Toxicological
Profile
for
DI-n-BUTYLPHTHALATE
U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES
Public Health Service
Agency for Toxic Substances and Disease Registry
TP-90-10
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TOXICOLOGICAL PROFILE FOR
DI-N-BUTYL PHTHALATE
Prepared by:
Life Systems, Inc.
Under Subcontract to:
Clement Associates, Inc.
Under Contract No. 205-88-0608
Prepared for:
Agency for Toxic Substances and Disease Registry
U.S. Public Health Service
December 1990
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ii
DISCLAIMER
The use of company or product name(s) is for identification only
and does not imply endorsement by the Agency for Toxic Substances and
Disease Registry.
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FOREWORD
The Superfund Amendments and Reauthorization Act (SARA) of 1986
(Public Law 99-499) extended and amended the Comprehensive Environmental
Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund).
This public law directed the Agency for Toxic Substances and Disease
Registry (ATSDR) to prepare toxicological profiles for hazardous
substances which are most commonly found at facilities on the CERCLA
National Priorities List and which pose the most significant potential
threat to human health, as determined by ATSDR and the Environmental
Protection Agency (EPA). The lists of the 250 most significant hazardous
substances were published in the Federal Register on April 17, 1987, on
October 20, 1988, on October 26, 1989, and on October 17, 1990.
Section 104(i)(3) of CERCLA, as amended, directs the Administrator of
ATSDR to prepare a toxicological profile for each substance on the list.
Each profile must include the following content:
(A) An examination, summary, and interpretation of available
toxicological information and epidemiological evaluations on the
hazardous substance in order to ascertain the levels of significant
human exposure for the substance and the associated acute, subacute,
and chronic health effects,
(B) A determination of whether adequate information on the health
effects of each substance is available or in the process of
development to determine levels of exposure which present a
significant risk to human health of acute, subacute, and chronic
health effects, and
(C) Where appropriate, an identification of toxicological testing
needed to identify the types or levels of exposure that may present
significant risk of adverse health effects in humans.
This toxicological profile is prepared in accordance with guidelines
developed by ATSDR and EPA. The original guidelines were published in the
Federal Register on April 17, 1987. Each profile will be revised and
republished as necessary, but no less often than every three years, as
required by CERCLA, as amended.
The ATSDR toxicological profile is intended to characterize succinctly
the toxicological and adverse health effects information for the hazardous
substance being described. Each profile identifies and reviews the key
literature (that has been peer-reviewed) that describes a hazardous
substance's toxicological properties. Other pertinent literature is also
presented but described in less detail than the key studies. The profile
is not intended to be an exhaustive document; however, more comprehensive
sources of specialty information are referenced.
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iv
Foreword
Each toxicological profile begins with a public health statement,
which describes in nontechnical language a substance's relevant
toxicological properties. Following the public health statement is
information concerning significant health effects associated with exposure
to the substance. The adequacy of information to determine a substance's
health effects is described. Data needs that are of significance to
protection of public health will be identified by ATSDR, the National
Toxicology Program (NTP) of the Public Health Service, and EPA. The focus
of the profiles is on health and toxicological information; therefore, we
have included this information in the beginning of the document.
The principal audiences for the toxicological profiles are health
professionals at the federal, state, and local levels, interested private
sector organizations and groups, and members of the public.
This profile reflects our assessment of all relevant toxicological
testing and information that has been peer reviewed. It has been reviewed
by scientists from ATSDR, the Centers for Disease Control, the NTP, and
other federal agencies. It -has also been reviewed by a panel of
nongovernment peer reviewers and is being made available for public
review. Final responsibility for the contents and views expressed in this
toxicological profile resides with ATSDR.
Wi i-
Administrator
Agency for Toxic Substances and
Disease Registry
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V
CONTENTS
FOREWORD i i i
LIST OF FIGURES ix
LIST OF TABLES xi
1. PUBLIC HEALTH STATEMENT 1
1.1 WHAT IS DI-N-BUTYL PHTHALATE? 1
1.2 HOW MIGHT I BE EXPOSED TO DI-N-BUTYL PHTHALATE? 2
1.3 HOW CAN DI-N-BUTYL PHTHALATE ENTER AND LEAVE MY BODY? 3
1.4 HOW CAN DI-N-BUTYL PHTHALATE AFFECT MY HEALTH? 3
1.5 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL
HEALTH EFFECTS? 3
1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE
BEEN EXPOSED TO DI-N-BUTYL PHTHALATE? 8
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE
TO PROTECT HUMAN HEALTH? 8
1.8 WHERE CAN I GET MORE INFORMATION? 9
2. HEALTH EFFECTS 11
2.1 INTRODUCTION 11
2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 11
2.2.1 Inhalation Exposure 12
2.2.1.1 Death 12
2.2.1.2 Systemic Effects 12
2.2.1.3 Immunological Effects 16
2.2.1.4 Neurological Effects 16
2.2.1.5 Developmental Effects 16
2.2.1.6 Reproductive Effects 16
2.2.1.7 Genotoxic Effects 16
2.2.1.8 Cancer 17
2.2.2 Oral Exposure 17
2.2.2.1 Death 17
2.2.2.2 Systemic Effects . 17
2.2.2.3 Immunological Effects 26
2.2.2.4 Neurological Effects 26
2.2.2.5 Developmental Effects 26
2.2.2.6 Reproductive Effects 27
2.2.2.7 Genotoxic Effects 28
2.2.2.8 Cancer 29
2.2.3 Dermal Exposure 29
2.2.3.1 Death 29
2.2.3.2 Systemic Effects 29
2.2.3.3 Immunological Effects 30
2.2.3.4 Neurological Effects 30
2.2.3.5 Developmental Effects 30
2.2.3.6 Reproductive Effects 30
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2.2.3.7 Genotoxic Effects ...
2.2.3.8 Cancer
2.3 TOXICOKINETICS 3JJ
2.3.1 Absorption 2q
2.3.1.1 Inhalation Exposure -jq
2.3.1.2 Oral Exposure
2.3.1.3 Dermal Exposure ... ^
2.3.2 Distribution ^
2.3.2.1 Inhalation Exposure ... ^2
2.3.2.2 Oral Exposure ^
2.3.2.3 Dermal Exposure .
2.3.3 Metabolism 33
2.3.3.1 Inhalation Exposure , to
2.3.3.2 Oral Exposure ^3
2.3.3.3 Dermal Exposure ... 25
2.3.4 Excretion ^
2.3.4.1 Inhalation Exposure . 25
2.3.4.2 Oral Exposure 35
2.3.4.3 Dermal Exposure
2.4 RELEVANCE TO PUBLIC HEALTH ....... 35
2.5 BIOMARKERS OF EXPOSURE AND EFFECT ' ' ' 3g
2.5.1 Biomarkers Used to Identify and/or Quantify Exposure
to Di-n-butyl Phthalate
2.5.2 Biomarkers Used to Characterize Effects Caused by
Di-n-butyl Phthalate ^
2.6 INTERACTION WITH OTHER CHEMICALS ...... ^
2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE .!.!... ^
2.8 ADEQUACY OF THE DATABASE !.!...... 42
2.8.1 Existing Information on Health Effects of Di-n-butyl
Phthalate ^2
2.8.2 Identification of Data Needs . 42
2.8.3 On-going Studies .... ^
3. CHEMICAL AND PHYSICAL INFORMATION 49
3.1 CHEMICAL IDENTITY ' ,q
3.2 PHYSICAL AND CHEMICAL PROPERTIES 49
4. PRODUCTION, IMPORT, USE, AND DISPOSAL
4.1 PRODUCTION ......
4.2 IMPORT 53
4.3 USE 53
4.4 DISPOSAL ......
5. POTENTIAL FOR HUMAN EXPOSURE
5.1 OVERVIEW ....
5.2 RELEASES TO THE ENVIRONMENT . . .
5.2.1 Air
5.2.2 Water
5.2.3 Soil
5.3 ENVIRONMENTAL FATE
5.3.1 Transport and Partitioning
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5.3.2 Transformation and Degradation 58
5.3.2.1 Air 58
5.3.2.2 Water 58
5.3.2.3 Soil 59
5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 59
5.4.1 Air 59
5.4.2 Water 60
5.4.3 Soil 60
5.4.4 Other Media 61
5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 61
5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 61
5.7 ADEQUACY OF THE DATABASE 61
5.7.1 Identification of Data Needs 63
5.7.2 On-going Studies 64
6. ANALYTICAL METHODS 65
6.1 BIOLOGICAL MATERIALS 65
6.2 ENVIRONMENTAL SAMPLES 65
6.3 ADEQUACY OF THE DATABASE 67
6.3.1 Identification of Data Needs 67
6.3.2 On-going Studies 69
7. REGULATIONS AND ADVISORIES 71
8. REFERENCES 75
9. GLOSSARY 99
APPENDIX 103
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ix
LIST OF FIGURES
2-1 Levels of Significant Exposure to Di-n-butyl Phthalate -
Inhalation 15
2-2 Levels of Significant Exposure to Di-n-butyl Phthalate - Oral ... 23
2-3 Metabolic Scheme for Di-n-butyl Phthalate in Animals 34
2-4 Existing Information on Health Effects of Di-n-butyl Phthalate ... 43
5-1 Frequency of Sites with Di-n-butyl Phthalate Contamination 56
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LIST OF TABLES
L-l Human Health Effects from Breathing Di-n-butyl Phthalate 4
1-2 Animal Health Effects from Breathing Di-n-butyl Phthalate 5
1-3 Human Health Effects from Eating or Drinking
Di-n-butyl Phthalate 6
1-4 Animal Health Effects from Eating or Drinking
Di-n-butyl Phthalate 7
2-1 Levels of Significant Exposure to Di-n-butyl Phthalate -
Inhalation . 13
2-2 Levels of Significant Exposure to Di-n-butyl Phthalate - Oral ... 18
2-3 Levels of Significant Exposure to Di-n-butyl Phthalate - Dermal . . 31
2-4 Genotoxicity of Di-n-butyl Phthalate In Vitro 39
2-5 On-going Studies on Di-n-butyl Phthalate 48
3-1 Chemical Identity of Di-n-butyl Phthalate ... 50
3-2 Physical and Chemical Properties of Di-n-butyl Phthalate 51
5-1 Estimated Levels of Human Exposure to Di-n-butyl Phthalate
for Nonoccupational Exposure 62
6-1 Analytical Methods for Determining Di-n-butyl Phthalate
in Biological Materials . . 66
6-2 Analytical Methods for Determining Di-n-butyl Phthalate in
Environmental Samples 68
7-1 Regulations and Guidelines Applicable to Di-n-butyl Phthalate ... 72
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1. PUBLIC HEALTH STATEMENT
This Statement was prepared to give you information about
di-n-butyl phthalate and to emphasize the human health effects that may
result from exposure to it. The Environmental Protection Agency (EPA)
has identified 1,177 sites on its National Priorities List (NPL).
Di-n-butyl phthalate has been found at 47 of these sites. However, we
do not know how many of the 1,177 NPL sites have been evaluated for
di-n-butyl phthalate. As EPA evaluates more sites, the number of sites
at which di-n-butyl phthalate is found may change. The information is
important for you because di-n-butyl phthalate may cause harmful health
effects and because these sites are potential or actual sources of human
exposure to di-n-butyl phthalate.
When a chemical is released from a large area, such as an
industrial plant, or from a container, such as a drum or bottle, it
enters the environment as a chemical emission. This emission, which is
also called a release, does not always lead to exposure. You can be
exposed to a chemical only when you come into contact with the chemical.
You may be exposed to it in the environment by breathing, eating, or
drinking substances containing the chemical or from skin contact with
it.
If you are exposed to a hazardous substance such as di-n-butyl
phthalate, several factors will determine whether harmful health effects
will occur and what the type and severity of those health effects will
be. These factors include the dose (how much), the duration (how long),
the route or pathway by which you are exposed (breathing, eating,
drinking, or skin contact), the other chemicals to which you are
exposed, and your individual characteristics such as age, sex,
nutritional status, family traits, life style, and state of health.
1.1 WHAT IS DI-N-BUTYL PHTHALATE?
Di-n-butyl phthalate is an odorless and colorless oily liquid. It
is a man-made chemical that is added to plastics and other chemical
products. Di-n-butyl phthalate has been used to make soft plastics,
carpet backing, paints, glue, insect repellents, hair spray, nail
polish, and rocket fuel.
Di-n-butyl phthalate does not evaporate easily, but small amounts
do enter into the air as a gas. Di-n-butyl phthalate also gets into air
by attaching to dust particles. In air, di-n-butyl phthalate usually
breaks down within a few days. Di-n-butyl phthalate does not dissolve
easily in water, but can get into water by attaching to dirt particles.
In water and soil, bacteria break down di-n-butyl phthalate. This may
happen in a day, or may take up to a month. The length of time it takes
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1. PUBLIC HEALTH STA'IT.MKNT
to break down di-n-butyl phthalate in soil or water depends on t:h(? kind
of bacteria present and the temperature. Further information on the
properties and uses of di-n-butyi phthalate and how it behaves in the
environment may be found in Chapters 3, 4 and r>.
1.2 HOW MIGHT I BE EXPOSED TO DI-N-BUTYL PHTHALATE?
Because di-n-butyl phthalate has so many uses in modern society ir
has become widespread in the environment, and most people are exposed
low levels in air, water and food. In most cases, the larpest *
• r- rr ¦* i . &a source or
exposure is from food that contains di-n-butyl phthalate. Some
di-n-butyl phthalate in food comes from the plastics used to package and
store the food, and some of it comes from di-n-buLy] phthalate tiken un
by fish, shellfish, or other foods. Levels of di-n-butyl phthalate in
food have been found to range from around SO to SOO parts nor h; 1 l ;
(ppb) . 1
Another way you can be exposed is by breathing ;iir containing
di-n-butyl phthalate. Low levels (0.01 ppb) are present around the
globe, and levels of 0.03 to 0.06 ppb are often found in city air
Higher levels can occur inside homes, especially when products'
containing di-n-butyl phthalate, such as nail polish, are used
Di-n-butyl phthalate is present in some drinking water supplies usuallv
at levels of around 0.1 to 0.2 ppb, ' j
As discussed in Section 1.5 (below), the levels of di-n-butyl
phthalate found in air, water, and food are usually low enough that thev
are not expected to cause any harmful effects. However, if you wire
exposed to higher - than-usual levels of. di-n-butyl phthalate," this might-
be of concern. Exposure to high levels could occur at a number of
places. For example, if you live near a factory that makes or uses
di-n-butyl phthalate, you could be exposed if the factory allowed
di-n-butyl phthalate to escape into the air that you breathe or into th
water that you drink. If the factory spilled or disposed of any 6
di-n-butyl phthalate on the ground you could also be exposed by Petting
the soil on your skm. You could be exposed to elevated levels of
di-n-butyl phthalate by these same ways if you live near a cheinicil
waste site that has allowed di-n-butyl phthalate to escape into the
environment. Di-n-butyl phthalate release into the air w-iter -mH -t
is also of concern at garbage dumps and landfills. This il l)eciu<. S
large amounts of dl-n-butyl phthalate-containing materials are "thrown
away at these sites, ana the di-n-butvl nhrhilnt-P r.i i
the products and get int° air, water, or soil ' °W ^ conie out of
Further 0n how you mlght be e d di_n_butv,
phthalate is given c"apter 5. Dutyl
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1. PUBLIC HEALTH STATEMENT
1.3 HOW CAN DI-N-BUTYL PHTHALATE ENTER AND LEAVE MY BODY?
If you eat or drink di-n-butyl phthalate in food or water, nearly
all of the di-n-butyl phthalate rapidly enters your body through the
digestive system. If you breathe air containing di-n-butyl phthalate,
it is likely that most of what you breathe in enters your body through
the lungs, but this has not been studied in detail. Di-n-butyl
phthalate can also enter the body through skin, although this occurs
rather slowly. Inside the body, di-n-butyl phthalate is changed into
other chemicals. Most of these are quickly removed from the body in the
urine. The rest are removed in the feces. Most of the di-n-butyl
phthalate that enters the body is removed within 24 hours, and virtually
all of it is gone by 48 hours after exposure. More information on how
di-n-butyl phthalate enters and leaves the body is given in Chapter 2.
1.4 HOW CAN DI-N-BUTYL PHTHALATE AFFECT MY HEALTH?
Adverse effects on humans from exposure to di-n-butyl phthalate
have not been reported. In animals, eating large amounts of di-n-butyl
phthalate can affect their ability to reproduce. Di-n-butyl phthalate
can cause death of unborn animals. In male animals, sperm production
can decrease after eating large amounts of di-n-butyl phthalate.
However, when exposure to di-n-butyl phthalate stops, sperm production
seems to return to near normal levels. Exposure to high levels of
di-n-butyl phthalate might cause similar effects in humans as in
animals, but this is not known. There is no evidence that di-n-butyl
phthalate causes cancer, but this has not been thoroughly studied.
Further information on the health effects of di-n-butyl phthalate
in animals can be found in Chapter 2.
1.5 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTS?
Di-n-butyl phthalate appears to have relatively low toxicity, and
large amounts are needed to cause injury. The levels of di-n-butyl
phthalate which cause toxic effects in animals are about 10,000 times
higher than the levels of di-n-butyl phthalate found in air, food or
water. If you were to eat di-n-butyl phthalate at levels equal to those
at which effects were seen in animals, about 1-2% of what you eat every
day would have to be di-n-butyl phthalate. Large amounts of di-n-butyl
phthalate repeatedly applied to the skin for a long time may also cause
mild irritation.
Tables 1-1 through 1-4 show the relationship between exposure to
di-n-butyl phthalate and known health effects. A Minimal Risk Level
(MRL) is also included in Table 1-3. This MRL was derived from animal
data for long-term exposure, as described in Chapter 2 and Table 2-2.
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PUBLIC HEALTH STATEMENT
TABLE 1-1. Human
Health Effects from Breathing Di-n-butyl Phthalate'
Levels in Air
Levels in Air
Short-term Exposure
(less than or equal to 14 days)
t pnpth of Exposure
y^pcjr-i-iption of Effects
The health effects result-
ing from short-term
exposure of humans to
air containing specific
levels of di-n-butyl
phthalate are not known.
Long-term Exposure
(greater than 14 days)
T.p,ngth nf Exposure
Dpgcription of Effects
The health effects result-
ing from long-term
exposure of humans to
air containing specific
levels of di-n-butyl
phthalate are not
known.
1 a discussion of exposures encountered in daily life
*See Section 1.2 tor a ais<-
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1. PUBLIC HEALTH STATEMENT
TABLE 1-2. Animal Health Effects from Breathing Di-n-butyl Phthalate
Short-term Exposure
(less than or equal to 14
days)
Levels in Air
Length of Exposure
Description of Effects
The health effects result-
ing from short-term
exposure of animals to
air containing specific
levels of di-n-butyl
phthalate are not known.
Long-term Exposure
(greater than 14 days)
Levels in Air (nob)
Length of Exposure
Description of Effects*
4,400
6 months
Increased lung weight and
decreased body weight
gain in rats.
*These effects are listed at the lowest level at which they were first
observed. They may also be seen at higher levels.
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1. PUBLIC HEALTH STATEMENT
TABLE 1-3. Human Health Effects from Eating or Drinking
Di-n-butyl Phthalate*
Short-term Exposure
(less than or equal to 14
days)
T^nfrt-h of Exposure
Description of Effects
The health effects result-
ing from short-term
exposure of humans to
food containing specific
levels of di-n-butyl
phthalate are not known.
Levels in Water
The health effects result-
ing from short-term
exposure of humans to
water containing
specific levels of di-
n-butyl phthalate
are not known.
Long-term Exposure
(greater than 14 days
)
T^nprh of Exposure
DescriDtion of Effects
22,000
Levels in Water
20 days
Minimal Risk Level (based
on animal studies; see
Section 1.5 for
discussion).
The health effects result-
ing from long-term
exposure of humans to
water containing
specific levels of di-
n-butyl phthalate are
not known.
*See Section 1.2 for a discussion of exposures encountered in daily life.
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1. PUBLIC HEALTH STATEMENT
TABLE 1-4. Animal Health Effects from Eating or Drinking
Di-n-butyl Phthalate
Short-terra Exposure
(less than or equal to 14 days)
Levels in Food (nob)
Leneth of Exposure
DescriDtion of Effects*
19,000,000
19,000,000
20,000,000
20,000,000
8 days
8 days
7 days
7 days
Death in mice.
Death of unborn mice.
Decreased body weight
in mice.
Decreased sperm
production in rats.
Levels in Water
The health effects result-
ing from short-term
exposure of animals to
water containing
specific levels of di-
n-butyl phthalate are
not known.
Long-term Exposure
(greater than 14 days)
Levels in Food (ppb)
Leneth of Exposure
DescriDtion of Effects'*
2,500,000
7,500,000
12,000,000
12,500,000
16,000,000
20 days
20 days
90 days
52 weeks
18 days
Decreased body weight of
newly-born rats.
Death of unborn mice.
Death of unborn rats.
Death in rats.
Birth defects in mice.
Levels in Water
The health effects result-
ing from long-term expo-
sure of animals to water
containing specific
levels of di-n-butyl
phthalate are not known.
*These effects are listed at the lowest level at which they were first
observed. They may also be seen at higher levels.
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1. PUBLIC HEALTH STATEMENT
The MRL provides a basis for comparison to levels which people might
encounter either in the air or in food or drinking water. If a person
is exposed to di-n-butyl phthalate at an amount below the? MRL, it is not
expected that harmful health effects will occur. Because these levels
are based only on information currently available, some uncertainty is
always associated with them. Also, because the method for deriving MRLs
does not use any information about cancer, a MRL does not imply anything
about the presence, absence, or level of risk of cancer.
Additional information on the levels of exposure associated with
harmful effects can be found in Chapter 7.
1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO
DI-N-BUTYL PHTHALATE?
Tests are available that can detect di-n-butyl phthalate in blood
and body tissues, and the major break-down products of di-n-butyl
phthalate can be measured in urine. However, there is not enough
information at present to use the results of such tests to predict the
nature or severity of any health effects that may result from exposure
to di-n-butyl phthalate. Since special equipment is needed, these tests
cannot be performed routinely in your doctor's office. Further
information on how di-n-butyl phthalate can be measured in exposed
humans is presented in Chapters 2 and 6.
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT
HUMAN HEALTH?
The federal government has developed regulatory standards and
advisories to protect individuals from the potential health effects of
di-n-butyl phthalate in the environment. The Environmental Protection
Agency recommends that levels of di-n-butyl phthalate in water not
exceed 34 parts per million (34,000 ppb). Any release of di-n-butyl
phthalate to the environment in excess of 10 pounds must be reported to
the federal government. The National Institute for Occupational Safety
and Health (NIOSH) has established a limit of 850 parts per million
(850,000 ppb) di-n-butyl phthalate in workplace air in order to protect
the health of workers.
Additional information on governmental regulations regarding
di-n-butyl phthalate can be found in Chapter 7.
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1. PUBLIC HEALTH STATEMENT
1.8 WHERE CAN I GET MORE INFORMATION?
If you have any more questions or concerns not covered here, please
contact your State Health or Environmental Department or:
Agency for Toxic Substances and Disease Registry
Division of Toxicology
1600 Clifton Road, E-29
Atlanta, Georgia 30333
This agency can also give you information on the location of the
nearest occupational and environmental health clinics. Such clinics
specialize in recognizing, evaluating, and treating illnesses that
result from exposure to hazardous substances.
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2. HEALTH EFFECTS
2.1 INTRODUCTION
This chapter contains descriptions and evaluations of studies and
interpretation of data on the health effects associated with exposure to
di-n-butyl phthalate. Its purpose is to present levels of significant
exposure for di-n-butyl phthalate based on toxicological studies,
epidemiological investigations, and environmental exposure data. This
information is presented to provide public health officials, physicians,
toxicologists, and other interested individuals and groups with (1) an
overall perspective of the toxicology of di-n-butyl phthalate and (2) a
depiction of significant exposure levels associated with various adverse
health effects.
2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE
To help public health professionals address the needs of persons
living or working near hazardous waste sites, the data in this section
are organized first by route of exposure -- inhalation, oral, and dermal
-- and then by health effect -- death, systemic, immunological,
neurological, developmental, reproductive, genotoxic, and carcinogenic
effects. These data are discussed in terms of three exposure periods--
acute, intermediate, and chronic.
Levels of significant exposure for each exposure route and duration
(for which data exist) are presented in tables and illustrated in
figures. The points in the figures showing no-observed-adverse-effect
levels (NOAELs) or lowest-observed-adverse-effect levels (LOAELs)
reflect the actual doses (levels of exposure) used in the studies.
LOAELs have been classified into "less serious" or "serious" effects.
These distinctions are intended to help the users of the document
identify the levels of exposure at which adverse health effects start to
appear, determine whether or not the intensity of the effects varies
with dose and/or duration, and place into perspective the possible
significance of these effects to human health.
The significance of the exposure levels shown on the tables and
figures may differ depending on the user's perspective. For example,
physicians concerned with the interpretation of clinical findings in
exposed persons or with the identification of persons with the potential
to develop such disease may be interested in levels of exposure
associated with "serious" effects. Public health officials and project
managers concerned with response actions at Superfund sites may want
information on levels of exposure associated with more subtle effects in
humans or animals (LOAEL) or exposure levels below which no adverse
effects (NOAEL) have been observed. Estimates of levels posing minimal
risk to humans (Minimal Risk Levels, MRLs) are of interest to health
professionals and citizens alike.
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2. HEALTH EFFECTS
Estimates of exposure levels posing minimal risk to humans (MRLs)
have been made, where data were believed reliable, for the most
sensitive noncancer end point for each exposure duration. MRLs include
adjustments to reflect human variability and, where appropriate, the
uncertainty of extrapolating from laboratory animal data to humans.
Although methods have been established to derive these levels (Barnes
et al. 1987; EPA 1989a), uncertainties are associated with the
techniques. Furthermore, ATSDR acknowledges additional uncertainties
inherent in the application of these procedures to derive less than
lifetime MRLs. As an example, acute inhalation MRLs may not be
protective for health effects that are delayed in development or are
acquired following repeated acute insults, such as hypersensitivity
reactions, asthma, or chronic bronchitis. As these kinds of" health
effects data become available and methods to assess levels of
significant human exposure improve, these MRLs will be revised.
2.2.1 Inhalation Exposure
Table 2-1 and Figure 2-1 summarize the health effects observed in
animals following inhalation exposure to di-n-butyl. phthalate. These
effects are discussed below.
2.2.1.1 Death
No studies were located regarding death in humans or animals
following inhalation exposure to di-n-butyl phthalate.
2.2.1.2 Systemic Effects
Workers exposed to di-n-butyl phthalate for 0.5 to 19 years at
concentrations of 1.7 to 66 mg/m3 exhibited hypertension and
hyperbilirubinemia at a frequency which increased with length of
employment (Milkov et al. 1973). These workers were also exposed to
other plasticizers, so the effects seen may not have been caused by
di-n-butyl phthalate exposure.
Limited information on inhalation exposure in rats is available.
Five days of exposure to 0.5 to 7 ppm di-n-butyl phthalate caused a
dose-dependent decrease in the cytochrome P-450 content of the lungs of
male rats (Walseth and Nilsen 1984). Rats exposed to 4.4 ppm di-n-butyl
phthalate 6 hours per day for 6 months had decreased body weight gain
and increased lung weight relative to body weight (Kawano 1980a). No
effects on liver and kidney weight relative to body weight were found,
and no effect was noted on hematocrit, hemoglobin, or red blood cell
count (Kawano 1980a). Small fluctuations in several serum chemistry
parameters were noted (serum enzymes, urea nitrogen, cholesterol), but
these were not clearly dose- or time-dependent (Kawano 1980a).
-------
TABLE 2-1. Levels of Significant Exposure to Di-n-butyl Phthalate - Inhalation
Figure
Key
Species
Exposure
Frequency/
Duration Effe.ct
LOAEL (Effect)
NOAEL Less Serious
(ppm) (ppm)
Serious
(ppm)
Reference
ACUTE EXPOSURE
Systemic
1 Rat
5 d
6hr/d
Resp
0.5 2.5 (deer, cyto P-450)
Walseth and
Nilsen 1984
INTERMEDIATE EXPOSURE
Systemic
2 Rat
3 Rat
4 Rat
5 Rat
Rat
Rat
3-6 mo
5d/vk
6hr/d
3-6 mo
5d/vk
6hr/d
3-6 mo
5d/wk
6hr/d
3-6 mo
5d/wk
6hr/d
3-6 mo
5d/vk
6hr /d
3-6 mo
5d/wk
6hr/d
Resp
0.044 4.4a (incr. lung wt. )
Hepatic 4.4
Hemato
Other 0.044 4.4a (deer. wt. gain)
Renal 4.4
Resp 0.044 4.4 (increased lung
weight)
Hemato 4.4
Hepatic 4.4
Renal 4.4
Other 0.044 4.4 (decreased weight
gain)
Kavano 1980a
Kavano 1980a
Kavano 1980a
Kavano 1980a
Kavano 1980a
Kavano 1980b
2C
>
r
H
re
m
o
H
00
-------
TABLE 2-1 (Continued)
Figure
Key
Species
Exposure
FrequencyI NOAEL
Duration. Effect (ppoa)
Less Serious
(ppm)
LOAEL CEffect)
Serious
(ppm)
Reference
InnunologicaL
8 Rat
3-6 mo
5d/vk
6hr/d
U.A
Kawano 1980a
Neurological
9 Rat
Reproduce ive
10 Rat
3-6 mo
5d/vk
6hr/d
3-6 mo
5d/wk
6hr/d
0.044
4.4 (incr. brain vt.)
Kavano 1960a
Kavano 1980a
^Converted to 4,400 ppb for presentation in Table 1-2.
LOAEL « lowest-observed-adverse-effect level; NOAEL * no-observed-adverse-effect level: roo = month; hr - hour; d * day;
resp * respiratory: incr. = increased; vt. = weight; deer. = decreased.
X
C*1
>
r
m
TJ
m
a
H
on
-------
FIGURE 2-1. Levels of Significant Exposure to Di-n-butyl Phthalate - Inhalation
ACUTE
(*14 Days)
Systemic
INTERMEDIATE
(15-364 Days)
Systemic
J*
/ /
(ppm)
10 i—
<4? /
> ~ //V
®1r
Ou
0.1
®2r ®7r O?' C>3r O* Q6r O* ®5r 37r Qsr ®9f
QZr Q7i
QSf OT O *
0.01
Key
r Rat 3 LOAEL for less serious effects (animals)
O NOAEL (animals)
The number next to each point corresponds to entries in Table 2-1.
-------
16
2. HEALTH EFFECTS
No studies were located regarding cardiovascular, gastrointestinal,
musculoskeletal, or dermal/ocular effects in animals following
inhalation exposure to di-n-butyl phthalate.
2.2.1.3 Immunological Effects
No studies were located regarding immunological effects in htimans
following inhalation exposure to di-n-butyl phthalate. Small
fluctuations in white cell counts and percent neutrophiles were found in
rats exposed to 0.044 or 4.4 ppm di-n-butyl phthalate 6 hours per day
for 3 or 6 months, but the changes were not dose- or time-dependent
(Kawano 1980a), and do not appear to be clinically significant.
2.2.1.4 Neurological Effects
Workers exposed to di-n-butyl phthalate for 0.5 to 19 years at
concentrations of 1.7 to 66 mg/m3 experienced neurological symptoms
(pain, numbness, spasms, weakness) and exhibited reflex disturbances,
elevated thresholds for pain sensitivity and olfactory stimulation, and
depression of vestibular function (Milkov et al. 1973). The frequency
and severity of these effects increased with increased duration of
exposure. The workers were also exposed to other plasticizers, so these
neurological effects may not have been caused by di-n-butyl phthalate
exposure.
In rats, a statistically significant increase in brain weight as a
percent of body weight was observed following exposure to 4.4 ppm
di-n-butyl phthalate for six months (Kawano 1980a). However, a
significant decrease in body weight gain was reported for this dose
group, and the absolute brain weight increase was small (1,58 g vs.
1.47 g in controls)-
2.2.1.5 Developmental Effects
No studies were located regarding developmental effects in humans
or animals following inhalation exposure to di-n-butyl phthalate.
2.2.1.6 Reproductive Effects
No studies were located regarding reproductive effects in humans
following inhalation exposure to di-n-butyl phthalate. In rats,
exposure to 0.044 °r -4 pm 6 hours per day for 3 or 6 months caused no
changes in relative testicular weight (Kawano 1980a).
2.2.1.7 Genotoxic Effects
No studies we^e located regarding genotoxic effects in humans or
animals following in"alation exposure to di-n-butyl phthalate.
-------
17
2. HEALTH EFFECTS
2.2.1.8 Cancer
No studies were located regarding cancer effects in humans or
animals following inhalation exposure to di-n-butyl phthalate.
2.2.2 Oral Exposure
Table 2-2 and Figure 2-2 summarize the health effects observed
following oral exposure of animals to di-n-butyl phthalate. These
effects are discussed below.
2.2.2.1 Death
No studies were located regarding death in humans following oral
exposure to di-n-butyl phthalate.
Di-n-butyl phthalate has low acute toxicity in animals. Single
doses of 8,000 mg/kg killed 4 of 9 rats in one study (Smith 1953), but
other studies indicate the acute oral LD50 in rats and mice is in excess
of 20,000 mg/kg (Hardin et al. 1987; White et al. 1983). The cause of
death in these studies was not reported. In mice, an LD10 of
2,500 mg/kg was reported by Hardin et al. (1987).
In a 52 week study in rats, half of the animals given 625 mg/kg/day
in feed died during the first week of the study. Because those animals
that survived the first week also survived to the termination of the
study and exhibited no pathology, the observed deaths may not have been
related to di-n-butyl phthalate exposure. No deaths were observed at
125 mg/kg/day (Smith 1953).
The highest NOAEL values and all reliable LOAEL values for death in
each species and duration category are recorded in Table 2-2 and plotted
in Figure 2-2.
2.2.2.2 Systemic Effects
Hematological Effects. Di-n-butyl phthalate has little or no
effect on the hematological system of animals. Biochemical parameters
and histopathological evaluation of the spleen of rats showed no effects
at doses up to 1,200 mg/kg/day (Nikonorow et al. 1973; Smith 1953).
Increased absolute and relative spleen weight was observed in rats at a
dose of 2,500 mg/kg/day (Murakami et al. 1986a, 1986b), but without
additional information on histopathological changes and evaluation of
hematological parameters, the significance of this isolated finding
cannot be determined.
-------
TAM,K 2-2. Levels of Significant Exposure to Di-n-butyl Fhtlialate - Oral
Exposure
Frequency/
LOAEL (Effect)
Figure Frequency/ NOAEL Less Serious
Key Species Route Duration Effect (mg/kg/d) (mg/kg/d)
Serious
(mg/kg/d)
Reference
ACUTE EXPOSURE
Death
Rat
W 1 4
6000
10000 (2/10 deaths)
White et al.
1983
Rat
Mouse
(G) 1 d
8 d
Gd6-13
lx/d
4000
8000 (4/9 deaths)
2500* (LD10)
Smith 1953
Hardin et al.
1987
Systemic
A Rat
(G)
Rat
Rat
Rat
Rat
Rat
(G)
(G)
(G)
(F)
1 d
lx/d
9 d
lx/d
(F) 7 d
5 d
lx/d
1 d
7 d
Resp
Hemato
Hepatic
Renal
Other
Other
Hepatic
Resp
Other
Other
0.044 4.4 (increased lung
weight)
4.4
4.4
4.4
0.044 4.4 (decreased weight
gain)
2000
1000 (deer, zinc
cone.)
278
4000 8000 (deer, body vt-)
1000
Kawano 1980b
Gray et al. 1982
Oishi and Hiraga
1980b
Walseth and
NLlsen 1986
Smith 1953
Oishi and Hiraga
1980b
X
P3
>
r
H
X
w
PJ
o
H
to
11
Rat (F) 7 d
Gn Pig (G) 7 d
lx/d
Hepatic
Other
1000 (incr . liver
enz. act.)
2000
Kavashlma et al.
1983
Gray et al. 1982
-------
TABLE 2-2 (Continued)
Exposure
Figure Frequency/ NOAEL
Key Species Route Duration Effect (mg/kg/d)
LOAEL (Effect)
Less Serious
(mg/kg/d)
Serious
(mg/kg/d)
Reference
12
Mouse (F) 7 d
Other
2600 (deer, body wt.)
Oishi and Hiraga
1980a
13
Mouse (F) 7 d
Hepatic
2600 (incr. liver wt.)
Oishi and Hiraga
1980a
14
Mouse (F) 7 d
Renal
2600 (deer, kidney wt.)
Oishi and Hiraga
1980a
15
Mouse
(G) 9 d
lx/d
Other
2000
Gray et al. 1982
16
Hamster (G) 9 d
lx/d
Other
2000
Developmental
17 Mouse
Reproductive
18 Rat
19
20
Rat
Rat
(G) 8 d
Gd6-13
lx/d
r1
H
a:
ti
n
o
H
21
Rat
(G) 4 d
lx/d
1000 (deer, testis wt.) Cater et al.
1977
22 Gn Pig (G) 7 d
lx/d
2000 (severe testie. Gray et al. 1982
lesion, deer,
testis wt.)
-------
TABLE 2-2 (Continued)
Exposure LOAEL (Effect)
Figure Frequency/ NOAEL Less Serious
Key Species Route Duration Effect (mg/kg/d) (mg/kg/d)
Serious
(mg/kg/d)
Reference
23
25
Mouse (F) 7 d
24 Mouse (G) 9 d
Ix/d
Hamster (G) 9 d
1*/d
2000
2600 (incr. testis wt. ) Oishi and Hiraga
1980a
2000 (mild testic.
lesion, deer,
testis wt.)
Gray et al. 1982
Gray et al. 1982
INTERMEDIATE EXPOSURE
Death
26 Rat (F) 52 vk
Systemic
27 Rat (F) 12 mo
28
Rat
Hemato
(F) 34-36 d Other
125
62
625°
250 (deer, body wt.)
Smith 1953
Nikonorow et al.
1973
Murakami et al.
1986a
29
30
31
32
33
34
Rat
Rat
Rat
Rat
Rat
Rat
(F) 21 d
(G)
(G)
(F)
(F)
90 d
Ix/d
90 d
lx/d
21 d
52 vk
(F) 34-36 d
Other
Renal
Hepatic
Hepatic
Hemato
Hepatic
1200
625
348 (deer, plasma
cholesterol)
120 120C (incr. liver vt.)
348 (incr. liver wt.)
250 (liver necrosis)
Bell 1982
Nikonorow et al.
1973
Nikonorow tz al
1973
Bell 1982
Smith 1953
Murakami et ai
1986a
35
Rat
(G) 90 d
lx/d
Hemato
1200
Nikonorow et al
1973
-------
TABLE 2-2 (Continued)
Exposure
Figure Frequency/ NOAEL
Key Species Route Duration Effect (mg/kg/d)
LOAEL (Effect)
Less Serious
(mg/kg/d)
Serious
(mg/kg/d)
Reference
36
37
38
39
40
41
42
43
44
45
46
47
48
Rat
(F) 35-45 d Other
Rat (F) 21 d Hepatic
Rat (F) 12 mo Other
Rat
Rat
Rat
Rat
Rat
49 Mouse
Developmental
50 Rat
(F) 12 mo
(F) 21 d
(F) 12 mo
Mouse (F) 105 d
Mouse (F) 126 d
Mouse (F) 126 d
Mouse (F) 105 d
Mouse (F) 18 d
Hepatic
Renal
(F) 35-45 d Hemato
Renal
(F) 35-45 d Hepatic
51
Rat
(F) 21 d
(F) 48 d
Gd0-Ld28
(G) 90 d
Hepatic
Hepatic
Other
Other
Other
Other
62
62
2500 (deer, body wt.)
628 (incr. liver wt. )
628 1248 (incr. kidney wt.)
2500 (incr. spleen wt.)
62
2500 (deer, mitoch.
oxidation)
1300
390 1300 (incr. liver wt.)
390 1300 (deer, body wt.-
oales)
390 1300 (deer, body wt.)
660
628 1248 (deer, body wt.)
62.5^ 125e (deer, pup wt.)
120
2100 (deer, body wt.)
600* (incr. no. of
resorptions)
Murakami et al.
1986b
BIBRA 1986
Nikonorow et al.
1973
Nikonorow et al.
1973
BIBRA 1986
Murakami et al.
1986b
Nikonorow et al.
1973
Murakami et al.
1986b
Lamb et al. 1987
Reel et al. 1984
Reel et al. 1984
Lamb et al. 1987
Shiota and
Nishimura 1982
BIBRA 1986
Killinger et al.
1988a
Nikonorow et al.
1973
X
m
>
5
X
p)
"3
PJ
n
H
cn
-------
TABLE 2-2 (Continued)
Exposure LOAEL (Effect)
Figure FrequencyI NOAEL Less Serious Serious
Key Species Route Duration Effect (mg/kg/d) (mg/kg/d) (mg/kg/d)
Reference
52
53
Mouse
Mouse
(?) US d
Gd0-Ld28
(F) 18 d
GdO-18
650
660
Killinger et al.
1988b
975* (fetal death)
2100*1 (malformations) Shiota and
NishLmura 1982
Reproduct ive
54 Rat
(F) 34-36 d
250
2500 (deer, testis wt.) Murakami et al.
1986a
55
56
57
58
59
Rat
Rat
(F) 48 d
Gd0-Ld28
(F) 35-45 d
1000 (no live pups)
Rat (F) 21 d
Mouse (F) 105 d
Mouse (F) 48 d
Gd0-Ld28
1248
390
Killinger et al.
1988a
2500 (deer, testis wt.) Murakami et al.
1986b
2131 (testic. atrophy) BIBRA 1986
1300 (deer. no. litters Lamb et al. 1987
and live pups)
2600 (no live pups) Killinger et al.
1988b
5C
rn
>
r1
H
x
*T3
TJ
m
o
H
ro
K>
aConverted to an equivalent concentration of 19,000,000 ppb in food for presentation in Table 1-4.
^Converted to an equivalent concentration of 20,000,000 ppb in food for presentation in Table 1-4.
cConverted to an equivalent concentration of 12,500,000 ppb in food for presentation in Table 1-4.
^Used to derive intermediate oral MRL; dose divided by an uncertainty factor of 100 (10 for extrapolation from animals to humans,
and 10 for human variability), resulting in an MRL of 0.62 mg/kg/day. This MRL has been converted to an equivalent concentration
in food (22,000 ppb) for presentation in Table 1-3.
eConverted to an equivalent concentration of 2,500,000 ppb in food for presentation in Table 1-4.
^Converted to an equivalent concentration of 12,000,000 ppb in food for presentation in Table 1-4.
^Converted to an equivalent concentration of 7,500,000 ppb in food for presentation in Table 1-4.
^Converted to an equivalent concentration of 16,000,000 ppb in food for presentation in Table 1-4.
LOAEL « lowest-observed-adverse-effeet level; NOAEL = no-observed-adverse-effeet level; rag = milligram; kg = kilogram; d = day;
(G) ¦ gavage; LD10 * lethal dose, 10Z mortality; Gd = gestation day; Ld * lactation day: lx = one time; (F) * food; deer. =
decreased; cone. « concentration; incr. = increased; enz. act. = enzyme activity; Resp * respiratory; wt. *= weight; histopath =
histopathological; testic * testicular: Gn * guinea pig: wk * week; mo » month; Hemato * hematological; mitoch. « mitochondrial;
no. « number.
-------
FIGURE 2-2. Levels of Significant Exposure to Di-n-butyl Phthalate - Oral
(mg/kg/day)
10,000
1.000
100
10
,8
>3m
ACUTE
(«14 Days)
Systemic
(J 13m (J'*11
®6r ®10r
O*
®4r 0*f
O*
3sr
_ ^ ®12mO«r
O"80l6<)l5mO5r
0»f
O
34r
~ _ •23tr#18r
#22g0zse#24m 0l9r
>20r»21r
a
m
>
5
ac
m
•n
m
o
H
w
N>
0.1
o
O
0.01
Key
r Rat V LOAEL tor serious effects (animals) [ Minimal risk level for
m Mouse ® LOAEL for less serious effects (animals) U, e"ects °tt)er ^lan cancer
s Hamster O NOAEL (animals)
g Guinea pig
The number next to each point corresponds to entries in Table 2-2.
-------
(mgftg/day)
10,000
1,000
100
10
1
0.1
0.01
FIGURE 2-2 (Continued)
INTERMEDIATE
(15-364 Days)
Systemic
J" r J?
51r
350rO51r
Osor
50m
l54r ®56r.
58m#55r
0^®m
Ow
>57r
3;
M
>
r
H
ac
w
w
o
H
on
ro
Key
r
Rat 9 LOAEL for serious effects (animals) i Minimal risk level for
m
Mouse 3 LOAEL tor less serious effects (animals) j, ertects other than
s
Hamster O NOAEL (animals)
9
Guinea pig
The number next to each point corresponds to entries in Table 2-2.
-------
25
2. HEALTH EFFECTS
Hepatic Effects. In animals, minimal effects on the liver are
observed after acute exposure to di-n-butyl phthalate, Increased
absolute liver weight was observed in rats and mice given di-n-butyl
phthalate at 2% in the diet (1,Q0C to 2.600 mg/kg/day) for 7 days (Qishi
and Hiraga 1980a, 1980b), and increased liver weight relative to body
weight in animals was observed in several studies with di-n-butyl
phthalate at doses of 348 mg/kg/day and higher for 21 days or more (Bell
1982; BIBRA 1986; Murakami et al. 1986a, 1986b; Nikonorow et al. 1973).
In these studies, the increases in relative liver weight may simply
reflect body weight decreases caused by di-n-butyl phthalate in those
animals.
Slight but statistically significant increases in microsomal enzyme
activity levels were observed in the livers of rats given di-n-butyl
phthalate by gavage for 5 days at doses of 2.8 and 27.8 mg/kg/day, but
not at 278 mg/kg/day (Walseth and Nilsen 1986). Why increased enzyme
activity was observed at the lower doses but not at the high dose was
not evident. The authors considered di-n-butyl phthalate to be a weak
inducer of microsomal enzymes. Increased microsomal enzyme activity was
observed in the livers of rats exposed to 1,000 mg/kg/day in the diet
for 7 days (Kawashima et al. 1983).
Longer exposure to di-n-butyl phthalate was found to interfere with
mitochondrial respiration. Mitochondrial respiration was inhibited in
rats fed di-n-butyl phthalate at 2,500 mg/kg/day for 35 days (Murakami
et al. 1986b). Evaluation of liver tissue by electron microscopy
revealed an increase in the number of mitochondria, suggesting that the
organ is compensating for the inhibitory effects of the di-n-butyl
phthalate on mitochondrial function (Murakami et al. 1986a). Liver
necrosis was noted at doses of 250 mg/kg/day and higher, an effect
possibly related to the effects of di-n-butyl phthalate on liver
mitochondria (Murakami et al. 1986a). Other studies using higher doses
have found no liver necrosis (BIBRA 1986, Nikonorow et al. 1973). No
explanation for the discrepant results is evident.
Proliferation of peroxisomes and increases in peroxisomal enzymes
have been reported in rat liver cells by several investigators (BIBRA
1986; Murakami et al. 1986a) at doses of 2,131 mg/kg/day for 21 days or
more. This response may contribute to the increase in liver weight
discussed above, especially in males (Murakami et al. 1986a, 1986b).
Renal Effects. Oral exposure to di-n-butyl phthalate has been
reported to cause decreased kidney weight after 7 days of exposure of
mice to 2,600 mg/kg/day (Oishi and Hiraga 1980a) and increased kidney
weight after 21 days of exposure of rats to 1,248 mg/kg/day (BIBRA
1986). No histopathologic lesions of the kidney have been observed in
-------
26
2. HEALTH EFFECTS
rats exposed to di-n-butyl phthalate (BIBRA 1986; Nikonorow et -il
1973).
Other Systemic Effects. No studies were located regarding
respiratory, cardiovascular, gastrointestinal, musculoskeletal, or
dermal/ocular effects in humans or animals following ingestion'of
di-n-butyl phthalate. Several studies have evaluated the effect of oral
exposure of animals to di-n-butyl phthalate on body weight (BIBRA 1986-
Gray et al. 1982; Lamb et al. 1987; Murakami et al. 1986, 1986b-
Nikonorow et al. 1973; Oishi and Hiraga 1980a; Reel et al. 1984[ Smith
1953). Body weight changes are generally insensitive indicators of
toxicity, and effects on testes are often found at doses causing no
change in body weights (Gray et al. 1982; Oishi and Hiraga 1980b).
The highest NOAEL values and all reliable LOAEL values for systemic
effects in each species and duration category are recorded in Table 9-9
and Figure 2-2.
2.2.2.3 Immunological Effects
No studies were located regarding immunological effects in humans
or animals following oral exposure to di-n-butyl phthalate.
2.2.2.4 Neurological Effects
No studies were located regarding neurological effects in humans or
animals following oral exposure to di-n-butyl phthalate.
2.2.2.5 Developmental Effects
No studies were located regarding developmental effects in humans
following oral exposure to dl-n-butyl phthalate.
Di-n-butyl phthalate has been demonstrated to be toxic to fetuses
in a number of animal studies (Hardin 1987; Killinger et al. 1988a b'
Nikonorow et al. 1973; Shiota and Nishimura 1982). Administration'of
di-n-butyl phthalate for « days at a dose of 2,500 mg/kg/day to pregnant
mice resulted in the deaths of i0% of treated animals and no viable
litters among the surviving females (Hardin et al. 1987). Oral doses of
600 mg/kg/day resulted in an increased number of resorptions when
di-n-butyl phthalate was administered to rats during pregnancy If
di-n-butyl phthalate was S^ven prior to mating, but discontinued on the
day of conception, no fet;otoxic effects were noted (Nikonorow et al
1973). Offspring of pregnJnt rats fed 2,500 ppm or more di-n-butyl
phthalate (125 mg/kg/day) £or 48 days experienced decreased weight gain
-------
27
2. HEALTH EFFECTS
(Killinger et al. 1988a). Pregnant mice fed 7,500 ppm or more for
28 days (975 mg/kg/day) had fewer live-born pups than controls
(Killinger et al. 1988b). No maternal toxicity was noted in either
study.
Limited data suggest that di-n-butyl phthalate may be teratogenic.
Mice given di-n-butyl phthalate in the diet on days 0-18 of gestation
and sacrificed on day 18 of gestation showed a borderline increase in
fetal neural tube defects (exencephaly and myeloschisis) (Shiota and
Nishimura 1982). The LOAEL for these malformations was 2,100 mg/kg/day
and the NOAEL for malformations was 660 mg/kg/day.
The highest NOAEL values and all reliable LOAEL values for
developmental effects in each species and duration category are recorded
in Table 2-2 and plotted in Figure 2-2. Based on the no effect level of
62.5 mg/kg/day in rats reported by Killinger et al. (1988a), an
intermediate oral MRL of 0.62 mg/kg/day was calculated as described in
footnote d in Table 2-2.
2.2.2.6 Reproductive Effects
A weak negative correlation was found between sperm density and
di-n-butyl phthalate concentration in semen from male university
students (Murature et al. 1987). No other studies were located
regarding reproductive effects in humans following oral exposure to di-
n-butyl phthalate.
Oral exposure to di-n-butyl phthalate has adverse effects on the
male reproductive system in several animal species (rats, mice and
guinea pigs). Oral exposure of male rats for up to 34 days at doses up
to 2,500 mg/kg/day resulted in decreased testicular weight, atrophy of
the seminiferous tubules, and decreased sperm counts (BIBRA 1986; Cater
et al. 1977; Gray et al. 1982; Murakami et al. 1986a, 1986b; Oishi and
Hiraga 1980b; Tanino et al. 1987). In rats, decreased spermatogenesis
and testes weight were observed as early as 7 days after initiation of
dosing with 1,000 mg/kg/day (Oishi and Hiraga 1980b).
Species differences are evident. While severe seminiferous tubular
atrophy was observed in rats and guinea pigs at 2,000 mg/kg/day for 7 to
9 days, only focal atrophy was reported in mice at the same dose and no
effects on the testes were seen in Syrian hamsters (Gray et al. 1982).
This difference may be related to the greater ability of hamsters than
other species to conjugate the primary metabolite of di-n-butyl
phthalate (see Section 2.3.3.2).
The testicular effects of acute exposure of rats to di-n-butyl
phthalate appear to be at least in part reversible. Tanino et al.
(1987) showed that two weeks after discontinuation of the administration
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28
2. HEALTH EFFECTS
of di-n-butyl phthalate (2,400 rag/kg/day for 7 days), some regeneration
of seminiferous tubules had occurred. Three weeks after treatment
ceased, active spermatogenesis was observed in almost all tubules.
However, vacuolation of germinal epithelium and decreased number of
sperm were still evident.
Testicular effects of di-n-butyl phthalate may be associated with
the effects of di-n-butyl phthalate on the metabolism of zinc. Zinc is
an essential element for the development of testes and administration of
di-n-butyl phthalate increases the urinary excretion of zinc and
decreases the zinc content of the testes of rats (Cater et al. 1977;
Oishi and Hiraga 1980a). Administration of zinc to young male rats
given 1,000 mg/kg/day di-n-butyl phthalate showed substantial protection
against'the testicular injury produced by di-n-butyl phthalate (Cater
et al. 1977).
High doses of di-n-butyl phthalate also appear to have an adverse
effect on reproduction in female animals. Pregnant rats or mice fed
20,000 ppm of di-n-butyl phthalate in the diet (equivalent to doses of
1 000 and 2,600 mg/kg/day, respectively) during gestation experienced
complete reproductive failure, possibly due to toxic effects on the
fetus (Killinger et al. 1988a, 1988b). No NOAEL for reproductive
toxicity was established in these studies becauses decreases in
fertility parameters seen at lower doses may have been related to fetal
toxicity. Exposure of male arid female mice to 1,300 mg/kg/day in the
diet for 98 days resulted in a reduced number of litters per mating
pair, fewer live pups per litter (possibly due to increased fetal
mortality), and lower proportion of pups born aiive (Lamb et al. 1987).
No effects on reproduction were seen at 390 mg/kg/day. Crossover mating
studies in which exposed females were mated with control males, and vice
versa showed that the effects °n reproduction were associated with the
female mice. The doses administered in the study appear to be below
those which cause effects on reproductive organs in male mice. Gross
and microscopic evaluation of *ePr°ductive organs of males in this study
showed no adverse effects (Ree et al • 1984).
The highest NOAEL and "ls-able LOAEL values for reproductive
effects are recorded in Table and plotted in Figure 2-2.
2.2.2.7 Genotoxic Effects
No studies were located genotoxic effects of di-n-butyl
phthalate in humans or anim*ls er oral exposure to di-n-butyl
phthalate.
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29
2. HEALTH EFFECTS
2.2.2.8 Cancer
No studies were located regarding carcinogenic effects of
di-n-butyl phthalate in humans after oral exposure to di-n-butyl
phthalate. Rats exposed for 15 to 21 months to doses of 100 to
500 mg/kg/day were reported not to develop cancer, but no details of the
study or the examination for tumors were provided (Krauskopf 1973). No
other studies on the carcinogenic effects of chronic ingestion of
di-n-butyl phthalate were located. Ati on-going study of the
carcinogenicity of di-n-butyl phthalate is listed in Section 2.8.3.
2.2.3 Dermal Exposure
Available data on the effects of dermal exposure to di-n-butyl
phthalate are presented in Table 2-3. These studies are discussed
below.
2.2.3.1 Death
No studies were located regarding death in humans following dermal
exposure to di-n-butyl phthalate.
The subchronic (90-day) dermal LD50 in rabbits has been reported to
be greater than 4,200 mg/kg/day (Lehman 1955).
2.2.3.2 Systemic Effects
Renal Effects. No information concerning renal effects in humans
following dermal exposure to di-n-butyl phthalate was located.
Histological evidence of slight kidney damage was noted in rabbits after
90 days of dermal application of 4,200 mg/kg/day (Lehman 1955). No
details about the study or specifics about the type of kidney damage
were given. In this study, a NOAEL of 2,100 mg/kg/day was identified.
Dermal/Ocular Effects. Some cosmetic preparations containing
di-n-butyl phthalate cause slight irritation to human skin (Cosmetic
Ingredient Review Panel 1985). A single dermal application of
520 mg/kg/day of di-n-butyl phthalate was reported to be slightly
irritating to skin and "quite irritating" to mucous membranes of rabbits
(Lehman 1955). In a 90-day study, doses up to 4,200 mg/kg/day were
described as slightly irritating, and slight dermatitis was reported.
No data were presented, and the no-effect level was not given.
Other Systemic Effects. No studies were located regarding
respiratory, cardiovascular, gastrointestinal, hematological,
musculoskeletal or hepatic effects in humans or animals following dermal
exposure to di-n-butyl phthalate.
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30
2. HEALTH EFFECTS
The highest NOAEL values and all reliable LOAEL values for systemic
effects in each species and duration category are recorded in Table 2-3.
2.2.3.3 Immunological Effects
Di-n-butyl phthalate does not appear to be a skin sensitizer. A
variety of cosmetic materials (e.g., deodorants, nail polish) containing
4.5% to 9% di-n-butyl phthalate were not skin sensitizers when tested on
50 to 250 individuals per sample (Cosmetic Ingredient Review Committee
1985). In a 90-day study in rabbits, there was no indication that
di-n-butyl phthalate was a skin sensitizer (Lehman 1955).
No studies were located regarding the following health effects in
humans or experimental animals after dermal exposure to di-n-butyl
phthalate.
2.2.3.4
Neurological Effects
2.2.3.5
Developmental Effects
2.2.3.6
Reproductive Effects
2.2.3.7
Genotoxic Effects
2.2.3.8
Cancer
2.3 TOXICOKINETICS
2.3.1 Absorption
2.3.1.1 Inhalation Exposure
NO studies were located regarding absorption in taans after
inhalation exposure to dl-n-butyl phthalate. The relatively 1™
concentration of di-n-butyl phthalate found in the lun„ !!v!
to 4.4 ppm of di-n-butyl phthalate for un t-n fi ^ rats exposed
indicate rapid absorption (Kawano 1980b) . However L^tah8?^^ t0
measured in this study, and so the lack of ano.im i '«-• tabolites were
lung metabolism rather than absorption. U & 100 cou*d be due to
2.3.1.2 Oral Exposure
No studies were located regardine ah^mn.n * u
exposure to di-n-butyl phthalate. " unians after oral
-------
TABLE 2—3. Levels of Significant Exposure to Di-n-butyl Phthalate - Dermal
Exposure LOAEL (Effect)
Frequency/ NOAEL Less Serious Serious
Species Duration Effect (mg/kg/d) (mg/kg/d) (mg/kg/d) Reference
ACUTE EXPOSURE
Systemic
Rabbit lx Derm/Oc 520 (slightly Lehman 1955
irritated)
INTERMEDIATE EXPOSURE
Death
Rabbit
Systemic
Rabbit
90 d
90 d Renal
lx/d
4200 (LD 50)
2100 4200 (kidney damage)
Lehman 1955
Lehman 1955
LOAEL " lowest-observed-adverse-effect level: NOAEL — no-observed-adverse-effect level; mg = milligram; kg « kilogram; d » day;
lx - one time; Derm/Oc — Dermal/Ocular; LD50 = lethal dose, 50Z mortality.
EC
m
>
f
H
EC
m
T)
m
n
H
cn
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32
2. HEALTH EFFECTS
Studies in laboratory animals indicate that di-n-butyl phthalate is
rapidly and extensively absorbed by the oral route. Extensive
absorption is indicated by the fact that in rats 63 to 97% of an orally
administered dose was accounted for in the urine within 24 hours after
dosing (Foster et al. 1982; Tanaka et al. 1978; Williams and Blanchfield
1975). Forty-eight hours after dosing, 85 to 100% of an oral dose of
14C-di-n-butyl phthalate was excreted in the urine (Tanaka et al. 1978;
Williams and Blanchfield 1975) . Similar results were obtained in
hamsters, where 79% of an orally administered dose of 1AC-di-n-butyl
phthalate was excreted in the urine within 24 hours (Foster et al.
1982). In vitro studies indicate that a metabolite of di-n-butyl
phthalate, monobutyl phthalate, is probably the main form absorbed
through the intestine (Lake et al. 1977; Takahashi and Tanaka 1989).
2.3.1.3 Dermal Exposure
No studies were located regarding absorption in humans after dermal
exposure to di-n-butyl phthalate, although in vitro studies using human
skin indicate that slow absorption by this route might occur (Scott
et al. 1987).
In rats, 10 to 12% of a dermal dose was excreted in the urine each
day for several days, reaching a total of 60% after 1 week (Elsisi
et al. 1989). These data suggest that di-n-butyl phthalate is
reasonably well absorbed at a constant rate across the skin.
2.3.2 Distribution
2.3.2.1 Inhalation Exposure
No studies were located regarding distribution in humans after
inhalation exposure to di-n-butyl phthalate.
In rats exposed to di-n-butyl phthalate by inhalation for 3 or
6 months, di-n-butyl phthalate was detected in all organs examined from
rats exposed at 4.4 ppm (Kawano 1980b). The highest concentrations were
found in brain, followed by lunS> kidney, testicles, and liver (Kawano
1980b). Organ concentrations varied considerably between rats. At
exposure to 0.044 ppm, di-n-butyl phthalate was consistently detected
only in brains of exposed rats (Kawano 1980b).
2.3.2.2 Oral Exposure
No studies were located regarding distribution in humans after oral
exposure to di-n-butyl phthala^-e-
Studies in rats on the distribution of 1AC-labeled di-n-butyl
phthalate indicate that it is distributed throughout the body and that
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33
2. HEALTH EFFECTS
no significant retention occurs in any organ (Tanaka et al. 1978;
Williams and Blanchfield 1975). Evaluation of tissues for UC at
intervals from 4 to 48 hours after dosing showed no accumulation. At
all of the time points evaluated^ no organ contained more than 0.7% of
the administered dose (Williams and Blanchfield 1975). Even when rats
were fed 0.1% di-ri-butyl phthalate in the diet for up to 12 weeks, no
accumulation in any organs was observed (Williams and Blanchfield 1975).
2.3.2.3 Dermal Exposure
No studies were located regarding distribution in humans following
dermal exposure to di-n-butyl phthalate.
A study in rats indicated that there was little or no accumulation
of di-n-butyl phthalate in the body 7 days after a single dermal
application of 44 mg/kg of 14C-labeled di-n-butyl phthalate (Elsisi
et al. 1989). Though approximately 65% of the dose had been absorbed
and eliminated, only small amounts were found in tissues. Of the
administered dose, 1.4% was in the skin, 1.1% in muscle, and 0.41% in
adipose tissue. All other tissues combined contained less than 0.5% of
the dose. About 33% of the dose remained at the site of application.
2.3.3 Metabolism
2.3.3.1 Inhalation Exposure
No studies were located regarding metabolism in humans or animals
following inhalation exposure to di-n-butyl phthalate.
2.3.3.2 Oral Exposure
No studies were located regarding di-n-butyl phthalate metabolism
in humans. Studies in animals indicate that metabolism of di-n-butyl
phthalate proceeds mainly by hydrolysis of one butyl ester bond to yield
monobutyl phthalate (MBP). The product that appears in the urine is
mainly MBP conjugated with glucuronic acid, with lower levels of
unconjugated MBP, various oxidation products of MBP, and a small amount
of the free phthalic acid (Figure 2-3) (Albro and Moore 1974; Foster
et al. 1982; Kawano 1980b; Tanaka et al. 1978; Williams and Blanchfield
1975).
Species differences in the excretion of conjugated and unconjugated
di-n-butyl phthalate in the urine of rats and hamsters have been
identified by Foster et al. (1982). Rats excreted a larger proportion
(14%) of the administered dose as unconjugated MBP than hamsters, in
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34
2. HEALTH EFFECTS
COO(CH2)3CH3
COO(CH2)3CH3
Di-n-butyl Phthalate (DBP)
1
COOH
COOH
COOH
COO(CH2)3CH3
COO Glucuronide
COO(CH2)3CH3
Phlhalic Acid
Monobulyl Phthalate (MBP)
MBP Glucuronide
COOH
COOH
COO(CHa)aCHOHCH,
coo(ch2)2chohch3 coo(ch2)3ch3oh
3-Hydroxy-butyl Phthalate 4-Hydroxy-butyl Phthalate
COOH
COOH
COO(CH2)2COCH3 COO(CH2)3COOH
3-Keto-butyl Phthalate 4-Carboxypropyl Phthalate
FIGURE 2-3. Metabolic Scheme for Di-n-butyl Phthalate In Animals
Source: Adapted from Albro and Moore 1974; Foster et al. 1982; Tanaka et al. 1978.
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35
2. HEALTH EFFECTS
which only 3.5% was excreted unconjugated. The authors indicated that
this difference might explain why exposure to di-n-butyl phthalate
causes greater testicular damage in rats than in hamsters (see
Section 2.2.2.6.)
2.3.3.3 Dermal Exposure
No studies were located regarding metabolism in humans and animals
following dermal exposure to di-n-butyl phthalate.
2.3.4 Excretion
2.3.4.1 Inhalation Exposure
No studies were located regarding excretion in humans or animals
following inhalation exposure to di-n-butyl phthalate.
2.3.4.2 Oral Exposure
No studies were located regarding excretion in humans following
oral exposure to di-n-butyl phthalate.
Studies in laboratory animals (rats, hamsters and guinea pigs)
indicate that 63 to 97% of an oral dose of di-n-butyl phthalate is
eliminated in the urine within 24 hours, with 85 to 100% recovered by
48 hours (Foster et al. 1982; Tanaka et al. 1978; Williams and
Blanchfield 1975). The fraction of the dose that was not accounted for
in the urine was present in the feces. Excretion was essentially
complete by 48 hours after administration of a single oral dose (Tanaka
et al. 1978).
2.3.4.3 Dermal Exposure
No studies were located regarding excretion in humans following
dermal exposure to di-n-butyl phthalate.
In rats, following a single dermal application of ^C-labeled
di-n-butyl phthalate, 10-12% of the administered dose was excreted in
urine and 1% was excreted in the feces (Elsisi et al. 1989). Seven days
after application, 60% of the applied dose had been excreted.
2.4 RELEVANCE TO PUBLIC HEALTH
Toxic effects caused by di-n-butyl phthalate exposure have not been
well characterized in humans. Based on the findings in animal studies,
toxic effects in humans would not be expected at typical exposure
levels, since effects in animals were seen only at very high doses (1-2%
di-n-butyl phthalate in the diet in oral studies).
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36
2. HEALTH EFFECTS
In animals, the main target for di-n-butyl phthalate is the
reproductive system. In males, atrophy of the seminiferous tubules and
decreased sperm counts have been observed in several species, with the
more sensitive species being those with less ability to conjugate the
primary metabolite of di-n-butyl phthalate. The testicular effects
observed were dose-related and were, at least in part, reversible
Developmental effects have also been observed. Di-n-butyl phthalate has
been demonstrated to be fetotoxic in rats and mice, and limited data
indicate that di-n-butyl phthalate may also be teratogenic.
Death. In laboratory animals, the oral LD50 from a single dose was
estimated to be between 20,000 and 25,000 mg/kg for the rat, with some
deaths occurring at 10,000 mg/kg (White et al. 1983). An LD10 of
2,500 mg/kg was identified in mice (Hardin et al. 1987). None of the
acute studies provided details about cause of death. No human deaths
have been reported as a result of exposure to di-n-butyl phthalate
Considering the high LD50 values for animals, it is unlikely that a
human would accidentally ingest an amount of di-n-butyl phthalate that
would be fatal.
Systemic Effects. A number of studies in animals indicate that di-
n-butyl phthalate may interfere with energy metabolism in liver
mitochondria, both in vivo (Murakami et al. 1986a, 1986b), and in vitrn
(Inouye et al. 1978; Melnick and Schiller 1985). Exposure in vivo
accompanied by an increased number of mitochondria in liver cells
suggesting a compensation for the inhibiting effects of di-n-butyl
phthalate (Murakami et al. 1986a). Zonal and focal necrosis of liver
cells was also observed in one study (Murakami et al. 1986a). This
could be related to the inhibition of mitochondrial activity, since when
the energy needs of cells cannot be met, the cells die. No di-n-butyl
phthalate associated liver injury has been reported in humans.
Several animal studies indicate that the kidney is not
significantly affected by di-n-butyl phthalate (Kawano 1980a; Nikonorow
et al. 1973; Oishi and Hiraga 1980a). Slight changes in kidAey weight
have been associated with oral exposure to di-n-butyl phthalate in rats
or mice (BIBRA 1986; Oishi and Hiraga 1980a), but in the absence of
other data, this does not constitute evidence of injury.
Exposure to di-n-butyl phthalate can decrease body weight in
animals (BIBRA 1986; Gray et al. 1982; Kawano 1980a; Nikonorow et al
1973), but this is generally not considered a sensitive or specific
indicator of toxicity.
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37
2. HEALTH EFFECTS
Immunological Effects. In human dermal sensitization studies,
cosmetic preparations containing di-n-butyl phthalate did not cause skin
sensitization. Negative results were also noted in rabbits (Cosmetic
Ingredient Review Committee 1985; Lehman 1955).
Neurological Effects. Limited evidence suggests that exposure of
humans to high levels of di-n-butyl phthalate may cause neurological
symptoms such as dizziness, pain, and numbness (Milkov et al. 1973).
Increased brain weight was found in rats following 6 months of
inhalation exposure to di-n-butyl phthalate (Kawano 1980a), but the
clinical relevance of this observation is not clear. Available studies
in animals do not suggest that the nervous system is a target organ
following oral exposure to di-n-butyl phthalate, but this has not been
formally investigated.
Developmental Effects. No developmental effects of di-n-butyl
phthalate have been reported in humans. In animals, di-n-butyl
phthalate has been demonstrated to be toxic to fetuses (Hardin et al.
1987; Killinger et al. 1988a,b; Nikonorow et al. 1973; Shiota et al.
1980; Shiota and Nishimura 1982). In some, but not all, cases, fetal
toxicity may have been related to maternal toxicity. Di-n-butyl
phthalate given to females during pregnancy resulted in an increased
number of resorptions and a decreased number of viable litters. In one
study in mice, di-n-butyl phthalate was reported to cause teratogenic
effects (Shiota and Nishimura 1982) , but teratogenicity has not been
observed in other developmental studies. Since the data are limited and
inconsistent, it is not possible to judge conclusively whether di-n-
butyl phthalate is a teratogen or not.
Reproductive Effects. High oral doses of di-n-butyl phthalate at
acute and intermediate exposure durations affect male reproductive
systems of rats and guinea pigs. Effects include decreased testes
weight, decreased number of spermatocytes and degeneration of the semi-
niferous tubules of the testes (BIBRA 1986; Cater et al. 1977; Gray
et al. 1982; Murakami et al. 1981a, 1986b; Oishi and Hiraga 1980b;
Tanino et al. 1987). Limited data suggest that exposure to di-n-butyl
phthalate may be associated with decreased sperm density in humans as
well (Murature et al. 1987), but this is not certain. Three weeks after
discontinuation of di-n-butyl phthalate administration to rats,
regeneration of seminiferous tubules and active spermatogenesis were
observed, suggesting these effects may be reversible (Tanino et al.
1987). In contrast to rats and guinea pigs, mice and Syrian hamsters
are relatively resistant to the testicular effects of di-n-butyl
phthalate (Gray et al. 1982). The basis of this species variation is
not known, but could be related to species differences in the ability to
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38
2. HEALTH EFFECTS
conjugate the primary metabolite of di-n-butyl phthalate (Foster et al.
1982) . Since no information was located concerning human metabolism of
di-n-butyl phthalate, the relevance of these observations to public
health is unknown.
Di-n-butyl phthalate also has adverse effects on reproduction in
females. Mice fed 1,300 mg/kg/day in the diet for 4 months before and
during breeding had fewer live pups per litter and a lower proportion of
pups born alive (Lamb et al. 1987; Reel et al. 1987). Similarly,
exposure of rats or mice to doses of about 1,000 mg/kg/day of di-n-butyl
phthalate in the diet during gestation resulted in marked increases in
fetal and neonatal mortality (Killinger et al. 1988a, 1988b). These
effects did not appear to be a result of maternal toxicity, indicating
that the fetus is more sensitive to di-n-butyl phthalate than the dam.
Still, it should be noted that significant fetotoxicity occurred only at
very high dose rates, and it does not seem likely that this effect is of
concern to humans exposed to the low levels of di-n-butyl phthalate
typically encountered in air, food or water.
Genotoxic Effects. Available in vitro genotoxicity data are
summarized in Table 2-4. Di-n-butyl phthalate has tested negative or
marginally positive in gene mutation and chromosomal aberration studies.
These results suggest that di-n-butyl phthalate may be weakly mutagenic
in vitro¦ The significance of these findings to the intact mammalian
organism is not known because in vivo genotoxicity studies have not been
conducted.
Cancer. The carcinogenic potential of di-n-butyl phthalate has not
been thoroughly studied. An early investigation did not detect any
carcinogenic effects in rats exposed for 15 to 21 months to doses of 100
to 500 mg/kg/day in the diet (Krauskopf 1973), but the data were too
limited and the doses were too low to draw a firm conclusion.
Carcinogenicity studies on other phthalate esters have been mostly
negative or equivocal, although there is sufficient evidence in animals
to conclude that di-ethyl hexyl phthalate (DEHP) causes hepatocellular
carcinomas in rats and mice (EPA 1987). The significance of this
observation to cancer risk of di-n-butyl phthalate is uncertain.
Consequently, it is not possible to evaluate the carcinogenic risk of
di-n-butyl phthalate to humans without more investigation.
2.5 BIOMARKERS OF EXPOSURE AND EFFECT
Biomarkers are broadly defined as indicators signaling events in
biologic systems or samples. They have been classified as markers of
exposure, markers of effect, and markers of susceptibility (NAS/NRC
1989).
-------
TABLE 2-4. Geootozicitj of Di-n-butyl Phthalate In Vitro
Results
End Point
Species (Test System)
With
Activation
Without
Activation
Reference
Prokaryotic organisms:
Gene mutation
Eukaryotic organisms:
Fungi:
Gene mutation
Mammalian cells:
Gene mutation
Chromosomal aberrations
Ce11 trans format ion
Salmonella typhimurium
S. typhlmurlum
S. typhimurium
Saccharomyces
cerevisiae
Mouse lymphoma
Chinese hamster
ovary cells
Balb 3T3
No data
No data
( + )
( + )
Florin et al. 1980;
Rubin et al. 1979;
Zeiger et al. 1985
Seed 1982
Agarwal et al. 1985
Shahin and Borstel
1977
Hazleton Biotech-
nologies 1986
Ishidati and
Odashima 1977
Litton Bionetics
1985a
a
S
r
H
sc
w
w
o
H
Xfl
u>
negative result: (+) = marginally positive; + = positive result.
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40
2. HEALTH EFFECTS
A biomarker of exposure is a xenobiotic substance or Its
metabolite(s) or the product of an interaction between a xenobiotic
agent and some target molecule or cell that is measured within a
compartment of an organism (NAS/NRC 1989). The preferred biomarkers of
exposure are generally the substance itself or subs tance - spec, i fi c
metabolites in readily obtainable body fluid or excreta. However,
several factors can confound the use and interpretation of biomnrkors of
exposure. The body burden of a substance may be the result of exposures
from more than one source. The substance being measured may be a
metabolite of another xenobiotic (e.g., high urinary levels of phenol
can result from exposure to several different aromatic compounds).
Depending on the properties of the substance (e.g., biologic half-life)
and environmental conditions (e.g., duration and route of exposure), the
substance and all of its metabolites may have left the body by the time
biologic samples can be taken. It may be difficult to identify
individuals exposed to hazardous substances that are commonly found in
body tissues and fluids (e.g., essential mineral nutrients such as
copper, zinc and selenium). Biomarkers of exposure to di-n-butyl
phthalate are discussed in Section 2.5.1.
Biomarkers of effect are defined as any measurable biochemical,
physiologic, or other alteration within an organism that, depending'on
magnitude, can be recognized as an established or potential health
impairment or disease (NAS/NRC 1989). This definition encompasses
biochemical or cellular signals of tissue dysfunction (e.g., increased
liver enzyme activity °r pathologic changes in female genital epithelial
cells), as well as phys^-°l°gic s^-Sris of dysfunction such as increased
blood pressure or decfea®e(i lung capacity. Note that these markers are
often not substance spe(^fic. They also may not be directly adverse,
but can indicate potential health impairment (e.g., DNA adducts).
Biomarkers of effects caused by di-n-kuty^ phthalate are discussed in
Section 2.5.2.
A biomarker of susceptibility an indicator of an inherent or
acquired limitation of fn organism s ability to respond to the challenge
of exposure to a specif10 Xeno iotic. it can be an intrinsic genetic or
other characteristic a Preexisting disease that results in an
increase in absorbed ciose> bio °gically effective dose, or target tissue
response. If exist' they are discussed in
Section 2.7, "POPULATlON ThaT RE UNUSUALLY SUSCEPTIBLE."
2,5.1 Biomarkers Used to identify and/or Quantify Exposure to
Di-n-butyl Pht*1® te
The presence of "^Di-n has been reported in a number
of human tissues and * f ¦ sUr Phthalate has been found in
adipose tissue obtain gg lirjij Procedures or autopsies (Mes
et al. 1974; Stanley 1 J • 1 Pld-rich atherosclerotic plaques
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41
2. HEALTH EFFECTS
(Ferrario et al. 1985), in seminal fluid (Murature et al. 1987), and in
blood serum (Ching et al. 1981a; Stanley 1986). No study identified the
source, amount, or duration of exposure to di-n-butyl phthalate
associated with levels in the body. A study comparing surgical patients
having known plasticizer exposure from intravenous bags and tubing with
controls without known exposure found no correlation between exposure
and serum levels of di-n-butyl phthalate (Ching et al. 1981a). There
was no quantitative relationship between the concentration of di-n-butyl
phthalate in seminal fluid and sperm count (Murature et al. 1987).
Thus, measurements of di-n-butyl phthalate in body tissues and fluids
can indicate that exposure has taken place, but not the amount or
duration of exposure.
2.5.2 Biomarkers Used to Characterize Effects Caused by Di-n-butyl
Phthalate
Effects caused by di-n-butyl phthalate exposure in animals include
liver changes and effects on development and reproduction. None of
these effects appear to be specific to di-n-butyl phthalate exposure.
Liver changes, such as altered enzymatic activity and peroxisome
proliferation, are induced by many other chemicals (Popp et al. 1989).
Testicular effects may be due to interference with zinc metabolism,
which can also be caused by exposure to cadmium, manganese, and other
substances (Foster et al. 1980). These and other effects associated
with di-n-butyl phthalate exposure do not appear to be sufficiently
specific to serve as biomarkers of effects.
2.6 INTERACTION WITH OTHER CHEMICALS
Administration of zinc provides some protection against the
testicular toxicity of di-n-phthalate exposure in rats (Cater et al.
1977). No other studies were located regarding the interaction of
di-n-butyl phthalate with other chemicals. Schulsinger and Mullgaard
(1980) reported that humans exposed to a mixture of three phthalate
esters, including di-n-butyl phthalate, did not develop dermal
sensitization, but since di-n-butyl phthalate is negative for skin
sensitization, these results shed little light on possible interactions.
2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE
There are no data in humans to suggest that any segment of the
human population is unusually susceptible to the effects of di-n-butyl
phthalate. However, in studies in animals, fetal death was reported at
dietary levels at which the mothers survived. This suggests that the
fetus may be somewhat more susceptible to di-n-butyl phthalate than the
adult, and that it may be prudent to consider pregnant females more
susceptible to di-n-butyl phthalate than other adults.
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42
2. HEALTH EFFECTS
2,8 ADEQUACY OF THE DATABASE
Section 104(i)(5) of CERCLA, directs the Administrator of ATSDR (in
consultation with the Administrator of EPA and agencies and programs of
the Public Health Service) to assess whether adequate information on the
health effects of di-n-butyl phthalate is available. Where adequate
information is not available, ATSDR, in conjunction with the National
Toxicology Program (NTP), is required to assure the initiation of a
program of research designed to determine the health effects (and
techniques for developing methods to determine such health effects) of
di-n-butyl phthalate.
The following categories of possible data needs have been
identified by a joint team of scientists from ATSDR, NTP, and EPA. They
are defined as substance-specific informational needs that, if met would
reduce or eliminate the uncertainties of human health assessment. In
the future, the identified data needs will be evaluated and prioritized,
and a substance-specific research agenda will be proposed.
2.8.1 Existing Information on Health Effects of Di-n-butyl Phthalate
The existing data on health effects of inhalation, oral, and dermal
exposure of humans and animals to di-n-butyl phthalate are summarized in
Figure 2-4. The purpose of this figure is to illustrate the existing
information concerning the health effects of di-n-butyl phthalate. Each
dot in the figure indicates that one or more studies provide information
associated with that particular effect. The dot does not imply anything
about the quality of the study or studies. Gaps in this figure should
not be interpreted as "data needs" information. Limited data are
available on effects in humans, consisting of an occupational study of
workers exposed to mixtures of plasticizers and dermal sensitization
studies conducted to evaluate the effects of di-n-butyl phthalate in
cosmetic products. Data from animal studies are more extensive. As a
result of early findings on testicular effects of di-n-butyl phthalate,
most studies have tended to concentrate mainly on developmental and
reproductive effects. A few studies provide data on systemic effects,
but since these appear to be minor, research in this area has not been
extensive. No data are available on the chronic effects of di-n-butyl
phthalate, or on its carcinogenic potential.
2.8.2 Identification of Data Needs
Acute-Duration Exposure. The male reproductive system appears to
be the most sensitive target organ for acute-duration oral exposure to
di-n-butyl phthalate in animals. However, acute-duration experiments on
developmental toxicity of di-n-butyl phthalate did not establish a
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43
2. HEALTH EFFECTS
SYSTEMIC
Inhalation
Oral
Dermal
HUMAN
SYSTEMIC
<§»
Inhalation
Oral
Dermal
ANIMAL
Existing Studies
FIGURE 2- 4. Existing Information on Health Effects of
Di-n-Butyl Phthalate
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44
2. HEALTH EFFECTS
threshold (Hardin 1987) so it is possible that developmental rather than
reproductive toxicity may be the critical effect for acute-duration
exposure. A LOAEL of 1,000 mg/kg/day was established for decreased
testis weight in rats following 7 days of gavage exposure (Oishi and
Hiraga 1980a); however, only one dose level was used in this study and
so the threshold for the effect is not reliably identified and no acute
oral MRL could be derived. The mechanism of testicular damage by
di-n-butyl phthalate may involve interference with zinc metabolism
(Foster et al. 1980), and further investigations to establish the
mechanism would assist in assessing the relevance of animal toxicity to
human risk. No information was located on effects in humans of acute -
duration oral exposure. Systemic effects caused by acute-duration oral
exposure in animals are generally mild, and include changes in liver and
kidney weight and changes in biochemical parameters. No information was
located concerning target organs following acute-duration inhalation or
dermal exposure to di-n-butyl phthalate in animals or humans, and no
acute inhalation MRL could be derived. Additional information
concerning the target organs and mechanism of toxicity of di-n-butyl
phthalate exposure by the inhalation, oral, and dermal routes would be
useful to assess the risks to populations surrounding hazardous waste
sites that might be exposed to di-n-butyl phthalate for brief periods.
Intermediate-Duration Exposure. For intermediate-duration oral
exposure to di-n-butyl phthalate, the developing fetus and the female
reproductive system appear to be the most sensitive target systems. An
intermediate oral MRL was derived based on decreased body weights of
offspring of female rats exposed during pregnancy and lactation for
48 days at dos&s of 125 mg/kg/day or more in the diet (Killlnger et al.
1988a). No information was located concerning the mechanism of
developmental toxicity, and such data would be useful to assist in
extrapolating the human developmental or reproductive toxicity of
di-n-butyl phthalate exposure. Systemic effects caused by intermediate -
duration oral exposure animals are primarily effects on the liver
(changes in enzyme activity, peroxisome proliferation), and inhalation
exposure causes changes in organ weights. Studies of toxicity using the
inhalation and dermal routes of exposure would be valuable tn
establishing the levels causing developmental or reproductive toxicity
in animals by these routes. Additional information concerning the
target organs and mechanism of toxicity of di-n-butyl phthalate exposure
by the inhalation, oral, and dermal routes would be useful to assess the
risks to populations surrounding hazardous waste sites that might be
exposed to di-n-butyl phthalate for intermediate durations.
Chronic-Duration Exposure and Cancer. No information was located
concerning the toxic effects of chronic-duration exposure to di-n-butyl
phthalate in humans or animals by any route of exposure. Studies to
establish the target organs and levels causing effects following
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45
2. HEALTH EFFECTS
chronic-duration exposure to di-n-butyl phthalate by inhalation, oral
and dermal exposure would be useful to assess the risks to populations
surrounding hazardous waste sites that might be exposed to di-n-butyl
phthalate for long periods of time.
No information was located indicating that di-n-butyl phthalate is
carcinogenic to humans or animals. A study of carcinogenicity of
dietary exposure in rats and mice is planned (Section 2.8.3). When
results of this study become available, they may suggest areas where
additional information would be useful for evaluating carcinogenic
potential, such as route dependence, mechanism of action, and species
specificity.
Genotoxiclty. A limited number of in vitro tests for genotoxicity
suggest that di-n-butyl phthalate may have weak genotoxic potential. No
in vivo studies have been conducted. In vivo genotoxicity studies would
be valuable in determining whether di-n-butyl phthalate has mutagenic
potential and, if so, what the possible mechanism of genotoxicity might
be.
Reproductive Toxicity. Oral exposure to di-n-butyl phthalate
causes testicular damage in male animals. Species differences are
apparent, with rats being more sensitive than mice. Limited information
suggests that testicular damage may not occur following inhalation
exposure in rats. Reproduction studies in rats and mice have shown that
oral di-n-butyl phthalate exposure has toxic effects on female
reproductive ability. No information is available on the effects of
di-n-butyl phthalate exposure on human reproduction, or on the effects
following dermal exposure in animals. A study of reproductive toxici ty
of dietary exposure in rats is planned (Section 2.8.3). After this
study is completed, it will be possible to identify additional work
where information would be useful to provide better understanding of the
mechanism of action of di-n-butyl phthalate on male and female
reproduction, route dependence, multi-generation effects, and species
differences. Such information would be useful to assess the
significance of the animal results to human reproductive risk.
Developmental Toxicity. Studies in rats and mice have shown that
oral di-n-butyl phthalate exposure of pregnant females is toxic to
fetuses, and one study in mice suggested that high levels of exposure to
di-n-butyl phthalate may be teratogenic. No data were located
concerning developmental effects in humans or by routes other than oral
in animals. A study of developmental toxicity of dietary exposure in
rats is planned (Section 2.8.3). Evaluation of the results of this
study may indicate areas where additional information concerning
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46
2. HEALTH EFFECTS
mechanism of developmental toxicity, species specificity, and route
dependence would be valuable to characterize the potential for
di-n-butyl phthalate exposure to cause developmental toxicity in humans.
Immunotoxicity. There are a number of studies in humans and
animals which indicate that di-n-butyl phthalate is not a skin
sensitizing agent following dermal exposure. Inhalation exposure does
not appear to cause immunologic effects, but only limited end points
have been investigated. No studies were located using oral exposure or
assessing the effects of di-n-butyl phthalate on other aspects of the
immune system. Tests of several additional endpoints of humoral and
cell-mediated immune function would be valuable in assessing the
sensitivity of this system to di-n-butyl phthalate.
Neurotoxicity. Limited data in humans suggest that high level
inhalation exposure to di-n-butyl phthalate may have the potential to
cause neurological damage. Additional studies designed to test for
neurological effects in animals would be useful to assess the levels of
di-n-butyl phthalate capable of causing neurotoxicity.
Epidemiological and Human Dosimetry Studies. Very limited
epidemiological studies have been performed, and generally involved
exposure to a mixture of plasticizets at poorly-characterized levels.
Studies of people occupationally exposed to di-n-butyl phthalate would
be valuable in assessing the effects of di-n-butyl phthalate on human
health. Since the most significant effects in animals are on
spermatogenesis and reproduction, epidemiology studies of reproductive
parameters in humans exposed to di-n-butyl phthalate would be
particularly relevant. Such studies would be most valuable if dosimetry
methods could be developed to provide reliable exposure data to
accompany health effects data. This would assist in establishing
cause/effect relationships and developing methods to monitor individuals
living near hazardous waste sites.
Biomarkers of Exposure and Effect The presence and concentration
of di-n-butyl phthalate can be measurea £n a variety of biological
tissues and fluids, but no information was located which would allow
correlation of body levels with s°utce route, amount, or duration of
exposure to di-n-butyl phthalate- The primary metabolite of di-n-butyl
phthalate in several species is monobutyl phthalate, and so monobutyl
phthalate or its glucuronide conjug^te couid possibly serve as a
specific biomarker of exposure to ^l-n-butyl phthalate. Additional
studies to determine the relati°nshlp between body levels of di-n-butyl
phthalate and monobutyl phthalate ar\d exposure would be valuable to
develop methods for identifying ant* monitoring populations with high
exposure to di-n-butyl phthalate.
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47
2. HEALTH EFFECTS
No known biomarkers of effect of di-n-butyl phthalate were
identified. Studies to identify some early indication of impending
injury to the male and female reproductive systems, perhaps based on the
interference of zinc metabolism, would be valuable in assessing likely
health consequences in people with above-average exposure to di-n-butyl
phthalate.
Absorption, Distribution, Metabolism, and Excretion. Studies in
laboratory animals indicate that di-n-butyl phthalate given orally is
readily absorbed, mainly as the metabolite monobutyl phthalate, and
subsequently is rapidly excreted. Limited data exist regarding
inhalation and dermal absorption. Studies on the absorption and
metabolism of di-n-butyl phthalate by the inhalation and dermal routes
would be valuable in evaluating human health risk by these routes of
exposure.
Comparative Toxicokinetics. Syrian hamsters appear to be
relatively resistant to the testicular effects of di-n-butyl phthalate
compared to the rat. A comparative metabolic study with rats and
hamsters indicated some quantitative differences between the two species
with respect to the excretion of metabolites in the urine. Additional
comparative studies, perhaps with other species, may add to our
understanding of the mechanisms of toxicity to the male reproductive
organs. Since it is well known that there are a wide variety of
esterases with varying affinity for different substrates, further
information on the substrate specificities of the esterases in various
species could help to understand the biological mechanisms behind the
species differences in response to di-n-butyl phthalate.
2.8.3 On-going Studies
Information located concerning on-going studies with di-n-butyl
phthalate is summarized in Table 2-5. These include studies to evaluate
the mutagenic and carcinogenic potential of di-n-butyl phthalate, as
well as effects on reproduction and development.
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48
2. HEALTH EFFECTS
TABLE 2-5. On-going Studies on Di-n-butyl Phthalate
Investigator
Affiliation
Research
Description
Sponsor
A.C. Peters
Batelle
Memorial
Institute
Prechronic
dietary study
in mice and rats
NIEHS
Batelle
Memorial
Institute
Carcinogenicity
study in rats
and mice (planned)
Reproductive/
developmental
toxicity in rats
NIEHS
ATSDR/NTP
NIEHS = National Institute of Environmental Health Sciences; ATSDR
Agency for Toxic Substances and Disease Registry; NTP = National
Toxicology Program.
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49
3. CHEMICAL AND PHYSICAL INFORMATION
3.1 CHEMICAL IDENTITY
Table 3-1 lists common synonyms, trade names and other pertinent
identification information for di-n-butyl phthalate.
3.2 PHYSICAL AND CHEMICAL PROPERTIES
Table 3-2 lists important physical and chemical properties of
di-n-butyl phthalate.
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50
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-1. Chemical Identity of Di-n-butyl Phthalate
Value
Reference
Chemical name
Synonyms
Trade names
Chemical formula
Chemical structure
Identification numbers:
CAS Registry
NIOSH RTECS
EPA Hazardous Waste
OHM/TADS
DOT/UN/NA/IMCO shipping
HSDB
NCI
Di-n-butyl phthalate
Butylphthalate;
dibutylphthalate;
DBP; 1,2-benzene -
dicarboxylic acid,
dibutyl ester
Caswell No. 292 ;
Celluflex DBP;
Polycizer DBP;
Staflex DBP;
Uniflex DBP
C16H22C>4
O
O H H H H
i< I i i I
C-O-C-C-C-C-H
i i i i
H H H H
H H H H
I i I i
C-O-C-C-C-C-H
II III!
o H H H H
84-74-2
TI0875000
U069
7216617
NA9095
922
No data
NLM 1988
NLM 1988
NLM 1988
NLM 1988
NLM 1988
HSDB 1988
NLM 1988
HSDB 1988
NLM 1988
NLM 1988
CAS - Chemical Abstracts Service; NIOSH - National Institute for
Occupational Safety and Health; RTECS - Registry of Toxic Effects of
Chemical Substances; EPA - Environmental Protection Agency; OHM/TADS -
Oil and Hazardous Materials/Technical Assistance Data System;
DOT/UN/NA/IMCO - Department of Transportation/United Nations/North
America/International Maritime Dangerous Goods Code; HSDB - Hazardous
Substances Data Bank; NCI - National Cancer Institute.
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51
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-2. Physical and Chemical Properties of Di-n-butyl Phthalate
Property
Value
Reference
Molecular weight
Color
Physical state
Melting point
Boiling point
Density at 20°C
Odor
Odor threshold:
Water
Air
Solubility;
Water at 20°C
Organic solvents
Partition coefficients:
Log octanol/water
Log Koc
Vapor Pressure at 25°C
Henry's law constant
Autoignition temperature
Flashpoint
Flanmiability limits
Conversion factors
278.35
Colorless to
faint yellow
Oily liquid
-35°C
340°C
1.047
Odorless
to slight ester
odor
Odorless
Odorless
8.7-13 mg/L
Soluble in alcohol,
ether, benzene
4.72-5.60
5.23
1. OxlO"5-1. 4xl0~5 mmHg
2 . 8xl0~7-4. 6xl0~7
atm-m3/niol
398.8®C
171°C
157.22°C
lower: 0.5% at 235°C
1 ppm - 11.4 mg/m3
1 mg/m3 - 0.088 ppm
Weast 1985
Verschueren 1983
HSDB 1988
Verschueren 1983
Verschueren 1983
Weast 1985
Weast 1985
Sax and Lewis
1987; HSDB 1988
DeFoe et al. 1990
Weast 1985
Mabey et al.
1982; Howard 1989
Mabey et al. 1982
Mabey et al.
1982; Howard 1989
Mabey et al.
1982; Howard 1989
Sax and Lewis
1987
Sax and Lewis
1987
ACGIH 1986
HSDB 1988
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53
4. PRODUCTION, IMPORT, USE, AND DISPOSAL
4.1 PRODUCTION
Di-n-butyl phthalate is produced commercially by the esterification
of phthalic anhydride with n-butyl alcohol in the presence of
concentrated sulfuric acid as a catalyst. Excess alcohol is recovered
and recycled and the di-n-butyl phthalate is purified by vacuum
distillation and/or activated charcoal (HSDB 1988; Perwak et al. 1981).
Production volumes published for di-n-butyl phthalate usually also
include the production volumes for diisobutyl phthalate. The available
data indicate that production of these compounds peaked at 17,200 kkg in
1973, dipped sharply to 5,600 kkg in 1975, and then increased gradually
to 11,400 kkg in 1987 (Perwak et al. 1981; USITC 1988).
Currently there are eight producers of di-n-butyl phthalate in the
United States: Aristech Chemical Corp., Neville Island, Pennsylvania;
BASF Corp., Kearny, New Jersey; Mobay Corp., Carteret, New Jersey;
Eastman Kodak Co., Kingsport, Tennessee; Hatco Corp., Fords, New Jersey;
Nuodex, Inc., Chestertown, Maryland; Union Camp Corp., Dover, Ohio; and
Unitex Chemical Co., Greensboro, North Carolina (SRI 1988; USITC 1988).
4.2 IMPORT
Imports of di-n-butyl phthalate were 747 kkg in 1977 and 303 kkg in
1981. No quantitative data were located on exports of di-n-butyl
phthalate. However, total phthalate ester exports in 1977 were
42,500 kkg and di-n-butyl phthalate is estimated to be about 1% of total
phthalate production. On that basis, about 425 kkg of di-n-butyl
phthalate were probably exported in 1977 (HSDB 1988; Perwak et al.
1981).
4.3 USE
Di-n-butyl phthalate is used primarily as a specialty plasticizer
for nitrocellulose polyvinyl acetate and polyvinyl chloride. It has
been used in plastisol formulations for carpet back coating and other
vinyl compounds. Di-n-butyl phthalate has also been used as an
adjusting agent for lead chromate pigments, as a concrete additive, as
an insect repellant for the impregnation of clothing, as a solvent for
perfume oils, and as a stabilizer in rocket propellants (Perwak et al.
1981; Sax and Lewis 1987; Windholz 1983). In 1977, about 45% of
di-n-butyl phthalate was used for polyvinyl chloride plasticizers, 50%
for other polymers, and 5% for nonplasticizer uses (Perwak et al. 1981).
Current usage information was not located.
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54
4. PRODUCTION, IMPORT, USE, AND DISPOSAL
4.4 DISPOSAL
Since di-n-butyl phthalate is listed as a hazardous substance
disposal of wastes containing di-n-butyl phthalate is controlled by a
number of federal regulations (see Chapter 7). Land disposal
restrictions (treatment/standards) currently apply to di-n-butyl
phthalate wastes. Di-n-butyl phthalate wastes may be incinerated by the
rotary kiln method or other suitable treatment methods (EPA 1.988a,
1989b).
It is estimated that wastes containing 6,300 kkg of di-n-butyl
phthalate were disposed in landfills and 200 kkg of di-n-butyl phthalate
were incinerated in 1977. In addition, 300 kkg of di-n-butyl phthalate
were released to air and 300 kkg to water during production,
transportation, etc. (Perwak et al. 1981).
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55
5. POTENTIAL FOR HUMAN EXPOSURE
5.1 OVERVIEW
Di-n-butyl phthalate is one of the phthalate esters which has been
widely used in making flexible plastics that are found in many common
consumer products, including home furnishings, paints, clothing, and
cosmetic products. Because of its many uses, di-n-butyl phthalate is
widespread in the environment and has been identified at low levels in
air, water, and soil. Therefore, humans may be exposed to di-n-butyl
phthalate both by inhalation and ingestion of water or food containing
di-n-butyl phthalate. Di-n-butyl phthalate has been identified in 47 of
1,177 NPL sites. The frequency of these sites within the United States
can be seen in Figure 5-1.
In air, di-n-butyl phthalate may be adsorbed to particulate matter
or occur as a vapor. Di-n-butyl phthalate is expected to decompose in
the air, or be transferred to water and soil by wet (snow or rain) or
dry (wind and settling) deposition. Di-n-butyl phthalate is taken up
from water by a variety of aquatic organisms. In water and soil,
di-n-butyl phthalate is subject to microbial degradation. Both aerobic
and anaerobic degradation of di-n-butyl phthalate have been reported.
Exposure of the general population to di-n-butyl phthalate may occur
through contact with contaminated air, water, or food.
5.2 RELEASES TO THE ENVIRONMENT
5.2.1 Air
Although di-n-butyl phthalate has low volatility, its widespread
use in many thin polymeric sheets and coatings provides large surface
areas for volatilization during the manufacture, use and disposal of
these products. In addition, disposal at dump sites and disintegration
of the plastics allow for dispersal of small particulates into the air.
It is estimated that 300 kkg of di-n-butyl phthalate were released to
air from these sources in 1977 (Perwak et al. 1981).
5.2.2 Water
Di-n-butyl phthalate may be released into surface waters from
industrial sources (Sheldon and Hites 1979). An estimated 300 kkg of
di-n-butyl phthalate were released to water in 1977 (Perwak et al.
1981).
Di-n-butyl phthalate has also been detected in 5% of the urban
runoff samples from 2 of the 19 cities tested by EPA (Howard 1989).
Concentrations in this urban wastewater ranged from 0.5 to 11 ti%/L.
Sewage sludge has been shown to concentrate di-n-butyl phthalate about
-------
FREQUENCY jj_l jj. II 1 SHE lllllllll 2 TO 3 SITES
6 SITES ¦¦¦ 17 SITES
FIGURE 5-1. Frequency of Sites with Di-n-butyl Phthalate Contamination
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57
5. POTENTIAL FOR HUMAN EXPOSURE
25-fold relative to the starting material. A concentration of 966 /ig/L
sludge was reported by Feiler et al. (1980). Disposal of secondary
sewage effluent by rapid infiltration into the subsurface has been
reported to produce a plume of contaminated groundwater over
3,500 meters long (Barber et al. 1988).
5.2.3 Soil
No specific release of di-n-butyl phthalate to soils has been
reported. Most data on the release of di-n-butyl phthalate to soil
relate to presence of di-n-butyl phthalate in lake, river and ocean
sediments. Di-n-butyl phthalate has been identified in river and ocean
sediments at points of sewage outflow from urban areas (Fallon and
Horvath 1985; Swartz et al. 1983). Also, di-n-butyl phthalate may seep
into soil from di-n-butyl phthalate containing sewage sludge that is
deposited on land.
5.3 ENVIRONMENTAL FATE
5.3.1 Transport and Partitioning
Although di-n-butyl phthalate has low volatility, it has been
reported as particulate in the atmosphere and as a vapor. In the air,
di-n-butyl phthalate is transported from its origin and is subject to
both wet (rain and snow) and dry (wind and settling) deposition on the
earth's surfaces (Atlas and Giam 1981). Eisenreich et al. (1981)
calculated that wet and dry deposition of di-n-butyl phthalate into the
five Great Lakes amounted to 48 kkg per year.
Although di-n-butyl phthalate is only poorly soluble in water, it
may be transported in water following formation of chemical complexes
between di-n-butyl phthalate and humic substances (Callahan et al.
1979). The adsorption of di-n-butyl phthalate onto particulate matter
is greater in salt water than in fresh water (Al-Omnan and Preston
1987). Adsorption onto soil and sediments appear to be a significant
sink for di-n-butyl phthalate. It has been demonstrated that di-n-butyl
phthalate is rapidly adsorbed from seawater onto marine sediment
(Sullivan et al. 1982).
In hazardous waste sites, the presence of common organic solvents
such as alcohols and ketones may increase the solubility of relatively
water insoluble compounds such as di-n-butyl phthalate, thus increasing
the amounts that may leach from the site into the subsoil and into
groundwater. For example, 1-octanol-saturated water increases the
solubility of di-n-butyl phthalate approximately 6 times its normal
water solubility (Nyssen et al. 1987).
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58
5. POTENTIAL FOR HUMAN EXPOSURE
Data indicate that di-n-butyl phthalate can be taken up by a
variety of organisms. Studies using radioactively-labeled di-n-butyl
phthalate have shown a substantial accumulation of radioactivity in
aquatic invertebrates (Sanders et al. 197 3) and fish (Wofford et al.
1980). Most of the accumulated radioactivity is apparently in the form
of the primary metabolite, monobutyl phthalate (Howard 1989). In
greenhouse studies, Shea et al. (1982) demonstrated dose-dependent
uptake of di-n-butyl phthalate from soils into corn, soybean and wheat
seedlings.
5.3.2 Transformation and Degradation
5.3.2.1 Air
In air, di-n-butyl phthalate in vapor form would be expected to
react with hydroxyl radicals with a half-life of about 18 hours (EPA
1987c), but this has not been studied. For di-n-butyl phthalate
adsorbed to airborne particles, the half-life may be considerably
longer, but this also has not been studied.
5.3.2.2 Water
In water, di-n-butyl phthalate may be degraded by several pathways.
A modeling system presented by Wolfe et al. (1980a) predicted that at
steady state nearly all of the di-n-butyl phthalate in a flowing stream
would remain in transit. In a pond, 3% could be expected to be lost by
hydrolysis, 1% by photolysis, 6% by volatilization, and 32% by
biodegradation. Under actual environmental conditions, the rate of
biodegradation in ponds and lakes will depend on conditions (e.g., the
level of degradative organisms present), and could be higher or lower
than this calculated value.
A relatively large number of water microorganisms appear to be
capable of biodegrading di-n-butyl phthalate. In Mississippi River
water, 172 microorganisms per mL of water were found that could utilize
di-n-butyl phthalate. In the delta area there were 55 microorganisms
per mL of water that were capable of degrading di-n-butyl phthalate.
Biodegradation studies of di-n-butyl phthalate in water from 6 sites in
Louisiana, Mississippi and Florida showed that the time to nondetection
was 2 to 27 days (Walker 1984).
In laboratory experiments, the time sequence for degradation of
di-n-butyl phthalate indicated microorganism adaptation (Cripe et al.
1987) . An initial lag phase of 1 to 2 days was followed by rapid loss
of the parent compound. Respiking the water sample with di-n-butyl
phthalate resulted in the rapid disappearance of di-n-butyl phthalate
without a lag period, indicative of the presence of a large induced
microbial population with the ability to degrade di-n-butyl phthalate.
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59
5. POTENTIAL FOR HUMAN EXPOSURE
Activated sludge wastewater treatment systems remove about 90% of
the di-ri-butyl phthalate from the sewage influent. The biodegradation
products have not been identified and may depend on the residence time
in the reaction system (Kurane et al. 1979; 0'Grady et al. 1985;
Petrasek et al. 1983). Under anaerobic conditions, activated sludge
completely degraded di-n-butyl phthalate to carbon dioxide and methane
over a period of 20 days (Hannah et al. 1986).
5.3.2.3 Soil
Microorganisms in soil and sediments appear to be capable of
degrading di-n-butyl phthalate rapidly (Inman et al. 1984; Johnson
et al. 1984; Taylor et al. 1981; Walker et al. 1984). In fortified
river sediment samples, di-n-butyl phthalate was degraded in 2 to
13 days (Walker 1984) , and lake sediment samples degraded di-n-butyl
phthalate in 28 days (Johnson et al. 1984). Inman et al. (1984)
demonstrated that di-n-butyl phthalate in soil was completely degraded
under both aerobic and anaerobic conditions within 100 days.
Johnson et al. (1977) evaluated the degradation of di-n-butyl
phthalate by a variety of soil microorganisms. A number of species
degraded di-n-butyl phthalate only to the monoester, while others
degraded the monoester to phthalic acid. Some microorganisms also
altered phthalic acid, probably via ring hydroxylation. The hydrolysis
of the monoester appeared to be the most difficult step. These data
indicate that degradation is likely to be most extensive in a mixed
microbial population.
5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT
5.4.1 Air
Di-n-butyl phthalate is globally distributed in the air.
Di-n-butyl phthalate levels of approximately 1 ng/m3 have been detected
over the Pacific and Atlantic Oceans (Atlas and Giam 1981; Giam et al.
1980). Over New York City, di-n-butyl phthalate levels of 3.3 to
5.7 ng/m3 have been detected (Bove et al. 1978), and in industrialized
areas along the Niagara River, levels of 4.5 ng/m3 as vapor and
6.2 ng/m3 as particulate have been reported (Hoff and Chan 1987).
The air from rooms recently covered with polyvinyl chloride tiles
contained 150,000 to 260,000 ng/m3 phthalate esters (EPA 1980b). High
levels of di-n-butyl phthalate could also be present in enclosed rooms
in which products such as white glue or nail polish were being used, but
no data on actual concentrations of di-n-butyl phthalate in indoor air
were located.
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60
5. POTENTIAL FOR HUMAN EXPOSURE
5.4.2 Water
Overall there appears to be considerable uniformity in the
concentration of di-n-butyl phthalate in the surface waters of the
United States, if locally contaminated areas are excluded. Water
samples taken along the Mississippi River at the origin of the river in
Minnesota, at the junction of the Ohio River, below Memphis, Tennessee,
and just below New Orleans, had di-n-butyl phthalate concentration of
0.15, 0.14, 0.15 and 0.14 /ig/L, respectively (DeLeon et al. 1986).
There was no apparent effect of input from cities, industrial sources,
or tributaries along the length of the river. These data suggest that
transport mechanisms rather than source factors play a major role in
distribution of di-n-butyl phthalate. This observation is consistent
with the continuous extensive wet and dry deposition from air (see
Section 5.3.1). At one site, Delaware River water contained 0.6 #g/L of
di-n-butyl phthalate that could be traced to industrial sources (Sheldon
and Hites 1979), but further downstream concentrations were considerably
lower (0.1 to 0.4 £ig/L).
Concentrations of di-n-butyl phthalate in water from the Inner
Harbor Navigation Canal (which connects Lake Ponchartrain to the
Mississippi River near New Orleans) were 0.5 to 0.7 ng/L (McFall et al.
1985b). These values are somewhat higher than found in the open river,
but may relate to the more impounded nature of the lake.
The results of a 10 city drinking water survey indicated the
presence of di-n-butyl phthalate in 6 of 10 city water supplies. Levels
ranged from 0.1 to 0.2 £ig/L for 5 cities, and was 5.0 ng/L for one city
(Keith et al. 1976).
Data from the Contract Laboratory Program (CLP) Statistical
Database (CLPSD 1988) indicated that di-n-butyl phthalate was detected
in surface water at 77 of 862 hazardous waste sites being investigated
under Superfund. The median concentration was 6 /ig/L. Di-n-butyl
phthalate was detected in groundwater at 90 of 862 sites, with a median
concentration of 5 /:g/L.
5.4.3 Soil
Most of the analytical data available for soils are on sediments or
sludges. Considerable variability is encountered. In a study of
sediments from Los Angeles Sanitation District's sewage outfalls,
di-n-butyl phthalate was reported at 5 sites with concentrations ranging
from 118 to 355 *ig/kg dry weight (Swartz et al. 1983). Similar values
were obtained along the Detroit River. Detectable di-n-butyl phthalate
concentrations were reported in 4 of 13 samples, with values ranging
from 190 to 650 /ig/kg dry weight. Marine sediment from San Luis Pass,
Texas, had approximately 15 to 93 /kg dry weight of di-n-butyl
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61
5. POTENTIAL FOR HUMAN EXPOSURE
phthalate (Murray et al. 1981). The CLP Statistical Database (1988)
reported that di-n-butyl phthalate has been detected in soil at 115 of
862 hazardous waste sites sampled, with a median concentration of
440 ^ig/kg.
5.4.4 Other Media
Di-n-butyl phthalate may be used as a plasticizer for synthetic
films used to wrap food products, and migration of di-n-butyl phthalate
into food products may occur. Di-n-butyl phthalate may also enter food
materials by uptake from the environment. For example, reported
concentrations of di-n-butyl phthalate in fish ranged from 78 to 200 ppb
(Giam and Wong 1987; Stalling et al. 1973; Williams 1973). Oyster and
clam concentrations of di-n-butyl phthalate ranged from 40 to 570 ppb
(McFall et al. 1985a; Ray et al. 1983). Ishida et al. (1981) reported
the presence of di-n-butyl phthalate in egg white (but not in yolk)
collected from six regions of Japan. Concentrations ranged from 50 to
150 ppb of di-n-butyl phthalate.
5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE
Table 5-1 summarizes estimated levels of exposure to di-n-butyl
phthalate for members of the general population. It should be noted
that the data used to estimate human exposure levels are mostly 10 or
more years old so current exposure levels might be different, and that
no reliable concentration measurements were located for foods other than
fish. Based on these data, the highest exposure to di-n-butyl phthalate
is most likely to come from food, possibly fish and seafood, with
smaller amounts coming from air or water. Exposure to di-n-butyl
phthalate via the dermal route would also be expected, but no data were
available that could be used to estimate doses from dermal exposure to
di-n-butyl phthalate. No data were located on typical exposure levels
in the workplace, but it is likely they could be higher in certain cases
than for the general population.
5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES
Individuals who manufacture or use specialty plasticizers would
have the highest potential for exposure to di-n-butyl phthalate. People
living near chemical factories or hazardous waste sites where di-n-butyl
phthalate is present could also have higher than average exposure.
5.7 ADEQUACY OF THE DATABASE
Section 104(i)(5) of CERCLA, directs the Administrator of ATSDR (in
consultation with the Administrator of EPA and agencies and programs of
the Public Health Service) to assess whether adequate information on the
health effects of di-n-butyl phthalate is available. Where adequate
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62
5. POTENTIAL FOR HUMAN EXPOSURE
TABLE 5-1. Estimated Levels of Human Exposure to
Di-n-butyl Phthalate for Nonoccupational Exposure"
Air
Concentration in
medium
Assumed rate of
intake of medium
Assumed absorption
fraction
Estimated dose
(^g/kg/day)
0.003-0.006 /ig/m3
20 m3/day
0.5
0.0005-0.0009
Water
0.2 ug/Lc
2 L/day
0.9
0.005
Fish
78-200 /^g/kgd
6.5 g/day
0.9
0.007-0.02
aAll calculations assume a 70-kg adult.
bBove et al. 1978; Hoff and Chan 1987.
°Keith et al. 1986,
dGiam and Wong 1987; Stalling et al. 1973; Williams 1973.
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63
5. POTENTIAL FOR HUMAN EXPOSURE
information is not available, ATSDR, in conjunction with the NTP, is
required to assure the initiation of a program of research designed to
determine the health effects (and techniques for developing methods to
determine such health effects) of di-n-butyl phthalate.
The following categories of possible data needs have been
identified by a joint team of scientists from ATSDR, NTP, and EPA. They
are defined as substance-specific informational needs that, if met would
reduce or eliminate the uncertainties of human health assessment. In
the future, the identified data needs will be evaluated and prioritized,
and a substance-specific research agenda will be proposed.
5.7.1 Identification of Data Needs
Physical and Chemical Properties. Data are available on the
physical and chemical properties of di-n-butyl phthalate (see
Chapter 3), and further research in this area does not appear to be
essential.
Production, Use, Release, and Disposal. Available data indicate
that di-n-butyl phthalate is produced in substantial amounts at several
locations in the United States, is widely used in a variety of consumer
products, and is subject to regulations concerning disposal. However,
in the specialty plasticizer market, the amounts of specific
plasticizers used in various applications often changes over time.
Authoritative sources of current data on imports, exports, specific
uses, releases to environmental media, and disposal methods were not
located. Collecting such data would be valuable in estimating human
exposure to di-n-butyl phthalate.
According to the Emergency Planning and Community Right to Know Act
of 1986 (EPCRTKA), (§313), (Pub. L. 99-499, Title III, §313), industries
are required to submit release information to the EPA. The Toxic
Release Inventory (TRI), which contains release information for 1987,
became available in May of 1989. This database will be updated yearly
and should provide a more reliable estimate of industrial production and
emission.
Environmental Fate. Although environmental fate is known to some
extent, there are still major gaps in our understanding of partitioning
and transport of di-n-butyl phthalate in the atmosphere as vapor and
particulate. The volatility of di-n-butyl phthalate from water is
unclear from the literature data. Little information is available on
the reactions of di-n-butyl phthalate in the atmosphere. Further
studies on these subjects would be helpful in improving models to
predict the dispersion and persistence of di-n-butyl phthalate in the
environment.
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64
5. POTENTIAL FOR HUMAN EXPOSURE
Bioavailability from Environmental Media. Exposure of the general
public occurs via air, water, food supply, cosmetics and soils.
However, the bioavailability of di-n-butyl phthalate in each of these
media has not been investigated. Data of this type, especially on the
availability by the inhalation, oral, and dermal routes of di-n-butyl
phthalate bound to soils, sediments and air particulates, would be
valuable in assessing the relative importance of these media to human
exposure.
Food Chain Bioaccumulation. Available data indicate that
di-n-butyl phthalate tends to be taken up and metabolized by
invertebrates and fish, but there are no data on biomagnification
through the food chain. Studies to obtain data of this sort would be
useful in relating environmental levels to potential human exposure via
the food supply.
Exposure Levels in Environmental Media. Information on exposure
levels in the environment are relatively sparse. Although a number of
atmospheric air levels have been reported, it would be useful to know-
more specifics about urban air levels. Wore extensive data on food and
drinking water levels of di-n-butyl phthalate would also be useful in
assessing total human exposure.
Exposure Levels in Humans. Few data are available on human tissue
levels of di-n-butyl phthalate, so it is not possible at this time to
assess the total impact of di-n-butyl phthalate on the human population.
More information relating exposure levels to levels in humans would be
valuable in assessing risks to populations surrounding hazardous waste
sites.
Exposure Registries. No exposure registries for di-n-butyl
phthalate were located. This compound is not currently one of the
compounds for which a subregistry has been established in the National
Exposure Registry. The compound will be considered in the future when
chemical selection is made for subregistries to be established. The
information that is amassed in the National Exposure Registry
facilitates the epidemiological research needed to assess adverse health
outcomes that may be related to the exposure to this compound.
5.7.2 On-going Studies
No information was located regarding on-going studies on the
environmental fate and transport of di-n-butyl phthalate or on levels of
human exposure to di-n-butyl phthalate.
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65
6. ANALYTICAL METHODS
The purpose of this chapter is to describe the analytical methods
that are available for detecting and/or measuring and monitoring
di-n-butyl phthalate in environmental media and in biological samples.
The intent is not to provide an exhaustive list of analytical methods
that could be used to detect and quantify di-n-butyl phthalate. Rather,
the intention is to identify well-established methods that are used as
the standard methods of analysis. Many of the analytical methods used
to detect di-n-butyl phthalate in environmental samples are the methods
approved by federal agencies such as EPA and the National Institute for
Occupational Safety and Health (NIOSH). Other methods presented in this
chapter are those that are approved by a trade association such as the
Association of Official Analytical Chemists (AOAC) and the American
Public Health Association (APHA). Additionally, analytical methods are
included that refine previously used methods to obtain lower detection
limits, and/or to improve accuracy and precision.
Di-n-butyl phthalate may be determined by high resolution gas
chromatography with an electron capture detector (HRGC/ECD) (Thuren
1986), gas chromatography/mass spectrometry (GC/MS) (Ching et al. 1981a;
Ho 1983) , high resolution gas chromatography/mass spectrometry (HRGC/MS)
(Stanley 1986), or high resolution gas chromatography/Fourier transform
infrared spectrometry (HRGC/FTIR) (EPA 1986d). Prior to analysis,
di-n-butyl phthalate must be separated from the biological or
environmental sample matrix and prepared in a form suitable for
introduction into the analytical instrument. Methods for extracting
di-n-butyl phthalate from biological materials and environmental samples
are discussed below.
6.1 BIOLOGICAL MATERIALS
Since di-n-butyl phthalate is relatively non-volatile and
lipophilic, most methods for separating it from biological materials
involve extraction into an organic solvent such as ether, heptane or
acetonitrile. In most cases, the material is homogenized in the solvent
to improve extraction efficiency. Additional sample clean-up steps may
be required to separate fats and other endogenous lipophilic materials
that co-extract from the biological material (Walters 1988). Several
analytical methods for the determination of di-n-butyl phthalate in
biological materials are summarized in Table 6-1.
6.2 ENVIRONMENTAL SAMPLES
Separation of di-n-butyl phthalate from environmental samples such
as water, soil, sediment or wastes is also usually accomplished through
extraction with an organic solvent. In some cases, di-n-butyl phthalate
may be separated without solvents by adsorption onto a suitable polymer
-------
TABLE 6-1. Analytical Methods for Determining Di-n-butyl Phthalate in Biological Materials
Sample
Detect ion Accuracy
Sample Matrix Sample Preparation Analytical Method Limit (X Recovery) Reference
Aquatic organisms
Extract with aceto-
nitrile and petroleum
ether
HRGC/ECD
0.1 ng/g
Thuren 1986
Adipose tissue
Extraction, bulk lipid
removal, Florisil
fractionation
HRGC/MS
10 ng/g
No data
Stanley
1986
Blood serum
Extraction, bulk lipid
removal, Florisil
fractionation
HRGC/MS
10 ng/g
No data
Stanley
1986
Blood serum
Cooked meat
Extraction with organic GC/MS
solvents (propanol,
heptane)
Remove with nitrogen gas GC/MS
trap, extract with
diethyl ether
No data
No data
No data
No data
Ching et al.
1981a
Ho 1983
HRGC * High resolution gas chromatography: ECD * electron capture detector; MS ¦ mass spectrometry;
GC » gas chromatography.
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67
6. ANALYTICAL METHODS
such as Tenax (Pankaw et al. 1988). Analytical methods for the
determination of di-n-butyl phthalate in environmental samples are given
in Table 6-2.
6.3 ADEQUACY OF THE DATABASE
Section 104(i)(5) of CERCLA, directs the Administrator of ATSDR (in
consultation with the Administrator of EPA and agencies and programs of
the Public Health Service) to assess whether adequate information on the
health effects of di-n-butyl phthalate is available. Where adequate
information is not available, ATSDR, in conjunction with the NTP, is
required to assure the initiation of a program of research designed to
determine the health effects (and techniques for developing methods to
determine such health effects) of di-n-butyl phthalate.
The following categories of possible data needs have been
identified by a joint team of scientists from ATSDR, NTP, and EPA. They
are defined as substance-specific informational needs that, if met would
reduce or eliminate the uncertainties of human health assessment. In
the future, the identified data needs will be evaluated and prioritized,
and a substance-specific research agenda will be proposed.
6.3.1 Identification of Data Needs
Methods for Determining Biomarkers of Exposure and Effect.
Sensitive and selective methods using high resolution gas chromatography
are available for the qualitative and quantitative measurement of parent
di-n-butyl phthalate after it is separated from the biological matrix of
tissue or fluid. However, methods for recovery of di-n-butyl phthalate
from such samples have not been extensively developed, and additional
work to improve and standardize sample extraction and preparation
methods for biological fluids and tissues would be valuable in providing
quantitative information concerning human exposure. The sensitivity of
existing methods may not be high enough to measure background levels in
the population, since an existing study failed to detect di-n-butyl
phthalate in several samples (Stanley 1986). Because of the widespread
use of di-n-butyl phthalate in laboratory equipment, cosmetics, and
other consumer products, studies to determine background levels in the
population must be done with care to avoid false positives from
inadvertent contamination. Since health effects occur only after high
levels of exposure, existing methods are probably capable of measuring
body levels at which effects would be expected to occur in humans. The
same method of high resolution gas chromatography could be adapted to
measure body levels of metabolites of di-n-butyl phthalate, primarily
monobutyl phthalate, which have the potential to be biomarkers of
exposure.
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TABLE 6-2. Analytical Methods for Determining Di-n-butyl Phthalate In Environmental Sangles
Sample
Detection
Sample Matrix Sample Preparation Analytical Method Limit Accuracy Reference
Air
Rainwater
Water
Water
Water
Soil
Wastes, non-
water miscible
Soil
Wastes, non-
water miscible
Soil/sediment
Wastes, non-
water miscible
Soil/sediment
Wastes, non-
water miscible
Adsorption/solvent extraction
with polyurethane foani plug
Adsorb on Tenax-GC columns,
thermally desorb
Extract with dichloromethane,
exchange to hexane, concentrate
Extract with dichloromethane
at pH 11 and 2, concentrate
Adsorb on small bed volume Tenax
cartridges, thermally desorb
Extract with dichloromethane,
cleanup, exchange to hexane
Extract with dichloromethane,
cleanup, exchange to hexane
Extract from sample, cleanup
Extract from sample, cleanup
Extract from sample, cleanup
Extract from sample, cleanup
Extract from sample, cleanup
Extract from sample, cleanup
HRGC/MS
GC/MS
GC/ECD
GC/MS
GC/MS
GC/ECD
GC/ECD
GC/MS
GC/MS
HRGC/MS
HRGC/MS
HRGC/FTIR
HRGC/FTIR
No data
<34 ng/L
0.36 ^g/L
2.5 ^g/L
Mo data
240 ng/kg
36 mg/kg
1.7 mg/kg
350 mg/kg
660 Mg/kg
50 mg/kg
10 /jg / Lb
10 (.g/Lb
115t5X*
No data
80±6Xa
8Qt6Xa
No data
96X
96%
96X
76X
76X
76%
No data
No data
Ligocki and
Pankov 1985
Ligocki
et al. 1985
EPA 1982a
EPA 1982b
Pankow
et al. 1988
EPA 1986a
EPA 1986a
EPA 1986b
EPA 1986b
EPA 1986c
EPA 1986c
EPA 1986d
EPA 1986d
aRelative recovery, percent, i standard deviation.
^Identification limit. Detection limits for actual samples are several orders of magnitude higher depending upon the sample
matrix and extraction procedure employed.
HRGC « high resolution gas chromatography; MS = mass spectrometry; GC — gas chromatography; ECD = electron capture detector;
FTIR - Fourier transform infrared spectrometry-
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6. ANALYTICAL METHODS
No information was located concerning biomarkers of effect of
di-n-butyl phthalate. Studies undertaken to determine biomarkers of
effect would be most useful if one component were to develop precise,
accurate, reliable, and specific methods for measuring background levels
of the biomarker of effect in the population as well as the levels at
which health effects, if any, occur.
Methods for Determining Parent Compounds and Degradation Products
in Environmental Media. Good methods with adequate sensitivity and
selectivity are available for detecting and quantifying di-n-butyl
phthalate contamination in water, air, soil, and waste samples. Soil,
water, and food are the media of most concern for human exposure to
di-n-butyl phthalate. The basic method of extraction followed by high
resolution gas chromatography has the potential to be sensitive enough
to measure background levels of di-n-butyl phthalate and its degradation
products in the environment, but care must taken to ensure that samples
are representative, volumes are sufficient, contamination is avoided,
preservation is adequate, and extraction and purification are complete.
In measuring of background levels in environmental media, contamination
can pose a particular problem because of the extensive use of di-n-butyl
phthalate in products found in laboratories. Existing methods should be
sufficiently sensitive to measure levels of di-n-butyl phthalate at
which health effects might occur.
6.3.2 On-going Studies
Research is ongoing to develop a "Master Analytical Scheme" for
organic compounds in water (Michael and Pellizzari 1988), which includes
di-n-butyl phthalate as an analyte. The overall goal is to detect and
quantitatively measure organic compounds at 0.1 £
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71
7. REGULATIONS AND ADVISORIES
Because of its potential to cause adverse health effects in people
if exposure were to occur, a number of regulations and guidelines have
been established for di-n-butyl phthalate by various national and state
agencies. These values are summarized in Table 7-1.
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72
7. REGULATIONS AND ADVISORIES
TABLE 7-1. Regulations and Guidelines Applicable to Di-n-butyl Phthalate
Agency
Description
Value
Reference
National
Regulations:
a. Air:
OSHA
PEL TWA
5 mg/m3
OSHA 1989 (29 CFR
1910.1000,
Table 2-1-A)
b. Water:
EPA OWRS
General permits under NPDES
General pretreatment regulations for
existing and new sources of pollution
No data
No data
AO CFR 122
(Appendix D,
Table II)
40 CFR 403
c. Nonspecific media
EPA
Oral RfD
Subchroni c
1mg/kg/day
Chronic
. 1mg/kg/day
IRIS 1988
EPA OERR
Reportable quantity
10 lb
EPA 1985a,
(40 CFR 302.4)
EPA OSW
Hazardous waste constituent
(Appendix VIII)
Land disposal restrictions
Groundwater monitoring list
(Appendix IX)
No data
No data
No data
EPA 1980a,
(40 CFR 261)
EPA 1988a, 1989b,
(40 CFR 268)
EPA 1987b,
(40 CFR 264)
EPA OTS
Toxic chemical release reporting
Preliminary assessment information
rule
Health and safety data reporting
Testing consent order (alkyl phthalates)
No data
No data
No data
No data
EPA 1988b,
(40 CFR 372)
EPA 1982c,
(40 CFR 712.30)
EPA 1988c, (40
CFR 716.120)
EPA 1989c, (40
CFR 799.5000)
FDA
Use as a component of adhesives and
coatings in food packaging
Indirect food additive polymer
Indirect food additive: paper and
paperboard component
No data
No data
Yes
21 CFR 175.105,
175.300,
175.380,
175.390
21 CFR 177.1200
177.1210,
177.2420,
177.2600
21 CFR 176.170,
176.180,
176.300
Guidelines:
a. Air:
ACGIH
N10SH
TLV TWA
IDLH
5 mg/m3
9300 mg/m3
ACGIH 1986
NIOSH 1985a
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73
7. REGULATIONS AND ADVISORIES
TABLE 7-1 (Continued)
Agency
Description
Value
Reference
b. Water:
EPA OWRS
Other:
EPA
Regulations:
a. Air:
Connect icut
Nevada
North Dakota
Vi rgini a
Ambient water quality criteria
Ingesting water and organisms
Ingesting organisms only
Carcinogenic classification
State
Acceptable ambient air concentration
34 mg/L
154 mg/L
Group Da
EPA 1980b
EPA 1980b
IRIS 1988
NATICH 1988
100 jig/m3 (8 hr)
0.1190 mg/m3 (8 hr)
0.05 mg/m3 (8 hr)
0.10 mg/m3 (1 hr)
80 iig/m3 (24 hr)
b. Water:
Kansas
Maine
Drinking water
FSTRAC 1988
770 /ig/L
2200 iig/L
aGroup D = not classifiable.
OSHA = Occupational Safety and Health Administration; PEL = Permissible Exposure Limit; TUA = Time-
Weighted Average; EPA = Environmental Protection Agency; OWRS = Office of Water Regulations and
Standards; NPDES = National Pollutant Discharge Elimination System; OERR = Office of Emergency and
Remedial Response; OSW = Office of Solid Wastes; OTS = Office of Toxic Substances; FDA = Food and
Drug Administration; ACGIH = American Conference of Governmental Industrial Hygienists; TLV =
Threshold Limit Value; NIOSH = National Institute for Occupational Safety and Health; IDLH =
Immediately Dangerous to Life or Health Level; RfD = Reference Dose.
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75
8. REFERENCES
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* - Cited in text.
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9. GLOSSARY
Acute Exposure - - Exposure to a chemical for a duration of 14 days or
less, as specified in the Toxicological Profiles.
Adsorption Coefficient (K,^) -- The ratio of the amount of a chemical
adsorbed per unit weight of organic carbon in the soil or sediment to
the concentration of the chemical in solution at equilibrium.
Adsorption Ratio (Kd) -- The amount of a chemical adsorbed by a sediment
or soil (i.e., the solid phase) divided by the amount of chemical in the
solution phase, which is in equilibrium with the solid phase, at a fixed
solid/solution ratio. It is generally expressed in micrograms of
chemical sorbed per gram of soil or sediment.
Bioconcentration Factor (BCF) -- The quotient of the concentration of a
chemical in aquatic organisms at a specific time or during a discrete
time period of exposure divided by the concentration in the surrounding
water at the same time or during the same time period.
Cancer Effect Level (CEL) -- The lowest dose of chemical in a study or
group of studies which produces significant increases in incidence of
cancer (or tumors) between the exposed population and its appropriate
control.
Carcinogen -- A chemical capable of inducing cancer.
Ceiling value (CL) -- A concentration of a substance that should not be
exceeded, even instantaneously.
Chronic Exposure -- Exposure to a chemical for 365 days or more, as
specified in the Toxicological Profiles.
Developmental Toxicity -- The occurrence of adverse effects on the
developing organism that may result from exposure to a chemical prior to
conception (either parent), during prenatal development, or postnatally
to the time of sexual maturation. Adverse developmental effects may be
detected at any point in the life span of the organism.
Embryotoxicity and Fetotoxicity -- Any toxic effect on the conceptus as
a result of prenatal exposure to a chemical; the distinguishing feature
between the two terms is the stage of development during which the
insult occurred. The terms, as used here, include malformations and
variations, altered growth, and in utero death.
EPA Health Advisory -- An estimate of acceptable drinking water levels
for a chemical substance based on health effects information. A health
advisory is not a legally enforceable federal standard, but serves as
technical guidance to assist federal, state, and local officials.
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9. GLOSSARY
Immediately Dangerous to Life or Health (IDLH) -- The maximum
environmental concentration of a contaminant from which one could escape
within 30 min without any escape - impairing symptoms or irreversible
health effects.
Intermediate Exposure -- Exposure to a chemical for a duration of 15-364
days, as specified in the Toxicological Profiles.
Immunologic Toxicity -- The occurrence of adverse effects on the immune
system that may result from exposure to environmental agents such as
chemicals.
In Vitro - - Isolated from the living organism and artificially
maintained, as in a test tube.
In Vivo -- Occurring within the living organism.
Lethal Concentration^) (LClq) -- The lowest concentration of a chemical
in air which has been reported to have caused death in humans or
animals.
Lethal Concentration(50) (LC50) -- A calculated concentration of a
chemical in air to which exposure for a specific length of time is
expected to cause death in 50% of a defined experimental animal
population.
Lethal DoseCu,) (LD^,) -- The lowest dose of a chemical introduced by a
route other than inhalation that is expected to have caused death in
humans or animals.
Lethal Dose(50) (LD50) -- The dose of a chemical which has been
calculated to cause death in 50% of a defined experimental animal
population.
Lethal Time(50) (LT50) -- A calculated period of time within which a
specific concentration of a chemical is expected to cause death in 50%
of a defined experimental animal population.
Lowest-Observed-Adverse-Effect Level (L0AEL) -- The lowest dose of
chemical in a study or group of studies which produces statistically or
biologically significant increases in frequency or severity of adverse
effects between the exposed population and its appropriate control.
Malformations -- Permanent structural changes that may adversely affect
survival, development, or function.
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9. GLOSSARY
Minimal Risk Level (MRL) --An estimate of daily human exposure to a
chemical that is likely to be without an appreciable risk of deleterious
effects (noncancerous) over a specified duration of exposure.
Mutagen -- A substance that causes mutations. A mutation is a change in
the genetic material in a body cell. Mutations can lead to birth
defects, miscarriages, or cancer.
Neurotoxicity -- The occurrence of adverse effects on the nervous system
following exposure to a chemical.
No-Observed-Adverse-Effect Level (NOAEL) -- That dose of chemical at
which there are no statistically or biologically significant increases
in frequency or severity of adverse effects seen between the exposed
population and its appropriate control. Effects may be produced at this
dose, but they are not considered to be adverse.
Octanol-Water Partition Coefficient (Kw) -- The equilibrium ratio of
the concentrations of a chemical in n-octanol and water, in dilute
solution.
Permissible Exposure Limit (PEL) -- An allowable exposure level in
workplace air averaged over an 8-hour shift.
qx* -- The upper-bound estimate of the low-dose slope of the dose-
response curve as determined by the multistage procedure. The qx* can
be used to calculate an estimate of carcinogenic potency, the
incremental excess cancer risk per unit of exposure (usually ^g/L for
water, mg/kg/day for food, and /ig/m3 for air).
Reference Dose (RfD) --An estimate (with uncertainty spanning perhaps
an order of magnitude) of the daily exposure of the human population to
a potential hazard that is likely to be without risk of deleterious
effects during a lifetime. The RfD is operationally derived from the
NOAEL (from animal and human studies) by a consistent application of
uncertainty factors that reflect various types of data used to estimate
RfDs and an additional modifying factor, which is based on a
professional judgment of the entire database on the chemical. The RfDs
are not applicable to nonthreshold effects such as cancer.
Reportable Quantity (RQ) -- The quantity of a hazardous substance that
is considered reportable under CERCLA. Reportable quantities are: (1) 1
lb or greater or (2) for selected substances, an amount established by
regulation either under CERCLA or under Sect. 311 of the Clean Water
Act. Quantities are measured over a 24-hour period.
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9. GLOSSARY
Reproductive Toxicity -- The occurrence of adverse effects on the
reproductive system that may result from exposure to a chemical. The
toxicity may be directed to the reproductive organs and/or the related
endocrine system. The manifestation of such toxicity may be noted as
alterations in sexual behavior, fertility, pregnancy outcomes, or
modifications in other functions that are dependent on the integrity of
this system.
Short-Term Exposure Limit (STEL) -- The maximum concentration to which
workers can be exposed for up to 15 min continually. No more than four
excursions are allowed per day, and there must be at least 60 min
between exposure periods. The daily TLV-TWA may not be exceeded.
Target Organ Toxicity -- This term covers a broad range of adverse
effects on target organs or physiological systems (e.g., renal,
cardiovascular) extending from those arising through a single limited
exposure to those assumed over a lifetime of exposure to a chemical.
Teratogen -- A chemical that causes structural defects that affect the
development of an organism.
Threshold Limit Value (TLV) -- A concentration of a substance to which
most workers can be exposed without adverse effect. The TLV may be
expressed as a TWA, as a STEL, or as a CL.
Time-weighted Average (TWA) -- An allowable exposure concentration
averaged over a normal 8-hour workday or 40-hour workweek.
Toxic Dose (TD50) -- A calculated dose of a chemical, introduced by a
route other than inhalation, which is expected to cause a specific toxic
effect in 50% of a defined experimental animal population.
Uncertainty Factor (UF) -- A factor used in operationally deriving the
RfD from experimental data. UFs are intended to account for (1) the
variation in sensitivity among the members of the human population, (2)
the uncertainty in extrapolating animal data to the case of humans, (3)
the uncertainty in extrapolating from data obtained in a study that is
of less than lifetime exposure, and (A) the uncertainty in using LOAEL
data rather than NOAEL data. Usually each of these factors is set equal
to 10.
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APPENDIX
PEER REVIEW
A peer review panel was assembled for di-n-butyl phthalate. The
panel consisted of the following members: Dr. Theodore Kneip, Director,
Laboratory of Environmental Studies, New York University Medical Center,
Tuxedo, NY; Dr. Mildred Christian, President, Argus Research
Laboratories, Inc., Horsham, PA; Dr. Sanford Bigelow, President,
Multisciences, Inc., Kensington, MD; Dr. Gail Charnley, Private
Consultant, Alexandria, VA; and Dr. Joseph P. Gould, Research Scientist,
School of Civil Engineering, Georgia Institute of Technology, Atlanta,
GA. These experts collectively have knowledge of di-n-butyl phthalate's
physical and chemical properties, toxicokinetics, key health end points,
mechanisms of action, human and animal exposure, and quantification of
risk to humans. All reviewers were selected in conformity with the
conditions for peer review specified in Section 104(i)(13) of the
Comprehensive Environmental Response, Compensation, and Liability Act,
as amended.
Scientists from the Agency for Toxic Substances and Disease
Registry (ATSDR) have reviewed the peer reviewers' comments and
determined which comments will be included in the profile. A listing of
the peer reviewers' comments not incorporated in the profile, with a
brief explanation of the rationale for their exclusion, exists as part
of the administrative record for this compound. A list of databases
reviewed and a list of unpublished documents cited are also included in
the administrative record.
The citation of the peer review panel should not be understood to
imply their approval of the profile's final content. The responsibility
for the content of this profile lies with the ATSDR.
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