LIST OF TABLES
Table
No.
1-1 Estimates of Carcinogenic Risk for Various Routes
of Exposure to Di(2-Ethylhexyl) Phthalate 1-2
3-1 Total Capacity of Phthalate Production, 1977 3-5
3-2 U.S. Production of Phthalate Ester Plasticizers 3-7
3-3 Applications for Phthalate Esters 3-9
3-4 Primary Assumptions Used in Materials Balance
Analysis for Phthalate Esters 3-19
3-5 Annual Phthalate Losses to the Environment in
the United States 3-20
3-6 Annual Phthalate Releases to Environmental
Compartments in the United States 3-21
4-1 Phthalate .Esters in Water and Sediment 4-2
4-2 Mean Phthalate Ester Environmental Levels in
Water and Sediment 4-8
4-3 Residues of Phthalate Esters in Aquatic Organisms 4-10
4-4 California Air Resources Board Reactivity
Classification of Organic Compounds, 1976 4-16
5-1 Incidence of Hepatocellular Carcinoma and Neoplastic
Nodules in Fischer 344 Rats Fed Di(2-Ethylhexyl)
Phthalate (DEHP) in the Diet for Two Years 5-3
5-2 Incidence of Hepatocellular Carcinoma and Adenoma in
B6C3F1 Mice Fed Di(2-Ethylhexyl) Phthalate (DEHP) in
the Diet for Two Years 5-4
5-3 Approved Uses of Phthalate Esters That Could Result
in Migration into Foods
5-4 Approved Uses of Phthalate Esters That Under Normal
Conditions of Use would not Reasonably 3e Expected
to Result in Migration Into Foods 5-12
5-5 Residues of Di(2-Sthylhexyl) Phthalate (DEHP) in Foods 5-13
5-6 Consumption of Di(2-Ethylhexyl) Phthalate (DEHP in Food 5-14
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LIST OF TABLES (Continued)
Table
No. Page
5-7 Concentrations of Phthalate Esters in Drinking Water 5-16
6-1 Reported Effects of Phthalate Esters on Fish 6-2
6-2 Reported Effects of Phthalate Esters on Aquatic
Invertebrates 6-3
6-3 The Relative Toxicity of Phthalates to Aquatic Organisms 6-6
7-1 Exposure of Humans to Di(2-Ethylhexyl) Phthalate 7-3
7-2 Carcinogenic Effects of Di(2-Ethylhexyl) Phthalate
in B6C3F1 Mice 7-5
7-3 Per Capita Lifetime Carcinogenic Risk to Humans Due
to Di(2-Ethylhexyl) Phthalate Ingestion at Various
Exposure Levels Estimated by Use of Four Extrapolation
Models 7-8
7-4 Per Capita Lifetime Carcinogenic Risk to Specific
Populations In the U.S. Due to Estimated Di(2-Ethyl-
hexyl) Phthalate Exposure 7-9
7-5 Effects of Phthalate Esters on Laboratory Animals 7-10
7-6 Calculated Allowable Daily Intake and Recommended
Water Quality Criteria for Phthalate Esters 7-12
A-l Materials Balance Worksheet for Phthalate Esters
(thousand kkg/yr) A_2
B-l Properties of Bis(2-Ethylhexyl) Phthalate B-2
B-2 Properties of Di-n-Butyl Phthalate B-3
B-3 Properties of Dimethyl Phthalate B-4
B-4 Properties of Diethyl Phthalate 3-5
B-5 Properties of Di-n-Octyl Phthalate B-6
3-6 Properties of Butyl Benzyl Phthalate 3-7
C-l Time Required co Reach 99% of Steady State,
Sediment and Water Concentrations at 99%
Steady State and Half-Lives Estimated From
Decay Simulation for the Whole System. c-2
viii
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LIST OF TABLES (Continued)
Table
No. Page
C-2 Half-Lives and % Load for the Chemical, Biological,
and Export Processes for DMP and DEHP in Five
Simulated Ecosystems _ O4
2-1 Chromosome Aberrations and Sister-Chromatid Exchange
(SCE) Produced by DEHP E-6
E-2 Chromosome Aberrations and Sister-Chromatid Exchange
(SCE) Produced by DBP E-7
E-3 Antifertility and Mutagenic Effects of DEHP in
Male Mice • E-15
E-4 Relative Organ Weights of Rats Fed DEHP E-18
E-5 Acute Toxicity of Phthalate Esters E-27
E-6 Human Tissue Concentrations * E-33
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ACKNOWLEDGMENTS
The Arthur D. Little, Inc. task manager for this study was Joanne
Perwak. Other major contributors were Muriel Goyer (Human Effects),
Alan Eschenroeder (Environmental Fate), Gerald Schimke (Materials
Balance), Douglas Wallace (Biotic Effects and Exposure), Kate Scow
(Biological Fate), Melba Wood (Monitoring Data), Joseph Fiksel (Risk
Considerations), Laura Williams (Editor), and Alfred Wechsler (Technical
Review). Irene Rickabaugh was responsible for typing and preparation
•of the final draft report.
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CHAPTER 1.0 TECHNICAL SUMMARY
The Monitoring and Data Support Division, Office of Water Regulations
and Standards, the U.S. Environmental Protection Agency, is conducting an
ongoing program to identify the sources of, and evaluate the exposure to
129 priority pollutants. This report assesses the exposure to and risk
associated with six phthalate esters: di(2-ethylhexyl) phthalate (DEEP),
di-n-butyl phthalate (DBP) , dimethyl phthalate (DMP). diethy1 phthalate
(DEP), jii-n-octyl phthalate (DNOP), and butyl benzyl phthalate (BBP).
Most of the conclusions this report are for DEHP, since most of the
data available are for this compound.
This work was originally completed in September, 1979. The current
report has been revised to include recent toxicological data (e.g.
carcinogenicity) and a re-evaluation of human risk. Other aspects of
the report have not been updated since the original date of completion.
RISK CONSIDERATIONS
Humans: Until recently, typical DEHP exposure levels of 0.3 mg/day,
and maximum exposure levels of about 10 mg/day were not thought to be of
much concern. These exposures were primarily attributed to food contami-
nation resulting from processing and packaging. Levels at which acute
and reproductive effects are observed are much higher even than maximum
exposure levels, although the relationship between humans and animals
regarding reproductive effects is unclear. Re-evaluation of these con-
clusions is, however, necessary as a result of recent evidence suggesting
the carcinogenicity of DEHP.
The relative carcinogenic risks of the major DEHP exposure routes
are shown in Table 1-1, using the range of risks estimated with various
extrapolation models. Considerable controversy exists concerning the
most appropriate method for extrapolating equivalent human doses from
animal data. Due to this uncertainty, the range of risk estimated by
the various models may under- or overestimate the actual risk to man
Overestimation appears more likely due to the conservative assumptions
utilized in the calculation of human equivalent doses.
Food represents the major source of exposure and risk to DEHP. Risks
associated with inhalation and consumption of drinking water appear to
be lower, but monitoring data are limited.
Certain subpopulations receive higher exposures and are thus at
higher risk because of DEHP exposure. For example, persons receiving
large quantities of blood or who are dialyzed regularly can be exposed
to^high levels of DEHP through medical tubing in hemodlalysis equipment
and other biomedical devices.
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TABLE 1-1. ESTIMATES OF CARCINOGENIC RISK FOR VARIOUS ROUTES
OF EXPOSURE TO DI(2-ETHYLHEXYL) PHTHALATE
Jliiiiti!
Typical Diet
Average DEHP
Level* (mg/day)
0.3
Population
Size*
221 x 106
Average Lifetime Estimated Incidence***
Per Capita Risk** (excess cancers/year)
4xlO~6 to 4xlO~5
13 - 130
Drinking water
0.02
221 x 106
lxlO~6 to 3xlO~6
3-10
Ambient air - urban
- rural
0.006
0.00006
166 x 106
55 x 106
3xlO~ 7 to 8xlO~ 7
3xlO~9 to 8xlO~9
0.7 - 2
0.002-0.006
lilood transfusion
- dialysis
- hemophilia
21 -45
0.7 - 2.1
4 x 10
2 x 10
1x10 3 to 9x10 3
lxlO~5 to 3x10-4
0.6 - 6
0.003 - 0.08
* Data taken from Section 5.2 of this report.
** Represents the range of per capita lifetime risk predicted
by several extrapolation models. See Chapter 7.0 of this report. The range of risk estimated
by the various models may under- or overestimate the actual risk to man. Overestimation appears
likely due to the conservative assumptions utilized in the calculation of human equivalent doses.
A*A Assuming a 70-year lifespan.
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Data on the effects and exposure to the other phthalate esters are
limited. Only BBP has been tested for carcinogenicity, and the prelimi-
nary results appear negative. DEP and DBF show evidence of teratogenicitv
in laboratory animals as does DEHP. Testicular injury has been observed '
for DBP, as well as for DEHP. The risks associated with the other
phthalate esters are expected to be considerably lower than DEHP, because
or their more limited use. However, the paucity of data provides little
basis for quantitative or even qualitative statements of risk regarding
these other chemicals.
3iota: Tne concentrations of phthalate esters that affect aquatic
organisms in laboratory studies are not commonly found in natural waters.
Data appear to indicate, however, that reproduction in Daphnia is
inhibited at 3 ug/1 for DEHP. Levels in this range are commonly found
in the United States. However, more data are required to establish risk
to aquatic organisms. Specifically, confirmation of the effects of
phthalate esters, as well as information regarding laboratory contami-
nation in monitoring data, are needed.
MATERIALS BALANCE
In 1977, the U.S. production of all phthalate esters amounted to
546,000 kkg, with about 478,000 kkg used in various flexible poly-
vinylchloride applications. DEHP, which was primarily used in poly-
vinylchloride applications, accounted for about 1/3 of the total produc-
Cu°n S 1F7* Production of DPB» DEP, DMP, and DNOP accounted for less
than 57, of the total production output ia 1977. BBP, used primarily in
vinyl flooring, is estimated to account for about 11% of production
DEP and DMP are used in the manufacture of celluloid. DMP is also used
as an insect repellent. Although DBP has diverse uses, it is primarily
used as a plasticizer for epoxy resins and polyvinylchloride applications
Discharge of phthalate esters occurs at various points during production
and_use. Between 70 and 90% of each of the esters ultimately is disposed
oi in landfills. Most of these esters are in the form of products
Losses of phthalate esters during production are small, but may be
important in localized areas since there are few production facilities.
During compounding of esters to plasticizers, losses to air and water
are significant. For DMP, the non-plasticizer routes to air and water
are the major loss route. For the five esters, DEHP, DEP, DBP, DMP, and
BBP an average of 3% is released to the air, 3% to water, 90% to land-
rills, and 3% is incinerated.
PHTHALATE ESTERS IN THE ENVIRONMENT
Monitoring data for phthalate esters in the environment are scarce
and are complicated by the prevalence of laboratory and sampling
contamination. Ambient water levels are gsnerallv less than 10 ug/i
Higher levels of these chemicals, primarily DEHP and DBP, are found^'
industrialized areas. Concentrations of 56 sg/kg DEHP in sediment -
seen reported, although levels of Less than 1 ag/kg are probablv
common.
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Levels or DEHP and DBF in air range from 0.5 ng/m3 to 3 ng/m3 in
unpolluted areas, although only limited data are available. Levels of
DEHP and DBF in the vicinity of" a municipal incinerator were approximately
300 ng/m-* and 700 ng/m3, respectively.
Phthalate esters are consistently found at low levels in biota.
Maximum levels in fish range from 1 mg/kg to 7 mg/kg; however, most
reported levels of DEHP and DBF are generally below 1 rug/kg.
The fate of phthalate esters in the aquatic environment depends on
the particular ester. DEHP is thought to be the most persistent. The
major loss mechanisms of DEHP are accumulation in the sediment and
export; however, in a steady-state system, export is thought to be the
major loss mechanism. Biodegradation and hydrolysis of other esters
make them less persistent in the environment than DEHP.
Phthalate esters disposed of in landfills are primarily in the form
of intact consumer products, with migration occurring relatively slowly.
Esters released from these products would be subject to biodegradation
and leaching.
Hydroxyl radical attack is the primary loss mechanism for phthalate
esters in the atmosphere. Adsorption to particulates and rainout are
not expected to be important loss mechanisms.
i—"4
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2.0 INTRODUCTION
The Office of Water Regulations and Standards, Monitoring and Data
Support Division, the U.S. Environmental Protection Agency is conducting
a program to evaluate the exposure to and risk of 129 priority pollu-
tants in the nation's environment. The risks to-be evaluated" include
potential harm to human beings and adverse effects on fish and other
biota. The goal of the task under which this report has been prepared
is to integrate information on cultural and environmental flows of
specific priority pollutants and estimate the risks based on receptor
exposure to these substances. The results are intended to serve as a
basis for developing suitable regulatory strategy for reducing the risk,
if such action is indicated.
This report provides a brief, but comprehensive, summary of the
manufacture, use, distribution, fate, effects, and potential risks of
several phthalate esters. In order to effectively use this report and
to understand the uncertainties and qualifications of the data presented
herein, several important underlying definitions and assumptions must be
presented.
• Phthalate esters include a large group of compounds;
six are considered here:
Di(2-ethylhexyl) phthalate - DEHP
Di-n-butyl phthalate - DBF
Dimethyl phthalate - DMP
Diethyl phthalate - DEP
Di-n-octyl-phthalate - DNOP
Butyl benzyl phthalate - BBP
• The term di-octyl phthalate, as reported in the
literature, often refers to either DEHP or DNOP.
In this report, di-octyl phthalate is used if the
identity of the chemical considered is unknown.
• This report deals primarily with DEHP since this chemical
has the largest production of those considered, and is
the most persistent in the environment. In addition,
research has concentrated primarily on DEHP in the past.
We have included information for the other phthalates
when available.
t Monitoring data for phthalate esters are limited as
has been the case for many trace organics. Further,
the analysis for phthalates is even ^ore complicated
by contamination in sampling and laboratory analysis,
since phchalate escerj ara used in plastic' cubing and
containers found frequently in sampling and analvsis
-------
equipment. Background contamination levels in
monitoring results are pointed out to the extent
possible. When these concentrations are not
mentioned, the level of contamination is unknown.
This work was originally completed in September 1979. The current
report has been revised to include recent toxicological data and a
re-evaluation of human risk. Other aspects of the report have not been
updated since the original date of completion.
This report is organized as follows:
Chapter 3.0 presents a materials balance for the phthalate esters
considered here, including information on production, use, and disposal.
Chapter 4.0 uses two points of view to examine the concentration
of phthalates in the environment. First, existing monitoring data are
summarized. Second, the significance and rates of various environmental
fate processes are considered in a modeling format, along with calcula-
tions to estimate possible environmental concentrations using loadings
based upon materials Balances. Comparisons of monitoring results and
fate estimates .are made where possible.
Chapter 5.0 summarizes the effects and exposure of humans to
phthalate esters.
Chapter 6.0 reviews the effects and exposure of aquatic organisms
to phthalate esters.
•
Chapter 7.0 integrates the information presented in earlier sections
to address the risks to humans and aquatic species resulting from expo-
sure to phthalate esters.
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3.0 MATERIALS BALANCE
3.1 INTRODUCTION AND METHODOLOGY '
This chapter presents the environmental materials balance for six
phthalate esters in the contiguous United States. The materials balance
summarizes the principal sources, uses, and environmental releases of
pnthalate esters to all environmental media. Phthalate esters are
released into the environment from both anthropogenic and natural sources.
For major sources of pollutant release, the amount of material released
is estimated, the environmental compartment (air, water, and land) ini-
tially receiving and transporting the material are identified, and the
locations at which the pollutant loadings take place are specified to the
degree possible. Data are cited to establish bases for estimates. Where
discrepancies occur, the highest figure has been assumed in order to
maintain a more conservative approach.
Anthropogenic sources of phthalate esters are widely distributed
throughout the environment as a result of the incorporation of phthalates
into consumer products, especially those derived from plasticized poly-
vinylchloride (PVC) and other plastics. Phthalate esters may be released
to the environment not only through their manufacture, but also through
processing, use, and disposal of plastic products containing them. Some
of the minor end-uses, e.g., as a carrier for pesticides or as an insect
repellent, may also release the substances into the environment, which
may result in direct human exposure.
In addition to anthropogenic sources, observations of natural
occurrences of phthalates in vegetation and animal life have been made
(Mathur 1974). In some instances, however, such occurrences may result
from contamination by materials used in handling and testing specimens.
Thus, the attributable factors to the natural prevalence of phthalate
esters are unclear (Graham 1973, Mathur 1974, Peakall 1975).
Data enabling the development of an accurate materials balance
do not exist. Production values are available for four of the six
phthalate esters of interest, i.e., di(2-ethylhexyl), di-n-butyl, diethyl,
and dimethyl phthalate; and it has been possible to estimate the produc-
tion of butyl benzyl phthalate. No substantive data on the production of
di-n-octyl phthalate have been found. Data concerning the amounts of
individual phthalates that are used in individual end-product categories
do not exist. In general, however, phthalate esters are used as plasti-
cizers, primarily with PVC. Production figures are available or can be
estimated for five phthalate esters. These figures account for nearly
aO* or tne total phthalate astar production in Che United States (U s"
International Trade Commission 1963-1978). Since much of the ^nforma-'on
on pncnalata use in products is presented on an aggregated basis -t has
oeen necessary to sake certain assumptions in order to asc-'siat- -he
amount of each type of ester that encars Che environment through various
pathways. The rollowing procedure was used:
j—i
-------
• The production and use patterns of phthalate esters
in the United States were developed from available
literature.
• 1977 production and export data for all phthalates
(including the five of interest), and production data
for each of the five individual phthalates were used.
Assuming that the export of phthalates is proportional
to the amount produced, the U.S. supply of each of the
five of interest was estimated.
• Using available data, estimates were made of the .
distribution of each of the phthalates among non-
plasticizer uses, PVC plasticizer uses, and other
polymer uses.
• An estimate of the fraction of each ester in various
product categories was made.
• Losses resulting from transportation, vaporization, and
manufacturers' waste were estimated and the amount
of plasticizer appearing in the inventory each year
was estimated.
• The annual loss rate of plasticizer to the air or water
was estimated by product category and multiplied by the
products' lifetime.
• The amount of ester remaining after accounting for the
above losses was assumed to enter the municipal solid
waste stream and be disposed of — 97% landfilled,
3% incinerated.
• The total amount of each ester entering into each
environmental compartment was estimated by summing
various contributions.
In these calculations, steady-state conditions are assumed. This
chapter presents information on the sources and quantities of phthalates
and the routes of entry of these substances into the environment.
Primary and secondary sources of information have been utilized in the
analysis. These sources include documents prepared by various federal
agencies, including the U.S. EPA, Department of Commerce, and other
agencies, as well as personal contacts with their representatives. In
some cases, contacts with industry have been made. The following sec-
tions address the manufacture, transportation, production, use, and
disposal of phthalate esters, and the release of these substances into
environmental compartments.
3-2
-------
3.2 PRODUCTION
3.2.1 Manufacturing Process
The esterification of phthalic anhydride with the appropriate
alcohol is the basic process for producing phthalate esters. The reac-
tions occur in the presence of esterification catalysts, including
sulfuric acid or p-toluenesulfonic acid. The process is essentially
the same for all lower alcohols. The excess alcohol usually employed
in the process is recovered and readily recycled. Generally, production
has been by the batch method; however, newer plants are highly automated
and operate on a continuous basis. Reactions are carried out at a
temperature of about 150°C, with agitation (Lowenheim and Moran 1975). As
noted in Figure 3-1, water, as a byproduct of the reaction, is either
recovered or becomes wastewater. Physical losses of the product probably
occur during washing/steaming operations and in filtering. Catalysts are
removed in a washing step. At that time, any volatile impurities are
removed as vapors and condensed. The product is then purified by vacuum
distillation and/or with activated charcoal to meet purity requirements
for plasticizer use. Yields of products from- the process are >9Q%, which
is relatively high (Hirzy et_ al. 1978).
For each phthalate ester, modifications may be required in the
process, particularly in the alcohol recovery step. In the production
of dimethyl and diethyl phthalates, alcohol recovery may be more compli-
cated because of benzene that is used to reduce the partial pressure of
the alcohol. This necessitates the removal and separation of the ternary
mixture of alcohol, water, and benzene. Benzene is returned to the
process and the alcohol is rectified for reuse (Lowenheim and Moran 1975).
In the process for di(2-ethylhexyl) phthalate, alcohol recovery is simpler
and this step may be eliminated.
3.2.2 Producers and Production Volume of Phthalate Esters
Production of phthalate ester plasticizers is concentrated among
a small group of companies, largely merchant producers. It is believed
that 19 companies have some phthalate ester production capacity.
However, it is also estimated that six of these companies account for
approximately 90% of the total phthalate ester capacity, which is esti-
mated at about 817,200 kkg for 1977. Because of the nature of the
production process and the fact that installations can be used to produce
other types of plasticizers and even non-plasticizer products, the
capacity for phthalate esters is variable. Table 3-1 presents capacities
of the major producers and the phthalate ester products for each company.
The existing phthalate ester production capacity is concentrated
in the Gulf Coast (Texas and Louisiana) and in the Northeast (New
Jersey and Pennsylvania). The combined capacities of plants in these
regions represent about 35Z of the cotal industry. Plants are also
located in other states, including Ohio, Tennessee, Maryland, Illinois,
Connecticut, North Carolina, and New York.
3-3
-------
FIGURE 3-1. ESTERIFICATION OF DI (2-ETHYLIIEXYL) PHTIIALATE
Mo I Wt.
0
V—C'
P-Toluene-
Sulfonic Acid
y-c
^\
0
Phthalic Anhydride
U8
Octyl Alcohol
130
(2-ethylhexanol)
0
0
PlichalaLu
Source: Darby (1968), Graham (1973).
-------
7A3LZ 3-1. TOTAL CAPACITY 07 PHTHALAT2 PaODUCTIOH, 1977
Company and Location
3AS5 Vyandotta Core.
South .
-------
In 1977, production of phthalate asters amounted to 546,000 kkg,
with about 478,000 '
-------
TABLE 3-2. U.S. PRODUCTION OF PHTHALATE
ESTER PLASTICIZERS
Annual Production (Thousand kkz)
1968
1969
1970
1971
1972
1973
1974
1975
1976
1977
1978
Di
(2-ethyl-
hexyl)
150.0
161.3
159.1
175.4
197.5
171.7
176.9
137.3
134.7
181.7
176.'13
Dibutvl
13.4
15.7
10.4
10.4
13.2
17.2
16.1
5.6
6.2
7.5
Jl
Diethvl
10.3
10.2
9.4
7.6
8.6
8.9
8.9
5.3
7.3
7.9
.
Dimethyl
3.0
3.3
3.7
4.8
4.4
5.1
4.5
3.1
4.0
4.5
Other Butyl- 9
Dioctvl benzvl~
6.9 45.4
-
-
47.7
_
3.7
2.5 56.3
4.5
7.8
5.3 60.0
Total Phthalate
Ester Plastic
381.6
401.2
388.2 "
444.1
520.1
546.2
548.1
410.3
473.5
545.9
Includes dicapryl phthalate and dioctyl isophthalate.
2
Source: Arthur D. Little, Inc., estimates.
Preliminary includes di(2-ethylhexyl) and other dioctyl phthalates,
Source: U.S. International Trade Commission (1968-1978).
-------
Plasticization occurs during fabrication when
the temperature reaches about 160°C.
• Plastisol formation ~ Plastisols, a stable liquid •
dispersion of resin in plasticizer, as formed during
this process.
• Resin dissolution — The dissolution of the resin in a
solvent is followed by mixture with a plasticizer to
make solvent cast film and surface coating materials.
The compounding of the resin and plasticizer takes place
at converting plants where flexible PVC products are
formed. It has been estimated that approximately 8000
plants convert plastic resins and additives into finished
consumer products (U.S. Bureau of the Census 1976). Of
these, some 5-10% are manufacturers of flexible PVC
products.
3.3.2 Distributed Use of Phthalate Esters
Examples of end-use applications of the subject phthalate esters
are presented in Table 3-3. Phthalate esters are used as plasticizers
to develop certain characteristics, and to exhibit varying properties
in a specific end use. Not all phthalate ester plasticizers have
similar applications in any given end use. For example, DEHP is
widely used as a plasticizer for certain types of electrical wire and
cable insulation, although it is not suitable for cable applications
where performance standards require aging of the insulation at 136-1538C.
Where aging in this temperature range is required, substitution of other
phthalic acid derivatives (e.g., ditridecyl or diundecyl phthalate)
occurs (Beeler and Finney 1978). Since DBP has a relatively high vola-
tility, it is unsuitable for application in electrical wire and cable
insulation, or other applications (e.g., automotive) where exudation or
volatilization of the plasticizer would be a problem.
Because of the relatively low volume of production for some of the
subject compounds, data on end use by market segment are not detailed,
except in the case of flexible PVC. The supply-demand relationships
indicated in Figure 3-2 are for all phthalate esters. The six phthalates
of interest represent about 50% of the total U.S. output, and are assumed
to represent a proportional share of demand. Allocation of consumption
in each end-use market by specific phthalate ester, for the most part,
can only be indicated in a qualitative manner. Figure 3-2 summarizes
the end-use pattern for all phthalate esters produced. While insuffi-
cient data are available to document the amount of the individual ester
consumed in each product group, the specific uses of each phthalate aster
of concern are described below.
As noted previously, DEHP is considered Che standard PVC plasti-
cizer and is primarily used for this purpose. It is preferred for
numerous reasons, including: a high degree of compatibility with
3-3
-------
TABLE 3-3. APPLICATIONS FOR PHTHALATE ESTERS
Phthalate Ester
Plasticizer
Polyvinyl Chloride
Vinyl Film and Sheeting
Vinyl Wire and Cable Insulation
Vinyl Flooring
Other Vinyl Applications
Other Extrusions
Injection Molded Items
Plastisols
Other Polymers and Resins
Polyvinyl Acetates,
Formals, Butyrals
Cellulosics
Polysulfides
Polyurethanes
Other •
Other Uses'
Perfumes and Cosmetics
Insect Repellent
Solvent
Pigment Adjuster
Concrete Additive
Microbiocide
Denaturant. Alcohol
a*
3
o
X
X
X
X
X
O>
=3
CO
*
X
X
x •
X
0-
u
^
X
X
X
X
Oi
i
•
X
X
1
X
CJ
S3
e
x -
X
X
X
X
X
0
z
XL
X
,
I
"Product group unspecified.
o
'Phthalate esters are used in those applications as carrier,
dispersing media, fixatives, additives, denaturants, adjusting agencs,
(see text).
Source: Sealer and Finnev (1973).
-------
1977
Total U.Sr
Production
545.9
U.S. Supply
503.4
•Exports
42.5
•Oioctyl
Phthalates
4.4-
•Other Polymers and
Resins 15.0
-^•Cellulosics
-*-Polyvinylacetates
-^Polyurethanes
-*-Other
PVC
Use as Plasticizer <
478.0
• Carr i er/D ispersi ng
Media 10.5
-^•Pesticides
•^Cosmetics
—^Colorants
—^-Catalysts
»0ther Phthalate Anhydride
Esters 38.1
•Building and Construction
122.2
•Home Furnishings and >
Housewares 91.0
• Electrical 87.6
—^Transportation 70.0
—» Apparel 47.7-
—+. Recreation 20.6
—»• Packaging 7.0
I—*• Miscellaneous 10.5
•Other PVC Uses 21.6
Flooring 108.1
Pool Liners 6.8
Weather Stripping 7.
•Wall Coverings, etc.
Furniture 53.6
Housewares 18.1
Wire and Cable 87.6
i—*• Auto Mats \ 16.2
|—+> Auto Tops j
'—»• Upholstery and Seat
Covers 53.6
• Baby Pants 3.2
• Footwear 30.4
•Outerwear 14.1
Toys 12.2
m Sporting Goods 8.4
CFilm 7.0
Sheet na
C Garden Hose 5.0
Medical Tubing 5.5
•Tools and Hardware
• Laminates
•Novelties
•Stationery Supplies
Note: The six subject phthalates accounted
for approximately 50% of 1977 production
na * Not available
Source: Versar (1978).
Figure 3-2 TOTAL PHTHALATE ESTER PRODUCTION SUPPLY/DEMAND
RELATIONSHIP, 1977 (Thousand kkgj
3-10
-------
tura, flexibility, and =omp«ibiU» wih PVC •
Such plasticizan are derived from hl^Lf ?M1M (Anon5™ous
or other sources, such « «MTlI^.5 "olecular "SighC linear alcohols,
continue to
7 "
MhUe DEHB has-
P' 1"
capacitors is a
polyvinyiidene loride
n of other polymers, such
as
typical Process
3-11
-------
pigments; use as a concrete additive to impart workability and other
mechanical properties; use in polyvinyl acetate emulsions; and it is
registered with U.S. EPA as an insect repellent. No specific informa-
tion is available on these miscellaneous uses.
Primarily, BBP is used in vinyl flooring as a plasticizer. It is
preferred for this use because of its resistance to staining and migra-
tion into, and softening of, flooring adhesives. Other applications
for BBP include use in vinyl coatings, polyvinyl acetate adhesives,
and acrylic caulking compounds.
Like other phthalate esters, DNOP has been used as a plasticizer
for PVC. However, little information is available regarding either the
volume of production or the extent of its use in this application.
3.4 RELEASES OF PHTHALATE ESTERS
The release of phthalates into the environment occurs during the
manufacturing process, transportation, product formulation and fabrica-
tion, product use, and product disposal.
The range of products containing phthalates is extremely broad and
includes products with lifetimes varying from less than a year to several
decades. Virtually all phthalate esters produced are incorporated into
other products. Some 98% of the U.S. supply is incorporated into various
plastic products; most of these are ultimately deposited at landfill
sites. The remaining 2% is distributed among pesticides, cosmetics,
colorants, catalysts, perfumes, solvents, etc. Since some of these
materials are applied directly to human skin, they are eventually dis-
charged into publicly owned treatment works (POTWs) when they are washed
off.
Sections 3.4.1 through 3.4.5 describe the basis for the assumptions
used to estimate environmental releases.
3.4.1 Manufacture
The loss of phthalate esters during their manufacture from the
phthalate anhydride is unknown, but it has been estimated as less than
0.5% of total production (Hirzy _et_ _al. 1978). The same authors report
that water from the secondary treatment facility at one production
facility contains concentrations of 1-2 ug/1, but that the major portion
of the process losses are captured in the sludge.
On the other hand, Versar (1978) reports an estimate of 0.2% of
production lost either in the wastewater stream from decanting, or in
the vacuum columns used in purification. However, this may not include
all the process losses. Therefore, for this analysis, production
losses are assumed to amount co 0.5£ of the U.S. supply of phthalaca
esters. Noca thac these losses do noc appear on Figure 3-3, because
they take place before phthalata production statistics are compiled.
3-12
-------
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-------
3.4.2 Transportation
Phthalata esters are widely distributed via the transportation
network to the large number of converting plants in various parts of
the country, for incorporation into calendered, extruded, and coated
flexible PVC. The phthalate esters are believed to be transported in
liquid form, primarily via unpressurized rail tank car (DOT Specifica-
tion 103) and/or motor carrier tank truck (Specification MC 310, 311,
312, or 331) and, to a lesser extent, in small quantities (i.e.! 55-'
gallon drums). The phthalate esters are not listed as hazardous
materials, which fall within the regulatory framework of the Department
of Transportation, Materials Transportation Bureau., However, transporta-
tion of these materials may fall within the regulatory jurisdiction of
other government agencies because of the possibility of releases to the
environment as a result of operator or mechanical failure.
The amount of loss associated with transportation (other than from
accidents) is not known but can be assumed to be a function of the size
of the shipping container and the remaining amount after the container
is empty." Most esters are shipped by rail tank cars or tank trucks to
distribution points and sites of major users. Some of the smaller opera-
tors among the 8000 compounders of plastics probably receive the plasti-
cizers in 55-gallon drums. Small operators using rotational molding,
coating processes, and small injection molding processes could possibly
obtain a major portion of their plasticizer in this manner. Products
made with these processes account for approximately 75,000 kkg of
phthalate esters and include the following products:
70% of footwear•
30% of outerwear
100% of weatherstripping
20% of furniture
100% of toys
100% of sporting goods
100% of garden hoses
100% of medical tubing
If it is assumed that 80% of this production is accounted for by 20% of
the companies who are large enough to purchase in tank car lots", then
the remaining 20%, or 15,000 kkg, might be delivered from the manufac-
turer to the compounder in 55-gallon drums. If between one cup and one
quart of plasticizer remains in each empty drum, then between 0.11% and
0.46% or between 18 kkg and 68 kkg could be wasted and released to the
environment when the drum is reconditioned, destroyed, or stored in a
manner that allows the remaining third to be released. The total amount
transported in drums, according to this calculation, would be approxi-
mately 3% of the total production.
While it is unknown what percentage of Che phthalate transported
in tank cars or tank trucks ramains after the material has bean" delivered
and the tank is "empty," an estimate of approximately one-tenth of one
-------
percent remaining may be reasonable (Arthur D. Little, Inc., estimate).
This amount will either be cleaned from the tank prior to loading another
commodity or will remain in the tank if the vehicle is in dedicated
service. Information on numbers of tank cars that are dedicated is
unavailable. For estimating purposes, it has been assumed that
0.1% of the material transported is cleaned and flushed with water.
The amount being transported in tank cars and tank trucks would be
approximately 97% of the total production. A weighted average of the
waste from the 3% delivered in 55-gallon drums and the 97% delivered in
tank cars is still approximately 0.1%. For calculating a materials
balance, it is assumed that one-tenth of a percent is lost because of
transportation-related causes.
3.4.3 Formulation and Product Fabrication
One significant transport path for PVC plasticizer-type esters is
volatilization during their compounding with PVC. During compounding,
stabilizers, lubricants, pigments, etc. are combined with PVC and 40 to
70 parts of plasticizer (per 100 parts of PVC). Subsequent processing,
which may include calendering (the placement of materials on hot rolling
mills to fuse the elements) or other processes that raise the tempera-
ture of the mixture to form a plastic product, can result in the vapori-
zation of an unknown amount of plasticizer. Hirzy ^t al. (1978)
estimate that approximately 2-4% of the plasticizer is volatilized
in this way. This percentage corresponds to a loss of 5200-10,300 kkg
per year.
It is assumed that in some of the larger processing facilities, the
vapors of plasticizer pass through a water spray for cooling and con-
densing the vaporized plasticizer. Some of the waste stream may be
recovered through, reprocessers, and some may be released directly to
water (Hirzy _e_t _al. 1978). In smaller operations, much of the plasti-
cizer vapor is probably vented directly to the atmosphere. In construct-
ing a materials balance, it was assumed that 65% of the vapors liberated
during the compounding process is released into the water and 35% is
released into the air. For calculation purposes, we assume that 3% of
the total phthalate plasticizers are volatilized in this manner.
Once the PVC and the plasticizer have been compounded and fabricated
into various products, other wastes are generated. These wastes can
range from 1 to 12% of the material processed, depending on the product
and the processing (Arthur D. Little, Inc., estimate). It has been
estimated that on the average approximately 2% of this manufacturing
waste is incinerated, while 98% is deposited to a landfill. Most of
this manufacturing waste is disposed of in private landfills, or removed
by private haulers contracted by the manufacturer. No data are available
regarding the division between private (industrial) facilities and muni-
cipal landfills; but an estimate of 75% to industrial landfills, and 25J,
to municipal landfills is not unreasonable (Arthur D. Little. Inc.,
estimates).
-------
The wire and cable product category is one area in which a higher
percentage of waste is incinerated. In some states, wire and cable
waste continues to be incinerated in order to recover copper wire.
Assuming that 10% of the wire and cable wastes can be incinerated,
159 kkg of DEHP used in wire and cable manufacture were incinerated
in 1977.
3.4.4 Products in Use
Estimating release rates of phthalates from products in use is
complicated and speculative at best. Insufficient data are available
on release rates under ambient conditions typical of product use. This
is true partially because of the wide variety of plastic products and
their use, and partly because the manufacturers are more interested in
relative performance of plasticizers than absolute emission rates.
Therefore, most studies have been comparative in nature and have been
conducted under temperature, pressure, and solvent conditions designed
to accelerate the release rates.
Studies under normal use have been limited and indicative rather
than definitive. In addition, the broad spectrum of manufactured products
containing phthalates makes it difficult to quantify accurately phthalate
release rates into air and water.
Peakall (1975) has given the best summary to date of phthalate use
and distribution in the environment. However, some of his'assumptions
require modification in light of more recent data, and other acknowledged
arbitrary assumptions are debatable. The conservative approach taken here,
is to maximize release rates within reason. This seems -justified because
the major portion of phthalates that are not released from products
during their useful lifetimes are disposed of in landfills where they
apparently remain bound indefinitely in the plastic matrix (Storm 1977).
Peakall (1975) has established a rough arrangement of plastic
products by groups in accordance with their environmental exposure during
use; this approach is useful in estimating release rates.
Estimates of releases to water from products that are in direct
contact with liquids (such as swimming pool liners, garden hoses, and
medical uses) are taken from Peakall (1975). The estimated maximum rate
of phthalates released from thes'e products is 1.0% per year.
The rate of release to air from film-type products with direct
contact to the air (such as flooring, weather stripping, furniture, wall
covering, auto mats and tops, auto upholstery and seat covers, apparel,
and food wrapping) is estimated as 0.2% for this study. This is within
the range suggested by Peakall (1975) but higher than'his assumed 0.1%,
which he states will occur mostly within che first raw weeks, wliile it
is clear that the rate at which plasticizers are volatilized (or leached)
is higher for new products, a long-term or continuing loss.may also
occur. In addition, high taaiperature tests indicate that much nore
3-16
-------
rapid loss rates are possible, e.g., 2.8% loss per hour for DEHP in a
milling test at 170°C (Gross and Colony 1973). Therefore, in line with
a conservative approach, the annual loss rate is assumed to be 0.2%.
For products having low surface contact such as wire and cable,
houseware, sporting goods and toys, and other PVC uses, Peakall (1975)
assigns a loss rate of 0.01%. This appears rather low considering that
some products in this category are subject to washing, exposure to high
temperatures, sunlight, and physical stress. Therefore, for this
analysis, the conservative rate of 0.4% is used, half of which is released
to the air and half to the water compartment.
Non-plasticizer uses of phthalate esters are found in applications
such as carriers and dispersing media for pesticides, cosmetics, color-
ants, and catalysts. Some of this material is sprayed directly into
the air or applied directly onto the skin for a relatively rapid transfer
to the water during washing. A maximum one-year lifetime is assumed for
this group and that 40% of the phthalate content is vented directly to
the air while another 40% is directly releas'ed into the water during
the product use. The remaining 20% is assumed to be adsorbed to sur-
faces or absorbed into plant or animal cells-.
Each of these assumptions is highly uncertain, and detailed investi-
gation could show that some of the assumed loss rates are actually lower
and some are actually higher. For example, the loss rate from flooring
is assumed to be directly released .to air at a rate of 0.2% per year.
However, flooring is subject to washing with detergents in which the
DEHP or other plasticizers are probably more soluble than water. Thus,
phthalates used in flooring may be directly released into water. Vari-
ables, such as solubility of the plasticizer in the particular detergent,
the transfer from the floor into the detergent, the frequency of washing,
and the amount of wear of the floor, have not been evaluated.
3.4.5 Disposal
Approximately 145,000 kkg of municipal solid waste were generated
in 1977 (Third Annual Report to Congress 1975; Arthur D. Little, Inc.,
estimate). The number of municipal incinerators currently operating
in the United States is estimated to be 50, with an average capacity of
250 tons per day (Arthur D. Little, Inc., estimate). Thus, approximately
3% of municipal waste is incinerated. Since the wide variety of plastic
products is assumed to follow the municipal waste stream, 3% of phthalates
in products are incinerated as well.
This contrasts with the 15% loss of phthalate products in incinera-
tion assumed by Peakall (1975) on the basis of a study of ?C3's by
Nisbet and Sarofim (1972). Part of the discrepancy may be attributed
to special measures used to destroy PC3'3 by high temperature incinera-
tion, and part is probably because of the reduction of open burning as
a rasult of the Clean Air Act. In any event, 97%'of ohthalates in"
used products is assumed to be deposited in landfills and 3% is destroyed
-------
by incineration. No allowance has been made for the uncollected waste
that is randomly distributed as litter along roads and streets because no
information is available on that percentage. However, it is expected that
litter would reduce the amounts deposited to landfills and incinerated.
3.5 SUMMARY
-Losses of phthalate esters (DEHP, BBP, DBF, DEP, and DMP) during
production and use are illustrated on Figure 3-3. No information was
available on DNOP. Various assumptions have been used in this analysis
and the major ones are summarized in Table 3-4. A more detailed descrip-
tion of losses for various use categories is given in Appendix A.
Vaporization during compounding accounts for a major portion of the
release of esters into the atmosphere and water for that portion of
esters used for plasticizers. DBP, DEP, and DMP also have major routes
into the air and water through non-plasticizer products. For DMP, the
non-plasticizer routes to air and water are the major routes. Table 3-5
shows a summary of annual losses for each step from production through
disposal and also shows the percent of the original production that is
deposited in landfills. Apparently, between 71 and 92% of each of the
esters ultimately is deposited in a landfill. Table 3-6 shows the
annual releases of phthalate esters into the various environmental
compartments. For these five esters, an average of 2.7% is released
into the air, 3.3% is released into water, 91.1% is deposited into land-
fills, and 2.9% is destroyed by incineration.
3-18
-------
TABLE 3-4. PRIMARY ASSUMPTIONS USED IN MATERIALS
BALANCE ANALYSIS FOR PHTHALATE ESTERS
Process
Production
Transportation
Compounding—vaporized
Solid waste-manufacture
Use
Non-plas ticizer
PVC
Direct contact with liquids
Film in contact with air
Low surface contact
Disposal
Loss Rate
(% loss/year)
0.5
0.1
3.0
1-7.3
80
1
0.2
0.4
100 (of
remaining)
Compartment
water
water
35% air, 65% water
97% landfill,3%
incineration
50% air, 50% water
water
air
50% air, 50% water
97% landfill
3% incineration
Source: See text.
•;-•' Q
-------
TABLE 3-5. ANNUAL PHTHALATE LOSSES TO THE ENVIRONMENT
IN THE UNITED STATES
Loss (thousand kkg/year)-
DEHP BBP DBF PEP DMP
Production 0.9 0.3 0.04 0.04 0.02
Transportation 0.2 0.1 0.01 0.01 0.01
Compounding (Total) 5.0 1.7 0.2 0.2 0.1
(to air) 1.8 0.6- 0.1 0.1 a.03
(to water) 3.3 1.1 0.1 0.1 0.1
Manufacturing 9.9 1.2 0.3 0.3 0.1
Product Use >3.4 >0.8 >0.3 >0.3 >10.1
Product Disposal 149.1 51.7 6.1 6.7 2.9
(97% to landfill)
Source: See text.
3-20
-------
TABLK 3-6. ANNUAL PIITIIALATE RELEASES TO ENVIRONMENTAL
COMPARTMENTS IN THE UNITED STATES
Keleased to air
Released to water
I and I ilied
I IK: i nerated
TOTAI/
1
DEIIP
4.3
5.2
154.1
4.9
]68.5
BBP
1.4
1.4
51.3
1.6
55.7
DBP
0.3
0.3
6.3
0.2
7.1
DEP
0.2
0.3
6.8
0.2
7.6
DMP
0.5
0.6
2.9
0.1
4.1
Total
6.8
7.9
221.3
6.9
242.9
Percentage
1.2
1.5
41.4
1.3
45.4
1
Includes process loss during production, estimated at 0.5% of production
released to water.
I in: I tides U.S. supply plus process loss during production.
Source: See Appendix A.
-------
-------
4.0 FATE AND DISTRIBUTION OF PHTHALATE
ESTERS IN THE ENVIRONMENT
MONITORING DATA
armyworn,
PUnt3' "Broach and
rrh*,., ,
when compared with
4-1'1 Levels in Water and
et al.
~
areas. However,
in to. bvs n
falls in Waukegan Harbor sfn FrancL^^ manuf Curing Plant out
Mississippi, Mx'ssouri Ind Srri'ack Rivers' ^ ^ 'f51^' Ulin°is'
surveys are shown in Table 4-2 Si? If f16 rSSUltS of thess
than those reported in Table 4-1 "' sli§hc1^
of levels of phthalate
unidentified substance Was entire^
cory contamination was reported thus
high. The levels reported by liam e?'
River Delta were xuch lower (0 07 u^
a i -
-
"
chat the
at limiti^ labora
^ unreal"ticallv
saai
,0.3
"
;n
action.
ESI1. and 1
-------
TABLE 4-1. PHTHALATE ESTERS IN WATER AND
T'EHP
DBF
DEP
DMP
Source
Mississippi River Delta
Black Bay, Lake Superior
•rural and industrial area)
Hananand Bay, Lake Huron,
Michigan (forested area) -
Lake Huron, Michigan
Missouri River, McBaina,
Missouri (turbid)
Charles River, Boston
Merrimack River
Unknown river downstream from
industrial inputs)
Nipigon Bay, Lake Superior
deceiving water of pulp and
paper mill)
Tama River, Tokyo
(industrial location)
Mississippi Delta
Gulf Coast
Open Gulf
Morth Atlantic
max. of
600
300
-
5.0
4.9
0.38 - 1.9
Detected
1-50
sediment
0.2-56 mg/kg
-
.3-7*
Mean .074
Range .023-
.225
Mean . 1305
Range . 006-
.316
Mean .0805
Range . 006-
.097
Mean t QQ49
«0 ,3
ta>
0.04
.09
2 2
Detected Detected
1-20
sediment
1.5-25 mg/kg
0.1-23
sediment,
1 sample -
70 mg/kg -dr>
weight
.0007-
.0035
Mean .09^
Range .0065-
'.471
Mean .Q743
Range .0034
.265
Mean .0935
Range .003-
U33
Not Detected
Corcoran
(1973)
Mayer et al.
(1972)
Mayer ec al.
(1972)
Mayer ec al.
(1972)
Maver et al.
(1972)
Kites (1973)
Detected2 HiCes <«")
Jungclaus
et.al. (1978
Brovnlee and
Strachan
(1977) •
Morita et al.
(1974)
- * Giam et al.
(1978)
Giam et al.
(1978)
Giam et al.
(1978)
Giam et al.
(1978)
ar concentrations in ug/l; sediment in mg/kg.
"Blanks judged acceptable for contamination.
JThe authors reported cnat care «as taken co avoid contamination, but a blank was not reportea.
"Possible overestimation of 10%.
'Typical blank <.001 ag/1 for D8P and < 0.0002 ug/l for OEHP.
-------
M ! »T
-------
FIGURE 4-2. DISTRIBUTION OF AMBIENT LEVELS OF DI-N-BUTYL
PHTHALATE IN SURFACE WATER
of obi|erv«tions
-------
JC
p:
> sc
> c
•z. -Z.
v. c
•n
z
i
-------
FIGURE 4-4. DISTRIBUTION OF AMBIENT LEVELS OF DIMETHYL PHTHALATE IN SURFACE WATER
100
I I
Concuiu ration (ug/1)
n
10
I- IWI
• ;J 1001 1000
IUOO IUOOU
100
*Ni>iUi^i of ol,:n: i vai I mib In river buutn.
£ •
r
W«I«H OuU
-a
\ J*^
0
r-
Couth C*nml
Loom Mm M.
'Source: STOKE I'
-------
'WUKE 4-5. DISTRIBUTION OF AMUJENT LEVELS OF 1)1 ETHYL PHTHALATE IN SURFACE WATER
too
Source: STORE?
-------
TABLE 4-2. MEAN PHTHALATE ESTER ENVIRONMENTAL
LEVELS IN WATER AND SEDIMENT1
Water (ug/1) Sediment frog/kg 1
DEHP
DMP
DEP
DBP
BBP
2
Mean Cone.
.085
N.D.
3.2
0.29
0.75
Freq.3
36
0
82
58
64
Mean Cone. FrecL.
0.89 46
N.D. 0
N.D. 0
N.D. 0'
0.43 25
N.D. - Not Detected
Fifty water and 28 sediment samples (not in the immediate
vicinity of sewage and waste outfalls) were analyzed.
2
Average concentration of only those samples containing the
particular phthalate ester.
Percent of samples containing the particular phthalate ester.
Source: Hirzy at al. (1978).
4-8
-------
4-1.2 Levels in Soil
; «.
soil, corrected for balkgrouJd It J^J *""* °'°'5 "*'** DEHP ^ <*«
vas not identified! baCiCgr0und' buc noc ^r recovery. The specific source
4.1.3 Levels in Air
tr
A recent study by Giao et *i no™? * plastlcs is "ell known
and 0.3 ng/m37(*Ln v^f^ sp c iveTl Jf" ^ °BP "
Mexico. Samples taken over \l I S ? , ' the air over the
tiona may be found. n s «
o£ these levels. mping ls needed to confirm the prevalence
4'l-4 Levels in Bioea
and DBP in aquatic organisms lIvS ShOW * C0nsiste*c ^ l^el of D2HP
industrial areas; howfver contamil^ Seem " ** Sli§htl7 higher
rural areas. '
consistent with the levels found in nrh J ? manufacturing plant are
facturing facilities do not se^ to create "0^^^ ^*>
maximum reported value for DEHP was 7 1 m«/v J ^ SP°tS' The
sharks from San Francisco Bav ??f 7'1.nig/ks found in smooth hound
the .. ' ta r^eTanl
of -.
--ported DEHP laveis oj ^ofl
.,
j.rom Arkansas rarms. DBF
-------
TABLE 4-3. RESIDUES OF PHTHALATE ESTERS IN AQUATIC ORGANISMS
SPECIES
Molluscs, freshwater
arthropods, small fish
Phytoplankton,
zooplankton
Bream
(Abranis brama)
muscle
liver
roe
?erch
gerea fluriafllis)
muscle
Pike (Esox facias)
auscle
liver
kidney
Roach (Rutilis rutilis)
muscle
roe
Pickerel
7 samples*
7 samples*
7 samples*
7 samples*
* samples*
* samples*
LOCATION
Finland, vicinity of
OEHF plane:
- ac mouth of brook
leading from dump
to brook
brackish bay
2 km from factory,
1 km from dump,
3 km from waste-
vater discharge
DEHP
(mg/kg)
0.1
COMMENT
SOURCE
Lake Ontario &
Lake Huron, Canada
0.5
0
0.2
0-0.1
0
2.3
0
1.1
0
DEHP
(mg/kg)
4 samples
3 showed
trace levels
corrected for background
(0.2 tag/kg) but not recovery,
(40%), results probably in
dry weight
corrected for background
(0.2 mg/kg) but not recovery,
(40%), results probably in
dry weight
DNBP
(mg/ks
Persson e_t al.
(1973)
Persson et al.
(1978)
Persson et al.
(1978)
Persson at'al.
(1978)
Persson et al.
(1978)
Persson ec al.
(1978)
Mobile Bay
Chesapeake Bay
Lake Erie
Lake Michigan
Calveston Say
Lower Mississippi
1 sample 0.22
Others MD
ND
Traee-0.2
0.08-0.22
^0-trace
ND-0.12
4 samples, Blanks .015 mg/kg Williams (1973)
3 showed for DEHP, and .01
trace levels for OBP. Levels less
than twice blank
designated as trace.
Levels of less than FDA (1974a)
0.2 tng/kg are suspect
due, to high levels
of DEHP in blanks
— FDA (1974a)
FDA (1974a)
MD-2.28 FDA (1974a)
FDA (1974a)
Trace-2.12 FDA i,1974a)
4-10
-------
TABLE 4-3. RESIDUES OF PHTHALATE ESTERS O AQUATIC ORGANISMS (Continued)
SPECIES
Macicaral and flounder
r samples*
samoles*
LOCATION
Long Island Sound
San Francisco Say
?uget Sound
DEHP
(mg/kg)
0.48-2.16
0.11-7.1
QNBP
(mg/kg)
COjjMENT
SOURCE
?DA (1974a)
FDA (1974a)
FDA (1974a)
DEHP
Seston
DNBP
Channel
Cacfish
Nipigon Bay. Lake
Superior, up co
6.3 km from krafc
pulp and paper mill)
Channel
Cacfish
Dragonfly
Naiads
Tadpoles
Walleve
Bellow Perch
Brook Crout
Eel
-acfiah
3 - Mot ietactaa
Comoosna or fish =?ecias.
Mississippi and
Arkansas (agricul-
tural and industrial
areas)
Fairport National
Fish Hatchery. Iowa
(water supply from
industrial area of
Mississippi River)
Black Bay, Lake
Superior. Ontario
(rural and industrial
areas)
Lake St. Pierre,
Canada
3.2
0.4
0.4
0.3
0.8
Spirit Lake, Iowa NO
(agricultural area)
Clover Leak Lake, CA ND
(10,300 ft elevation)
0.104
Trace
Trace
Trace
0.2
0.5
MD
.VD
2/20 samples showed Brownlee and
trace levels, care Strachen (1977)
taken to avoid con-
tamination but no
blank reported.
Approximate detection
limit .01 mg/kg dry weight.
Detection limits, 0.1 Mayer et al
and 0.5 mg/kg for ' (19797"°
DNBP and DEHP, res-
pectively, contami-
nation reduced, but
unreported.
Mayer st_ al.
(1972)
Mayer e_t al.
(1972)
Mayer ^et al.
(1972)
Mayer e£ al.
(1972)
Mayer e_t al.
(1972)
Mayer _a£ aj..
(1972)
for DNBP.
Levels less cnan
:wica blank
Jesignacad as :raca
-------
was found in one sample at trace levels. No DEHP was detected in fish
from Georgia farms. The detection of phthalates in hatchery-reared fish
is not surprising, however, considering Mayer's _et al. (1972) report
of 2-7 mg/kg DEHP in commercial fish food.
Little information is available on phthalate esters in terrestrial
organisms. Perrson _et _al. (1978) reported 2.8 mg/kg in soil arthropods
sampled in the vicinity of a DEHP manufacturing plant. Egg yolks of
double-crested comorant and herring gulls contained 0.014-0.019 mg/kg
DBP (Zicko 1973).
The results described above suggest that DEHP and DBP are commonly
found in aquatic organisms, although generally at low levels (less than
1 mg/kg). Insufficient information is available on levels in terrestrial
organisms; therefore, generalizations can not be assumed.
4.2 FATE OF PHTHALATE ESTERS IN THE ENVIRONMENT
4.2.1 Methodology
Materials balance data' (Chapter 3.0) and monitoring data (U. S. EPA1979a,
Morica et .al. 1974, U.S. EPA 1974, Giam _ec al. 1978) suggest pervasive
release and occurrence of phthalate esters throughout the environment.
Since phthalate esters are largely contained in PVC products, the wide
distribution of these products suggests several million pounds per year
of the material are released to both the atmosphere and surface waters
over a broad area of the United States. In addition, several hundred
million pounds of phthalate esters are disposed of in landfills yearly.
This examination of the fate of six phthalate esters is based on
DEHP as a prototype because of its large releases into the environment
and its greater persistence in water. In addition, monitoring data
show that DEHP is the most prevalent phthalate. The assessment of
transport and transformation in the environment is based on work conducted
by the U.S. EPA (Wolfe .at .al. 1979). The physical and chemical data used
in fate analyses were provided primarily by a literature search (Versar
1979a,b). The data bases provided in this literature search and in the
model calculations (Wolfe .et al. 1979) are re-evaluated to determine if
any trends other than those indicated by the calculations should be
anticipated.
In the assessment of the fate of DEHP, a single compartment model
is used as a first step. This represents a. "worst case" situation in
which the discharge of the chemical is confined to a single environmental
medium, i.e., water. No degradation processes or transfers to other
media are considered to determine the maximum level of concentration in
the compartment in question. Available models were then used to examine
the effects of the degradation processes.
While "he single compartment approach is utilized for the water
portion of the analysis, degradation in the atmosphere can be estimated
4-12
-------
as a surrogate; and first order lecav n™ ? U81n8 an lnert
obtain the concentration estates T^ """ s^^imPosed
are based on the two measured ll^s^lr^^'^3 °£ Chese
available in the literature ?ate oroIL C°nCentraCion ^" currently
derived largely from experimental ohI ln 01°ta and 3oil ««
result in estimates oH"c«?r«io« Jn"^- -TheSe ^^ eff°r£s
importance of various fate processes addic"*> they confirm the
4.2.2
Physical and Chemical PT^^^
-o -w wilt gcuetaj. CiaSS of
They exist'gen^Uy^riiquid'^itr110 "" ^h°*h^' acid).
moderately soluble to essentially insolubl^ S°lubxlit:Les ranging from
tively stable, breaking down'slowlv to L™'^?1? con»pounds are rela-
acid. Appendix B presfnts the physical-cheS^ ^S °* C° Phthalic
Phthalate esters considered ^r^ysical-chenil^l properties of the six
4-2.3 Fate in
d
results are given in Aplx C The « ? u descriPtions <* these
chemical loss mechanisms, including photolv, Sh°W.,that for ^HP, the
and biological degradation are insfgLLcant In" °J "" ^drol^sis'
the export of DEHP is the primary ITsl TmecSni J *n Stead^stace system,
is more rapidly lost because of^ more ~o?J iT,.00 the °ther hand' DMP
biodegradation rate. ln lakes and 00^,^ alkaline ^drolysia rate and
Primary loss mechanism,
in a ccST rn'oTl (19?8) '
state discharge followed by a Say Sear±f as|umea 30-day steady-
parameters were used than L Wolf. L £ £9™
Appendix C. At the end of the 30-dff feViS ?)f
was found in the sediment, with '" '" °f
can
in
' concentrations
P"sented above (Chapter 3.0)
Watar
°f the annual
c
indicates that 5.3 x 103 kkj/jr D
Using Nisbet and Sarofim's (1972)
off for the United States reaches
-s estimated at a steady-state of'o g/
a uotal run-off of 2.4 x 10^5 i/vr ,-nlf~ ms/
(1977). Thus, the results of the° °§
1979) should be scaled do^n ov a r -
Hows in the environment. The ~alcui*rJ rerlect rhe relative
result in an apnroxiniation of 0^- ^/' f C°ncenCracion ='or DEHP vili
EPA's concentration estimat s res ^ ?°1IUC3d areaa ' 3incs
,
^ calculation assumes
sua°««« of 7eMzian
4-13
-------
the U.S. EPA simulation is directly proportional to water concentration
because of the linearity of all the processes, concentration in sediment
of approximately 10 mg/kg might be expected. This number should be used
with some caution, however. According to the input data in the U.S. EPA
results, the octanol/water partition coefficients were input in place of
the organic carbon partition coefficients for the simulation' (see Table
B-l). For DEHP, the organic carbon partition coefficient is twice as
large as the octanol/water partition coefficient. It is difficult to
perform a similar scaling" procedure for the model used by Neely (1978)
because it is confined to a single scenario of a small pond in transient
state.
The formula derived by Southworth (1979) was utilized to confirm
the low rate of volatilization from water for DEHP used in the U.S. EPA
work. A discrepancy of 20 was found, suggesting that the volatilization
rate predicted by 'the modeling exercise may be overestimated. The high
value of the coefficient does not affect the results, however, because
volatilization was negligible.
A confirmation of the low biodegradation of DEHP was-sought in the
literature. Saeger and Tucker (1976) found that DEHP was 70-78% degraded
in 24 hours by activated sludge organisms. Mississippi River organisms
degraded 1 mg/1 DEHP by 60% in 21 days. Johnson and Lulves (1975) found
that pond hydrosoil organisms degraded 41% of introduced DEHP in 30 days
under aerobic conditions, while no degradation took place under anaerobic
conditions. In addition, Mayer (1976) and Stalling _et ail. (1973) reported
degradation of DEHP by fathead minnows; 21-40% was degraded in 56 days.
Although these results are from laboratory studies, they suggest
that the biological half-life shown in Table C-2 (1.5 x 106 days - 1.3 x
10^ months) may be over estimated for DEHP, at least under aerobic condi-
tions. Thus, the concentration estimate should be considered a maximum.
The results presented above suggest that DEHP reaching aquatic
ecosystems will be largely accumulated in the sediment and exported.
Chemical loss mechanisms as well as volatilization do not appear impor-
tant. However, biodegradation of DEHP may be an important loss mechanism.
We conclude that concentrations of phthalates in water in the ug/1
range seem reasonable from the rough steady-state calculations and the
relative roles of various fate processes illustrated in the model simula-
tion. These concentration estimates are based on materials balance and
run-off estimates coupled with the fact that pathways other than export
are extremely long-lived by comparison. The estimate of 0.02 mg/1 in
water may be high because of the continuing transient state of sorption
of the material onto sediments. River simulation indicates that 176 days
are required to reach 99% steady state; lakes and rivers require over
100 months.
The monitoring data for ambient water levels of DEHP indeed exhibit
concentrations in Che low ug/1 range (U.S. EPA 1979a, U.S. EPA 1974, Morita
a_t _al. 1975, Giam _§_£ _al. 1978). Occasional readings much higher than
4-14
-------
or
4.2.4 Fate in Air
o
hydroxyl (OH) radicals in th atmosZr^T T^ ^ raacti^7 with
in the photochemical cyc?e of S^«S • /ydroxyl "dicals participate
in the presence of sunliglt to fo™ *ll? **? "* °rSaniC Va?ors raa
c7cle is comonlv assorted with^hnf ^ P"ducts. Although this
ing degrees throughout the miCEl 3m°S' ic occurs in ^a
the °H-
.essf-
is 1.4 x 10-U Cm3 Mc-l (Doyle eralL^TT "f S °f °H W±th °-Xyle
the California Air Resources Boa?d lc^ 2 '• An/dvisory committee for
£-
^^
Class III ranges from 1 11*° i^ll""!^-!* \t0 * X 10'U ^ s
states that appreciable amounts of Class I ^L ^ ^ (19?6) rePort
after a 10-hour irradiation oeriod ir, =°«Pounds remain unreacted
fraction of Class III compounds perhap's'o^O^" *"' * Sufasta^ial
irradiation period. Perhaps 40-60^, is consumed in a 10-hour
on -.iob arS C° ChSSe ^"- «. base,
.
the phthalate esters basen ?he abovf'f6 "" C°nStanC ranSes ^«=h
constants of analog compounds and III Lf S!!Vations of act^l rate
the acetate/prooioSate ?ate constants Z" ", eSCimates' Considering
the reactivity assignments sho^ ?n "able I*7 "" C0nstant'
- a"' we "t
n ae
10-2 co 5 x 10fU cm3 ac£-ia' we "timate a range of
ror the phthalate esters of'ince-ast It ^L^*^™ ^^ With OH
pnthaiate is at the lower -nd of ^e'-an" g ™ exPec"d that dime
and brancaed chain al.yl 3h'thaUte"s c^C ^ '" '^ ^ °haia
^e range of atmospheric half-i^ea for an rS UPPSr and °f =he r
— ves cor an uraan atniospners typified
b
-------
TABLE 4-4. CALIFORNIA AIR RESOURCES BOARD REACTIVITY
CLASSIFICATION OF ORGANIC COMPOUNDS, 1976
Class I
(Low Reactivity)
Cj_-C3 paraffins
Acetylene
Benzene
Benzaldehyde
Acetone
Methanol
Tert-alkyl alcohols
Phenyl acetate
Methyl benzoate
Ethyl amines
Dimethyl formamide
Perhalogenated
hydrocarbons
Partially halogenated
paraffins
Phthalic anhydride**
Phthalic acids**
Acetonitrile*
Acetic acid
Aromatic amines
Hydroxyl amines
Naphthalene*
Chlorobenzenes*
Nitrobenzenes*
Phenol*
Class II
(Moderate Reactivity)
Mono-tert-alkyl-benzenes
Cyclic Ketones
Alkyl acetates
2-Nitropropane
C.+ paraffins
Cycloparaffins
n-alkyl Ketones
N-methyl pyrrolidone
N,N-dimethyl acetamide
Alkyl phenols*
Methyl phthalates**
Class III
(High Reactivity)
All other aromatic
hydrocarbons
All olefinic hydrocarbons
(including partially
halogenated)
Aliphatic aldehydes
Branched alkyl ketones
Cellosolve acetate
Unsaturated ketones
Primary & secondary C.4-
alcohols
Diacetone alcohol
Ethers
Cellosolves
Glycols*
C2+ alkyl phthalates**
Other esters**
Alcohol amines**
C,+ organic acids +
di acid
C3+ di acid anhydrides**
Formin**
(Hexa methylene-tetramine)
Terpenic hydrocarbons
Olefin oxides**
* Reactivity data are either nonexistent or inconclusive,
but conclusive data on similar compounds are available;
therefore, rating is uncertain but reasonable.
-^Reactivity data are uncertain.
4-16
-------
a^ -to** ct i-Uia
are only about 1/10 that of
hours to 3.3 days. Both of uae
required to adsorb onto aerosol particles in
-"1ical concentrations
atmosPheres will therefore be 13
**iov the ^
or rainout.
radical "action
*« ~Ce —rolling
To estimate concentrations In air a slmni= t
Appendix 0) . asing che range of °°del "as usad
previously, a concentration
afcer 2
Ihe v c.
range of observed values in a i?™^^ the previous section
brackets the predicted range
the previous P^^^
than those in Ontario. These observaMnn
rapid decay of this material the atlcnhSUSSeSC
is approximately three times the *
^scaling of the materials
-««l.t«,«.
. The wide
°f SampleS (0-0004-0.3 ug/m-3
describe^
much low^
co^innation of the
hlgh Value 'in Ont""
4-2-5 Fate in Biota
are
t
»«
ne eesers . h
included a terrestrial .- tmuna-Lace esters. The laboratory system
The rate of up^kfanl ?££ oTn^^l * •~'1«^ "ophic chain.
that partitioning occurs .tr£g£ ?' the ll^L"^1^ ^ °f DDT ^
bxomagnification occurs in the food chaL Bi! P ntS ^ animals and
occurred by a factor 53,890 in OedLo • / ^^concentration of DEEP
107,670 in Culex (mosqultc > 1*^^20*^ f'480/" Ihvsa (snails) .
results suggest that DEHP faioaccumulltes in ,n *f"Sla (f ish) • Th«e
be metabolized by fish. The lioo ^ ^ PlantS
supported by high values of
acc^amulation in the fat
concentration. Similar observtion
in the spleen, liver, lung ? Ind
rapid intake «d
a rinal 3teady-stata
DEH?
-------
The model calculations by the group "at Dow Chemical Company (Neely
1978) indicate a fish bioconcentration factor of 635. This value is
high relative to the results for Gambusia quoted above; however, other
laboratory studies reported the accumulation of DEEP by fathead minnows
to levels 160 to 1130 times the concentration in water (Harris and
Eschmeyer 1974). Despite the size of the bioconcentration factor in the
model calculations, only 0.3% of the total DEHP introduced into the
system accumulated in the fish tissue during a 30-day simulation period.
The calculations indicate an infinite half-life for clearance after the
source of DEHP is removed. This appears to be an artifact of the input
data for the calculation because metabolism within the fish compartment
is not considered. In contrast to the model studies (Neely 1978), the
laboratory studies of Mayer (1976) suggest biotransformation and elimina-
tion by fathead minnows with a half-life of 12.2 days after removal from
a continuous exposure to DEHP. The data generally indicate that both
transformation and degradation in biological materials are significant
in determining the fate of the phthalate esters as a group. The informa-
tion available suggests that these processes appear to be slower for
DEHP than they are for the other compounds in the family.
4.2.6 Fate in Soil
Limited information is available on the fate of phthalate esters in
soil, although the materials balance (Chapter 3.0) indicates that the
primary entry point in the environment is the soil. However, the migra-
tion of phthalate esters out of plastics into water or saline solutions
is considerably slower(Wildbrett 1973, Jaeger and Rubin 1973). Thus, the
amounts of phthalate esters that are available for transport or degrada-
tion would be low. Migration could be increased by the presence of an
organic material or by increased temperature (Penn 1972).
Previous sections have demonstrated that phthalates concentrate in
sediment; available phthalates would probably be adsorbed onto organic
matter in soil. The formation of soluble complexes, such as phthalates
with fulvic acid, may increase the mobility of phthalate esters (Ogner
and Schnitzer 1970).
In addition, biodegradation of available phthalates may occur.
Versar (1979a) has reviewed the literature regarding faiodegradation; it
is not included here. The conclusions were that degradation in soil is
highly variable and rates cannot be established. However, the authors
felt that biodegradation would be an important fate process in soil.
4.3 SUMMARY
The consideration of fate mechanisms indicates that export of DEHP
is the primary fate mechanism in water. The U.S. EPA model (EXAMS)
predicts that neither chemical (oxidation, hydrolysis, and photolysis)
nor biological processes will determine the fata of DEHP. It has also
been demonstrated that volatilization is unimportant. Laboratory studies
suggest that biodegradation by fish and microorganisms may be more
-------
, «• —ed
li« these chemicals. Adsorption S'nnr " De able C° metab°-
a steady-state system, altho^EHP iTc^S^S'^" *
mechanism for DMP in vers s Tai ^ T* The ^^ face
however, biodegradation dominates °ther SquaCic ac°sys tarns,
hydroxyl atcdr?cion bv
not expected to be important? Peculates and rainout is
land-
would be Subjec to
-d observed
trations in soil expected to bTs^Tr^6^3 °f interes't- Con«n-
Phthalates from plastics in Lndf?n ^ ' bf°aUSe the ext"ction of -
data were available for co^centrf tion in Lil" ?*?"' N° ^"oring
vas excluded from Figure 4-6 T?e °ou,h LtL^ thuS/his Compartment
a water concentration of 0.02 mg/1 IretncertS^ :•» conducted hera giving
factor of 10. Therefore rh» J,^ J « ^f in by an approximate
the calculated concentrakon 1« T - °-006-°-060 m8/l i« shown as
mately bracket th? "JnJ Sd^Sn^h"8'- - K^^ Values aPPro^-
because of the proximity o ^sources and dlSf iU?Y °f C0ncent"^°n
The sediment calculations systematical sLw f? VelS °f dilutio^
tration compared with those reporteJin rh T- Wer range °f concen-
Here again, a factor of 10 uncertainty b I h K*'"" (U'S' E?A 1974^
the calculated values. The disparity her haS been assi§^ to bracket
concentrations may result from the eTJEiT" Calculated and observed
tions and from the relatively^e masi ^lb^™ a^umptions in the calcula-
tnodel compartment for hydrosoil For eithf "dlments as^§ned to the
values, the quantity of DEHP partitlL!^ ! calculated or observed
is large compared with thafpartitlned i£ S*dlBenC "-Payment
the model calculation demonstrated that 98 oTl^' ** mentioned ab°->
vas exported at equilibrium ?his occurs on?^ f6 maCerial introduced
i.e., the sediment compartment has reached its r I SatUration is attained;
possible reason for the disparity couldho r\ 3tea^^tata load. Another
tative were the samples taken ror sediment in" IT^™ °* ^ «?«««'
Because of fallout and resuspens ion it i f% ?• ? measurem^ts program.
vertical concentration gradients of' Ch. J ??ly possible that shar^
sediment layers. S^aients of the adsorbed material exist in
a.on. ar.: (1) :he bui
eacnaa a relatively hlgn ,alue c
i-19
-------
Mostly Degraded
by OH-reaction
t
AIR
Remote
Calc. 0-.008
Obs. .0004
[concentrations in
Urban
.02-. 09
.3
»Jg/m)
f
4.3 x 10 kkg/yr
1
o
SEDIMENT
Calc. 5-50
Obs. 20-200
(concentrations in mg/kg)
J. J A \V KB.g/ y I
1
WATER
Calc. t006-.06
Obs. .001-. 05
(concentrations in mg/l)
i— — —
FISH
Calc. 4-38(30-day exposure)
Obs. 0.3-3
(concentrations in mg/kg)
Mostly Exported
FIGURE 4-6.
SUMMARY OF FATE ANALYSES FOR DI(2-ETHYLHEXYL PHTHALATB COMPARING
CALCULATED VALUES AND ACTUAL OBSERVATIONS
-------
calcuiation
coupling occurs between the air ar,^
. oecause, in the case of DEHP *r iaa««. d water compart-
water and very little rainsoufof th*' **** i^1* volaeili"s 'from
largely exported to the oJan and thf J"' T™ WSter fracc^n is
quickly by reactions with the'hydroxvl SL 1"!° ** de§raded relatively
compartment is shown as a separate entity in v'ieull*S^ T"0"' Che ?^
concentrations are calculated nr nK = ^ I I *l8ure 4-o. Extremely lot
sources of DEHP being emoted into thTair ^"T ^^ fr°m iike1^
levels are estimated to be n.n^-n no .../_i' n.the other hand' urban
eng emitted n ey
levels are esti^ted^to be 0 o'o 09 L/1?' h°Vhe °ther ^ Urban
as 0.3 ug/m3 have been reJQ^^ 0.09 ug/m3, whlle observations as high
measurement of concentration and ^h\dlspar1^ between the surface
concentration may arise r"ro™ I? ! box-average calculation of the
released from the" Si.^%^2, 2^^°^ ?' " ^ °EHP i
"
™
released from the .%2, 2^^°^ ?' " ^ °EHP is
tration levels decline sharply Sth altitu^ " • llkely that the "ncen-
Che difference in factors. altitude. This could easily explain
DE d low
mere rapidly in both the water and Sh bl°de§raded «nd hydrolyzed
lower discharge rate compared with th"t 0"^^'- BeCaUS6 °f their
would be expected to be even smaller rL ,? ' heir con«ntrations
Rapid degradation in air ho!ds thf I °S& Sh°Wn in Fi«ure 4-6.
compartment to *^t±^£^^™?^r*** *» th. atmospheric
mg further experimental and fi^H sediments are areas requir-
relatively high' P-rSSi.^?^^!'?10"- ^^ °f their
cules may tend to accumulate 2 ! t£« i iedia. ^ phthalate est" ~le-
-------
-------
5.0 HUMAN EFFECTS AND EXPOSURE
5.1 HUMAN TOXICTTY
.
^
in tissues of individuals with no orevin however, detected DEHP
biomedical devices or catheters ?H! exP^ure to DEHP-treated-
the source of DEHP cognation ^ ttl^^ anvir°™e»"l exposure as
-y present a health hazard to humans iLre'Se"™ d** ^^ "tn*
the assessment of the toxicitv ofThL ^ an lnterest in
report will review the toxicitv L ^ f!lpOUnds- This Action of the
esters considered in this aSSeL-nt b°llSm °f Ch6 SiX Phthalate
tt. as dioctyl phchal-
abbreviations for the »tltlilaHtl?t \ terminology. The correct
older nomenclature (DO^wL retailed wh "^ utilized« but the
what material was used! recained whenever uncertainty exists as to
3f the six
iies~ — <---—^u uexow. Additional information on
5.1.1 DEHP
found, and less than 3% of the urJ™ ev^dence or conjugation vas
free phthalic acid. "^ MCabolicea were in the fora of
Recent evidence suggests that- nF'4P -,• =. -, •
-^ ~
sex ac 0.0, 0.3 or o« o( -
rf^se:r ^- ^-
in ate..- :a ..c.
™ -- -
-------
gain was seen but survival was adequate, with better than 50% of the
animals in each group surviving until termination. Neoplastic liver
nodules were significantly elevated in all treatment groups compared with
controls (see Table 5-1) and the combined incidences of neoplastic
nodules and hepatocellular carcinoma were significantly elevated in high
dose male rats and in both high and low dose females. The incidence of
hepatocellular cancinoma alone was statistically significant only for
high dose female rats (NTP 1980).
A dose-related decrement in mean body weight gain was also noted in
36C3F1 mice, particularly in females from week 25 to the end of the
study. Increased incidences of hepatocellular carcinoma were observed
in high dose male mice and in both low and high dose females (see
Table 5-2). The combined incidences of hepatocellular carcinoma and
hepatocellular adenoma were also elevated in these groups (NTP 1980).
Negative carcinogenic effects, however, were reported in two other
long-term studies. Carpenter _et _al. (1953) reported no adverse effects
in two generations of Sherman strain rats maintained on diets containing
up to 0*4% DEEP for periods of 1-2 years. In another study, dose-related
enlargement of the liver was observed at 3 and 6 months in rats admini-
stered 0.1% or higher of DEHP in the diet with kidney enlargement noted
in females given 0.5% DEHP in the diet. Because of the high mortality
(apparently unrelated to the concentration of DEHP in the diet), only a
small number of animals was available for examination at 24 months when
the study was terminated. No changes that were strictly attributable to
DEHP were reported. However, two of three surviving high dose males
(0.5% level) exhibited testicular atrophy and necrosis of.the testes -
(Harris et al. 1956).
Testicular changes and liver enlargement were also reported in sub-
chronic studies. Gray et_ al. (1977) noted liver enlargement and testi-
cular changes in rats administered 1% DEHP in the diet for 17 weeks.
Significant liver enlargement was also observed in rats administered 2%
DEHP in the diet for 21 days (Bell et al. 1978, Moody and Reddy 1978).
Similar pathology has been reported in mice (Ota et al. 1974, Yamada
1974) and guinea pigs (Carpenter _et_ al. 1953). Dogs fed 30 mg/kg/day
(5 days/week) for 4 weeks, and then 60 mg/kg/day (5 days/week) for an
additional 48 weeks did not manifest any anomalous clinical or pathologi-
cal signs (Carpenter _et al. 1953). In another study, however, chronic
cholecystitis and some hemosiderosis of the spleen were noted in two
dogs given 5000 mg DEHP/kg/day by gavage for 14 weeks. No indications
of toxicity were noted in two other dogs similarly treated with 100 mg/
kg/day (Harris et al. 1956).
With respect to reproductive changes, the addition of 200 mg DEHP/
kg/day to the diet of rats for two years produced no adverse effects on
che reproductive functions (Carpenter _et al. 1953). Bilateral cubular
degeneration and atrophy of the testes vere seen, however, in 90% (43/43)
of Fischer 344 rats administered 1.2% DEHP in the diet for two years
O6QO aig/kg/day for a 300 g rat) compared with 5% (2/44) and 2% (1/50) for
-------
5-L
THE DIET FOR TWO YEARS
Hepatocellular
Hepatocellular Carcinoma
Males
Control
0.6%
1. 27 '
Females
Control
0.6%
1.2%
______ _ -NtsuDj.astic Nodules
1/50 (2%) 2/50 (4%)
1/49 (2%) . 5/49 uo-j
5/49 10%) 7/49 (14Z)
0/50 (0%) 0/50 (Q%)
O//.Q//cw\
_/tt7 \^&) 4/&Q f'^?'^
8/50 <"I£?n n=n noo ?ie* ,,~~,
olus Neoola^rir MoH 1
3/50 (6%)
6/49 (12%)
12/49 (24%) p-0.01
0/50 (07)
6/49 (12%) p=0.012
Source: NTP (1980).
-------
TABLE 5-2. INCIDENCE OF HEPATOCELLULAR CARCINOMA AND ADENOMA
IN B6C3F1 MICE FED DI(2-ETHYLHEXYL) PHTHALATE IN
THE DIET FOR TWO YEARS
Males
Control
0.3%
0.6%
Females
Control
0.37,
0.6%
Hepatocellular
Carcinoma
9/50 (18%)
14/48 (29%
19/50 (38%) p-0.022
0/50 (0%)
7/50 (14%) p»0.006
17/50 (34%) p <0.001
Hepatocellular Carcinoma Plus
Hepatocallular Adenoma
15/50 (30%)
25/48 (52%) p-0.013
29/50 (58%) p-0.002
1/50 (2%)
12/50 (24%) p»0.001
18/50 (36%) p <0.001
Source: NTP (1980).
5-4
-------
£#-£'£ s r^riS-
of.Che tastes were° also noted in r°s £ ?±r "J^7 ^ d«»««at:ion
greets vere observed at the 40? mg/?g/day9?eve? r^ ^ *" 9° dayS; n°
.esticular damage has also been observed ^nTnon " ~ 19'5) '
terret, red 1% DEHP for 14 months (S2 « al. S8" SPeCieS' Che
try
trations in 5-veek-old JCL^?«ar^ ? f r ^ Serum zinc Concen-
the diet for one week (Oishi and H^ga'^SO)?" '% °f
At high doses (4.9 a/kz^ HPHP ^-
adenosine triphoaphatai. aS b.Sf^l P-5 SUCCinic ^hydrogenase,
(Seth^t al. 1976) and produces JoSn^T^? leVelS in rat 8OMdi
1972) and in mice orally (agi et "117 (Slngh a1
2 g DEHP/kg/day was
out
eternal weight gain and increase ^ res'orp ioTf ?** ^^ ^ d—e
and above. At 0.4 and U all of ^Sorpt^on rates at doses of 0.2% DEHP
the malformation rate was increased at £pla?ted °V* died 1- utero and
significance p^O.05) compared with the °'2% §r°UP
mg/kg/d^y (Shioc
lung «uDp/ aa°nS "e" "ot=d to h™ f«al
ha»Ster celis (UO™/
S1H. 1976, Ishidate and
. °e
25 hours co 1 x 10-3, 10-4,oo-3 v
'
T
-------
patch test followed by a challenge application 7 days later. No erythema
or other reactions were observed (Shaffer _et j.1. 1945).
5.1.2 DMP
No increased incidence of neoplasms was noted in female rats admini-
stered up to 8% DMP in the diet for two years; however, adverse effects
on growth were noted in the 4 and 8% DMP treatment groups and chronic
nephritis among rats in the 82 treatment group (Lehman 1955).
Increased resorption, increased fetal deaths, decreased fetal weight,
and gross and skeletal abnormalities in rats followed intraperitoneal
injection of pregnant dams with doses of 0.338 ml/kg DMP or larger doses
on days 5, 10, and 15 of gestation (Singh_et .§1. 1972). DMP was also
highly embryotoxic in chick embryo studies (Haberman et. ail. 1968, lijo
1975, Bower-.et al. 1970, Lee ejt al. 1974a). Administration of 1400 mg
DMP/kg/day by gavage to young male rats for 4 days had no effect on
testicular tissue or zinc excretion (Foster et. al. 1980). No information
on the mutagenic effects of DMP was found.
•In humans, ingestion of DMP has been reported to cause irritation of
the buccal mucosa, nausea, vertigo,'vomiting, coma, and a decrease in
blood pressure (Doehring and Albritton 1944). DMP is not a skin irritant
but does produce a painful sensation if applied directly to the eyes or
mucous membranes (Gosselin et al. 1976).
5.1.3 PEP
No long-term feeding, carcinogenicity or reproductive studies con-
ducted with DEP are available. Rubin JMC al. (1979) reported that DEP
was mutagenic in the Ames Salmonella assay in the base-pair mutant strain
TA 100 in the absence of metabolic activation. Adding the liver micro-
somal fraction to the culture eliminated this response.
Skeletal abnormalities were observed in 30-50% of rat fetuses from
dams injected intraperitoneally with 0.5-1.7 ml/kg DEP on days 5, 10,
and 15 of gestation (Singh e_t al. 1972). Injection of DEP into fertilized
chick eggs was teratogenic (lijo 1975) and also increased embryo mortality
(Bower .et £l. 1970). Foster and coworkers (1980) noted no change in
testicular tissue in young male rats given 1600 mg DEP/kg/day by gavage
for 4 days.
Short-term feeding studies with rats at dietary levels of 0.2% and
above produced a reduction in body weight gain and enlargement of the
liver and other organs (Brown et ail. 1978, Moody and Reddy 1978). On
the other hand, mice showed no signs of toxicity during a 6-week study
consisting of daily intraperitoneal injections with 125 mg/kg DEP.
Autopsy ravealed peritonitis in all animals (Galley e_t al. 1966) . In
humans, the lowest reported oral lethal dose of DEP is 500 tag/kg (RT2CS
1977).
-------
5.1.4 DBP
°£~ rats fed diets
»g/kg DBP
/
DBP and above l
rat,lc chtc (Wen T* ""^ Cera"S
" al. 1968, Petars and ' — ^' 197°-
- P'a"
op -Jat
gestation resulted in decreased SItSS veilh? 2ain a-
resorption rate at the 1.0Z level (^2100 ms/S/dfv) 1"creased
exos - rog/Kg/day).
e . evel (^2100 ms//dv) Of
exposed in the 17 zrmm ^i« T -, rog/Kg/day). Of the fetuses
compound for one
in Chinese h^ter'cells i^LISS £ O^T^ToBlrlrLrs
triced* risis "3' Verti8"'
5.1.5 BBP
reporhatr^antra" ^S £S aVaUable' ^» ^ ^ (19
3 times weekly for 8 weeks with un to «nn I ln^cte^ ia t rap eri tonally
incidence of pulmonary adenomas compared wit'hf 1 ™ d±S^^ ™ increa
(0.20 lun tumo ' contro
enomas compared with
(0.20 lung tumors/mouse for the 800 mg/k/BBP
controls). Negative carcinoaeni? »ff , § P VS °'19 for saline
1-22 33P in the diet for 103 ^ effe"sjwere noted for 36C3F1 mice fed
concentration to Fischer 3" !at~M ^^ adminis"^ion of chis
incidence of Uu^S f^aU Lt^ ^.d^n aSS°CifC£d ^Ch » ^r.
denca of this lesion in simi^ ^ - variaole and hi-her inc—
3BP ». noc "
increased
-------
Male rats were not adequately tested in this study (NCI 1981).
Rubin et al. (1979) reported no mutagenic activity for BBP in the
Ames Salmonella system in either strain TA 98 (frameshift mutant) or
Ta 100 (base-pair mutant).
Injection of BBP into the chorio-allantoic membrane of chick embryos
increased embryo mortality when compared with controls (Haberman et_ al.
1963) and daily intraperitoneal injection of 500 mg/kg BBP into rniceTor
6 weeks resulted in pathological changes in the liver and spleen, including
periportal hepatitis and extra medullary hematopoiesis in both the liver
and spleen (Galley ei: al. 1966).
5.1.6 DNOP
No carcinogenic, mutagenic, reproductive, or chronic studies were
available for this ester. Increased embryo mortality was noted in the
chick embryo exposed to OOP, but mortality values for controls were also
elevated. Five of 66 DOP-treated chicks, however, exhibited neurologic
abnormalities (Haberman et al. 1968).
Foster jst al. (1980) observed no adverse effects in testicular
tissue or zinc excretion in young male rats given 2800 mg DNOP/kg/day
by gavage for 4 days. Similar findings were noted for rats administered
2% mono-n-octyl phthalate, the major metabolite of DNOP, in the diet for
one week (Oishi and Hiraga 1980).
Oral administration of 500 or 1000 mg/kg DNOP to male Wistar rats
and dd strain mice for 48 weeks produced interstitial nephritis in all
mice and approximately one-half of the rats at 1000 mg/kg with some
evidence of the disorder present in both species at the 500 mg/kg level
(Negasaki st al. 1974).
The only data available on humans were results of skin testing with a
10% solution of DOP. A slight skin reaction was observed in 13 of 100
test subjects (Mallette and Von Haam 1952).
5.1.7 Overview
The ubiquitous use of phthalate esters in our society, and recent
discoveries that phthalate plasticizers leach from polyvinyl chloride
blood bags and other biomedical devices have raised concerns regarding
the safety of phthalate esters to humans. Phthalates have been found in
human tissues but appear to be linked to individuals who have received
blood transfusions or hemodialysis therapy.
It has recently been demonstrated that DEHP is a liver carcinogen in
both sexes of Fischer 344 rats administered 1.2% DEHP in the diet for
2 years; and in both sexes of 36C3F1 niice administered 0.3% DEHP in the
diet, producing hepatocallular carcinoma and aeo-plastic nodules. No
5-3
-------
as:
centration of 0.2% DEHP neural
scered 0.9 g DEHP/kg/dy for
ii JUlia; at a con-
"" adnlni-
also reported in a non- rodent species ^ §) ' Testicular d^age was
for 14 months. species, the ferret, administered 1% DEHP
hav, produced
"on rate and neural tube
administerad « DBF in the ecrin
esters directly into developing chick
BBP, or DMP and a siml. i
questions as to the
3.2 HUMAN EXPOSURE
£rom
A"
"ere.notad
JIn;lsctl01' of Phthalate
produced no «rata with DBP,
2.2.1 Food
FDA regulates che use of
-------
phthalate esters in food packaging. Table 5-3 shows the approved uses
that might result in the migration of phthalates into foods. DEHP, DEP,
DBF, and BBP are approved for one or more of these uses, however, DEHP
is only approved for use in the packaging of foods with high water con-
tent (as opposed to high fat content). Table 5-4 contains allowed uses
of phthalate esters that would probably not result in migration of
phthalates into foods. DNOP and DMP are approved for one or more of
these uses (Shibko and Blumenthal 1973). Generally, these regulations
are supported by rates of migration. Unfortunately, it is difficult to
use such data when estimating dietary intake. Though most foods indi-
cate low or no detectable residues of phthalate esters, fatty foods
show higher residues.
Pfab (1967) placed cheese and lard in contact with film containing
150 ug DBP/cm2 for one month at 25°C. Less than 1% of the plasticizer
migrated into the food, and concentrations in the food were less than
2 mg/kg DBP. ^Woggon and Koehler (1967) found levels of DEHP of less
than 3 mg/kg in food as a result of migration from food wrap.
Tomita e_t al. (1977) investigated residues of DEHP and DBP in
Japanese foods. They found levels of up to 80 mg/kg in tempura powder,
and up to 60 mg/kg in instant cream soup.
To investigate further the contamination of food by phthalate
esters, FDA undertook a survey in 1974. The survey was conducted in
seventeen districts where they collected food, including margarine,
processed American cheese, meat (bacon, weiners, or ground beef), ready
to eat cereal, eggs, milk, white bread, canned corn, corn meal, and
baked beans. Most samples contained DEHP levels of less than 1 mg/kg
Table 5-J illustrates the results for DEHP. FDA (1974fa) stated that the
concentration levels reported for milk and cheese were considered un-
reliable because of problems with sample contamination. However, we
have included them as a maximum expected concentration. Table 5-5 also
includes the levels reported for fish by FDA (1974a).
The diffusion of phthalates from PVC milk tubing has been extensive-
ly studied (Wildbrett 1973). These studies, however, primarily investi-
gate the rates of extraction and not ultimate concentrations in milk
reaching the consumer. Thus, this work has limited use in assessing
risk. Table 5-6 shows food items containing DEHP, and the average per
capita consumption as reported by the USDA (1978). Using these values,
the estimated maximum consumption would be about 2 mg/day/person. Be-'
cause certain persons consume larger amounts of these foods than those
indicated in Table 5-6, a worst case example was established assuming a
diet comprised of 10% fat containing 56 mg/kg DEHP. This value was
based on^a maximum level found in margarine (lipid basis). Assuming a
consumption of 2 kg food/day/person, a maximum exposure would be 11.2 ng/
day/aerson.
5-10
-------
TABLE 5-1 APPROVED USES OF PHTHALATE ESTERS THAT
COULD RESULT IN MIGRATION INTO FOODS*
Regulation No. Approved Uses
Substances employed in the manufacture of food
packaging material (section 5.2.1)
121'2511 Plasticizers in polymeric substances
121-2514 Resinous and polymeric coatings
121.2550 Closurs3
poljolefin
121.2507 CeUophan.
21 ^
5-11
-------
TABLE 5-4. APPROVED USES OF PHTHALATE ESTERS THAT
UNDER NORMAL CONDITIONS OF USE WOULD
NOT REASONABLY BE EXPECTED TO RESULT IN
MIGRATION INTO FOODS
Regulation No. Approved Uses
121.2577 Pressure-sensitive adhesives
121.2562 Rubber articles intended for repeated use
121.2571 Components of paper and paperboard in contact with
dry food
121.2519 Defearning agents used in the manufacture of paper
and paperboard
121.2529 Adhesives
Sources: Code of Federal Regulations 21 (1972) and Shibko and Blumenthal
(1973).
3-12
-------
TABLE 5-5. RESIDUES OF DI(2-ETHYLHEXYL) PHTHALAT? IN FOODS
Food
baked beans
corn meal
canned corn
white bread
eggs.
cereal
meat
bacon
weiners
ground beef
Total meat
margarine
processed American
cheese
milk
fish
No.
Samples
34
34
34
34
34
34
11
21
2
34
34
34
34
77
No.
Detected
7 (21%)
21 (62%)
8 (24%)
22 (64%)
17 (50%)
21 (62%)
8 (73%)
11 (52%)
0
19 (56%)
13 (38%)
30 (88%)
30 (88%)
43**(56%)
Concentration
Mean
(of all samples)
trace
0.2
trace
0.1
0.1
0.2
0.7
0.3
0
0.6
2.5*
5.4*
7.9*
0.2
(mg/k?
Maxim
2.0
2.3
• o.i
1.2
0.6
3.4
3.0
1.2
0
3.0
56.3*
35.3*
31.4*
7.1
Source: FDA (1974a,fa)
* Twenty-nine of these were below 0 ? ,a/kB -nH
co laboratory contamination. §
suspect due
5-13
-------
TABLE 5-6. CONSUMPTION OF DI(2-ETHYLHEXYL) PHTHALATE IN FOOD
Average Daily Intake (me/dav)
Food Consumption* (g/day) Average
baked beans
corn meal
canned corn
white bread
eggs
cereal
meat
margarine**
processed American
.cheese**
milk**
fish
Total
7.0
9.6
7.1
12.0
43.5
37
210
15.5
13.3
230
21.4
trace
0.002
trace
0.01
0.004
0.01
0.13
0.03
0.02
0.04
0.004
0.25
Maximum
0.01
0.02
0.001
0.14
0.03
0.13
0.63
0.69
0.12
0.14
0.15
2.1
Sources: USDA (1978), FDA (1974a, b), USDA (1972).
*Please note that some of the categories of consumption do not exactly
fit the sampled food items. For example, consumption of all meat,
bread rolls, and biscuits are included; whereas only certain
items within these groups were sampled. No estimate of consumption
was found for baked beans, so 7.0 g/day was assumed.
**Consumption of these foods has been corrected for fat content: mar-
garine, 80% fat; cheese, 25% fat; and milk, 2% fat.
5-14
-------
5-2.2 Drinking Water
in ten clCles reported DEHP DBF and DEP in°
locations. The maximum reported evel' was 30 L/i -
Florida. Morita at al riQ7/^ S/ DEHP ln
•ni DBP can° be refifhur J^'^TJS*,.^ e8Be"""i«»-
in both r« and created -ace? "" " ; h°°eV"' "«•«««<>«
DEHP va, 1000 ug/1
that che intake of
demonstrate
3£ -02-
5.2.3 Inhalation
5-2.3.1 Occupational
are
previous Actions of
' " 6
the predominant esters
^
alkyl Phth^tes are
trial Hygienists for
an-reconnnen
s 0.1 ag/n3 DB?
ed ?C3
-
standard :or concencrani
ence of
on
5-15
-------
TABLE 5-7. CONCENTRATIONS OF PHTHALATE ESTERS IN DRINKING WATER
Concentration (uR/1)
C/l
I
Location
Miami, FL
Philadelphia, PA
Lawrence, MA
Terrebonne Parish, LA
Seattle, WA
Ot Cumwa, Iowa
New York, NY
Cincinnati, OH
Tokyo, Japan
shallow welIs
raw water
cleaned water
(after coagulation)
tap water
Pacific Northwest -
25 water supplies
DEHP
30
0.5
0.8
0.04
ND
ND
ND
ND
DNBP
5
0.05
0.01
0.02
5
0.1
ND
ND
• •' • • ' " -'-
DNOP DEP
— 1
0.05
0.04
ND
0.01
ND
0.01
0.1
ND
ND
2.7 mean 4.5 mean
1.8
1.8
3.4
2.3
PMP Source
U.S. EPA (1975)
U.S. EPA (1975)
U.S. EPA (1975)
U.S. EPA (1975)
U.S. EPA (1975)
U.S. EPA (1975)
U.S. EPA (1975)
U.S. EPA (1975)
Morita et al. (1974)
Morita £t a_l. (1974)
Morita et ail. (1974)
Morita et al. (1974)
ND at 15 ND at 10 ND at 10 ND at 10 ND at 10 STORET
ND-=not detected.
llyphen=not sampled or not reported .
-------
3-2-3.2 General Population
discu
and distribution of phthalates i*rt discussion of the fate
^^L-jiS^
^ rsd ~< ^ - ^r;s l13
1°haUti°n "P""" «»» >
5=== -
8...
rCerDEH,BBpBEp,::rLethat ma7 ^ «P°^ » P**-'".
(Holzer and Oro 1976). PhthaL^es h,™ h "P""1"1 in «S«rette smoke
1975), which MT be £he source of %heDhEh^ T'""" la "baCC° (Peaka11
tion during burnin. "ther than the to"»a-
o eDEh
tion during burning. Hovevr cnti ,
analyses . Hol2er °n, Qrl n%7^
•ir rtth cig^fcL3"!0,:0 ^ uS'SSJe"™ -
smoke may be higher; however no inf! ,' *• ™ lnhaled "ainstream
of exposure. However, no information is available on this rype
5'2'4 Per»al Absorption
ud absorption °f
low (see section i. 1 . -) ".£* \"' 'T"8 =°"«ntratlons in water ar,
vouid result in lov ,XDO3uce ' "°""o1 "umans or »"« "iti. P'/C
-------
such as cosmetics and insect repellent, would result in a higher expo-
sure; section 5.1.1, however, indicated that patch tests with undiluted
DEHP resulted in no irritation after 7 days exposure. All of the
phthalates considered here have a low dermal toxicity in the range of
3-20 g/kg, which is well above the expected use levels in cosmetics
and repellents. However, the long-term effects of such exposure are
unknown.
5.2.5 Medical Exposures
Humans may be exposed to phthalate esters through tubing and fluid
storage bags used in medical practice. Though this exposure route is
widespread, only a small subpopulation would receive continuous exposure.
.Blood stored in PVC blood bags has been shown to contain DEHP
(Jaeger and Rubin 1970). Jaeger and Rubin (1973) found that blood
accumulates 0.25 mg DEHP/100 ml/day over a 21-day period. They also
found that persons receiving from 4 to 63 units of blood received from
14 to 600 mg DEHP depending on the storage time for each unit of blood
(see Table E-6, Appendix E). Although these persons died as a result
of other causes, a survivor of such a transfusion would not receive
continuous exposure. On the other hand, cryoprecipitate packs may con-
tain 0.8-1.9 mg DEHP. Although this level is lower than that found in
blood, hemophiliacs may receive 400 bags of cryoprecipitates/year
(Marcel 1973). Thus, a hemophiliac may receive 2 mg DEHP/day. It
should be noted, however, that not all hemophiliacs receive cryoprecipi-
tates.
Phthalate esters may also be released to blood or other fluid from
PVC tubing. Exposure may occur through a IV apparatus, especially dur-
ing a long-term hospitalization, such as in the case of a burn victim.
However, blood concentrates DEHP more efficiently than aqueous solutions,
and thus would be more of a problem in cardiopulmonary bypass and hemo-
dialysis apparatus. Jaeger and Rubin (1970) found that plasma circu-
lating for 4 hours in medical tubing contained 0.01-0.05 mg/ml DEHP.
Jaeger and Rubin (1973) found 9.24 mg DEHP/100 ml blood after 3 hours
of circulation in a Travenol hemodialysis unit; however, 7.75 mg/100 ml
were found initially. An increase in blood concentration from 5.04 to
5.70 mg DEHP/100 ml was observed after 5 hours circulation in a Travenol
cardiopulmonary bypass unit. Fayz _e_t _§_!. (1977) points out that equil-
ibrium concentrations in blood would not be reached because DEHP may
accumulate in body tissue.
Christensen e_t £l. (1976) reported releases of DEP from medical
tubing that was primarily DEHP and PVC. They found a maximum of 50 mg
DEP/1 in blood after a long perfusion time (7 days). These results are
surprising sinca DE? was not an original component of the tubing.
3-L3
-------
Assuming a 5-
DEHP per
1.5 mg DEHP/100 ml in the
(Jaeger and Rubin 1973).
5.3 SUMMARY
s apparatus
concentration of
attribuCad to PVC tubing
low; DEHP
average exposure levelsTrabouTo ^/Lv^?*7 Source°f DEHP/with
2 mg/day. Intakes from drinking water inL^M ^^ UvelS °f about
low in comparison, although ocwoationli ' and absorPtion are
s-s^asssss-r
-------
6.0 BIOTIC EFFECTS AND EXPOSURE
EFFECTS ON
6-1-1 Aquatic Organ j
Presence"
tebrate species (and a
species are combined.
''
«•
°"
at '
Data on marine and freshwater
the more toxic
^ teStinS DEHP
its relative
0-7 g DBpandDE p
of the two compounds; however the or oh? ! Wa
(see Section 6.1.1.1) Pre^Int ' drawing con'Lslo'nf **
toxxcity. The only data available™ ^nclu^lons a
of Phthalate esters pertained to Ingested DEHP o
cess in two species of fish. A levfl nJn nf „ ^ reProdu"ive suc-
reproduction in zebra fish It ll^ff °;°5 mg/kg in food red"^d
LC50 values (lethal conc^ra ion to W^f 'th'! co^" *•" data with
different exposure routes were invo?voH 1 PoPulation) because
effects at levels greater S2 29 ^/l In wat'er "
only LC5Q reportedfor
effect on egg mortaliy
^arable studies on
conciusions
speci she'raL'b" ^ ' 6
^
' *** mor£ali^ but had no
ranged from 1.9 mg/1 to 92
effects were reported at
v
Phthalate^
Acute LC.ns
Reproductive'0
and aasorption onto glass and'
-------
TABLE 6-1, ^PORTED EFFECTS OF »HTHAtATE ESTE3S OH FISH
a) Exposure Through Water
Concentration
Comoound ("Kj/11
OBP .731
1.2
1.3
2.91
5.47
10.0
OEHP .005
.014
> 10.0
100.0
3BP 43.3
W5.0
DEP 29.6
98.2
DMP 49.5
OHP 58. 0
Slueglll, fathead minnow, channel
Compound Concentration
OEHP 50 ng/g food
'00 ng/g food
Species
3lucg1ll
(Lepomls macrachlrusl
•
Fathead Minnow
[Plmepnales prone las)
Channel Catfish
(Ictalurus aunctatus i
Rainbow Trout
ISalmo qairdnerli
aiueglll
(Lepgmls, macroehlrus)
Rainbow Trout
(Saliao galranerl)
Flsn1
Slueglll
(Lepoml* MCrochlrus)
81ueg111
Sheepshead .Minnow
(Cygrinodon yarleqatus)
Sheepshead Minnow
(Cyprinodon. varlegatusi
Slueglll
(Lesomls macroehlrus)
(Lepomls tnacrochlrus)
Sheepshead Minnow
(Cyprinoden varleqatus)
catfish and rainbow trout.
b) Exposure Through
Species
Zebra F1sh
(Sracnvdanio ~rio)
Guopy
(Poee-iHa ratleuUtusl
Effect
96 hr. LC5Q
96 hr. LC5Q
96 hr. LCM
96 hr. LCjg-
96 hr. LCSQ
96 hr. LC5Q
No effect level
on sac fry
mortality
(100 days)
Significant
Increase
(P < 0.05) In
• sac fry morta 1 1 ty
96 hr. LC50
96 hr. LC5Q
96 hr. LC5(J
96 hr. LC5Q
96 hr. LCSQ
96 hr. LC5Q
96 hr. LCSO
96 hr. LC5Q
tngestlon
Effect
.More spawns,
fewer eggs per
spawn, fewer
oercentage
survival
Sligntly signer
se'-esnc soortions,
slignt eduction
in lumoer of 'ry
(not TUCH Jiff.
'"rom control )
Conditions
17'C, static
static
17'C, static
17*C, static
12*C. static
not reported
10*C, flow-
through
10*C, flow-
through
17"C, static
not reported
Static
static
static
static
static
static
Conditions
Source
Mayer i Sanders
(1973)
U.S. EPA (1978)
Mayer 1 Sanders
(1973)
Mayer 1 Sanders
(1973)
Mayer i Sanders
(1973)
Julin (1975)
as citea
-------
TABLE S-8. REPORTED EFFECTS OF PHTHAUTE ESTERS ON AQUATIC INVERTEBRATES
DEHP
Concentration
(rag/1)
.
0.10 (0.0034-0.2)
0.31 (0.02-0.6)
1.0
2.1
Irt A
1Q.O
10
10-50
0.003
0.01
0.03
1.0
2.0
11.1
13.0
32.0
3. IS
Species
Marine Olnoflagellate
(Gymnod1n1un preve)
„
Mud Crab
tRhlthropanooeus harr1s11)
Sruri
JvUO
(GaiMiarus pseudollmnae.Kl
Crayfish
(OreoneetM nals)
Brine Shrimp
(Artemla saHna)
Grass Shrimp
(Palaemonetes puqlo)
Oaphnla
(Paohnla rcagna)
M
„
Grass Shrimp
(Palaemonetes puqlo 1
Oaphnla
(Oaphnla inaqnal
H
Scud
(Gammarus 3se
-------
TABLE 6-2. REPORTED EFFECTS OF PHTHAUTE ESTERS ON AQUATIC INVERTEBRATES (Continued)
Concentration
Compound '"q/11
asp 1.9
2.4
3.7
9.63
92.3
OEP 4.5 (3.0-6.1)
7.59
10
28.2 (23.5-33.0)
50
52.1
OMP 1.0
10
33.0
331
73.7
75.0 (54.0-96.0)
100
i.3 (125.0-135.3)
Soeeies
Oaphnla
(Oaphnla maqna)
„
Effect
48 hr. LC3Q
Conditions
Lake water with
250 ppm fulvic
acid added
Source
Hirzy at al.
(1973)'~ ~~
River water with Hirzy at aj..
„
Mysid Shrimp
(Mysidoosij bahla)
Oaphnla
(Oaphnla maqna)
Marine Olnoflagellate
(Gymnod1n1um breve)
Mysld Shrimp
(Hysidposis oahla)
Brine Shrimp
(ArtewU sallnal
Marine Olnoflagellate
(Symnodlnlua breve)
Brine Shrimp
(Artemia sallna)
Oaphnla
(Oaphnva maqna 1
Mud Crab
(Rhlthrooanopeus harr1s11l
Srine Shrimp
(Art ami a sallnal
Oaphnia
(Dapnnia maqnai
-
Marine Olnoflagellate
(Gymnodlnium breve)
Srass Shrimo
'. Pa 1 aemonetes jugio)
.'tartne Olnoflaqellate
(Symnodimum jreve)
96 hr. LC5Q
48 hr. LC5Q
Median growth
limit concen-
tration
96 hr. LC5Q
Hatching success
did not vary
from control
96 hr. LCM
Hatching success
significantly
lower than
controls
(p < 0.05)
48 hr. LCSQ
Old not signifi-
cantly alter
larvae develop-
ment
Hatching success
did not vary
from control
48 hr. LC5Q
LC50
Median Growth
Hm1t concen-
tration
36 «r. LC.Q
natural cone.
of 250 ppm
fulvic acid
Lake water only
static
static •
25'C
static
25'C, pH 3.3
25"C
26'C, pH 8.3
static
25-C, 15S
salinity
25°C, pH 3.3
static
not reported
25°C
22°C, 151
salinity
25<>C
(1978)
Hirzy et al.
(1978)
U.S. EPA (1978)
U.S. EPA (1978)
Wilson et
aj_. (1978)
U.S. EPA (1978)
Sugawara (1974)
Wilson «
JL (1971)
Sugawara (1974)
U.S. EPA (1978)
Laugh 1 In at
al- (1977)
Sugawara (1974)
U.S. iPA (1978)
Hirzy at al.
(1978)
Wilson it
iL- 0973)
Laugnlin «r
1L (1977)
^flson it
a 1 . 1 1 973)
3—-i
-------
£i°chroush
ci —
after mixing was 742 of t i^ i ratl°n measured immediately
et al. 1977). Droplets of phthSll", ".^ Concentra
unmodifi.d lake water \LC* -TS me/n' M JLC5S " 13*° mg/1) than ^
1978) report BBP as havinfa hl»h i u .flth°ugh Hir2^ a"d coworkers
not vary significantly i^the dx^e're'nt me'dif' ^ ^^"^ leVels did
not describe how the test was conducted Th± Unfortunatel?> ^hey did
" "
6'1-1'2 Relative Toxicitv of
,. the six phthaiates
toxlcitv under identical cond't^ons and - ^ C° ^SU^ their
several st.ecies. So available ^ H • ^° aXamine =heir affec£s ^
snip becveen che six "thalates ? ^^.^stlgated this relacion-
in che same experiment. Table ^-3 IrTsll Its^ ?nfalaC2s "«« =escad
coxicicy reported in the literature ° °* ?hchaiaca
3-:
-------
TABLE 6-3. THE RELATIVE TOXICITY OF PHTHALATES
TO AQUATIC ORGANISMS
Order
OBP- DLP> OMP
Species
Brine Shrimp
(Artemia salina)
Type of Study
Reproduction and
Development
Source
Sugawara (1974)
I)UP> OMP
Grass Shrimp
(Palaemonetes pugio)
Development
Laughlin et aj.. (1977)
DLHP> BUP (plain lake
water)
BOP- DEHP (water with
250 nig/1
tulvic acid)
Daphnia
(Daphnia magna)
Acute toxicity
Itirzy et al. (1978)
DEI IP
1
Scud
(Gammarus pseudolimnaeus)
Acute toxicity
Sanders et aj. (1973)
DBP> DEHP
1
Fish
(Pimephales promelas.
Lepomis Macrochirus.
Ictalurus punctatus.
Salmo gairdneri
Acute toxicity
Mayer & Sanders (1973)
DBP. DtP> DMP> DEHP
1
Marine Dinoflagellate
(Gymnodinium breve)
Acute toxicity
Wilson et aK (1978)
(he low solubility of DEHP may attribute to this ranking.
-------
.
other phthalates, were generally observ^ It es .reaterh
le xs possible, therefore, -that DEEP is '
-------
not reported. In several metabolism studies (Mehrle and Mayer 1976
Mayer 1976, Stalling et al. 1973) on fish (fathead minnows, rainbow'
trout, channel catfish), DEHP was found to metabolize into monoesters
and phthalic acid. The monoesters were predominant; this was attributed
to the more polar metabolites being excreted. No information on the
toxicity or monoesters to fish were available; therefore, it was unclear
whether the metabolic process was one of detoxification.
5.1.2 Terrestrial Organisms
Acute toxicity data on bird species were only available for two
phthalates, DBF and OOP. Both compounds were reported to be non-toxic
at levels of 5000 mg/kg administered in the diet (Heath _et al. 1972).
Another study analyzed the effects on the eggs of ring doves
(Streptopelia risorla) administered DBF and DEHP in the diet (Peakall
1974). No significant changes were reported in the eggs of birds fed
10 mg/kg DEHP (exposure time not reported). At the same concentration
DBP caused a decrease in eggshell thickness (p <_ 0.01), a reduction in'
egg weight (p ^< 0.01), an increase in shell permeability to water
(p _< 0.05), and an increased rate of water loss (p <_ 0.05). Egg weight '
and shell thickness recovered to normal measures when DBP-exposed birds
were fe'd a clean diet for an unspecified period of time.
No information on the acute toxicity of DEHP to birds was available.
Based on the Peakall (1974) study and other mammalian studies, however
it is unlikely that DEHP is more toxic to birds than DBP. Additional
data are needed on DEHP's effects on birds and other wildlife species
because'of the compound's widespread use and existence in the environment.
6.2 EXPOSURE TO BIOTA
Aquatic organisms are potentially exposed to phthalate esters
through contact with water. In a survey of major river basins (STORET)
concentrations of DBP, DNOP, DEP, DMP, and DEHP are usually reported
within the range of 0-10 ug/1. Some incidences of all these phthalates
have occurred at concentrations in the 10-100 ug/1 range. DBP and DEHP
were both found at concentrations of 100-1000 ug/1 in two river basins,
the south central lower Mississippi River Basin and the Western Gulf
River Basin. Other investigations have reported even higher concentra-
tions of other phthalates (see section 4.1).
It is difficult to generalize about phthalate concentrations in
marine and estuarine waters. The STORET data did not include marine
open waters but did include some estuarine habitats at mouths of major
rivers. In these locations, average concentrations for DBP and DEHP
were higher than other river basin concentrations (see section 4.1).
Perhaps this implies a greater risk zo organisms inhabiting these lower
river/estuarine habitats. Concentrations reported in the Mississippi
Delta were also high. The few open water marine water concentrations
reported vere considerably lower than freshwater concentrations (see
section 4.11.
6-3
-------
tthe
tion available indicates th»t rt. of rlver systems. The Inrorma-
environment with the only loss.» com?ou"d 'lows through the aquatic
4.2). Depending on the dyn^cs S^SaT.SV*11-" ("e secti-
"here ..dimencatloToccu™' surt if a«™"l"ed la the sediment; thus
concentrations of ' ^ " *
rivers (e.g., in Oreson) cannor %f ! ! , °f other COI°Parable
data are collected! determined until more comprehensive
••—=•"
DEHP, therefore
ment^ of DBF
incidences of level greater than
tion on other phthalaCs was
apparently bioconcentrate at
'
concentrations of
The f- -asure-
enerally lower, although two
aquatic organisms
-------
-------
7.0 RISK CONSIDERATIONS
7.1 METHODOLOGY
of the
as a proxy for
of dose/response data Co eh. Depopulation
of
effects of BEHP on humanso • ™ Potential carcinogenic
h~" thr°ugh ««-
the actual carcinogenicity of DEEP to humans
Assuming that the positive findings indeed provide a
basis for extrapolation to humans, the estimation J
equivalent human doses involves
-------
In dealing with the extensive uncertainties inherent in extrapolation
to humans, we applied three commonly-used dose-response models in order
to establish a range of potential human risk.
In this risk assessment, we have also chosen to compare the exposure
and effects data for animals with the corresponding data for humans. Several
scenarios were developed to compare the lowest reported effects levels
for several phthalates with maximum and possible exposures of humans
to phthalates. The margins of safety (ratios of effects levels to
exposure levels) that result were examined. This process can demonstrate
the relative risk of various phthalate esters, and provides some indica-
tion of the significance of phthalate esters as a potential environmental
hazard to humans in areas other than carcinogenicity.
In the case of risks to other forms of biota, insufficient data are
available on most toxic effects and on exposure values to assess risk
quantitatively. However, possible risks to various species can be
described and are presented herein.
7.2 HUMAN EXPOSURE
A series of possible exposure scenarios for humans, with an indica-
tion of the size of the population at risk, possible exposure routes and
levels, and key assumptions in the exposure estimates are presented in
Table 7-1. Data for this table were developed in other sections of the
report. For the general population, exposure to phthalates, as indicated
by exposure to DEHP, results primarily from food ingestion. By comparison,
water ingestion and inhalation of ambient air account for much less
exposure. The combined exposure level for an "average individual"
(average in that the person has a "normal" diet and "average" water
drinking habits) would be about 0.27 mg/day DEHP. The maximum exposure
could be as much as 10 mg/day.
Certain subpopulations might have significantly greater exposure
to phthalates. Persons who work in plastics manufacture or in formula-
tion, calendering, or other processes in which phthalate esters are
used, might have exposures as high as 6.3 mg/kg/8-hour exposure. Note
that this is a worst case exposure value reported in the literature and
may not represent current manufacturing processes. Hospital patients
who receive large quantities of blood, or who are dialyzed regularly,
could also receive fairly large exposure to DEHP or other phthalates.
These populations are probably small. Another worst case consists of a
small population who eat primarily a high fat content diet of pre-
packaged foods. In the example presented here, the person's diet was
assumed to be equivalent to 2 kg/day and containing 10% fat. This
represents an upper level exposure for this subpopulation (11 rug/day).
•^ i
-------
ibunb eating
average diet
d« Ink lug water
221 X 1(1°
x 10
6**
i l«i» 0.02
Avir?ood."'"'"' """"^ "'-""^ »"»•—
Maximum - s,um ,,| Wjxllttlllll ri.j>oi,uij vitflu.^
food. In tomhinaliu,, will, ty,.|Ldl
conb-uui|>t Ion
Average - real...,tU ,,m,er limit (ol
concentration^ I,, di Inking water.
I
Ui
Viaoi,!, l,,uaihl,,g ambient aii
Imloo, contact (uxuo.cd tu ,.laatlcs)
IUIAI
ujial lonal Situation
uantity blood rL.cl
hlgl, fat diet
very
10
2 x 1(1
very small
4***
Ulli.ilat inn
Inlialatlon
Inhalation
•s: f
large
large
»"t>:i
14-6011 (Total)
0.7-2. 1
11.2
Based on
ed ai, .uun.to.ing data.
Meauurement of uHf in air over tiled ro
Absuue b.nue ,i.
u 4-bJ mill.-, .,1
1,1,
AM*""«e a =>-' I blood «ol,.uij. ailj
1.5 wg Dlilll'/lOl) ml.
IHet coi»,,o«td at UK tat a^uiued a
maximum of i(, IU(./KI, '
-------
7.3 THE CARCINOGENICITY OF DEHP
The preliminary results from the NCI study of DEHP were described
in Chapter 5.0. For extrapolation purposes, the data that demonstrates
increased hepatocellular carcinomas in both male and female mice were
selected. These data are listed in Table 7-2. Similar carcinomas
were observed in rats, but the implied dose-response relationships were
much less severe.
The first step in extrapolating the carcinogenic effects of DEHP
to humans was to calculate the equivalent human dose rate corresponding
to the experimental treatment. The approach recommended by the U.S. EPA
1979b), which normalizes the dose rate according to body surface area
was followed. This approach is conservative in that it results in a.
lower equivalent human dose than would be obtained from simple multipli-
cation of animal dose rate (mb/kg/day) by human body weight. Whether
surface area or body weight is a. more appropriate normalization factor
is still open to debate. The former method yields a dose rate approxi-
mately 6 times lower for rats, and approximately 14 times lower for
mice. Thus, this method introduces into the risk estimates an addi-
tional uncertainty of roughly an order of magnitude on the conservative
side.
The calculation of a human equivalent dose was performed using the
following formula:
(2/3
human weight
animal weighty
The three dose-response models used to extrapolate human risk were
the linear "one-hit" model, the log-probit model, and the multistage
model. The latter is actually a generalization of the one-hit model, in
which the hazard rate was permitted to be a quadratic rather than a
linear function of the dose. All of these models are well known in the
literature, and a theoretical discussion may be found in Arthur D. Little
(1980). The one-hit models assume that the probability of a carcinogenic
response is described by
P (response at dose X) - 1 -e~h(x)
where h(x) is the "hazard rata" function. The log-probit model assumes
that human susceptibility varies with dose, according to a log-normal
distribution. Due to their differing assumptions, these dose-response
models usually give widely differing results when effects data are extra-
polated from high laboratory doses to the low doses typical of environ-
mental exposure.
For the linear extrapolation, we solved for the coefficient 3 in Che
following equation:
-------
TABLE 7-2. CARCINOGENIC EFFECTS OF DI(2-ETHYLHEXYL)
PHTHALATE IN B6C3F1 MICE
Human Equivalent -
Dosage fag/kg 1 Cme/dav) o * Excess over
i-^L img/dayj Response* Percent Controls <"')
-Male Mice Q n ~
U 0 9/50 13
3000 1300 14/43 79 u
6000 3600 19/50 38 2Q
Female Mice
0
3000
6000
0
1800
3600
0/50
7/50
17/50
0
14
34
34
*Hepatocellular carcinoma.
Source: NTP (1980).
-------
giving
3 = log
*
x e 1 - P(X)
where ?(0) is the control group response.
For example, from the low dose male mice, we find an estimate
1 i" 1 - -18
3 * 1800 mg/day "* X ' '29 " 8xl0"' ?er *«/d^
It was found that the female mouse data indicated a higher rate of
excess cancer incidence, yielding a conservative estimate of 3 = 10"^,
roughly. The inferred human per capita risk at low dose levels may then
be found simply by multiplying the coefficient B by the dose in tag/day.
Prob. of response s B (dose)
The expected incidence of cancer in a given population may -then be
found by multiplying the probability of response times the size of the
population.
•
For the log-probit extrapolation, we solved the "probit" intercept
A in the following equation:
Prob. of response * $ A 4- log-- (dose)
where $ is the cumulative normal distribution function.
This equation makes the usual assumption that the log-probit dose-
response curve has unit slope with respect to the log-dose. Again, the
more conservative results for female mice were utilized to estimate A,
though in this case the difference was less important. Using tables of
the standard normal distribution, we find that A is approximately equal
to -4.0. This value may then be used to find the probability of a
response at various dose levels from the above equation.
The multi-stage model, using a quadratic hazard rate function
h(x) - ax2 + bx + C,
was fit to both the male and female mouse data combined. To estimate
the parameters a, b, and c, we used a maximum likelihood method aided
by a computer program, which performed a heuristic search for the best
fit. It was found that the parameter b dominated for small values of
the dose x, so that the dose-response function was essentially linear
in the low-dose region.
The U.S. EPA Office of Pesticides and Toxic Substances (OPTS) applied
Che linear one-hit aoael co data from the same studies, but used different
assumptions as to carcinogenic response (Personal communication, Mike Slimak,
-------
Monitoring and Data
FPA> r
v
tions of these finding far^n7 r ™Sp*Ct C° the Possible implica-
te, of agreement l*g pa^ogis s* ordlaf13,31^"011 ariS6S ?r°m a
fying hepatic lesions as benign or malL^S ? Crit6ria f°r classi-
was based on the combined Scf dene e of Sr aeOplasia- The OPTS estimate
nodules; the ADL estimate was ba =arcin°mas and P«-aeoplastic
carcinomas only. Based
B - 9.1 x 10"3 per mg/kg/day
3 1.3 x 10"4 per mg/day,
assuming a human mass of 70 kg.
st, *our
risk. Pemit S °°re ««««ta or definitive assessment of human
excess cancers/year, fer
Che
population size, however akes
general population, the niSs?
exposure to DEHP in the dift
and,processin8, and ^'
Monitoring data on which exoosur*
were based are limited? eXP°SUre
are
acs. The srnal!
Io"' In tha
with
r .
for air and drinking water
RISKS ASSOCIATED WTT* OTH£R
laboratory, animals are
level
°'4 3 ^HP/kg
Chapter 5.0. Note that the
genicity) reported for the
for =eratogenicity in mic!
reported to be 0.07 3/k" estcur ar
and ,ice as a result^of %W".;»C S 5. S f ^ Jp
reported effects Cave's -'or -KQ • . g DEHP/kS- -^st or che
10 i/kg of body weigh" " °"er ?nt^iacas range from I ?/kg ,0
-------
TABLE 7-3. PER CAPITA LIFETIME CARCINOGENIC RISK TO HUMANS DUE TO
DI(2-ETHYLHEXYL) PHTHALATE 1NGESTION AT VARIOUS EXPOSURE
LEVELS ESTIMATED BY USE OF FOUR EXTRAPOLATION MODELS*
Ji*l cumulation Model
Excess Cancer Risk at Exposure Level (mR/day)a
0.01 0.1 1 10
100
Linear model
1 x 10~6 1 x 10 5
1 x 10
1 x 10
-3
1 x 10
-2
Log-1> rob it model
off scale
3 x 10
-7
3 x 10
-5
1 x 10
-3
2 x 10
-2
i
Ou
Mulii-utage model
5 x 10"7
5 x 10
-6
5 x 10
-5
5 x 10
5 x 10
OPTS linear
1.3 x 10 6 1.3 x 10 5 1.3 x 10 4 1.3 x 10 3 1.3 x 10~2
Probably conservative, i.e., tending to overestimate risk.
-------
water
lillialaliuii
uiliaii
mi a I
Average
Exposure 1'opulaUon
Size
0.02
0.006
0.00006
Linear
One-lii t
220.6xl0 3xlO
~5
2x10
-6
165.6x10'' 6x10
55.Jxl06 6x10"
-7
Ki.sk liitimate.l (l.y m.rf..i
off scale
off scale
off scale
Multi-
1x10
3x10
-7
JxlO
-9
OI'TS
Linear
4x10
1x10
-6
tixlO
a* 10
-1
Kai»j;e of
E.st im.iled
I 1-1 10
J-10
. 002- . 006
^1-45 4.5x10^
0.7-2.1 1.9xU)4
' -4xlO~3 4x10 3-
1x10 5-lxlO
lxlO~3-2xllf
9x10
0.6-6
0.00 1-0. O8
j-.ol-.il.ly ,:o,,sUrvatJ»e. i.e. tuilj,IlK to overstate risk
-------
TABLE 7-5. EFFECTS OF PHTHALATE ESTERS ON LABORATORY ANIMALS
Adverse Effects
DEHP
Testicular Atrophy
Embryo toxicity
Teratogenesis
Oral LDjQ
Hepatocellular Carcinoma
plus Neoplastic Modules
Hepacocellular Carcinoma
plus Adenoma
DMP
Chronic Nephritis
Embryotoxicicy
Oral LD.0
PEP
Teracogenesis
Oral LD-0
Lowest Lethal Dose
DBF
Taracogenesis
Oral LD.0
Testicular injury
DROP
Oral LD-,
BBP
Periportal Hepatitis
Carcinogsnicity
Species
Mouse
Rat
Mouse
Mouse
Rat
Rat
Mouse
Rat
Chick/Embryo
Rat
Rac
Rabbit
Human
Mouse
Rac
Rac
Mouse
Mouse
Mouse
Lowes c Reported
Effects Levels
0.72
0.6
0.83
0.4
31.0
0.6
0.36
4.0*
0.005/egg
8.2
1.9
1
0.5
2.1
8-10
2
> 13
0.5
-
'> Incidence
14
90
100
-
50
26
52
_
100
50
81
50
-
-
50
-
50
-
-
Mo Apparent
Effects Levels
S/kjj
0.36
0.3
-
0.07 "
-
-
-
-.2.0
-
-
_
-
-
0.8
-
-
-
-
1.4
T
Based on a JOO g rat sating 30 g/kg body weight
containing 3% DM?.
7-10
-------
r
r ~
.-«1"S;,.';::,r,;';™'f S.T "•"." ;"-
or other «i«r«T'h^ i"88"* ^ Crlteria*
nay need to be re-exaSnld Phthalate esters, specifically DEHP,
7-5 RISK TO BIOTA
^^
^-1^--
low as 940 ug/1 and 3 ug, respeSi^ely ad £?** " concentr^ions as
for more sensitive specif (u!S Sfl^jf "!! °^ " 10WSr levels
available, concentrations of the phtha!!tes a^e^i^ * "^ °f the d
were usually greater than lOOn ,%/i . affecting aquatic organisms
100,000 ug/i (see SectiS 52? 8^ r"8"8 ^ 19°° U8/1 to over
to affectaquatic organisJ 3* ug % SSZL*?***^0* °f °EHP f°und
by 60% (Sanders et al. 1973 Si i^ "2d reProd^tion in Daphnia
which ^- 8 of
Theef
are very close to the detection liJt for DEHp C0?"nt5ations <* 3 ug/l
chemical vas measured and detected \r , ?? Thererore, wherever the
on these organisms. However thl woo^f f?""061*117 haVe an effect
confirmed, since this level Is rel^f ** 3t 3 Ug/1 should **
observed effects. relatively low compared with other
DBF of 100 ug/1 is roc
reported a -.nificanr^errr:^:^;^0:!^:;.^ riv«
-or the
ions affecting fish vere
-------
TABLE 7-6. CALCULATED ALLOWABLE DAILY INTAKE AND RECOMMENDED
WATER QUALITY CRITERIA FOR PHTHALATE ESTERS
Phthalata
DMP
DEP
DBP
DEEP
ADI1
(mg/day)
700.0
438.0
12.6
42.0
Recommended Criteria
(mg/1)
160
60
5
10
For 70 kg person with a safety factor of 100 from a
no-effect dose.
2
Based on a consumption of 2 I/day of drinking water
and a consumption of 18.7 g of fish assuming
various bioaccumulation factors.
Source: U.S. EPA (1980).
-------
rno
It is difficult to dateine whL COTmn°nly deteCted in the
in Daphnia would have on the h^hT imPaCt reproduccive impa
th. indirect risk oT"Sorta" ' ^ °n ^ Thus»
-contact with,
ilaole
s
because of the insuft-ient data ^tho T*^ °^«±s*s is "t possible
available that present levels of^E^in^" ^^ fr°m the data
to some invertebrates. ££ appearf t h ^h^envirotm^t may pose a risk
Phthalates and the most ubiquitous in thJ ," ^^ persistant of the
The effects data for DEHP do not JL£j wvlroj»eat (see Section 4.2).
Phthalates Therefore the other phthalatM'rS ^ th°Se f°r °ther
because of the lack of effects StS n™f K? ( " nOt included
aquatic organisms than DEH? } Pr°bab1^ P°se 1«« of a risk to
sanothefispcish °
for their susceptibility to nJthlll, n0t been Studied «t«nslv«l7
available does Sot indicate ?hat JhU " *'"• ^ Umited ^f°^tion
Phthalates than warm water fxsh Sgn \ ^^ Sensiti^ to any of the
probable that in cold water if is !f ? Ver7 lw solubility; it is
conditions, which ar'e S^JJ c'onS?^ 25 if1^^ -d- laboratory
a cold water system, therefore mav h- ^- S' 7 effects of
Monitoring data of hthalatrconc^r^tions^inl.?
extensive enough to support speculation S.
dK
-bra fish and guppies se Section Tl? ^r3"'6 SffeCtS °f DEH? on
of 50 ug/kg and 100 ug/kg sliStlv r ^ ^ Concentrations in the food
and guppxes, respectively'. GuppiL ^^1^°^^ ** Z&^ £±sh
braces (Collins 1959). ^PP^es teed primarily on aquatic inverts
representin , , 1* *"
claared by flsh ln
The high tissue concentrations reported for fish in Ser-'nn ' .
co contradict this, ^ost of -HP ^,~ i'ut.I--sn ^-n bection u.l appear
""° ° ^ ir3 T'e
of -HP ,~ .
entire bodv. One soec -""° ° r3 T'eaSUrad f°r
T-13
-------
food sources, therefore, may have little effect on aquatic organisms
that eat them. Only speculations can be made at this point until further
investigation is conducted in this area.
Phthalates, at least DBF and DNOP, do not appear to pose an acute
risk to birds through ingestion of contaminated food because of the
high concentrations required to produce acute effects (see Section 6.1).
}To effects information was available for other phthalates. The highest
concentration of any phthalace reported in water or biota (and assuming
it to be a potential food source) was 7.2 tag/kg (see Section 6.2). It
is unlikely that concentrations of these two phthalates are high enough
in the environment to cause acute effects. Because DEHP is abundant in
the environment and appears to be the most slowly metabolized of the
phthalates, an assessment of its risk requires data on the effects on
avian species. Also, phthalates may have subacute effects on birds at
lower concentrations that could conceivably be attained through biocon-
centration. Further investigations on the acute effects of other
phthalates and subacute effects are required to determine realistically
the risk phthalates pose to birds.
-------
8.0 REFERENCES
Anonymous, 1978a. Plasticizers. Plastics World 5:60-6!.
Beeler, A.D. and D.C.
Encyclopedia 1977-78,
1978! FS^ieS 1" "
in
Od - 1976-
(DEHP) in mice and a model ecosystem ? dl:2-eth£lhe*n phthalate
on Pharomcol., Urbana, U1.PP 225-35 th Internat'
~- — —-*-»••*-^&iACi wcxcnnzscnsr Zs ** t* T1 h r t. "" osi sinwi^TiCunff
103:413-24, as cited in LeFauxI R?1963 ' ^^SUCh- Forsch'
Bower R :<. , S. Habenaan and ?.D. Mint on 1970 -
Che cmck embryo caused bv esters of nhrhal -/ C°genlc "fect3 on
Ther. 171:314-24. ' ?nchalic acid. J. Pharmacol. S:cp.
3roxvn, 3., ;<.a. Suttervorth, I.?. Qaun^ ? r
-978. Short-cerm oral "ox-'c-'tv =r • "• ^^asso and 5.D. Gangolli.
?ood Cosaet. Toxicol. 16:i*5-^ °r aiech^i ?hthalate in the rat.
3-1
-------
Brownlee, B. and W.M. J. • Strachan. 1977. Distribution of some ogranic
compounds in the receiving waters of a kraft pulp and oaper mill
J. Fish. Res. Board Can. 34:830.
Cagianut, B. 1954. Keratitis erosiva und nephritis toxica nach
einnahme von dibutylphchalata. Schweiz . Med. Wschr. 34:1242 as cited
in Williams, 1973.
n o7292
Regulations and Standards, U.S. Snvironmental Protect"; Jgency
Wasnington, D.C. <•=«- — un ,-igenc/,
GARB, 1976. Adoption of a System for the Classification of Organic
Compounds According to Photochemical Reactivity^ California Air
Resources Board Staff Report 73-3-4. Appendix V.
Carpenter, D. , C.S. Weil and H.F. Smyth, Jr. 1953. Chronic oral toxi-
city of di(2-ethylhexyl) phthalate for rats, guinea pigs and dogs.
AMA Arch. Ind. Hyg. Occup. Med. 8:219-26.
Cater, B.R. , M.W. Cook, S.D. Gangolli and P. Grasso. 1977. Studies on
dibutyl phthalate-induced testicular atrophy in the rat: Effect on
zinc metabolism. Toxicol. Appl. Pharmacol. 41:609-18.
Chambon, P., M. Riotte, iM. Davdon, R. Chambon-Mougenot, and J. Bringuier.
1971. Metabolism of dibutyl phthalate and diethyl phthalate in the rat.
C. R. Acad. Sci. Series D 273(22) :2165-2168.
Chiou, C.T., V.H. Freed, D.W. Schmedding, and R.L. Kohnert. 1977.
Partition coefficient and bioaccumulation of selected organic chemicals.
Environ. Sci. Tech. 11:475.
Chris tens en, D., J. Neergaard, B. Nielsen, V. Faurby, and O.F. Nielsen.
1976. The release of plasticizers from PVC. Proc. Int. 6th Congr.
Pharmacol. 6:191.
Cifrulak, S.D. 1969. Spectroscopic evidence of phthalates in soil
organic matter. Soil Sci. 107:63, as cited in Mathur, 1974.
Collins, H.H. , Jr. 1959. Complete Field Guide to American Wildlife.
Harper and Row Publishers, New York.
Corcoran, E. 1973. Gas chromatographic detection of phthalate acid
esters. Env. Health Perspect. 3:13.
County of San Diego. 1978a- The San Diego Revised Regional Air Quality
Strategy: California State Implementation Plan Submittal. A report
from the San Diego Air Pollution Control District: and Comprehensive
Planning Organization.
Daniel, J.W. 1973. Toxicity and metabolism of phthaiate esters. Clin.
Toxicol. 130:257-03.
-------
Daniel, J.W. and H. Bratt
at diz
Environ. Sci Tech. 9()
Camber.
Fayz, S., R. Herbert, and A.M
ohloride
PhthaUte
survey,
Fishfaein, L. and P W
of tta
Fukuhara, M. and E. Takafaacaka 1977 c,. A-
induced by diecary administration o : d±(' ^^ ^ 1±Ver «largement
J. Toxicol. Sci. 2(l):U-23 dx(2-echylhexyl) phchalace (DEHP) .
Garvin, P.J., j.G. Schmidt and R.?. Wallin
or plasma solucions of di-2-arhylhexvl
in racs. Toxicol. Appl.
c -
Sty
(1) :
— -ly
Garvin, ?.J., >LE. Lavandowski and R.? Val^'n TQ-SK -
evaluation of piasma-soluole axt-ac-s or n T t - A tarac°^gic
Phanaacologisc 18-32^ as MH ^ ?ol:rviaylchlorice olascics.
3 au ioo^_, as -_caa in ihomas ec ai. , 1973.
3-3
-------
Giam, C.S., H.S. Chan, G.S. Neff, and E.L. Atlas. 1978. Phthalate
ester plasticizers: a new class of marine pollutant. Science, 199:419-21.
Gleibenaan, S.E., S.N. Bolandova, O.Y. Kemirits and L.N. Merenkova.
1975. Toxicology of the repellent phenoxyacetic acid n, n-diethylamide
(P-203) and its mixtures with dimethyl phthalate. Med. Parazitol.
Parazit. Bolezni. 44(6):693-98, as cited in CA 084/116586J and HEEP
77/00625.
Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.S. Gleason, ads. 1976.
Clinical Toxicology of Commercial Products, 4th edition. The Williams
and Wilkins Co., Baltimore, Maryland.
Graham, P.R. 1973. Phthalata esters: why and how are they used.
Env. Health Persp. 3:3-12.
Gray, T., Jr., K.R. Butterworth, I.F. Gaunt, P. Grasso and S.D. Gangolli.
1977. Short-term toxicity study of di(2-ethylhexyl) phthalate in rats.
Food Cosmet. Toxicol. 15(5):389-400.
Gross, F.C. and J.A. Colony. 1973. The ubiquitous nature and objec-
tionable characteristics of phthalate esters in aerospace technology.
Environ. Health Persp. 4(3):37-43.
Habenaan, S., W.L. Guess, D.F. Rowan, R.O. Bowman and R.K. Bower. 1968.
Effects of plastics and their additives on human serum proteins, anti-
bodies, and developing chick embryos. SPE (Soc. Plastics Eng.) J.
.24:62-9.
Hamano, Y., A. Kuwano, K. Inoue, Y. Oda, H. Hamamoto, B. Mitsuda and
N. Kumita. 1977. Studies on toxicity of phthalic acid esters. Part I.
Teratogenic effects in mice when administered orally. Osaka-furitsu
Koshu Eisei Kenkyusho Kenkyu Hokoku, Shokukin Eisei Hen. 8:2933, as
cited in CA 089/001257P.
Hansch, C., J.E. Quillan, and J.L. Lawrence. 1968. The linear free-
energy relationship between coefficients and the aqueous solubility of
organic liquids. J. Org. Chem. 33:347-350.
Harris, R.S., H.C. Hodge, E.A. Maynard, and H.H. Blanchet, Jr. 1956.
Chronic oral toxicity of 2-ethylhexyl phthalate in rats and dogs. AMA
Arch Industr. Health 13:259.
Harris, V.T. and P.H. Eschmeyer. 1974. Sport Fishery and Wildlife
Research 1972. Bureau of Sport Fisheries and Wildlife, Fish and
Wildlife Service, U.S. Department of the Interior.
Heath, R.G., J.W. Spann, S.S. Hill, and J.F. Kraitzer. 1972. Compara-
tive dietary coxicities of pesticides do birds. Spec. Sci. Report: NTo.
152. U.S.D.I., Washington, D.C.
-------
catheters and blood products. New England J. Med. ^92-381-6
Jacobson, M.S., L.N. Button, W.A. Watson, B.I Barwick
- Button'
3-5
-------
Jaeger, R.J. and R.J. Rubin. 1970. Plasticizers from plastic devices
extraction metabolism, and accumulation by biological systems. Sci
170:460.
Johnson, B.T. and W. Lulves. 1975. Biodegradation of di-n-butyl
phthalate and di-2-ethylhexyl phthalate in freshwater hvdrosoil. J. Fish
Res. Board Can. 32(3):333.
Johnson, B. _§_t al. 1974. Dynamics of phthalic acid esters in aquatic
organisms in I.E. Suffed (ed.) Fata of Pollutants in Air and Water
Environments. Part 2. New York, NY: Wiley Intersciance Publishers.
Jones, A.E., R.H. Kara, J.T. Groves, and E.A. Napier. 1975. Phthalata
ester toxicity in human cell cultures. Toxicol. Appl. Pharmacol.
31:283-89.
Julin, A. 1975. Personal communication as cited in Johnson et al
(1974). -
Jungclaus, G.A., V. Lopez-Avila, and R.A. Hites. 1978. Organic com-
pounds in an industrial wastewater: a case study of their environ-
mental impact. Environ. Sci. Technol. 12(1).-38.
Kaneshima, H., T. Yamaguchi, T. Okui and M. Naitoh. 1978. Studies on
the effects of phthalate esters on the biological system. Part 2. In
vitro metabolism and .biliary excretion of phthalate esters in rats.
Bull. Environ. Contam. Toxicol'. 19(4) :502-09.
Karickhoff, S.W., D.S. Brown, and T.A. Scott. 1979. Water Research
(in press). ~~
Kasuya, M. 1974. Toxicity of phthalate esters to nervous tissue in
culture. Bull. Environ. Contam. Toxicol. 12(2):167-72.
Kasuya, M. 1976. Toxicity of phthalate esters to tissue cultures.
Proc. Internat. Congr. Pharmacol. 6th, 6:215-24.
Kitanaka, E., Y. Sakagami, T. Shimada, and M. loku. 1977. Studies on
absorption, distribution, and extraction of phthalates. J.SCC. J.
ll(l):48-54, as cited in CA 089/071760W.
Lake, 3.G., J.C. Phillips, J.C. Linnell, and S.D. Gangolli. 1977.
The in vitro hydrolysis of some phthalate diesters by hepatic and
intestinal preparations from various species. Toxicol. Appl. Pharmacol.
39(2):239-48b.
Lake, 3.G., P.G. Brantom, S.D. Gangoili, K.R. Butterworth, and ?. Grasso.
1976. Studies on the effects of orally administered di(2-ethylhexyi)
phthalate in the ferret. Toxicol. 6(3):341-56.
Lake, 3.G., S.D. Gangoili. ?. Grasso, and A.G. Lloyd. 1973. Studies
on cne hepatic affects of orally administered di(2-etnylhexyl) phthalate
in che rat. Toxico. Aopl. Pharmacol. 32:355-67.
3-0
-------
Laughlin R.B., Jr., j.M. Meff, and C.S. Giam. 1977. Effects of
' !°llMa" -
A.C. !979.
Ind. Hygiene 6:231.
-------
Hathur, S. 1974. Phchalate esters in the environment: pollutants or
natural products? J. Environ. Quality 3(3):189.
*
Mayer, F.L. 1976. Residue dynamics of di(2-ethylhexyl) phthalate in
fathead minnows (Plmeohales promelas). J. Fish. Res. Board Can.
33:2610.
Mayer, F.L., Jr., and H.O. Sanders. 1973. Toxicology of phchalic acid
asters in aquatic organisms. Environ. Health Parspect. 3:153.
Mayer, F.L., Jr., D.L. Stalling and J.L. Johnson. 1972. Phthalate
esters as environmental contaminants. Nature 238:411.
Mehrle, P.M. and F.L. Mayer. 1976. Di(2-ethylhexyl) phthalate:
residue dynamics and biological effects in rainbow trout and fathead
minnows, pp. 519-24. In Trace substances in environmental health.
Univ. of Missouri Press, Columbus, Mo.
Mes, J., D.E. Coffin and D.S. Campbell. 1974. Dibutyl and di(2-ethyl-
hexyl) phthalate in human adipose tissue. Bull. Environ. Contam.
Toxicol. 12(6):721-25.
Mes, J. and D.S. Campbell. 1976. Extraction efficiency of polychlori-
nated biphenyl, organochlorine pesticides and phthalate esters from
human adipose tissue. Bull. Environ. Contam. Toxicol. 16(1):53-60.
Metcalf, R.L., G.M. Booth, C.K. Schuth, D.J. Hansen and P. Lu. 1973.
Uptake and fate of di(2-ethylhexyl) phthalate in aquatic organisms and
in a model ecosystem. Environ. Health Perspect. 3:27-34.
Milkov, L.E., M.V.. Aldyreva, T.B. Popova, K.A. Lopukhova, Yu. L.
Makerenko, L.M. Malyar and T.K. Shakhova. 1973. Health status of
workers exposed to phthalate plasticizers in the manufacture of artifi-
cial leather and films based on PVC resins. Environ. Health Perspect.
4(3):175-78.
Moody, D.E. and J.K. Reddy. 1978. Hepatic peroxisome (microbody)
proliferation in rats fed plasticizers and related compounds. Toxicol.
Appl. Pharmacol. 45(2):497-504.
Morita, M., H. Nakamura, and S. Mimura. 1974. Phthalic acid esters in
water. Water Res. 8:781.
Morton, S.J. and R.J. Rubin. 1979. Effects of dietary di(2-ethylhexyl)
phthalate (DEHP), and its primary metabolites, mono(2-ethyIhexyl)
phthalate (MEHP) and 2-ethyihexanol (2-EH) on hepatic lipid metabolism.
18th Annual Meeting, 3oc. of Toxicol., Mew Orleans, Louisiana,
.1-15, 1979, Abstract 249.
3-3
-------
heSirohthSC^OSynPrS8raia (NTP)- C«cinogenesis
S, P5thalate- Draft" ^search Triangle Park,
^escing rrogram, National Toxicoloev Prn^-ra™ TT c
« ^ • •«•• *v W .feW £ J i •twltid.Bw U « J
Human Services; 1980. DHAS km^a^«, Number 81.177^
Nagasaki, H., S. Tomii, T. M
1974. Chronic toxicity of d:
mice. J. Nara. Med. Assoc.
preliminary
Neeley, W.B. 1978. A
exposure to be expected from
aquatic ecosystem. Intern. J
Neergaard, J. , 3. Nielsen, V.
1971. Plasticizers in PVC an
dialysis unit. Scand. J. Uro
Nisbet, I.c.T. and A.F. SarofU
of PC3s in the environment.
Ogner, G. and M. Schnitzer.
dialkyl phthalate complexes a
170:317-18. .
Ohyama, T. 1977. Effects of ,
dehydrogenase and other enzynu;s
/. n/o\.^ff«/-j **
40(2):355-64.
Oishi, S. and K. Hiraga. 1975
gonadal function in male rats
Oishi, S. and K. Hiraga. 1980
acid monoesters: effects of
Toxicol. 15:197-202.
Health and
ga, K. Hirao, Y. Shinohara and N. Ito
octyl phthalate (DOP) in male rats and'
5 (6):649-54.
. assessment of the environmental
the addition of a chemical to a simulated
of Environ. Studies (in press) '
Faurby, D.H. Christensen and O.F. Nielsen.
the occurrence of hepatitis in a hemo-
1. Nephrol. 5:141-45.
_ 1972. Rates and routes of transport
•uviron. Health Perspect. .1:21-38.
.970. Humic substances: fulvic acid-
•d their role in pollution. Science
Phthalate esters on glucose 6-phosphate
sin vitro. Toxicol. Appl. Pharmacol.
• Effect of phthalic acid esters on
Bull. Environ. Contam. Toxicol. 21:65-67.
Testicular atrophy induced by phthalic
-nc and testosterone concentrations.
endocrinological
phthalate (DEEP). I. fic of d«? dminiscerin§ bi3(2-ethvl
of DEHP on the gonadal function of "ale ra's7
Res. Lab. Public Health 26(2) .•127-30%^
°nda, H. , H. Kodama, jr. Yamada and H Ota 197fi
ester on reproductive oerformance in rat r* II <
31(4):507-12, as ci:ad"n CA 086/134070^
*ff
eCt °f
3-9
-------
•Ota, H., H. Onda, H. Kodama and N. Yamada. 1974.' Histopathological
studies on the effect of phthalic acid esters on the biological system
of mice. Nippon Eiseigaku Zasshi 29(5) :519-24, as cited in
CA 083/054131S.
Otake, T. , S. Akasaka, Y. Murata, H. Uda and T. Kitaura. 1977. The
effect of di(2-ethylhexyl) phthalate (DEHP) on male mice. I. Osaka-
furitsu koshu eisei kenkyusho kenkyu hokuku. Koshu Eisei Hen 15-129-38
as cited in CA 39/123/a.
Patty, F.A. (ed.). 1963. Aromatic and cyclic dicarboxylic ac
-------
, S.C. and X. Shecrraod. i
edition, McGr.v-HiU Book
Cosmet. loxico!. 15(ll
'«« »« "quids.
• 1977-
concents of the r«. Food
in vinyl pstic
Rubin, R.J. and P.P. Mair
England J. Med. 238:915
iq?? ui - * • •
Plasticxzers in human
tissues. New
Rubin, R.J. , w. Kozumfao and R. Kroll T070
a series of phthalic acid esters Lii
and diethyl esters in IA 100 ,™ >' ^ ^
Toxicol., New Orleans, Louisiana, J £3"
Rutter, H.A. 1973. Toxicology of pia.tic devices
A
" muta8enic ^say of
v '"' dimethyl
Meeting Soc'
contact
Schulz, C.O., R.J. Rubin and G.M. Hutchins 1975
3-11
-------
Schumacher, J.N., C.R. Green, F.W. Best and M.P. Newell. 1977. Smoke
composition. An extensive investigation of the water-soluble portion
of cigarette smoke. J. Agric. Food Cham. 25(2) :310.
Seth, P.K. , S.P. Srivastava, O.K. Agarwal and S.V. Chandra. 1976.
Effect of di(2-ethylhexyl) phthalata (DEHP) on rat gonads. Environ.
Res. 12 (2): 131-38.
Shaffer, C.3., C.P. Carpenter and H.F. Smyth, Jr. 1945. Acute and sub
acute toxicity of di(2-ethylhexyi) phthalata with nota upon its metabo-
lism. J. Ind. Hyg. Toxicol. 27:130-35.
Shibko, S.I. and H. Blumenthal. 1973. Toxicology of phthalic acid
esters used in food-packaging material. Environ. Health Perspect. 4(3):
Shiota, K. , M.J. Chou, and H. Nishimura. 1979. Embryotoxic effects of
di-2-ethylhexyl phthalate (DEHP) and di-n-butyl phthalate (DBP) in mice.
Environ. Res. 22:245-53.
Simmons, V.F., K. Kauhanen and R.G. Tardiff. 1977. Mutagenic activity
of chemicals identified in drinking water. Dev. Toxicol. Environ.
Sci. 2:249-53.
Singh, A.R. , W.H. Lawrence and J. Autian. 1972. Teratogenicity of
phthalate esters in rats. J. Pharmacol.. Sci. 61:51-55.
Singh, A.R. , W.H. Lawrence and J. Autian. 1974. Mutagenic and anti-
fertility sensitivities of mice to di(2-ethylhexyl) phthalate (DEHP)
and dimethoxyethyl phthalate (DMEP) . Toxicol. Appl. Pharmacol.
29(1): 35-46.
Smith, C.C. 1953. Toxicity of butylstearate, dibutyl-sebacate,
dibutyl-phthalate, and methoxy ethyloeate. Arch. Ind. Hyg. Occup . Med.
April: 310ff ," as cited in Lefaux, 1963.
Smith, J.H. , W.R. Mabey, N. Bohonos, B.R. Holt, S.S. Lee, T-W. Chou,
D.C. Bomberger and T. Mill. 1977. Environmental pathways of selected
chemicals in fresh water systems. Part I: Background and experimental
procedures. SRI International Report to U.S. EPA, EPA-600/7-77-113.
Sollman, I. 1957. A manual of pharmacology. U.S.A.: tf.B. Saunders Co,
Southworth, G.R. 1979. The role of volatilization in removing poly-
cyclic aromatic hydrocarbons from aquatic environments. Bull, of
Environ. Contam. Toxicol. 21:507-14.
3-12
-------
Stanford Research Institute International (SRI> 797* A . j r
industrial data on candidate chemicals for testing L 560/5 ?8°on2
Washington, DC: Office of Toxic Subst^a* n c ^ , 560/5-78-002.
tion Agency. Substances, U.S. Environmental Protec-
Third ..nnua! Report t8 Con?rass - lesource Raco.ery «* »Mt.
3-1.
-------
Thomas, G.H. 1973. Quantitative determination and confirmation of
identity of trace amounts of dialkyl phthalates in environmental samples.
Environ. Health Perspect. 3:23-28.
Thomas, J.A., P.R. Felice, L.G. Schein, P.K. Gupta and R.E. McCafferty.
1979. Effects of monoethylhexyl phthalate on pregnant rabbits and
their offspring. 18th Annual Meeting Soc. of Toxicol., New Orleans,
Louisiana, p A33.
Timofievskaya, L.A., M.V. Aldyreva and I.M. Kazbekov. 1974. Experi-
mental research on the effect of phthalate plasticizers on the body.
Gig. Sanit. 12:26-28, as cited in CA 082/107114K.
Tomita, I., et al. 1977. Phthalic acid esters in various foodstuffs
and biological materials. Ecotoxicology and Environmental Safety 1:275.
U.S. Bureau of the Census. 1976. County business patterns.
U.S. Department of Agriculture. 1972. Food and nutrient intake of
individuals in the United States. Agricultural Research Survey,
Household food consumption survey 1965-66. Report No. 11.
U.S. Department of Agriculture. 1973. Food consumption, prices, and
expenditure. Economics, Statistics and Cooperative Service, supplement
for 1976 to Agricultural Economic Report No. 138.
U.S. Department of Commerce. 1980. Statistical abstract of the United
States. Washington, DC: Bureau of the Census.
U.S. Environmental Protection Agency. 1974. Enclosures with letter
from M.J. Lewis to J. Hesse. Phthalates.
U.S. Environmental Protection Agency. 1975. Report to Congress,
preliminary assessment of suspected carcinogens in drinking water.
Office of Toxic Substances.
U.S. Environmental Protection Agency. 197S. In-depth studies on health
and'environmental impacts of selected water pollutants. U.S. EPA Contract
No. 68-01-4646.
U.S. Environmental Protection Agency. 1979a. STORET. Washington, D.C.:
Monitoring and Data Support Division, Office of Water Planning and
Standards, U.S. EPA.
U.S. Environmental Protection Agency. 1979b. Guidelines and
methodology used in the preparation of health affect assessment chapter
of the consent decree watar quality criteria. Federal ?,egistar 44(52):
15641.
3-14
-------
U.S. Environmental Protection Agency 1980 A K-
criteria for phthalate esters. S -SO 0^
8°-°67
aate esters. ^O/S-SO 0 n.
Regulations and Standards U S Fn, L. /5 8°-°67- Office of Wa
Washington, D.C. Environmental Protection Agency,
of Water
' "68-1978. Synthetic organic
««• priorSinT
report to U.S. EPA, EPA-560/l!77-002
' Inc"
Versar, Inc
to
Washington, D.C.
(Uc-DEHP)
Appl. Pharmacol. 39:339-5
Uveu in «.
Protection
»". The
-2-ethylheXyl
autoradiography. Toxicol.
•««•
3-1;
-------
Wilson, W.B., C.S. Giam, I.E. Goodwin, A. Aldrich, V. Carpenter, and
Y.C. Hrung. 1978. The toxicity of phthalates to the marine dino-
flagellace Gymnodium Breve. Bull. Environ. Contam. Toxicol. 20:149-54.
Woggon, H. and U. Koehler. 1967. The testing of plastics consumer
goods. Polarographic determination of fais(2-ethylhexyl) phthalate and
study of its migration tendency. Kunststoffe 57:583, as cited in
Peakall 1975.
Wolfe, JLL., W.C. Steen, and L.A. Burns. 1979. Use of Linear Free
Energy Relationships and an Evaluation Model for Phthalate Transoort
and Fate Estimations. U.S. Environmental Protection Agency, Environ-
mental Research Laboratory draft manuscript.
Yagi, Y., K. Tutikawa, and N. Shimoi. 1976. Teratogenicity and
mutagenicity of phthalate ester. Teratology 14:259-60.
Yamada, A. 1974. Toxicity of phthalic acid esters and hepatoxicity of
bis(2-ethylhexyl) phthalate. Shokuhin Eiseigaku Zasshi. 15(3):147-52,
as cited in CA 083/054100Q.
Zitko, V. 1973. Determination of phthalates in biological samples.
Internat. J. Environ. Anal. Chem. 2:241.
3-16
-------
APPENDIX A. MATERIALS BALANCE WORKSHEET
on. All amounts are in 1000 kkgs.
Column (A) - The fraction of total U.S. phthalate production
represented by the particular ester.
CB) - The amount of the particular ester remaining in
the United States after exports.
(C) - Transportation loss (calculated as 0.1% of the
U.S. supply) assumed to be lost directly to water.
" fzl JrTi0n °f eaCh SSter consumed ^ three use
categories: non-plasticizer, PVC plasticizer
other polymer plasticizer. P^sticizer,
(E) - The fraction of ester (within each use category)
consumed in the production of various product
catesories
(G) - The amount of ester vaporized during compounding
57 to :L :v«;f (F))- »
JJ/i to axr, and 65% to water.
(H) -
sites and 25z
ed as
7f
3-9' (H) x (F) to aacount for vaporization !os3
(-) - -Amount of astar remaining in che Varlou3 ,roduc
A-I
-------
lABl.t A I
MAltKlAtS ttVI.ANCIi
tv/y (..
I'l.lt... lu
Liiti.1
I'rodu. -
I iun
f A|il.l I .1
u s.
Supply
U 01
,-H
a
1
*/i
.-*
"o
o
(II)
164.6
55 4
J 0
7.5
4.0
?
•u
*
1
1 (
i^
c •»
S8
H ^
O.2
O.I
1
?• *
C 1*
*t O
g S
44 U
u
ss
1*. 9
(0)
N,,n fUslUlict
Other polymer* .05
PVC »la>lli.l«er 0.4
ullli liquid*
with air
5
1?
s
So'
six
£3
<«
-
I.O
uwlMln* pool O.OU
liners
jtartlea luwea O.01O
HMftllcal unea O.ll
flooring .226
weather »tr!ppl»£ .015
furniture .112
wall covering .040
auto upholbtry 4
ueat covers .112
apparel .100
food wrap .015
Jwlre I cable . 101
houbeware .018
Nuit-plu&r Ic I zer
Other polyiuuit) .15
I'VC pluallUzei .85
U.U1 Noii-nUatlcUer .05
0.01
0.004
-
Other polymer* .50
Nuu-plaiil Iclzer .05
Celulo*tUk .95
Non-pla*! Itlzer .10
Celulo*ttt-s .70
-
spurt goodtf i toy? .043 |
other PVC uaes .045
I.O
vinyl flooring .900
other PVC uaes .IOO
I.O
1.0
cunt act u/dlr ijrj* .6iS
iuw surface contact . 110
1.0
1.0
I.O
I.O
.015
.655
.110
-
i
1
gi
m
-
«.4
5.6
IO4 2
49.1
U. J
42. J
4.}
0.4
1.5
II. 1
2.1
I.O
O.4
7.2
1.2
2. a
-
«H
C (^
t* *•<
a
*3
^•a
3|
of
• 1
> O
«;>
-
0.3
0.2
J |
1.5
1x1
wire
0.1
1.1
O.I
-
O.I
O.OOI
n.l
O.OI
-
0.2
-
n.l
-
4» '
M *O
33?
eijs
r.g
« M U
•325
1 ••'
KM N
(u)
-
0.02
0.02
0.03
O.02
..i. 1.4
t e.U.
0.02
O.OI
0.01
!
0.02
0.02
0.01
0.02
'?
O.O2
7
0.02
-
"•
ac
Js
(I)
-
0.4
0.2
7. 4
l.«
10.2
ha
11.4
0.4
ll.l
?
O.I
1 IKK
0.04
''
0.1
7
0 1
-
M
|
|
»< »-*
li
(j>
-
1.1
5.2
91. 7
45.*
1 6
40.7
4.2
sl
Is
3 i
:!
•1 A*
3°
JK «4
(H)
l.OOStowalur
U.001 1° tt'r
O.OOI^Io air
fc water
7
O.OOI to dlr
?
0.4 \fl.2 air
1. 1
0. 1
(1.9
0.4
6.7
1.2
2.6
-
O.2 water
7
O.OOiwater
0.001 air
O.(l»2xulr
water
•T-0.2 alr
0. 2 water
7
\0.2 »'f
(1.2 Wllt-
II!
OK'
a.z
0 2
0 01
0 1
Trn
Hill
s
bur •
iitr
i.tif
ifNiif
-------
(K) - Phthalate release rate (in percentage per year)
ror each product category (assumed to ^constant)
(L) - Amount of phthalates released each year of the
product's litetime (assumed to be constant).
(M) - Average lifetime of the product catagorv or srouc
or categories (Arthur D. Little, Inc", estJLLs)'
(N) - Total amount of phthalates released over the
product's lifetime, calculated as (L) x (M)
This assumes that a steady state has been reached
so that the phthalate inventory in products being
used is not growing. This is approximately trS
for products with DEEP, which has had a VJ C^
growth rate over the past 10 years.
(0) - Amount of phthalates in products that have ended
their useful lives and will be disposed of
Municipal landfills will receive 97% of this
amount annually, and 37, will be incinerated
-------
-------
APPENDIX B. PHYSICAL-CHEMICAL PROPERTIES
•
The
were selected for
3-1
-------
TABLE B-l. PROPERTIES OF BIS(2-ETHYLHEXYL) PHTHALATE
chemical structure
Alternate Names
DEHP
Di(2-ethylhexyl) phthalate
Bis(2-ethylhexyl) ester phthalic acid
Di(2-ethylhexyl) orthophthalate
Di-sec-Octyl phthalate
2-Ethylhexyl phthalate
1,2-Benzene dicarboxylic acid bis(2-ethylhexyl) ester
SOTE:
Bis(2-ethylhexyl) phthalate is sometimes mistakenly reported as its
isomer, Di-n-octyl phthalate (DOP), in the literature.
Molecular Weight 391.0
(Patty 1963)* ' '
Melting Point -50°C
(Patty 1963) *
Boiling point at 5 torr 231°C
(Lowenheim and Moran, 1975)
—8
Vapor pressure at 25°C 6.8 x 10 torr
(Wolfe ej: al. 1979)
Solubility in water at 25°C 0.40 ± 0.05 mg/1
(Wolfe sk §L-
Log octanol/water partition 4.89
coefficient
(Wolfe jt al. 1979)
CAS NO. 117-31-7
TSL NO. TI 03500
*As cited in Versar (1979b)
3-2
-------
TABLE B-2. PROPERTIES OF DI-N-BUTYL PHTHALATE
chemical structure
Molecular Weight " 278.34
Melting Point -35°c
(Verschueren 1977>
Boiling point at 760 torr 340°r
(Patty 1963)-*
Vapor pressure at 25°C 2 0 x 10~A
(Wolfe et al. 1979) X
Solubility in water at 258C 4 5 me/i
(Wolfe et a. 1979) 8
Log octanol/water partition 4.94
coefficient
(Wolfe zt al_. 1979)
CAS NO. 84-74-2
TSL NO. TI 08750
• ^^^^"•""•^^•^™^^^^™™^^^^M^—,^^M^^^
rAs ciced in Versar (1979
3-3
-------
TABLE B-3. PROPERTIES OF DIMETHYL PHTHALATE
chemical structure
0
l!~~ *3
o
Alternate Names
DMP
1,2-Benzenedicarboxylic acid, dimethyl ester
Phthalic acid dimethyl ester
Methyl phthalate
Molecular Weight 194,18
Melting Point 08C
(Verschueren 1977)*
Boiling point at 760 torr 282°C
(Veschueren 1977)*
Vapor pressure at 25°C 2.2 x 10 torr
(Wolfe et al. 1979)
Solubility in water at 25°C 4320 ± 0.37 mg/1
'(Wolfe g£ al. 1979)
Log octanol/water partition 1.90
coefficient
(Wolfe e£ al. 1979)
CAS NO. 131-11-3
TSL NO. TI 15750
*As cited in Versar (1979b)
3-4
-------
TABLE B-4. PROPERTIES OF DIETHYL PHTHALATE
chemical structure
r,
— C-0—C,H.
,i 2 o
Alternate Names
DEP
1,2-Benzendicarfaoxylic acid, diethyl ester
Ethyl phthalate '
Molecular Weight
(Patty 1963)*
Melting Point
(Patty 1963}*
Boiling point at 760 torr
(Verschueren 1977)*
Vapor pressre at 25aC
(Wolfe et al. 1979)
Log octanol/water partition
coefficient
(Wolfe et_ al_. 1979)
CAS NO. 84-66-2
TSL NO. TI 10500
222.23
-4Q.5aC
298°C
4.1 x 10 torr
2.94
3-5
-------
TABLE B-5. PROPERTIES OF DI-N-OCTYL PHTHALATE
chemical structure
0
-C-C-CH,
3,7
Alternate Names
DNOP
o-Benzenedicarhoxylic acid, dioctyl ester
n-Dioctyl phthalate
Octyl phthalate
Dioctyl-o-benzenedicarboxylate
NOTE:
Di-n-octyl phthalate is sometimes mistakenly reported as its isomer,
bis(2-ethylhexyl) phthalate, in the literature.
Molecular Weight 391.0
(Patty 1963)*
Melting Point -25°C
(Patty 1963) *
Boiling point at 4 torr 220" C
(.Patty 1963) *
Vapor pressure at 25°C 2.6 x 10~ torr
(Wolfe .et al. 1979)
Solubility in water at 25°C 3 ± 0.5 mg/1
(Wolfe .e_t al. 1979)
Log octanol/water partition 4.77
coefficient
(Wolfe e_t al. 1979)
CAS NO. 117-84-0
TSL NO. TI 19250
*As cited in Versar (1979b)
3-6
-------
TABLE B-6. PROPERTIES OF BUTYL BENZYL PHTHALATE
chemical structure
_C-0— C.H
'4* 9
-C_CH.
Alternate Names
BBP
Benzyl butyl phthalate
Molecular Weight
312.0
Melting Point
(EPA-OHMTADS 1977)*
Boiling point at 760 torr
(EPA-OHMTADS 1977}*
Vapor' pressure
Solubility in water at 25"C '
(Fishbein and Albro 1977)*
Log octanol/water partition
coefficient (The exact value
is not calculated due to an
unknown contribution by mole-
cular folding. The partition
coefficient for diethyl phthalate
is 4.42, calculated as per
Leo et al. (1971) * The log P for
butyl benzyl phthalate is con-
sidered to be greater than that of
the short chain phthalacc ester).
-35°C
377°C
Not available
Insoluble
> 4.42
CAS NO.
TSL NO.
85-68-7
TH 99900
*As cited in Versar (1979b)
-------
-------
APPENDIX C. FATE IN WATER - MODELING RESULTS
The analysis of phthalate esters in water utilized the water model
results provided by the U.S. EPA (Wolfe et, a^. 1979). Because of insuf-
ficient hydrolysis data on the compounds of interest for pure water,
the investigators measured second order alkaline hydrolysis rate con-
stants. The rate generally decreased with an increase in chain branching,
and variability over three factors of ten was noted. Also, aqueous
solubilities reported in Tables B-l through B-6 were measured in this
investigation and found to vary over three factors of ten. The acid
catalyzed and neutral pathways of hydrolysis are slow compared with the
second-order alkaline pathway that was measured. To provide inputs for
the models, vapor pressure values were extrapolated to 25°C, using the
Clausius-Clapyron equation (Reid and Sherwood 1958). In addition to the
octanol/water partition coefficients listed in Tables B-l through B-6,
alternative values were computed using a correlation suggested by Hansch
and coworkers (1968) that relates the partition coefficient to the
aqueous solubility for organic liquids. Although differences as large
as factors of 10^ are reported, no comments explained the reasons for
such disagreements. Sediment and biomagnification partition coefficient
were also computed for the esters of interest.
To test the relative importance of fate mechanisms and to estimate
concentrations, a model known as EXAMS (Exposure Analysis Modeling
System) under development at the U.S. EPA Athens laboratory was employed.
EXAMS is based on methodology developed at SRI (Smith et al. 1977) and
modified by the authors of the environmental assessment of phthalate
esters (Wolfe .at ail. 1979). The model is intended for use with water
bodies such as rivers, ponds, lakes, and reservoirs. Transport from one
portion of a water body to another is represented by flows of water
containing the chemical contaminant of interest from one compartment to
another. Each compartment is a homogeneously mixed region containing
either water or sediment. The lake model version employs vertically
arrayed compartments, whereas the river model represents the flow by a.
linear horizontal succession of compartment pairs. One member of each
pair represents the flowing water and the other the associated sediment.
Thus, transfers from compartment to compartment and from water to sedi-
ment are represented. Pollutant discharge inputs are prescribed, and
flow characteristics are selected from among a set of prototype environ-
ments. Chemical transformation and loss by volatilization are considered.
Both dynamic and steady-state operation of the models are permitted as
options.
Each of five phthalate esters was evaluated in each of five siau-
lacad ecosystems: 1) a river, 2) a pond, 3) a eutrophic lake, 4) an
oligotrophic lake, and 3) a reservoir.
Results were reported for only two of che five astars, DMP and DEHP.
Table C-l summarizes Che time to reach 99% of staady stata, cha decay
C-l
-------
TABLE C-l. TIME REQUIRED TO REACH 99% OF STEADY STATE, SEDIMENT AND WATER
CONCENTRATIONS AT 99% STEADY STATE AND HALF-LIVES ESTIMATED FROM
DECAY SIMULATION FOR THE WHOLE SYSTEM.
o
I
DM I'
DEMI'
Time for 99% Decay Simulation
Concentration at
Steady State
Ecoajatem
Kivur
I'ond
En trophic Lake
O| igotrophic
Lake
Heaervoi r
Hi ver
I'ond
Eut roplric Lake
O| igoirophic
Lake
K^rvolr
Steady State
38 hr
96 hr
288 hr
144 hr
264 hr
176 day
384
840 mo
120 mo
880 mo
Half-Life
6.9 hr
13 hr
26 hr
19 day
26 hr
18 day
52 mo
103 mo
12 mo
110 mo
Water mg/1
2.2xlO-5
1.9xlO-3
4.4x10-4
3.6xlO~3
3.6xlO~4
0.099
0.099
0.098
0.098
0.094
Sediment nig,
1.5xiO~7
5.3xlO~6
3.8xlO~7
4.6xlO~6
3.5xlO~7
46
2. Ox 1C)2
3. xlO2
1.5X101
2.7xl02
Eaier concentrations with no loss processes is 0.1 mg/1.
Source: Wolfe et al. (1979).
-------
.
a total for all loss mechanises ££ r™* "^ half~life "presents
percentage loading for t^Sicalf LcI V^T^ half-lives «d
hydrolysis, biological and ex^rt nrc^ 1°* P^to^sis» option and
each of the five alaulat* aS"^""^".^ Same *" C0**°-ds -
tion are not included in these or^S*!; . ^°latlli2aci0* and sedimenta-
C-l show that these processes in IT^ri' h°WeVer' the r^ults in Table
loss mechanisms, are £S£3ic«t In ^ CH ChemiCal and bioi°S^l
Export or transport accouS for 98- 99 97 S^TT' ^^ ^ DEHP'
other hand, DMP exhibits far loJer staadv aL 10SS6S f°r DEHP' On che
both the water and the sediment^ concentrations in
more rapid alkaline hydrous ^atf and "bVn ^i"7 bSCaUSe °f the much
No,e that except in tL riJer! r^^
no
form an upper bound for the concentration/^ ^f"' ? the simu^tion
set. Not only do the other members £jf? th' °ther members of the
oient, but they also hydrotyze and biodHr 7" ™leSiSeS C° the environ-
is dramatically exhibited in t^sle^l^0^ ™P±dl7' ™S tenden
between DMP and DEHP. Levels of SfTfH £ con«ntration comparison
orders of magnitude below those ofLS ^"^^ input are several
tially that of a closed compartment wUh a^t^d HPf"lculation ^ essen-
s.tuation occurring between^he
twe ^ironmental Exposure
Che individual fate of DE^P an! ele^n^theTcT ?•?* .197» ««-P«*
oeo,t SSL t^eSSSLi^f^3^^^- ^
The PEEC computes concentrations In sldf " ^ E?A S7Stem Was 0-°3-
fixed set of environmentalvariables Rate ;0n%ter' ^ fiSh f°r a
experimental measurements or by means o?a'%co^stants «e determined from
in terms of empirical relationships Th'e PE?c 'LT ^°d°10^S -P«c«i*
which a steady-state discharge of !^»™ f dynamic analysis in
for a thirty-day period , foUowel by a ^J?S T° ^ P°nd la ^^^ned
charge rate used for each o oil llLr ff ^"^'^ clearance. The dis-
for the thirty days! oSp'soiS ^ilitv us I ^ f^ WaS °'15 S111^—
0.4 given in Table B-l ^e vaoor nL *" * mg/1 in c°ntrast with
in contrast to 6.3 x ^ - 2'28 X 10 ^ Hg
and
mass ratios in the two simulations Ire «s«S2?£ *? sedlm«nt to water
found a considerably higher watar to -J 7 the same' Neel? (1978)
the U.S. EPA (Wolfe'et al 1979) Ita*dlMaf. «*««ration ratio than
in partitioning rasults~-om <-h ' *• • ^OSol°^e that this difference
m^-t*«^»T-r»T*/^ , , " " —.iG w i atlS i^TlC n.3. t7ll"P 1^1* *•^^!l ^*-»_J • -.
?EEC and the higher soluh-f-f »-r ^ T 1
-------
TABLE C-2. HALF-LIVES AND % OF LOAD FOR THE CHEMICAL, BIOLOGICAL, AND
EXPORT PROCESSES FOR DMP AND DEHP IN FIVE SIMULATED ECOSYSTEMS
Chemical
Export
Compound Ecosystem
DMP Kiver
Pond
En trophic
Lake
Ol igotrophic
Lake
o
4: Reservoir
DEHP Kiver
Pond
Eutrophlc
Lake
Ol igotrophic
Lake
Reservoir
2.
2.
2.
4.
8.
2.
3.
t
6xl04 hr
3
7x10 hr
O
7x10 hr
i
9x10 hr
2xl04 day
2x10 mo
o
7x10 mo
505 mo
3.
2x10 mo
% Load
0.
0.
0.
0.
0.
0.
1.
1.
1.
04
47
90
96
01
23
7
7
9
— . — . u
t
111 hr
13 hr
27 hr
27 hr
1.5x10 day
l.OxlO5 mo
4
3.5x10 mo
1.3xl05 mo
2.9xl04 mo
% Load
9.4
97
98
99
0.0
0.05
0.18
0.05
0.2
t % Load
11.5 hr 00
693 hr 1.
5.2xJ03 hr 0.
5.3x10 hr 0.
4.7 day 99.
51 mo 99
64 mo 98
8.9 mo 98
.62.5 mo 98
0
51
47
9
Soui-ce: Wolfe et al. (1979).
-------
Chlorpyrifos l th
of
C-5
-------
-------
APPENDIX D. FATE IN AIR - MODELING RESULTS
To estimate concentrations in air, we can assume a constant back-
ground concentration or OH-radical and write a simple expression
describing the concentration variation in a box with a uniform area
source at the surface level and a first order reaction throughout ics
volume. Imagine the box with unit horizontal area and height H (the
mixing height). It moves along with the wind for a cime t over an area
emission source strength Q. This situation is described in equation 1
as follows:
dt H
where
X • mass concentration
t * time
Q * area source strength
H = mixing height
k » first order rate constant
For a background concentration of xn and a final concentration after a
time t of xf the solution is:
Using this expression to estimate the atmospheric concentration of a
phthalate ester requires not only knowing its decay rate but also the
source strength, the mixing height, and an appropriate residence time
for an urban area. We have chosen to use dichlorodifluoremethane as a
surrogate tracer to determine the atmospheric diffusion characteristics.
This compound, like phthalate esters, is associated with widely dispersed
sources related to the cultural environment. Measurements in La Jolla,
California by Su and Goldberg (1973) give concentrations of 0.0053 ug/m3.
We allocate CC12F2 emissions by population in order to scale them to the
population of San Diego County, which was 1,656,300 in 1977 (County of
San Diego 1978a). The prorata share of the national emissions of
93340 mt yr-1 (Eschenroeder et al. 1979) is 22.3 gm sec'l or 3.7 x
10~8 gin af- 3ec-l assuming an area of emission approximately 600 km2
for San Diego County. On a typical June day, the' inversion' base at La
Jolla is 1400 ft (427 a). This value is taken from a racent air quality
analysis (County of San Diego 1973b). Su and Goldbers (1973) also report
a iichiorodifluoromethane concentration of 0.007 ug m^ in the desert
-------
100 km away from San Diego. This will be used for the background concen-
tration XQ- Since dichlorodifluoromethane is nonreactive on the urban
scale in the lower atmosphere, k can be neglected. Expanding the expo-
nential in equation 2 by a Taylor series, cancelling the k in the leading
term, and taking the limit as k approaches zero, we obtain the following
axprassion for the nonreactive concentration:
Qt ,
•2
-------
APPENDIX E. HUMAN TOXICITY*
S.I METABOLISM
E.I.I DEHP
the administered DEHP is excrei--rf <„ VK - aion, so that most or
little DEHP 7. f excreted in the urine as derivatives of MEHP.
"
sinsie
-
••
dose U
«cr.t.d » av«.g. of
«d 57S !» fsces Schin
experiment, rats habituated to DE for 7 dy*
«om)
»
aosa of i+c
(38%) and 1
of
aa in Che li
ver
erar-ncas, see Chapcar 3.0.
-------
urine and feces increased. In parallel studies, chey found that animals
fed daily oral doses of DEHP (5000 mg/kg in diet) for 49 days had steady-
state liver concentrations of 120 mg/kg of labelled residue. When DEHP'
dosing was stopped, detectable activity quickly disappeared from liver
tissue (half-life of 1-2 days).
Tanaka at _al. (1975) also performed tissue distribution studies
following administration of a single oral dose of 500 mg/kg of 14C-DEHP
(as a 257, solution in Tween 30) to male Wistar rats. A total of 45% of
the administered 14ODEHP was localized in the stomach and intestine
1 hour after dosing with activity in the liver peaking at 3-6 hours.
. Schulz and Rubin (1973) found that intravenously administered doses
of l C-DEHP were not only cleared more slowly than oral doses (54.6 vs
80% clearance in 24 hours of the 200 mg/kg dose), but also that a higher
dose was cleared more slowly than a lower dose in male rats. One hour
after injection, only 8.0% of a 200 mg/kg dose had been converted to
water-soluble metabolites (i.e., MEHP and its derivatives); whereas, 25%
of the smaller 0.1 mg/kg dose had undergone this conversion. The unmeta-
bolized DEHP was found primarily in the liver, spleen, and carcass.
After 24 hours, 54.6% of the higher dose had been recovered in the water-
soluble fraction, while more than 95% of the lower dose was accounted for
as water-soluble material in the feces, urine, and intestinal contents.
These authors also measured the disappearance of labelled DEHP from
the blood of intravenously injected male rats. They found that the half-
life (t 1/2) of the first phase of the biphasic clearance of DEHP was
shorter for the low dose (4.5 minutes) than for the higher dose (9.0
minutes). The second clearance phase had a t 1/2 of 22 minutes for the
low dose; insufficient data precluded calculating t 1/2 for the higher
dose. The authors attributed the differential clearance of DEHP from
the blood and tissues in part to the efficiency of the compartment that
carries out the primary metabolism, but also suggested that solubility
problems may be significant in the metabolism of the higher dose (Schulz
and Rubin 1973).
Booth et al. (1976) noted that intravenously injected ^C-DEHP
(200 uCi/kg body weight in a 1% Tween 80-saline vehicle) was eliminated
far more slowly in deer mice (Paromyscus maniculatus) than in laboratory
mice and rats. Two weeks after injection, an average of only 42.53% of
administered activity had been excreted.
Tanaka _et _al. (1975) administered 2.3 uCi of carbonyl-labelled
1 C-DEHP intravenously to male Wistar rats. Within 5-7 days subsequent
to injection, 75-80% of the administered activity was recovered in urine
and feces; the activity was negligible in expired CO-?.
Tanaka at al. (1975) also studied the distribution of intravenously
administered' JH-DEHP in the organs of three mala rats sacrificed
1,2,3,5,12,24, or 168 hours after receiving a 50 mg/kg dose (1.03 uCi
per rat). They found chat the Liver and intestine accumulated mosc of
-------
in
2.293 ug (0.968
E.I. 2 DBF
that
in the urine (Tanaketal 1978
Ariyoshi et al. 1976)" M^haUc acid
"""» °f
'
SUiQea P^s demonstrate
P^halate (MBP) and excrete
* lanchfield
. - -
biliary excretion of DBF in rats alfeftral L • reP°«ed significant
during the first administration, particularl
thereafter.
, but
steadily
saooon, nan), che
mc.scine (rat, terret,
3-3
-------
E-l-3 DMP. PEP, DNOP. and BBP
Kitanaka et al. (1977) reported that 82 and 90% of the activity of
orally administered ^C-DEP and ~4C-DMP, respectively, was excreted in
the urine of rats and mica. No additional details were available.
When incubated in vitro with the contents of the isolated rat small
intestine, DEP and DMP have been shown to undergo hydrolysis to their
corresponding monoesters (Rowland at al. 1977). Laka et al. (1977) also
round that intestinal cell preparation from rat, cerretT blboon, or man
and hepatocytes rrom rat, farret, and baboon were able to hvdrolyze DMP
DEP, and DNOP to their monoalkyl derivatives in vitro.
u J — — ' (1978) reP°rted that 5 ml of rat liver homogenata
hydrolyzed 100% of a 2 mg dose of DMP and 75% of an equivalent amount
of DNOP In vitro in 3 hours. An equivalent amount (5 ml) of rat kidney
homogenate hydrolyzed approximately 75% of a 2 mg dose of DMP in 3 hours
but required 5 hours to hydrolyze the same amount of DNOP.
No data were found on the BBP ester.
E.2. ANIMAL STUDIES
E.2.1 Carcinogenic ity
The carcinogenicity study conducted for DEHP was described previ-
ously. No long term carcinogenicity studies have been conducted for the
other phthalate esters. However, no- increased incidence of neoplasms
were noted in lifetime feeding studies with DEHP (Carpenter et al. 1953
Harris et al. 1956), DBP (LeBreton 1952) and DMP (Lehman 19557 at dietary
levels from 200-500 mg/kg/day.
Groups of twenty strain A male mice injected intraperitoneally three
times weekly for 8 weeks with 150, 400, or 800 mg/kg of BBP displayed no
increased incidence of pulmonary adenomas compared to saline-injected
controls (0.20 lung tumors/mouse for the 800 mg/kg BBP group vs 0.19 for
saline controls). Mice exhibited a marked lung tumor response (19.6
tumors /mouse), however, to the positive control, 1000 mg/kg urethan
(Theiss .et al. 1977).
E.2.2 Mutagenicity
E.2.2.1 DEHP
Stenchever et _al. (1976) found no statistically significant increase
in chromosome aberrations in human laukocytas exposed for 4 hours fo
concentrations of 60.0, 6.0, 0.6, or 0.06'ug/ml of DEHP, or in human
fetal lung cells exposed for 5 days in a aedium containing 6.0 ug/1 of
the iiestar.
-------
clear dose-
, no
TA ,., IA U37, IA 15J8
E.2.2.2 DBP
S
41"'
E.2.2.3 DEP
effect of ,
diester to a non-o,utagen±c MtaboUt.
and the station fraqL=v ob"ined
•«•*«••• the positive
conversion of the
"' °E? t""d
Z.2.2.4 3BP
No nucagsnic activicy was discove
ertouc miWM ia :he toes Sa'
-------
TABLE E-l. CHROMOSOME ABERRATIONS AND SISTER-CHROMATID
EXCHANGE (SCE) PRODUCED BY DEHP
Dose (M) Breaks/Cell . SCE/Call -
BUdR * ethanol 0.0575 3.73 + 0.32
1 x 10"11 0.08 9,97 + 0.72 (p <0.05)
-4
1x10 0.06 9.50+0.58 (p <0.05)
1 x 10 0.08 11.0 + 0.9 (p <0.05)
Source: Abe and Sasaki (1977).
-------
TABLE E-2. CHROMOSOME ABERRATIONS AND SISTER-CHROMATID
EXCHANGE (SCE) PRODUCED BY DBF
Dose M) Breaks/Cell SCS/Cell ± SE
BUdR + ethanol 0.575 8.78 ±0.32
1 X 10 ° °'10 10-6 ± 0.72 (p 0'16 13.6 + 1.00 (p<0.05)
1 x 10"3
Source: Abe and Sasaki (1977).
-------
TA 98 (frameshift mutant) or strain TA 100 (base substitution mutant).
The concentration of BBP was not given (Rubin _e_t al. 1979).
E.2.2.5 Summary
No definitive conclusions can be-drawn on the genetic risk from
exposure to phthalata esters at the present time. Conflicting studies
on ;he mutagenic activity of DEHP show no increase in chromosomal
aberrations in either human leukocytes (60 ug/ml) or Chinese hamster
cells (150 ug/ml), while a third study notes an increase in the frequency
of both chromosome breaks and sister chromatid exchanges in Chinese
hamster cells exposed to a much lower concentration of DEHP (1 x 10~5 M
or 0.3 ug/ml). However, these increases in the frequencies of sister
chromatid exchange and aberrations were less than two-fold the control
value and without a clear dosage effect. Consequently, the ability to
make extrapolations is confounded. No information was found on the
mutagenic potential of either DMP or DNOP and no _in vivo mutagenesis
data were available for any of the phthalate esters.
A single study reported that DEP was mutagenic in an in vitro
microbial study with Salmonella typhimurium TA 100 but only in the
absence of metabolic activation, while BBP was not mutagenic with or
without metabolic activation in strains TA 98 (frameshift mutant) or
TA 100 (base-pair mutant).
E.2.3. Teratogenesls
E.2.3.1 DEHP
Rat
Singh _ejt al. (1972) injected groups of five pregnant Sprague Dawley
rats intraperitoneally with 5 or 10 rag/kg of DEHP on days 5, 10, and 15 of
gestation. Fetuses were examined on day 20. No increase in deaths was
observed in DEHP-treated rats but a dose-related increase in the inci-
dence of fetal resorptions was reported (26.8 and 8.2%, respectively,
for the high and low dose groups compared with 6.8% for cottonseed-oil
controls). Fetal weight (p <0.01) was significantly decreased in both
DEHP-treated groups; and the number of live fetuses was slightly reduced,
with an incidence of 91.8% live fetuses in the 5 ml/kg group and 73.2%
in the 10 ml/kg group compared with 93.2% in cottonseed-oil controls.
A 22% incidence of gross abnormalities including anophthalmia, absence
of tail, twisted hind legs, and hematomas was seen in the high dose
group but no abnormalities were seen at 5 ml/kg. No skeletal abnormali-
ties were observed among any of the DEHP-treated fetuses.
Garvin _et_ _al. (1976b) intravenously injected pregnant rats with
daily doses of lag/kg or 3.7 ag/kg of DEHP in a sterile rac plasma on
days 5-15 of gestation. Mo differences between control and created
animals were noted in reras of growth rates of dams, littar size, pup
weights, or incidence of dead or resorbed fetuses.
S-3
-------
Mouse
available.
Rabbit
was 94% compared »ith"alu2 of 89 87 afd 777 ?"T *° """^ *«"P«
1id
-
E.2.3.2 DMP
irs STI
.sr.s: rs ".1-'
3-,- 5 ' ' 1 '
3-,-l.t.! aono^ukes
tiv.lv.
-------
abnormal skull bones were the most common skeletal deformities
(Singh £t £l. 1972).
Chick embryo studies have demonstrated DMP as highly embryotoxic
(Haberman et al. 1968, lijo 1975, Bower et al. 1970, Lee at al. 1974a).
Haberman at_ ad. (1963) reported 100% mortality among chick embryos
injected in ovo on day 9 with 0.1 ml of a 57. emulsion of DMP in Hank's
balanced salt solution compared with 24.0% mortality in vehicle controls.
Lee _at al. (1974a) found 70% mortality among chick embryos injected on
day 3 with 0.05 ml of Ringer's solution saturated with DMP. Controls
injected with Ringer's solution alone showed 19% mortality. In another
study, injection of 0.5 ml of the undiluted diester into day 3 chick
embryos caused 87% mortality compared with 18% mortality in controls
(Bower et al. 1970).
Lee at, al. (1974a) tested the effects of different concentrations
of DMP in agar on the development of explanted streak-stage chick
embryos. The embryos were grown on agar containing 0.05, 0.1, 0.5, 1.0, or
2.0 mg/ml of DMP. At the three lowest concentrations, 33, 18, and 7%
of the embryos, respectively, developed normally; whereas none of the
embryos grown on agar containing 1.0 mg/ml or above of DMP showed normal
development. The defects most commonly observed were those affecting
neural tube fusion and somite development.
E.2.3.3 PEP
Singh et: al. (1972) administered DEP via intraperitoneal injection
to groups of five pregnant Sprague Dawley rats on days 5, 10, and 15 of
gestation. Each group received 1.686, 1.012, or 0.506 ml/kg/injection.
Four sets of control animals were either untreated or injected with
distilled water, normal horns and fetuses were removed from dams on day
20. No fetal deaths were noted in any DEP-treated dams. The number of
resorptions was markedly increased in the dams receiving the lowest
(44.4%) dose and slightly at the highest dose (3.6%). Although the
intermediate dose did not produce any resorption sites, the reason for
this is not clear. The average fetal weight was significantly reduced
in all DEP-treated groups (p <0.01), but no gross abnormalities were
observed among fetuses from any of the DEP-treated dams.
Skeletal abnormalities in 30-50% of the fetuses examined were
increased 31.3, 47.1, and 26.3% in the fetuses from dams injected with
and incomplete or missing skull- bones were the most prominent skeletal
abnormalities. These defects were not observed in untreated or dis-
tilled water-injected controls, while those receiving 10 ml/kg of
cottonseed oil or normal saline had skeletal abnormality frequencies of
10.7 and 14.3%, respectively.
Bower at al. (1970) injected 0.025 ml of DEP into the yolk sac of
fertilized chicken eggs. DEP-injaction increased the number of chicks
that died befora hatching (63.7%) compared with 44.3%, 53.4%, and 31.1,"
2-10
-------
available.
E.2.3.4 DBF
24, -and 21% respectively for the hi h .uses *Xamned **re increased
rj-z-T-- - :-£:- "
had reduced birth weigJts' No addLL T, " *?' higheSt d°Se §r°uP also
1971). weignts. No additional details were available (Piekacz
.
receiving 4 ml/kg (4 2 a/LT nf nnS f lltter ln Sprague Dawley rats
group, were bom without eyes. Utters ln the 2 ml/kg
in
of
-------
Injection of 9-day chick embryos with 0.1 ml of a 5.0% suspension
of DBF in Hank's balanced salt solution produced 59% mortality compared
with 24.4% controls. No teratogenic effects were observed (Haberman
!£ jtl. 1968).
£.2. 3. 5 BBP
Nine-day chick embryos jLn ovo were injected with 0.1 al of a 5%
suspension of BBP in Hank's balanced salt solution (Haberman at_ al. 1968).
Injections were made into either the allantoic cavity or the chorio-
allantoic membrane (CAM); vehicle controls were established for each site
of injection. BBP injected into the CAM caused 68% of the embryos to die
before hatching, compared with 27% mortality in controls. Injection of
BBP into the allantoic cavity caused 28% of the embryos to die _in ovo
compared with 18% embryo fatality in controls. All BBP-treated chicks
that hatched were alive at 21 days post-hatching. Only one of 26 chicks
that hatched from eggs injected in the allantoic cavity was reported to
have suffered adverse neurologic effects.
Bower et al. (1970) injected 0.05 ml of undiluted BBP into the yolk
sac of fertilized chick eggs between 'the 65th and 72nd hour of develop-
ment. A total of 48.8% of the BBP-treated embryos died before hatching
compared with fatalities of 31.1, 53.4, and 44.8% in uninoculated con-
trols, in vegetable-oil controls, and sesame oil controls, respectively.
None of the hatched chicks showed any congenital malformation.
E.2.3.6 POP
Bower .at al. (1970) injected 0.1 ml DOP undiluted into fertile eggs.
No significant effect was reported on the viability or development of
chick embryos. Injection of 0.1 ml of a 5% suspension of DOP in Hank's
balanced salt solution into eggs containing 9-day chick embryos, however,
caused 53% of the embryos to die before hatching compared with 24%
mortality in controls. Of those that hatched, 5 OOP-treated chicks out
of 66 had neurologic abnormalities, such as a staggering gait and severe
lethargy; these effects were not observed among 377 controls chicks.
One-third of the DOP-treated chicks were dead at 21 days post-hatching,
compared with a 9% mortality in controls (Haberman et_ al. 1968).
E.2.3.7
In summation, DEHP at high doses ( > 5 ml/kg) is capable of inducing
gross abnormalities in both rats and mice. DMP (0.3 ml/kg), DB?
(0.3 ml/kg) and DEP (0.5 ml/kg) have also produced skeletal malforma-
tions in rats. Injection of phthalate esters directly into developing
chick eggs produced no cerata with DBP, BBP, or DMP and a single inci-
dence of malrotation of Che leg with DEP. Increased embryo mortality
was no tad for DMP, DEP, DBP, DOP, and BBP. However, mortality values
for controls were also elevated raising questions as to the value of
these findings.
-------
E.2.4 Reproductive Effects
E.2.4.1 Oral Administration
- Shaffer _et _al. (1945) was the first to report changes in the testes
of rats that had been fed diets containing 0.9 g/kg/day or 1.9 g/kg/day
of DEHP for 90 days. The authors noted tubular atrophy and degeneration
in the tastes, resembling senile changes, in all animals at these two
dose levels. No effect was seen in rats given 0.2 g/kg/day or 0.4 g/kg/
day of DEHP for the same period. Similarly, Oishi and Hiraga (1976)
reported a decrease in testis weight (attributable to an actual decrease
in the number of testicular cells) in male rats fed 1 or 2% DEHP in the
diet for 10 days. An increase in the levels of testicular lipids was
also noted.
No adverse reproductive effects were noted in two generations of
Sherman rats fed 0.4, 0.13, or 0.04% DEHP in their diets for one (F]_
generation) or two years (P^ generation). Litters born, total number
of pups born, mean number of litters per female, mean size of litters,
maximum number of litters by any female, pups stillborn or killed at
once by the mother, and mean age at last litter were recorded from
treated and control animals. The only change noted among the DEHP-treated
animals was a decrease in the mean number of litters per female among Fi
rats at the 0.4% level when compared with controls. This difference,
however, was attributed to an unusually prolific F^ control group, as
the mean number of litters born to the DEHP-treated F^ rats was not
significantly different from that of PJL controls or DEHP-treated animals
at any dose'level (Carpenter _e_t ad. 1953).
In another study, seven mature male albino ferrets were.fed 1% DEHP
in the diet for 14 months. Examinations of sections of testes from both
control and DEHP-treated animals revealed active spermatogenesis with
spermatids or spermatozoa identifiable in the seminiferous tubules of
all animals. However, three out of seven DEHP-treated males exhibited
complete or nearly complete absence of germinal epithelium in a few
tubules. The relative testes weights per 100 g body weight for the
control and treated animals were 0.28 + 0.02 g and 0.37 + 0.02 g,
respectively. The absolute testes weights in treated animals were
significantly different from those of controls; i.e., 3.42 + 0.09 g
for controls vs 3.10 + 0.21 g for treated animals (Lake e_t al. 1976).
E.2.4.2 Intraperitoneal Administration
Daily intraperitoneal injections of 1.25 g/kg of DEHP for 5 days
consecutively caused a 29% reduction in the concentration of testosterone
in the testicular blood of nine male rats (0.29 + 0.04 ug/ml vs 0.41 4-
0.^0^ ug/ml in control animals). The decrease of testosterone secretion
after DEHP administration may have resulted in a reduction of tiastis
weight and fertility. DEHP administration also caused a 22" reduction
in testosterone sacration following human chorionic gonadotropin (hCG)
-------
stimulation. Several control animals injected intravenously with
100 I.U. of hCG 15 minutes prior to blood sampling had a testicular
testosterone concentration of 1.36 ± 0.15 ug/ml vs a concentration of
0.96 +0.09 ug/ml in ten treated animals following hCG stimulation.
This suggests that DEHP may inhibit the biosynthetic production of
testosterone from cholesterol (Oishi and Hiraga 1979).
In a study of the effects of phthalate esters on reproduction in
Sprague Dawley rats, Peters and Cook (1973) found that DEHP prevented
implantation in seven of ten rats when injected intraperitoneally at
3, 6, and 9 days of gestation at concentrations of 2 ml/kg or 4 ml/kg
body weight. These doses also had an adverse effect on parturition.'
Two of the three rats died during parturition. Excessive bleeding was
noted in all three DEHP-treated females at parturition.
In a second experiment, Peters and Cook (1973) found that the
developmental stage at which the DEHP was administered determined the
effect. Only those rats treated on or before day 6 of pregnancy with
2 ml/kg of DEHP show a reduction in the number of implants. When the
same dose is administered after day 7, effects include excessive maternal
hemorrhaging and fetal retention. FX females born in this study had
normal reproductive functions.
In another study designed to test the reproductive effects of DEHP
on male ICR mice, Singh _et al. (1974) administered a single intraperi-
toneal dose of 12.78, 19.17, or 25.56 ml/kg (12.6, 18.9, or 25.2 g/kg)
prior to the initiation of a 12-week mating period. Ten DEHP-treated
males as well as ten untreated controls were mated to two untreated
virgin females; females were replaced on a weekly basis for 12 weeks.
Pregnant females were sacrificed shortly before parturition. An anti-
fertility effect was noted at all levels tested but was most pronounced
in the high dose group; only 25% of females mated with high dose males
became pregnant compared with a 71% incidence of pregnancy in controls
(see Table E-3). The number of implants and the number of live fetuses
per pregnancy were also reduced in females mated with high dose males
(15 and 22%, respectively). A marked increase in early fetal deaths
was noted at all dose levels with the incidence in the high dose group
more than double that observed for controls.
These data indicate that DEHP at the dose levels tested produces
dominant lethal effects in male mica. Furthermore, if the data ara
analyzed in light of the developmental stage of the sperm at the time
of DEHP injection, the most severe effects are manifested in gametes
exposed to DEHP at a post-meiosis stage.
E.2.4.3 Intravenous Administration
Twenty prapufaertai female and tan adult aala rats racaived 5 ml
(4.9 g/kg/'day) DEHP undiluted by intravenous injection on days 1, 5,
and 10 of a 22-day study (Seth at al. 1976). Control animals were
-------
TABLE E-3. ANTIFERTILIIY AND MUTAGENIC EFFECTS
OF DEHP IN MALE MICE
rJ/r. DIncide^e of Implants per
-iSS&Sl Pregnancies to Pregnancy
0.0 71
12.6 56
18.9 59
25.2 95
6.J
11.04 +
11.2 + 0
"11.2 + 0
9.4 + 0
0.17
.18
.17
.48
Early Fetal Deaths Live Fetuses
per Pregnanev n^r pr^»nnr,r.T
0.43 ±
0.79 +
0.57 +
0.89 +
0.05
0.11
0.06
0.35
11.0 ± 0.17
10.4 +
10.6 +
8.6 +
0.23
0.18
0.65
Source: Singh et al. (1974).
-------
injected with normal saline. Animals were sacrificed on day 22, and
Che organs were removed and submitted to gross, microscopic", and bio-
chemical examination.
Assays for several of the enzymes involved in energy metabolism
revealed DEHP-related changes in activity in the ovaries and testes of
treated animals as compared with controls. The activity of succinic
dehydrogenase was decreased by 38% (p <0.01) in ovaries and 42%
(p <0.001) in testes. Likewise, the activity of ATPase was decreased
by 34% in ovaries and by 29% in testicular tissues (p <0.001 for both).
3-glucuronidase activity was increased in ovary and testis; 50 and 67%,
respectively (p <0.001 for both).
On gross examination, the scrota of all DEHP-treated males appeared
to be enlarged when compared with those of control animals. Histopatho-
logical examination of the testes from DEHP-treated males, however,
showed abnormal pathology" with changes including a markedly thickened
tunica albuginea, edema of the testicular capsule and interstitium,
degeneration of the epithelium of the seminiferous tubules, eccentric
nuclei and vacuolization of the cytoplasm in spermatogonial cells, and
degeneration of spermatids. The blood vessels of the testes were
congested and red blood cells were seen lying free in the edematous
fluid of interstitial spaces. Histopathological examination revealed
normal pathology of the ovary and testis in control animals and of the
ovary of -treated animals, despite the enzyme activity alterations in
the latter.
Thus, in rats, administration of 0.4% DEHP in the diet (M3.2 g/kg/day)
for 2 years produced no adverse effects on reproductive functions, but
tubular atrophy and degeneration of the testes were noted in rats admini-
stered 0.9 g/kg/day DEHP for 90 days. No effects were seen at 0.4 g/kg/
day. At high doses, DEHP disrupts succinic dehydrogenase, adenosine
triphosphatase, and betaglucuronidase levels in rat- gonads (4.9 g/kg) and
produces dominant lethal and antifertility effects in mice after a single
intraperitoneal injection (12.8 ml DEHP/kg). Testicular damage has also
been reported in a non-rodent species, the ferret, administered 1% DEHP
for 14 months.
No information was found on the reproductive effects of DMP, DEP,
DBP, 3BP, or DNOP.
E.2.5 Other Toxicoloqical Effects
E.2.5.1 Chronic Studies
DEHP
No adverse affects on mortality, hematological parameters, or
fertility and no incidence of neoplasms were noted in two generations
of Sherman strain rats maintained on diats containing O.i, 0.13, or
0.04S DEHP (corresponding Co 0.2, 0.06, and 0.02 g/kg/day, respectively)
E-16
-------
for periods of 1-2 years. Three-fourths of the parental generation
nil gr°UP) and thS Fl ^neration w"* killed after 1 ^ear on the
DEHP diet. Mean bodv weishfn nf P-, -,~j T? • ,
i» these
rats 0.0,
Harris ^t al (1956) fed groups of 43 male and 43 female tfiatar
4
based on a
3 6 "ere e™" in aniaals sacrificed at
-
.
DBF
DMP
3.01 DKP ln
-------
TABLE E-4. RELATIVE ORGAN WEIGHTS OF RATS FED DEHP
i
»-••
QJ
% DKIIP
" 1
MALES
0.0
0. I
l''EMALES_
0.0
O.I
mg/p Body Weight (% Change from ControIs)
3 months
30
33
43
27
33
40
Liver
.2
.9 (12 )
.3 (43)
.6
.9 (23)
.4 (46)
Kidney
7.4
7.7 (4)
7.9 (7)
7.3
8.1 (11)
8.1 (11)
6 months
Liver
26.4
30.4 (15)
32.3 (22)
27.2
29.9 (10)
35.3 (30)
Kidney
7.0
6.9 (1)
6.7 (4)
7.0
7.5 (7)
7.9 (13)
N
8
8
8
8
8
8
12 months
Liver
32.4
' 30.0
28.7
31.8
33.0
27.3
7.
(7) 7.
(11)7.
7.
(4) 7.
(14)7.
Kidney N
1 1
0 (1) 2
0 (1) 2
4 1
A (0) 2
6 (3) 4
24 months
Liver
41.9
34.4 (18)
41.9 (0)
42.8
35.0 (18)
37.6 (12)
Kidney
8.1
7.7
8.1
8.5
8.0
8.0
(5)
(0)
(6)
(6)
Sonic:*.!: Harris et al. (1956).
-------
£-2.5.2 Subchronic Studies
DEEP
Oral Administration
,
were 1.9, 0.9 04 n 2 ,-,,-nn /i 7T days. The doses received
2.0%
and 2.0. !eve!
paired feeding study reveaUd chat
~4t"
0. 0.2, 1.0, or
" "» 1'°
conco°il:an'
a decrease in packed cell vlum g PS' - °th6r tOXic effects in=
ft diet for
admini"ered 2'. 0%
Five-week-old rats were siven DFWP fny te. A
of 0.01, 0.025, 0 05 0 5 or i nJ DEHPufor 16 days at concentrations
°« i
were de = h
or the livers from aal.
die:, rne amounts of Uver jivcos-n
non-coUagen) .ere sigmfloanti v '
controls. «. tttlTitiM o, ,he
0 5 or o-
rf ^ f ;
(p < 0 ^
-
decer-
""""
la ths
-------
acid phosphatase, and cytochrome c oxidase were also increased signifi-
cantly (p <0.01) when expressed per gram of liver weight. Examinations
of the activity of the hepatic microsomal mixed function oxidases (per
gram of liver weight) in animals fed 0.5% DEHP revealed the following:
microsomal protein and cytochrome P-450 levels were elevated in males;
and aminopyrine N-demethylase and aniline hydroxylase were elevated in
females but decreased in males.
In a similar study conducted by Moody and Reddy (1979), five male
rats were fed chow containing 2% DEHP for 3 weeks. They were then
sacrificed for liver studies in which a significant liver enlargement
was observed (p <0.001). Enzyme assays revealed a doubling in catalase
activity and a seventeen-fold increase in the activity of carnitine
acetyl transferase. Similar effects, although of lesser magnitude,
were produced by the dietary administration of a 27, concentration of
the DEHP metabolite, 2-ethylhexyl alcohol or its structural analogs,
2-ethylhexanoic acid, and 2-ethylhexyl aldehyde.
Otake et al. (1977) administered 200 mg/mouse of DEHP orally to
male mice every 3 days for 3 weeks. Liver enlargement, swelling of
renal tubules, decreased spermatogenesis, and an increase in hepatic
cytochrome P-450 were noted. Microscopic examination of the heptocytes
revealed proliferation of the smooth endoplasmic reticulum, disorders
in the distribution of the rough endoplasmic raticulum, swelling of
the mitochondria, and a decrease in glycogen content. Similarly,
Yamada (1974) found that 1-4 ml/kg/day of DEHP, given orally to mice
for 3 weeks, caused.liver enlargement and a decrease in liver glycogen
content.
Young male rats given DEHP at a dose of 2 g/kg/day for 21 days had
liver weights that were more than double those of control animals
(Lakelet al. 1975). The activities of several hepatic enzymes were
determined with results as follows: succinic dehydrogenase and glucose-
6-phosphatase activities were decreased by 40%; aniline-4-hydroxylase
activity was decreased 30%; alcohol dehydrogenase activity increased 50%
by day 14, then decreased to 120% of control activity by day 21. The
microsomal P-450 content was increased 34% at day 4, but was elevated
only 13% over control activity by day 21.
Guinea pigs were fed 0.13 or 0.04% DEHP in the diet for 1 year.
This corresponds to a mean intake of 0.064 of 0.019 g/kg/day over the
course of the study (Carpenter et_ _al. 1953). A dose-related increase
in food consumption was observed for males and females, although signifi-
cantly elevated body weights were seen only in animals at the lower dose
level. Females in both dose groups had elevated liver weights.
Ota _2t: jil. (1974) found that oral administration of 0.5 g/kg/day or
3.0 g/kg/day of DEEP for 1-3 months resulted in liver and kidney degenera-
tion in aica.
2-20
-------
da H
H3S
areas of the liver, as well Is moder^t congestion In subcapsular
in the kidney. moderate congestxon and cell enlargement
the
DEEP r alohrioha "" OMl d°Sa °' 120°
that of coutro! anilL aL et'n", "* 1'**
•ent was noted at 14 months i
Conversely, DEHP- treatment produced a .iSfLa^ resPe«ively.
activity of the follou-fn^ . uucea a significant increase in the
in th. r -ction and ,orphology
6 Uv
and severe DeritonitS « wt»« e°lars!mant' "sticular atrophy,
-------
production fay human chorionic gonadotropin reduced compared with controls
(Oishi and Hiraga 1975).
Lawrence ejc al. (1975) calculated "chronic" LD$Q values for mice
based on a 12-week study in which the animals received varying doses of
DEHP via intraperitoneal injection. They found that the acute LD5o (ip)
for mice (37.3 g/kg) was much greater than the chronic LD5Q, which thev
calculated to be 1.37 g/kg.
Intravenous Administration
Several animal studies have been designed to more closely simulate
the conditions of human exposure to DEHP. Garvin et_ al. (1967a) injected
rats intravenously, twice weekly, for 63 days with doses of 1.0 mg/kg/day
or 3.7 mg/kg/day of DEHP. The higher dose is considered equivalent to
the maximum dose of DEHP that a 70 kg human would receive in 12 units of
blood that had been stored at 4°C for 21 days in polyvinyl chloride blood
storage bags. No toxicologically significant differences were observed
between treated and control animals in survival rates, growth rates,
general behavior, hemograms, serum chemistry values, liver function,
absolute and relative organ weights, or histopathology.
Rutter (1975) reported no adverse effects in ten beagle dogs that
received intravenous doses of 0.5, 0.75 or 1.4 mg/kg/day daily for 3
weeks. The DEHP administered was obtained by storing the plasma of dogs
fed high fat diets in polyvinyl chloride blood storage bags at 36°C.
Bags were stored for 4, 6, or 12 weeks, respectively, to allow leaching
of DEHP into the plasma. The test animals were then given the doses
noted above.
In another study, rhesus monkeys received weekly or biweekly
transfusions of plasma or platelet-enriched plasma that had been stored
in polyvinyl chloride blood storage bags for periods up to 1 year
(Jacobsen ej: al. 1975, 1977). The cumulative concentration of DEHP
received by rhesus monkeys during this period ranged from 6.6 mg/kg
to 33 mg/kg. At the end of 1 year, six of seven monkeys showed signs
of abnormal liver pathology including vacuolization or proliferation of
Kupffer cells, foci of parenchymal necrosis, or chronic inflammatory
cell infiltrates. Four of seven animals had abnormaJ 99mxc liver-spleen
scan ratios (indicates severe or moderate impairment of hepatic perfu-
sion); these changes persisted as long as 14 months after transfusion
in the three animals that had received platelet-rich plasma. Six of
seven animals showed abnormal clearance of sulfobromophthalein. Traces
of DEHP could still be found in liver tissue of animals that had been
transfused with platelet-rich plasma obtained by biopsy up to 14 months
after transfusion.
Daily intravenous injections of 50, 100, 300, or 500 mg/kg of DEHP
were given zo beagle dogs for 14 days. One of two dogs receiving the
300 mg/kg dosa died on day 4. The two dogs receiving 500 mg/kg died on
-------
•-
PEP
weeks. The total bLv ^J^J^^i!.!*^2:0* dietary DEP for 3
waoles TVi^ *»*..i i. j , , a '•'<"• «j.«tary utr tor 3
increased (18 and 196% above controls, respectively).
16 weeks. These
.r
significantly at all dose levels with a ?lf in w*« enlarged
Additionally, males and feSs at the 5 Jf levI^H 'Y^ 5'°% leVSl'
increases in the relative weights of th.'h levej.fowed significant
• ' -r°m -onc-°^ ''alues at the termination of che 3'udv.
E-23
-------
Despite the enlargement observed in most of the organs studied,
only the liver and kidney tissues were found to show any pathological
changes. Some fatty degeneration and slight vacuolation was seen in the
liver, with occasional pyelonephritis and lymphocytic invasion of the
kidney. Those lesions, however, were not dose-related.
Galley ec al. (1966) injected from twenty to thirty white mice (io)
with an emulsion of DEP in 3% acacia (125 mg/kg) daily for 6 weeks.
These animals did noc show any significant differences from vehicle
control animals when compared in terms of body weight gain; organ weight
body weight ratios for liver, heart, lungs, kidneys, spleen and tastes;
or hemato logical parameters, including hemoglobin concentration, hema-
tocrit, and white count. All of the test animals had some degree of
peritonitis at autopsy.
To determine a subchronic LDso value, Lawrence _et al. (1975)
injected ten male mice intraperitoneally five times per week for 14
weeks with a series of doses of undiluted DEP. They calculated a chronic
ip LD5Q value of approximately 1.56 g/kg compared with an acute value of
3.22 g/kg.
DMP
Lawrence et al. (1975) found that DMP was more toxic when adminis-
tered in a series of intraperitoneal doses five times per week for 18
weeks than it was in a single ip dose. The "chronic" ip LD50 value of
DMP in mice was calculated to be 1.4 g/kg compared with an acute LD5Q
value of 3.98 g/kg. Daily topical application of 4.0 ml/kg (4.8 g/kg)
of DMP to rabbits' skin for 90 days produced lung edema, chronic
nephritis, and slight to moderate liver damage; the skin itself was
unaffected (Lehman 1955). •
Repeated dermal applications of DMP were reported to retard weight
gain, decrease total blood protein, and increase serum gamma-globulin
in rats and produce elevated serum bilirubin levels in rabbits. Both
rats and rabbits were noted to have developed swelling and granular
dystrophy of the epithelium of the convoluted renal tubules, changes
of the spermatogenic epithelium, myocardial changes (rabbits), hyper-
volemia of the brain (rats), and hypervolemia and hemosiderosis of the
spleen (both species) (Gleiberman _et al. 1975). The quantity and
frequency of dosing and duration of the experiment were not given.
DBP
Bornmann jet _al. (1956) administered 260 mg/kg or 520 mg/kg DBP to
rats twice weekly for 52 weeks. They reported no adverse effects on
fertility, hemato logical parameters, or pathology as a result of this
treatment.
In another study, rats fad 0.01, 0.05, 0.25, or 1.25% DB? in the
diet for 12 months displayed no toxic af faces axceoc at the 1.25% level.
-------
were not given.
on
this group
in mice reiving
orally for 1-3 months. lng
50
3*°
or
.5 g/kg/day of DBF
and
2000 o
produced testicular injur and a 30 40?
testes, but did not af fe^t the veJghts of
with com oil controls. In addition
vhile testicular 2inc levels were
studies with 400 mg/kg or 800
Principle metabolite o'f DBF °
reproducible vith MBP at half
receing
increased liver weights with
-lustration of
ratS f°r 4 davs
** W6iSht °f the
* Or kidneys COmPared
"^ f cretion increased"
decreased. Subsequent
(MB?) ' the
- f«««
that rats
°r 126° ffl8/k8/^y) had
DNOP
nephritis in all mice and ost Ll
level with some evidence of thll
level (Nagasaki et a! !974)
°f DNOP
interstitial
ratS at the 10°° m8/kg
b°th sPecies « thl 500 mg/kg
in
days/week over a 12-week perioVthaTit
They calculated the "chronic ip "
05.78 g/kg value calculated for
3BF
more toxic
inJe"ions 5
acute
3'°2
in
inj<
-------
twenty to thirty mica. BBP had no effect on final body weight or organ
to body weight ratios for liver, heart, lungs, kidneys, spleen, and
testes. Some pathological changes were noted in the liver and spleen
of BBP-treated mice, including acute peritonitis, periportal hepatitis
in the liver, and extra medullary hematopoiesis in both the liver and
spleen. In addition, one testis was found to have an abscess resulting
from an unknown cause.
E.2.5.3 Acute Studies
The acute oral LD50 values for the individual phthalate esters
generally range from 4 g/kg to 34 g/kg for rats, mice, rabbits, and
guinea pigs. A single study conducted with DEP, however, reported an
oral LD5o value of 1 g/kg in the rabbit (RTECS 1977). A similar range
of LD5Q values has been observed in rabbits and guinea pigs following
dermal application of phthalate esters. LD5Q values encountered in
the literature are listed in Table E-5.
DEEP
The oral toxicity of DEHP is of a low order, with LD5Q values of
31 g/kg for rats and 34 g/kg for rabbits (RTECS 1977). Shaffer et al.
(1945) reported that a single oral dose of 79.5 g/kg DEHP killed eight
of ten rats. Histological findings included a generalized cloudy
swelling of the cells of the liver and kidneys and granular secretions
in kidney tubules.
Although rabbits can absorb DEHP through the skin, doses as high
as 25 ml/kg are necessary to produce 50% lethality (RTECS 1977). Topic-
ally applied, undiluted DEHP does not produce skin or eye irritation in
rabbits (Fassett 1963). Marked inflammation was noted in rabbits,
however, following intradermal injection of 0.2 ml of a 100 mg/ml
emulsion of DEHP in 37, acacia (Galley et_ al. 1966).
In another study, a total dose of 650 mg/kg of DEHP was admini-
stered serially in 50 mg/kg aliquots to rabbits via heart cannulation.
Each 50 mg/kg dose produced a brief (3-minute) decrease in blood pres-
sure, reducing it to about 78% of baseline values. A slight increase
in respiratory rate was noted in conjunction with the change in blood
pressure, but no lasting untoward effects were produced (Galley et al.
1966).
Three of five rats given 300 mg/kg DEHP intravenously in a 100%
Tween 80:25% DMSO:65% normal saline vehicle became cyanotic and died
as a result of respiratory arrest within 90 minutes (Schulz and Baetjer
1974, Schulz et al. 1975). Histopathological observation of all five
animals revealed significant enlargement and hemorrhagic congestion of
che lungs with edematous swelling of the alveolar wall and infiltration
of the lung tissue by poiymorphonuclear laukocytas. Treatment of rats
wich che Tween 30-DMSO-saiine vehicle or emulsions of DEH? (500 mg/kg)
in 3% acacia or 4" bovine serum albumin did aoc oroduca this reaction.
1-26
-------
TABLE E-5. ACUTE TOXICITY OF PKTHALATE ESTERS
DEEP
DMP
DE?
Species
Man
Rat
Rabbit
Guinea pig
Rat
Mouse
Rat
Rat
Guinea pig
Rabbit
Human
Rat
Mouse
Chicken
Rabbit
Cat
Mouse
Rat
Mouse
Mouse
Human
Rabbit
Guinea pig
Human
Mouse
Mouse
Mouse
Mouse
Rat
Rabbit
Route
oral
oral
oral
dermal
dermal
intraperitoneal
intraperitoneal
intravenous
oral
oral
oral
oral
oral
oral
dermal
inhalation
intraperitoneal
intraperitoneal
intraperitoneal
intraperitoneal
oral
oral
dermal
inhalation
intraperitoneal
intraperitor.eal
intraperi coneal
intraperitoneal
intraperi coneai
intravenous
LD,0 (g/kg)
0.143 (TDLo)1
31.0
34.0
•9.9 (10 ml/kg)2
24.7 (25 ml/kg)2
14.2
30.7
0.3 (LDLo)3
2.4
4.4
5.0 (LDLoJ3
6.9
7.2
8.5
11.9 (10 ml/kg?
1.0 g/m3 (LCLo)4
1.6
3.38
3.6
3.98
0.5 (LDLo)3
1.0
3.0
1.0 g/m3 4
2.75
2.3
2.33
3 . 22
5.06
0.1 (LDLo)3
Reference
RTECS (1977)
RTECS (1977)
Fishfaein and Albro
(1972)
RTECS (1977)
RTECS (1977)
RTECS (1977)
Calley et al. ( 1966)
RTECS (1977)
• Fassett (1963)
RTECS (1977)
RTECS (1977)
Fassett (1963)
Fassett (1963)
RTECS (1977)
Fassett (1963)
RTECS (1977)
RTECS (1977)
RTECS (1977)
Fassett (1963)
Lawrence et al.
(1975)
RTECS (1977)
Fassett (1963)
RTECS (1977)
RTECS (1977)
RTECS (1977)
Fassett (1963)
Calley _at al. (1966)
Lawrence at al. .,'137.
Singh e_t al. (1972s,
RTECS (1977)
-------
TABLE E-5. ACUTE TOXICITY OF PHTHALATE ESTERS (cont'd)
Soecies
Route
DBF
Human
Human.
Rat
Mouse
Rabbit
Rat
Mouse
Mouse
Rat
oral
oral
oral
oral
dermal
intraperitoneal
intrap eri toneal
intraperitoneal
intramuscular
LD.Q (g/kg)
Reference
0.141
5.0
8.0 - 10.0
16.6 (15.9 ml/kg)"
>20.9 (20 ml/kg)2
3.05
3.50
4.0
>8.0
RTECS (1977)
RTEC3 (1977)
Smith (1953)
Yamada (1974)
Lehman (1955)
Singh et al. (1972)
Lawrence et al. (197
Galley et al. (1966)
Smith (19 53-)
BBP
Mouse
intraperitoneal
3.16
Galley et al. (1966;
DNOP
Mouse
Guinea pig
Mouse
Mouse
oral >13.0
dermal > 4.9 .
intraperitoneal 14.19"
intraperitoneal 65.7
(5.0 ml/kg)
Fassett (1963)
Fassett (1963)
Galley _et _al. (1966
Lawrence et al. (19
Lowest published toxic dose.
HDose reported in ml/kg - converted to g/kg using
d = 0.9861 (DEHP), d » 1.0465 (DEP), d = 0.978 (DNOP),
d - 1.189 (BMP.
Lowest published lethal dose.
Lowest published lethal concantration.
"'The wide discrepancy in these values probably resulted
because Galley's group injected the diester as an emulsion
in 3. 3% acacia vehicle, while Lawrence and coworksrs used
che undiluted compound.
-------
and Bratt 1974).
DMP
(Daniel
dose s
while "very large" doses were repored to
general anesthesia. ' reported to
15 °inutes '
a SCate similar tQ
eyes,
irritation.
DEP
of __ c _wc
rabbit P^ducerrtransient^ardecrJasfin^S011 ^ W anesthet-~-
dose compared with controls receiving ? Pressure with each
Administration of 100 mg/kg produced a 71 27 5* ^^ had n° effact)
rate. A total of 650 mg/kg of DEP wal llvl ^ncr^ase ln respiratory
significant effect 81Ven tO the animal without
»**
3%
tory response
» J-
et al
a marked
rats eD
respectively). Radeva and DiJoeva Q966?
tion, immobility, difficult resplratio^
in rats receiving a single oral'dose o^'
Visceral tissues from mic* -n-a"-^
undiluted DBF and killed 1 ? Y 7
iadistinguishable, both gr^ss'iv Ind'
or control aniaals injecrad vi^h a?-
(Lawrence £t al. 19-5). ai-
and 7
of
"*
^«*.
"C"P6rito«ally vlth 2.1 g/kg
^^ ^
r , ' "^ Che :issues
cottonseed or aineral oil
-------
Galley et 3.1. (1966) found a. single intradennal injection of 0.2 ml
of a 100 mg/ml emulsion of DBF in 3% acacia produced a moderate inflam-
matory response in rabbits within 26 minutes of injection. Lawrence et al.
(1975), on the other hand, noted no inflammation in rabbits injected with
0.2 ml of undiluted DBF. Instillation of 0.1 ml of the diester into Che
rabbit eye also did not produce any observable degree of irritation.
3BF
Intradermal injection of 0.2 ml of a 100 atg/ml emulsion of BBF in
acacia into the backs of cleanly shaven rabbits produced a moderate
inflammatory response within 26 minutes of injection (Galley et al.
1966). Timofievskaya _et al. (1974) reported that BBP was not a skin
irritant; however, the species tested, the dose, and the means of
administration were not stated.
DNOP
Lawrence et al. (1975) reported that DNOP did not produce a response
of irritation when injected intradermally in mice, nor when instilled
directly into the eye (species and amount not given).
E.3 HUMAN EXPOSURE
Few controlled studies have been conducted on the direct effect
of phthalate esters on humans. Recent findings that phthalate plasti-
cizers leach from polyvinyl chloride blood bags and other biomedical
devices have raised concerns regarding the safety of phthalate esters
for humans. Evidence of any in vivo toxicity in recipients of blood
transfusions is lacking. Rubin and Jaeger (1973), however, note that
microquantities of phthalate esters can increase platelet adhesiveness
and suggest that phthalate esters may be a factor in the formation of
pulmonary emboli in the "shock lung syndrome" frequently seen after
massive blood transfusions. Because of the ubiquitous use of phthalate
esters in our society, however, the potential for human exposure to
phthalate esters is not limited to medical devices but may occur from
ingestion, dermal contact, or inhalation.
2.3.1 Controlled Human Studies
E.3.1.1 OEHF
No erythema or other reaction was noted in a patch test with
undiluted DEHP applied to the backs of twenty-three human volunteers
for 7 days and subsequently examined 10 days later (Shaffer _et_ a_l. 1945).
E.3.1.2 DE?
The lowest reported oral lethal dosa or diechyi phthalate in. humans
is 300 ag/kg (RTECS 197~). ^The lowest published ccxic concentration in
air for humans is 1000 -ag/m^ (RTSCS 197~).
Z-30
-------
E.3.1.3 DBF
2.3.1.4 DM?
DM? produces J painzTsenSi^if'££?! r*c Sr£V h^"S'
-OU3 Cranes, but tt dees not ^P.1 SrSS^J:^^^ ^
E.3.1.5 OOP
^«re^ed thirteen suwectr;er.":n::.:r.!^!'i,sub3e«s
Von Haam 1952).
E-3.2. Epldemlologjcal
periods ranging t. 6 months o 19 years' e1* (lnlxed."««)
2-31
-------
reported in women occupationally exposed to phthalates. Additional
details were not readily available "(Aldyreva et_ al. 1975).
The levels of phthalate esters in hviman tissues are summarized in
Table E-6. These data were gathered from people receiving variable
exposures, but most are from the general population.
E.4 IN VITRO STUDIES
£.4.1 Biochemical Studies
The jLn vitro respiration of rat liver mitochondria was not greatly
affected by the presence of 1.0 mM DEHP, DMP or DNOP (i.e., the uptake
of 02 was within \IQZ of that observed for controls.) The same concen-
tration of DEP or DBF resulted in decreases in 02 uptake of 38 and 19%
respectively (Takahashi 1977).
In another study, Bell et al. (1978) examined lipid and sterol bio-
synthesis in livers excised from rats fed DMP (0.5%), DBP (0.7%), or DEHP
(1.02) in the diet for 21 days. 14C-acetate incorporation into trigly-
cerides, steryl ester and squalene was significantly reduced by DBF and
DEHP. DEHP-treatment caused additional reductions in 14C-acetate
incorporation into phospholipid and sterol (63% and 71%, respectively).
Livers from DMP-treated animals showed non-significant increases in
14C-acetate incorporation into the above-mentioned lipids and sterols.
Morton and Rubin (1979) found that ingestion of 50-2500 ing/kg of
either DEHP or MEHP in the diet for 6 days significantly lowered hepatic
triglyceride accumulation in animals subsequently fed 1% orotic acid in
the diet for 6 days (species" unspecified). Concurrently, they found that
the activities of hepatic carnitine acetyltransferase and carnitine-
palmitoyl transferase were increased, as was the 3-oxidation of lipids in
the liver.
Ohyama (1977) studied the inhibitory effects of phthalate esters on
a variety of enzymes. He noted that the activity of glucose-6-phosphate
dehydrogenase was decreased 50% by 8.1 x 10~% DEP, 1.8 x 10~4M DBP,
1.6 x 10-% DNOP, and 2.2 x 10-% DEHP.
Although binding has been reported between DEHP and the A and G
fractions of rabbit blood in vitro (loku e_t al. 1977), Hafaennan and
coworkers (1968) noted that exposure to DEHP, DBP, or DNOP did not affect
the agglutinating capabilities of the blood grouping antibodies or the
morphological integrity of human red blood cells. DMP (0.25 ml per 5 ml
of human antisera) caused a destruction of human red blood cell antibodies,
Varying results have been raportad concerning the affect of phthal-
ate astar ? re treatment on barfaituata-inducad sleeping time. Hidaka at_ al.
(1977) raportad that ?ratreatment of imnaturs famala mica orallv vith
0.1-3.0 g/kg of DEHP decreased hexcharbital-induced sleeping time.
Danial and Sratt (1974) noted similar results in mala and famala rat3
-------
TABLE E-6. HUMAN TISSUE CONCENTRATIONS
Di-2-ethylhexyl phthalate (DEHP)
1'ojHi 1 a t J on
Human
1'ost-moriein
saili)>l es
Post-mortem
samples
Infants
cat-hei Ized
with or
w i I limit a
-------
TABLE E-6. HUMAN TISSUE CONCENTRATIONS (Continue!)
Chemical Di£HP
I'l
I
Geographic
Population Region Tissue
Post-mortem Illinois,
samples Michigan,
Minnesota
Abd. fat
Axill. fat
Blood
Brain
Heart
Kidney
Liver
Lung
Omen. fat
Spleen
Number
Sampled
LAB I/
LAB 2
17/9
17/9
11/7
9/6
16/6
15/9
17/9
16/10
14/9
17/9
Distribution
LAB
M8/K
1.79
2
3
3
4
4
5
4
3
4
.52
.74
03
.08
.23
.11
.59
.44
.86
jh
±
±
±
±
J:
±
4-
±
±
±
I1
LAB 22
SD
1.8
3.
1.
2.
3.
1.
3.
4.
5.
4.
7
95
04
06
9
99
54
16
85
l»g/g Hh SD
ft
19.85 ± 53.94
21
6
1
6
2
2
5
9
2
.51
.31
.45
.03
.24
.09
.97
.65
.36
±
±
±
±
±
±
±
±
±
60.16
11.98
3.55
14 . 58
3.25
3.92
10.82
21.28
3.12
Remarks Reference
Wallin et a I
(1974)
The wide discrepancy
in results between
• the two laboratories
seems to be primarily
attributable to the
very high values found
in one 64-year-old
patient with no history
• of blood transfusion,
included in the Lab 2
sampler
^1 was entered au 1.0 in calculation of means.
'N«i delectable" wab entered as 0 in calculation of means.
-------
TABLE E-6. HUMAN TISSUE CONCENTRATIONS (Continued)
Chemical DEilP
Geographic Number
Population Region Tissue Sampled
Post -mortem Baltimore, Lang
s.uuples Maryland Liver Sex
Spleen
Abdominal
fit •
H
M
M
M
iL M
M
M
M
M
F
F
M
Distribution
Units Blood Amt. DEHP^
Rec'd Rec'd (mg)
18 43.8
4 14.0
20 ? '
8 128.0
6 16.8
14 ?
4 22.5
?2 ?
? ?
31 ?
2 ?
13 ?
63 600.0
Lung
91.5
24.5
22.1
17.9
ND1
ND
21.2
20.8
13.4
ND
ND
—
ND
6M/1F not transfused none
Remarks'
Tissue Levels (pg/g)
Liver Spleen Abd.fat
69.5 25.3 — J
— — — — — _
ND
ND ND
ND ND ND
ND 5.0
NF>
ND
ND
ND ND
270.0
ND
ND
Reference
Jaeger and
Rubin (1972)
Not
table (<0.5 - 3 ug/g)
known, l>nL multiple transfusions received.
Not,
Tbis waa calculated from the known storage time of each unit and
tlie previously calculated DEIII1 migration rate of 0.25 mg/100 ml/day.
-------
Chemical DEHP
TABLE E-6. HUMAN TISSUE CONCENTRATIONS (Continued)
Geographic
Population Region Tissue
llemodlalysis Cleveland, serum
Patients Ohio
y 50 dialysis treatments . • «
Adult males Ual t Imore, plasma
Mary 1 and
i
.j
h
Adult males Ualtimore, urine
Maryland
Number
Sampled Distribution Remarks Reference
ug/1 +• S.D. Serum sampled immedi- Lewis et al.
ately post-transfusion (1978)
, . 15 558 -f 221
. . 13 973 + 446
Immediately Patients transfused Rubin and
Pre-transfusion Post-transfusion with platelets Schiffer (1976)
6 200 |ig/l + 200 S.D. 6966.7 ug/1 + 1817.3 S.I).
2 Total DEHP 24-hour DEHP excretion in urine
received (mg) (mg DEHP and/or its metabolites) Rubin and
Schiffer (J'J76)
Pre-transfusion Post-transfusion
62.2 9.01 55.9 (90%)2
67.8 13.8 40.0 (60%)
A 12-lumr t-ol lection (1250 ml urine).
t
Number iu parent lies is represents percent of total DEHP received (urine volumes not given).
-------
TABLK E-f>. HUMAN TISSUE CONCENTRATIONS (Continued)
Chemical Dl-n-butyl phthalate (DBF)
Geographic
Population Region
Poat-iiiurtem Canada
Post-mortem Canada
Number
Tissue Sampled
Adipose
Adipose
44
Remarks
0.0 - 1.0
0 52 0 70
0.52-0.79
p«fprpnrr
Mas et al.
(iy/6)
Campbell
i
I..J
-------
given^a single 500 mg/kg oral dose of DEEP, but reported an increase in
sleeping time when the diester was administered intravenously (600 mg/kg).
Similar increments in sleeping time following intraperitoneal or intra-
venous pretreatment with phthalate esters have been reported by
Swinyard at. al. (1976), Rubin and Jaeger (1973), Galley et al/ (1966),
and Seth _et aJL. (1976). Lawrence and coworkers (1975) reported signifi-
cant increases in pentobarbital-induced sleeping time in male mice
pretreated with three intraperitoneal injections (7.5 g/kg/day) of
either DEEP or DNOP but no significant effects in mice pretreated with
DMP, DEP, or DBF.
E.4.2 Tissue Culture Studies
Several studies have been conducted concerning the toxicity of the
phthalate esters to cultured cells. Galley et al. (1966) saturated
porous pads with 0.05 ml of a 50 mg/ml emulsion of DBP, DMP, DEHP, DEP,
or BBP in 3% acacia, then placed the pads directly on agar supporting
the growth of either chick embryo cells or mouse L929 fibroblasts. None
of the esters produced toxic effects in chick embryo cells but DMP, DEP,
and BBP all showed toxicity to mouse fibroblasts.
Lee _e_t al. (1974b) found that aortic cells from 9-day chick embryos
exposed in culture to 0.05 mg/ml of DEHP or 0.1 mg/ml of DMP for 10 hours
developed cytoplasmic vacuoles and began to retract their protoplasmic
processes. (The normal "spindle" shape of cultured aortic cells is
conferred fay these processes.) DMP, at concentrations of 0.6 mg/ml or
greater, resulted in extensive cell death within 12 hours.
Kasuya (1974, 1976) found that fibroblast-growth and the outgrowth
of nerve fibers from cultured rat cerebellar tissue were inhibited by
DNOP, DMP, DBP, and DEP at concentrations of 0.13, 0.31, 0.78, and 0.51 mM,
respectively.
Jones Jit al. (1975) determined the concentration of DBP, DNOP, and
DEHP necessary to produce a 50% growth inhibition of human WI-38 fibro-
blasts. The LD50 values were 135, 170, and 70 uM for DBP, DNOP, and
DEHP, respectively.
In a more extensive investigation of the specific effects of DEHP
on WI-38 cells, Jones et al. (1975) found that a concentration of 160 uM
of DEHP in the culture medium caused a decreased cell density within 6
days, and a cessation of cell viability after 9 days of exposure. Cells
grown in 160 uM DEHP for 3 days and then replated in untreated (control)
medium for 5 days showed only 60£ of control growth (as measured by cell
protein concentration). Concentrations of 51 or 69 uM DEHP produced
dose-related decreases in cell protein and longer generation times, but
the cells remained viable at 9 days.
Contrary to the findings of Jones e_t al. (1975) , Jacofason e_t al.
(1974) found chat inhibition of human diploid fibroblasts by DEHP was
reversible. They grew fibroblasts cultured from human skin biousies in
Z-38
-------
untrel H C°"cen"atl?n ot D£H? for 6 days, then refed the cells with
*** * ' * wich
on day 0
tL iL I!' J Sirth WaS measured in terms of incorporation of
the labelled ammo acid into cell proteins. DEHP-exposed cells incor-
porate^ 320% more 3H-thymidine than cells grown in control med^ for
E-39
------- |