1,4-DICHLOROBENZENE
Q
-I
I-
<* Q.
Agency for Toxic Substances and Disease Registry
U.S. Public Health Service
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ATSDR/TP-88/14
TOXICOLOGICAL PROFILE FOR
1,4-DICHLOROBENZENE
Date Published — January 1989
Prepared by:
Life Systems, Inc.
under Contract No. 68-02-4228
for
Agency for Toxic Substances and Disease Registry (ATSDR)
U.S. Public Health Service
in collaboration with
U.S. Environmental Protection Agency (EPA)
Technical editing/document preparation by:
Oak Ridge National Laboratory
under
DOE Interagency Agreement No. 18S7-B026-A1
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DISCLAIMER
Mention of company name or product does not constitute endorsement by
the Agency for Toxic Substances and Disease Registry.
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FOREWORD
The Superfund Amendments and Reauthorization Act 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 (also known as SARA) 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 list of the 100
most significant hazardous substances was published in the Federal
Register on April 17, 1987.
Section 110 (3) of SARA 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 epidemiologic evaluations on a
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.
(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 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 SARA.
The ATSDR toxicological profile is intended to characterize
succinctly the toxicological and health effects information for the
hazardous substance being described. Each profile identifies and reviews
the key literature that describes a hazardous substance's toxicological
properties. Other literature is 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.
ILL
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Foreword
Each toxicological profile begins with a public health statement,
which describes in nontechnical language a substance's relevant
toxicological properties. Following the statement is material that
presents levels of significant human exposure and, where known,
significant health effects. The adequacy of information to determine a
substance's health effects is described in a health effects summary.
Research gaps in toxicologic and health effects information are
described in the profile. Research gaps that are of significance to
protection of public health will be identified by ATSDR, the National
Toxicology Program 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 front 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. We
plan to revise these documents in response to public comments and as
additional data become available; therefore, we encourage comment that
will make the toxicological profile series of the greatest use.
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, EPA, the Centers for Disease Control,
and the National Toxicology Program. It has also been reviewed by a
panel of nongovernment peer reviewers and was made available for public
review. Final responsibility for the contents and views expressed in
this toxicological profile resides with ATSDR.
f~-
James 0. Mason, M.D., Dr. P.H.
Assistant Surgeon General
Administrator, ATSDR
iv
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CONTENTS
FOREWORD iii
LIST OF FIGURES ix
LIST OF TABLES xi
1. PUBLIC HEALTH STATEMENT 1
1.1 WHAT IS p-DICHLOROBENZENE? 1
1.2 HOW MIGHT I BE EXPOSED TO p-DICHLOROBENZENE? 1
1.3 HOW DOES p-DICHLOROBENZENE GET INTO MY BODY? 1
1.4 HOW CAN p-DICHLOROBENZENE AFFECT MY HEALTH? 2
1.5 IS THERE A MEDICAL TEST TO DETERMINE IF I HAVE BEEN
EXPOSED TO p-DICHLOROBENZENE? 2
1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL
HEALTH EFFECTS? 2
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT
MADE TO PROTECT HUMAN HEALTH? 6
2. HEALTH EFFECTS SUMMARY 7
2.1 INTRODUCTION 7
2.2 LEVELS OF SIGNIFICANT EXPOSURE 8
2.2.1 Key Studies 8
2.2.1.1 Lethality/decreased longevity 14
2.2.1.2 Systemic/target organ toxicity 14
2.2.1.3 Developmental toxicity 16
2.2.1.4 Reproductive toxicity 17
2.2.1.5 Genotoxicity 17
2.2.1.6 Carcinogenicity 18
2.2.2 Biological Monitoring as a Measure of
Exposure and Effects 20
2.2.3 Environmental Levels as Indicators of
Exposure and Effects 20
2. 3 ADEQUACY OF DATABASE 20
2.3.1 Introduction 20
2.3.2 Health Effect End Points 21
2.3.2.1 Introduction and graphic summary 21
2.3.2.2 Descriptions of highlights of graphs 24
2.3.2.3 Summary of relevant ongoing research .... 24
2.3.3 Other Information Needed for Human
Health Assessment 25
2.3.3.1 Pharmacokinetics and mechanisms
of action 25
2.3.3.2 Monitoring of human biological samples .. 25
2.3.3.3 Environmental considerations 25
3. CHEMICAL AND PHYSICAL INFORMATION 27
3.1 CHEMICAL IDENTITY 27
3.2 CHEMICAL AND PHYSICAL PROPERTIES 27
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Contents
4. TOXICOLOGICAL DATA 31
4.1 OVERVIEW [][' 31
4 . 2 TOXICOKINETICS .' '_ 3 L
4.2.1 Overview 31
4.2.2 Absorption 32
4.2.2.1 Inhalation 32
4.2.2.2 Oral 32
4.2.2.3 Dermal 32
4.2.3 Distribution 32
4.2.3.1 Inhalation 32
4.2.3.2 Oral 33
4.2.4 Metabolism 34
4.2.4.1 Inhalation 34
4.2.4.2 Oral 34
4.2.4.3 Dermal 34
4.2.5 Excretion 35
4.2.5.1 Inhalation 35
4.2.5.2 Oral 35
4.2.5.3 Dermal 35
4.2.6 Discussion 35
4. 3 TOXICITY '.'.'.'.'. 36
4.3.1 Lethality and Decreased Longevity 36
4.3.1.1 Overview 36
4.3.1.2 Inhalation 36
4.3.1.3 Oral ' 35
4.3.1.4 Dermal 38
4.3.1.5 Discussion 38
4.3.2 Systemic/Target Organ Toxicity 38
4.3.2.1 Overview 33
4.3.2.2 Central nervous system effects 39
4.3.2.3 Liver effects 40
4.3.2.4 Renal effects 44
4.3.3 Developmental Toxicity 46
4.3.3.1 Overview 46
4.3.3.2 Inhalation 46
4.3.3.3 Oral 47
4.3.3.4 Dermal 47
4.3.3.5 Discussion 47
4.3.4 Reproductive Toxicity 48
4.3.4.1 Overview 48
4.3.4.2 Inhalation 48
4.3.4.3 Oral \\\'m 43
4.3.4.4 Dermal 48
4.3.4.5 Discussion 48
4.3.5 Genotoxicity 48
4.3.5.1 Overview 48
4.3.5.2 Microbial systems 49
4.3.5.3 Higher plants 49
4.3.5.4 Mammalian systems 49
4.3.5.5 Discussion 50
vi
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Contents
4.3.6 Carcinogenicicy 50
4.3.6.1 Overview 50
4.3.6.2 Inhalation 50
4.3.6.3 Oral 51
4.3.6.4 Dermal 52
4.3.6.5 Discussion 52
4.4 INTERACTIONS WITH OTHER CHEMICALS 53
5. MANUFACTURE, IMPORT, USE, AND DISPOSAL 55
5.1 OVERVIEW 55
5.2 PRODUCTION 55
5.3 IMPORT 55
5.4 USE 55
5.5 DISPOSAL 56
6. ENVIRONMENTAL FATE 57
6.1 OVERVIEW 57
6.2 RELEASES TO THE ENVIRONMENT 57
6.2.1 Anthropogenic Sources 57
6.2.2 Natural Sources 58
6.3 ENVIRONMENTAL FATE 58
6.3.1 Atmospheric Fate Processes 58
6.3.2 Surface Water/Groundwater Fate Processes 58
6.3.3 Soil Fate Processes 59
6.3.4 Biotic Fate Processes 59
7. POTENTIAL FOR HUMAN EXPOSURE 61
7.1 OVERVIEW 61
7.2 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 61
7.2.1 Levels in Air 61
7.2.2 Levels in Water 62
7.2.3 Levels in Soil 64
7.2.4 Levels in Food 64
7.2.5 Resulting Exposure Levels 64
7.3 OCCUPATIONAL EXPOSURES 65
7.4 POPULATIONS AT HIGH RISK 67
7.4.1 Above-Average Exposure 67
7.4.2 Above-Average Sensitivity 67
8. ANALYTICAL METHODS 69
8.1 ENVIRONMENTAL MEDIA 69
8.1.1 Air 69
8.1.2 Water 71
8.1.3 Soil 71
8.1.4 Food 71
8.2 BIOMEDICAL SAMPLES 71
8.2.1 Fluids and Exudates 71
8.2.2 Tissues 71
9. REGULATORY AND ADVISORY STATUS 73
9.1 INTERNATIONAL 73
9.2 NATIONAL 73
9.2.1 Regulations 73
9.2.2 Advisory Guidance 76
9.2.3 Data Analysis 77
vli
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Concencs
9.3 STATE 78
9.3.1 Regulations 78
9.3.2 Advisory Guidance 78
10. REFERENCES 79
11. GLOSSARY 91
APPENDIX: PEER REVIEW 95
viii
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LIST OF FIGURES
1.1 Health effects from breathing p-DCB 3
1.2 Health effects from ingesting p-DCB 4
1.3 Health effects from skin contact with p-DCB 5
2.1 Effects of p-DCB--inhalation exposure 9
2.2 Effects of p-DCB--oral exposure 10
2.3 Effects of p-DCB--dermal exposure 11
2.4 Levels of significant exposure for inhalation of p-DCB 12
2.5 Levels of significant exposure for ingestion of p-DCB 13
2.6 Availability of information on health effects of p-DCB
(human data) 22
2.7 Availability of information on health effects of p-DCB
(animal data) 23
ix
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LIST OF TABLES
3.1 Chemical identity of p-DCB 28
3.2 Physical and chemical properties of p-DCB 29
4.1 Reports of human exposure to p-DCB 37
7.1 Estimated human exposure to p-DCB by ingestion of
drinking water 66
8.1 Analytical methods for p-DCB in environmental samples 70
8.2 Analytical methods for p-DCB in biological samples 72
9.1 Regulations and guidelines applicable to p-DCB 74
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1. PUBLIC HEALTH STATEMENT
1.1 WHAT IS p-DICHLOROBENZENE?
The compound 1,4-dichlorobenzene is most commonly referred to as
para-DCB or p-DCB, but there are approximately 20 additional terms used
for this chemical. Some of these names include Paramoth, para crystals,
and paracide, reflecting its widespread use as a moth killer. It is also
used to make deodorant blocks used in restrooms. At least 70 million
pounds of p-DCB are used each year in the manufacture of these two types
of products. It is also used in the manufacture of certain resins;
smaller amounts are used in the pharmaceutical industry and as a general
insecticide in farming.
At room temperature, p-DCB is a colorless solid with a
characteristic penetrating odor. When exposed to air, it is slowly
transformed from its solid state into a vapor; the released vapor then
acts as a deodorizer and insect killer.
1.2 HOW NIGHT I BE EXPOSED TO p-DICHLOROBENZENE?
p-Dichlorobenzene is released to the environment during both its
manufacture and use. Heavily populated and/or industrialized areas tend
to have the highest concentrations of p-DCB in air and in water,
including surface water, groundwater, and drinking water; whereas some
areas, especially rural areas, may have lower or undetectable levels.
Air is the major source of exposure to p-DCB.
The persons most likely to be exposed to p-DCB are those who work
directly in its manufacture or processing, those who live in the
vicinity of any industrial area where it is produced, and some persons
who use it. People who live near chemical waste disposal sites may also
be subject to higher exposure due to local air or water contamination.
In addition, consumers are exposed to p-DCB through commonly used
household products, such as mothballs and deodorant blocks used in
public and household bathrooms. Thus, people can be exposed to p-DCB in
the air, via drinking water, or from handling products containing p-DCB.
1.3 HOW DOES p-DICHLOROBENZENE GET INTO MY BODY?
The major way that p-DCB enters the body is through the lungs. For
example, this occurs when a person breathes p-DCB released from
industrial processes or from home use of p-DCB products.
p-DCB can also get into our bodies when we drink water. p-DCB has
been found in drinking water in various locations throughout the United
States.
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2 Section 1
p-DCB may also enter our bodies through the skin if we touch
products that contain it, such as certain kinds of mothballs and toilet
deodorizer blocks.
There is also a possibility that p-DCB used in the home can be
accidentally swallowed, especially by young children. When p-DCB is used
in mothballs or deodorant blocks, these products may be freely
accessible in the closets or bathrooms.
1.4 HOW CAN p-DICHLOROBENZENE AFFECT MY HEALTH?
There is no evidence that brief low-level or moderate-level
exposures to household products containing p-DCB cause human health
problems. Higher p-DCB levels in air, such as the levels that are
sometimes associated with industrial exposure, can cause headaches and
dizziness. Levels that would result in death would be associated with an
odor so intense that it would be very unpleasant, if not intolerable,
and would serve as a danger warning. In industrial settings, workers
exposed to p-DCB at high levels are usually directed to wear
respirators.
In laboratory animals, breathing or ingestion of p-DCB can cause
toxic effects in the liver and kidney. Although there is no evidence
that p-DCB can cause cancer in humans, laboratory animals treated with
p-DCB in lifetime studies had increased rates of cancer when compared
with animals not exposed to p-DCB. Based on the results of these animal
studies, a potential exists that p-DCB may cause cancer in humans. Based
on two animal studies, there is some evidence that p-DCB exposure can
result in birth defects.
1.5 IS THERE A MEDICAL TEST TO DETERMINE IF I HAVE BEEN EXPOSED TO
p-DICHLOROBENZENET
A urine test can determine if a person has been exposed to p-DCB
and can give a rough estimate of the exposure level. This test has been
used in industrial settings in surveys of occupational exposure. There
is a specific compound (2,5-dichlorophenol) that is produced in the body
after exposure to p-DCB. Detection of this chemical in the urine will
indicate that the person has been exposed to p-DCB within the previous
day or two. The amount of this substance in urine is also a fairly good
indicator of the level of p-DCB in the air, when air is the route of
exposure. There is also a blood test to measure levels of p-DCB in the
bloodstrean.
1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTS?
The graphs on the following pages (Figs. 1.1 and 1.2) show the
relationship between exposure to p-DCB and known health effects. In the
first set of graphs, labeled "Health effects from breathing p-DCB,*
exposure is measured in parts of p-DCB per million parts of air (ppm).
In the second set of graphs, the same relationship is represented for
the known "Health effects from ingesting p-DCB." Exposures are measured
in milligrams of p-DCB per kilogram of body weight per day (mg/kg/day).
Figure 1.3 shows known health effects in rats as a result of exposure to
p-DCB by skin contact. Exposure is also measured in milligrams of p-DCB
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Public Health Statement
SHORT-TERM EXPOSURE
(LESS THAN OR EQUAL TO 14 DAYS)
LONG-TERM EXPOSURE
(GREATER THAN 14 DAYS)
EFFECTS
IN
ANIMALS
CONG IN
AJR
(ppm)
1000
EFFECTS
IN
HUMANS
QUANTITATIVE
DATA WERE
NOT
AVAILABLE
EFFECTS CONC IN
IN AIR
ANIMALS (ppm)
1000
EFFECTS
IN
HUMANS
QUANTITATIVE
DATA WERE
NOT
AVAILABLE
BIRTH DEFECTS. — 800
REDUCED MATERNAL
WEIGHT GAIN
(RABBITS)
600
400
LIVER AND
KIDNEY EFFECTS-
INRATS
(1 5 YEARS)
200
150
100
50
800
600
400
200
150
100
50
Fig. 1.1. Health effects froa breatfaiag p-DCB.
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Section
SHORT-TERM EXPOSURE
(LESS THAN OR EQUAL TO 14 DAYS)
LONG-TERM EXPOSURE
(GREATER THAN 14 DAYS)
EFFECTS
IN DOSE
ANIMALS (mg/kg/day)
DEATH (RATS) 4000
DEATH (GUINEA
PIGS)
EFFECTS
IN
HUMANS
QUANTITATIVE
DATA WERE
NOT AVAILABLE
EFFECTS
IN DOSE
ANIMALS (mg/Vg/day)
4000
EFFECTS
IN
HUMANS
QUANTITATIVE
DATA WERE
NOT
AVAILABLE
2000
2000
1000
BIRTH DEFECTS—500
(RATS) I
1000
500
300
250
200
150
100
50
LIVER AND KIDNEY
EFFECTS (MICE
AND RATS)
300
250
200
150
100
50
Flf.1.2. Hcaltfc rffcco tnm lagmiM p-DCB.
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Public Health Scacemenc
SHORT-TERM EXPOSURE
(LESS THAN OR EQUAL TO 14 DAYS)
LONG-TERM EXPOSURE
(GREATER THAN 14 DAYS)
EFFECTS
IN
ANIMALS
DEATH (RATS)
DOSE
(mg/kg/day)
6000
EFFECTS
IN
HUMANS
QUANTITATIVE
DATA WERE
NOT AVAILABLE
EFFECTS
IN
ANIMALS
QUANTITATIVE
DATA WERE
NOT AVAILABLE
EFFECTS
IN
HUMANS
QUANTITATIVE
DATA WERE
NOT AVAILABLE
Flf. 1J. Heahfc effects froa akta cootect with p-DCB.
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6 Section 1
per kilogram of body weight per day (mg/kg/day). In all graphs, effects
in animals are shown on the left side, effects in humans on the right.
These figures are based only on studies in laboratory animals,
usually mice and rats. Although there have been several reports of
harmful effects in humans exposed to p-DCB, the levels and duration of
exposure are unknown.
Decreased body weight gain has been observed in pregnant animals
breathing p-DCB at similar levels (800 ppm) for a few days. Slight
abnormalities have also been observed in the circulatory systems of
their offspring.
The results of tests in which rats and mice were administered p-DCB
orally are shown in Fig. 1.2. When small amounts (20 mg/kg) were
administered, even for a few days, subtle effects on the liver were
seen. At much higher levels (over 1600 mg/kg), a single dose resulted in
the death of test animals. With long-term exposure, administering p-DCB
orally at levels of 150 mgAg/day led to damage to the liver and kidneys
and, at 300 mg/kg/day, resulted in cancer in these organs.
Although there is no certainty that the same health effects would
occur if humans were exposed to p-DCB under the same conditions as the
animals in these studies, scientists use the results in animals as a
general guide to predict the potential toxicity of p-DCB in humans.
Based on the results of the cancer studies in rats and mice, the excess
risk of cancer in humans resulting from exposure to p-DCB has been
calculated. The number of excess cases of cancer in populations of
10,000. 100,000, 1,000,000 or 10,000,000 individuals exposed to
1 microgram of p-DCB per liter (/*g/L) of drinking water for their entire
lifetime is estimated to be 0.0063, 0.063, 0.63 and 6.3, respectively.
It should be noted that these risk values are upper-limit estimates.
Actual risk levels are unlikely to be higher and may be lower. It is
also important to note that in the case of p-DCB, there is additional
reason to view these values as probably being overestimates of the
possible cancer risk to humans, since the results that were reported for
these test animals cannot be directly related to human tissue or to the
usual route and mode of human exposure.
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT
HUMAN HEALTH?
The federal government has taken a number of steps to protect
humans from p-DCB. First, the Environmental Protection Agency (EPA) has
included p-DCB on the list of Hazardous Waste Constituents and subjected
the chemical to hazardous waste regulations. Second, the EPA has issued
test rules requiring environmental and health effects testing of p-DCB.
Third, the EPA has promulgated a maximum contaminant level of
75 micrograms per liter of water for p-DCB in drinking water. Fourth,
all pesticides are registered with EPA, and their manufacturers must
submit certain kinds of information to EPA in order that they be allowed
to be used as pesticides. Finally, the Occupational Safety and Health
Administration (OSHA) has a maximum permissible exposure limit to p-DCB
in workplace air of 75 parts per million.
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2. HEALTH EFFECTS SUMMARY
2.1 INTRODUCTION
This section summarizes and graphs data on the health effects
concerning exposure to p-DCB. The purpose of this section is to present
levels of significant exposure for p-DCB based on key toxicological
studies, epidemiological investigations, and environmental exposure
data. The information presented in this section is critically evaluated
and discussed in Sect. 4, Toxicological Data, and Sect. 7, Potential for
Human Exposure.
This Health Effects Summary section comprises two major parts.
Levels of Significant Exposure (Sect. 2.2) presents brief narratives and
graphics for key studies in a manner that provides public health
officials, physicians, and other interested individuals and groups with
(1) an overall perspective of the toxicology of p-DCB and (2) a
summarized depiction of significant exposure levels associated with
various adverse health effects. This section also includes information
on the levels of p-DCB that have been monitored in human fluids and
tissues and information about levels of p-DCB found in environmental
media and their association with human exposures.
The significance of the exposure levels shown on the graphs may
differ depending on the user's perspective. For example, physicians
concerned with the interpretation of overt 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 frank effects (Frank Effect Level, FEL). 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 (Lowest-Observed-Adverse-Effect Level,
LOAEL) or exposure levels below which no adverse effects (No-Observed-
Adverse -Effect Level, NOAEL) have been observed. Estimates of levels
posing minimal risk to humans (Minimal Risk Levels) are of interest to
health professionals and citizens alike.
Adequacy of Database (Sect. 2.3) highlights the availability of key
studies on exposure to p-DCB in the scientific literature and displays
these data in three-dimensional graphs consistent with the format in
Sect. 2.2. The purpose of this section is to suggest where there might
be insufficient information to establish levels of significant human
exposure. These areas will be considered by the Agency for Toxic
Substances and Disease Registry (ATSDR), EPA, and the National
Toxicology Program (NTP) of the U.S. Public Health Service in order to
develop a research agenda for p-DCB.
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8 Section 2
2.2 LEVELS OF SIGNIFICANT EXPOSURE
To help public health professionals address the needs of persons
living or working near hazardous waste sites, the toxicology data
summarized in this section are organized first by route of exposure--
inhalation, Ingestlon, and dermal--and then by toxicological end points
that are categorized Into six general areas--lethality, systemic/target
organ toxicity, developmental toxlcity, reproductive toxicity, genetic
toxicity, and carclnogenlcity. The data are discussed in terms of three
exposure periods--acute, Intermediate, and chronic.
Two kinds of graphs are used to depict the data. The first type is
a "thermometer" graph. It provides a graphical summary of the human and
animal toxicological end points (and levels of exposure) for each
exposure route for which data are available. The ordering of effects
does not reflect the exposure duration or species of animal tested. The
second kind of graph shows Levels of Significant Exposure (LSE) for each
route and exposure duration. The points on the graph showing NOAELs and
LOAELs reflect the actual doses (levels of exposure) used in the key
studies. No adjustments for exposure duration or Intermittent exposure
protocol were made.
Adjustment reflecting the uncertainty of extrapolating animal data
to man, Intraspecles variations, and differences between experimental vs
actual human exposure conditions were considered when estimates of
levels posing minimal risk to human health were made for noncancer end
points. These minimal risk levels were derived for the most sensitive
noncancer end point for each exposure duration by applying uncertainty
factors. These levels are shown on the graphs as a broken line starting
from the actual dose (level of exposure) and ending with a concave-
curved line at Its terminus. Although methods have been established to
derive these minimal risk levels (Barnes et al. 1987), shortcomings
exist in the techniques thac reduce the confidence in the projected
estimates. Also shown on the graphs under the cancer end point are low
level risks (10'4 to 10'7) reported by EPA. In addition, the actual dose
(level of exposure) associated with the tumor incidence is plotted.
2.2.1 Kay Studies
Figures 2.1 through 2.3 are graphic presentations of the adverse
health effects that have been identified in studies using inhalation and
ingestion data, respectively. None of the available human studies were
considered acceptable. There are various limitations and deficiencies in
these studies. For example, neither the duration nor the intensity of
exposure is clearly known or stated in any of these reports. In
addition, it cannot be stated with certainty that each of these persons
was exposed to only p-DCB. Therefore, only animal studies are designated
as key studies for p-DCB. Studies using dermal exposure were not located
in the available literature.
Figures 2.4 and 2.5 present data for the various toxicity end
points for the inhalation and oral routes of exposure, respectively. The
details of these studies are presented in the following subsections. In
addition to data on the NOAELs and LOAELs available from the various
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tfealch Effects Summary 9
ANIMALS
1000
100
10
OlL.
• RABBITS. DEVELOPMENTAL EFFECTS. 13 DAYS
(• RATS. UVEH AND KIDNEY EFFECTS 78 WEEKS
\ • RATS DEVELOPMENTAL EFFECTS. 10 DAYS
O RABBITS. DEVELOPMENTAL EFFECTS. 13 DAYS
O RATS. UVER AND KIDNEY EFFECTS. 76 WEEKS
• LOAEL FOR ANIMALS
O NOAEL FOR ANIMALS
HUMANS
(PP«n)
1000
r QUANTITATIVE
DATA WERE
NOT AVAILABLE
100
01
APPROXIMATE
ODOR THRESHOLD
Fig. 2.1. Effects of p-DCB—inhaUtkw
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10 Section 2
ANIMALS
(m(j/kfl/day)
10.000 r-
HUMANS
V.OOO
100 L.
(100% LETHALITY)
• GUINEA PIGS (100% LETHALITY)
• RATS. LQso
O GUINEA PIGS (0% LETHALITY)
- ORATS (0% LETHALITY)
• MICE. UVER EFFECTS. 13 WEEKS
• MICE. UVER TUMORS. 2 YEARS6
• RATS. DEVELOPMENTAL EFFECTS. 10 DAYS
O MICE. UVER EFFECTS. 13 WEEKS
/f • RATS. KIDNEY EFFECTS. 13 WEEKS
_ J • RATS. KIDNEY TUMORS. 2 YEARS
1 • MICE. UVER AND KIDNEY EFFECTS. 2 YEARS
lO RATS. UVER EFFECTS. 2 YEARS
O RATS. DEVELOPMENTAL EFFECTS. 10 DAYS
f • RATS. KIDNEY EFFECTS, 2 YEARS
IO RATS. KIDNEY EFFECTS. 13 WEEKS
QUANTITATIVE DATA
WERE NOT AVAILABLE
LOAEL ONOAEL
Flg.L2. Effects of j-DCB—oral exposure.
-------
tfealch Effects Summary 11
ANIMALS
(mg/kg/day)
10,000
1.000
100
10
0.1
0.01 •-
RATS, LD5Q
HUMANS
QUANTITATIVE
DATA WERE
NOT AVAILABLE
Fig. 2J. Effects of p-DCB—dermal exposure.
-------
12 Section 2
ACUTE
(S14 DAYS)
DEVELOPMENTAL
INTERMEDIATE
(15-364 DAYS)
(ppm)
10.000 r
1.000
100
10
0.1
0.01
0.001 L-
QUANTITATIVE DATA
WERE NOT AVAILABLE
r RAT
h RABBIT
| MINIMAL RISK FOR EFFECTS
i OTHER THAN CANCER
CHRONIC
(>365 DAYS)
SYSTEMIC
r (LIVER)
• LOAEL
O NOAEL
Fig. 2.4. LerebofdptflcaM
for
of fDCB.
-------
Healch Effects Summary 13
ACUTE
(S14 DAYS)
INTERMEDIATE
(15364 DAYS)
CHRONIC
(>365 DAYS)
DEVELOP- TARGET REPRO- TARGET TARGET
LETHALITY3 MENTAL ORGAN DUCTION ORGAN ORGAN CANCER6
(mg/kg/day)
10.000 r
1.000
100
10
01
001 -
0001 -
00001 -
000001 -
0 000001 L-
r RAT
m MOUSE
g GUINEA PIG
r (KIDNEY) f m (LIVER)
O i
• m
I
• m (LIVER.
r (KIDNEY) KIDNEY>
V
i
ESTIMATED
UPPER-BOUND
HUMAN
CANCER
RISK LEVELS6
io-4i
10-5-
io~6-
io-7j
J MINIMAL RISK FOR EFFECTS "f MINIMAL RISK LEVEL ESTIMATED
I OTHER THAN CANCER i FROM INTERMEDIATE EXPOSURE DATA
J, sir
• LOAEL
O NOAEL
'Available Irtwlliy daa ar» not eontidarvd ad*qua» tor ealeUaong an MRL.
'Combined adenomas plua cananomat.
'Further anelyM of me reaulta of the NTP (1987) bwa*My nae nwed quetdona at » tfw ratewanoe
lor humana of tfie ooaerxed tumota In raa and mice.
FIg.U. Lercb of
forhferttaofp-DCB.
-------
14 Section 2
studies, these figures present estimates of minimal risk levels for each
of the durations of exposure where data permit.
The estimation of minimal risk levels is based on the use of
uncertainty factors with the results of acceptable studies. When a NOAEL
has been determined from an adequate animal study of appropriate
duration, that NOAEL is divided by an uncertainty factor of 100. For
example, if a NOAEL of 450 ppm has been determined for reproductive
effects in an adequate study using mice, a level of 4.5 ppm would be
considered to present minimal risk for this effect to humans. If a LOAEL
has been used because a NOAEL was not available, an uncertainty factor
of 1000 is used. These uncertainty factors are intended to account for
interspecies variation and intrahuman sensitivity.
2.2.1.1 Lethality/decreased longevity
No animal or human studies provided adequate data to evaluate
lethality or decreased longevity as a toxicity end point for p-DCB
exposure via inhalation. Deaths reported in animal studies (and in human
case studies) with exposure to p-DCB via inhalation have been attributed
to massive renal or hepatic damage.
One study on the lethality of p-DCB administered by gavage to rats
(groups of 5 to 15, mixed sex) and guinea pigs (groups of 5, mixed sex)
was reported by Hollingsworth et al. (1956). In rats, a single dose of
1000 mg/kg resulted in no lethality, whereas 4000 mg/kg resulted in 100%
lethality. In guinea pigs, 1600 mg/kg resulted in no lethality, whereas
2800 mg/kg resulted in 100% lethality. These data are presented in Fig.
2.5. Gaines and Linder (1986) reported that oral LJ>50 values for p-DCB
in adult rats were 3863 and 3790 mg/kg for males and females,
respectively. In the same study, these authors reported that the dermal
LD50 for p-DCB in rats was greater than 6000 mg/kg in both sexes.
2.2.1.2 Systemic/target organ toxicity
The organ systems designated as primary toxicity end points for
p-DCB are the central nervous system (CNS), the liver, and the kidneys.
Central nervous system effects. CNS toxicity has been reported in
a few case studies of humans exposed to p-DCB at unspecified levels via
inhalation in the home and in the workplace. Effects have included
headache, dizziness, nausea, clumsiness, and slurred speech. However,
because of various limitations and deficiencies associated with these
studies, they can be viewed only as suggestive evidence that p-DCB
inhalation by humans can result in CNS effects. Detailed descriptions of
these studies are presented in Sect. 4.3. There is no acceptable
evidence of CNS effects in animals exposed to p-DCB by inhalation.
CNS effects have not been adequately confirmed in association with
ingestion of p-DCB by humans, and no data are available in test animals.
Also, dermal studies are not available in any species.
Hepatotozlcity. Hepatic effects including degeneration, necrosis,
porphyria, and/or changes in enzyme levels have been reported in animal
studies by both oral and inhalational exposure during short-term (as
brief as 3 days) or long-term (2 years) exposures. Evidence of liver
damage in humans exposed by inhalation include jaundice, cirrhosis, and
-------
Healch Effects Summary 15
acute yellow atrophy of Che liver. Dose-response data, however, are not
available for humans. Hepatic effects have not been reported in humans
ingesting p-DCB, and dermal studies are not available for either humans
or animals.
Hepatotoxicity. inhalation. Hepatic effects in humans exposed to
p-DCB via inhalation for durations of a few months or more have been
reported in several case studies. However, there are no dose-response
data associated with these reports. A single study in animals provides
quantitative data for hepatic effects associated with long-term
inhalation exposure to p-DCB. Riley et al. (1980) reported a NOAEL of
75 ppm for increased liver weight and slight increases in urinary
coproporphyrin in rats exposed to p-DCB for 76 weeks. The LOAEL was
500 ppm for these effects. This study serves as the basis for the
minimum risk level shown in Fig. 2.4.
Hepatotoxicity, oral. No acceptable data are available on the
hepatic effects of short-term, intermediate, or chronic oral exposure of
humans to p-DCB. However, hepatic effects have been observed following
oral exposures of animals to p-DCB.
Available data on intermediate exposure of test animals to p-DCB
via ingestion indicate that various adverse hepatic effects are observed
in 13-week mouse studies at doses of 600 mg/kg/day and higher. A NOAEL
of 338 mg/kg/day was identified.
In a 2-year NTP (1987) bioassay of p-DCB, male F344/N rats were
dosed by gavage at ISO or 300 mg/kg/day and females at 300 and 600
mg/kg/day. Hepatic effects were not observed in rats. In the same study,
male and female B6C3F1 mice were dosed by gavage with p-DCB at 300 or
600 mg/kg/day. p-DCB increased the incidences of nonneoplastic liver
lesions in male and female mice, including alteration in cell size
(cytomegaly and karyomegaly), hepatocellular degeneration, and
individual cell necrosis. Therefore, the LOAEL for hepatic effects in
mice has been identified as 300 mg/kg/day.
Hepatotoxicity, dermal. There are no available data on hepatic
effects resulting from short-term, intermediate, or long-term dermal
exposure to p-DCB by humans or animals.
Renal effects, inhalation. No acceptable data are available on
renal effects following inhalation exposure of any duration by humans to
p-DCB. In a long-term animal study by Riley et al. (1980), increased
renal weights were reported in rats exposed to p-DCB via inhalation for
76 weeks. The NOAEL for these effects was 75 ppm, and the LOAEL was
500 ppm.
Renal effects, oral. There are no available data to suggest that
renal toxicity is associated with short-term oral exposure to p-DCB by
humans or test animals. Likewise, there are no quantitative data
available on the renal effects of intermediate or chronic oral exposure
of humans to p-DCB. However, adverse renal effects have been reported in
several subchronic studies in animals exposed to p-DCB by gavage.
Hollingsworth et al. (1956) reported a NOAEL of 18.8 mg/kg/day and a
LOAEL of 188 mg/kg/day for increased renal weight and cloudiness and
swelling of the renal tubular epithelium in female rats administered
p-DCB for 6 months.
-------
16 Section 2
In two NTP (1987) 13-week pilot studies, F344/N rats and B6C3F1
mice were dosed with p-DCB by gavage. In the first study, rats were
dosed with 300 to 1500 mg/kg/day. Because histologic changes were
observed in the kidneys of male rats at all doses, a second 13-week
study was performed at doses of 38, 75, 150, or 600 mg/kg/day.
Renal tubular cell degeneration was observed in male rats receiving
300 mg/kg/day or more in the first study, but only slight changes were
seen at 300 mg/kg/day in the second study. The kidney weight to brain
weight ratio was increased in male rats receiving doses of 600 mg/kg/day
or more. The blood urea nitrogen level was increased slightly in male
rats dosed with 900 mg/kg/day or more. Based on the combined results of
both studies, a LOAEL of 300 mg/kg/day and a NOAEL of 150 mg/kg/day were
identified in rats. This study serves as the basis for the minimum risk
level shown in Fig. 2.5.
Charbonneau et al. (1987a,b) and Bomhard and Luckhaus (undated)
reported that p-DCB administered by gavage to Fischer-344 rats under a
wide variety of dosage regimens resulted in an increase in renal hyaline
droplet formation in males but not in females. The Charbonneau et al.
(1987a) study showed that, after administration of a single 500-mg/kg
dose of l^C-p-DCB, the radioactivity in the kidney cytosol was found to
be reversibly associated with the protein a-2ft-globulin.
Renal effects have also been observed in one study of chronic oral
exposure to p-DCB. In the NTP (1987) bioassay, described above, male
rats exposed to p-DCB at 150 mg/kg/day and 300 mg/kg/day for 2 years
exhibited nephropathy, epithelial hyperplasia of the renal pelvis,
mineralization of the collecting tubules in the renal medulla, and focal
hyperplasia of the renal tubular epithelium. There were increased
incidences of nephropathy in female rats dosed with p-DCB at 300
mg/kg/day and 600 mg/kg/day, as compared with vehicle controls.
Therefore, the LOAEL for renal effects in rats was 150 mg/kg/day.
Because this was the lowest level tested in this phase of the study, no
estimate of the NOAEL in rats is available. p-DCB at both 300 mg/kg/day
and 600 mg/kg/day in this study also increased the incidences of
nephropathy in male mice and renal tubular degeneration in female mice.
Therefore, 300 mg/kg/day was the LOAEL for renal effects in mice.
Renal effects, dermal. There are no available data appropriate for
determining a significant level of human exposure for renal effects
resulting from short-term, intermediate, or long-term dermal exposure to
p-DCB by humans or animals.
2.2.1.3 Developmental toxicity
There are limited data suggesting that p-DCB is a developmental
toxicant at levels of exposure that result in maternal toxicity.
Inhalation. Exposures of pregnant rabbits to p-DCB at 800 ppm
resulted in slight maternal toxicity and developmental effects (an
increased incidence of retroesophageal right subclavian artery) . Hodge
et al. (1977, as summarized in Loeser and Litchfield 1984) reported that
500 ppm (the highest dose tested) was the NOAEL for maternal toxicity
and fetotoxic and teratogenic effects in rats exposed to p-DCB on days 6
to 15 of gestation. Hayes et al. (1985) reported a NOAEL of 300 ppm for
-------
Health Effects Summary L7
maternal and developmental toxicity In rabbits. There was a significant
increase (P < 0.05) in the incidence of retroesophageal right subclavian
artery at 800 ppm. The authors did not consider this increase in
incidence to be a teratogenic effect. However, this effect was reported
as an observed structural anomaly in the development of these fetuses,
therefore, 800 ppm is the LOAEL for this study which serves as the basis
for the minimum risk level shown in Fig. 2.4.
Oral. In a gavage study using rats, Giavini et al. (1986) reported
that p-OCB at levels of 500 mg/kg/day and above (administered on days
6 through 15 of gestation) resulted in retarded maternal weight gain and
the presence of an extra rib in the fetuses. The latter effect was not
considered by the authors to be a teratogenic effect; however, other
teratologists consider any structural anomaly to be a significant event
in the development of the organism. Thus, based on a conservative
approach, the NOAEL was 250 mg/kg/day. This study serves as the basis
for the minimum risk level shown in Fig. 2.5.
Dermal. There are no available dermal studies on the potential
developmental effects of p-DCB exposure in humans or test animals.
2.2.1.4 Reproductive toxicity
There are no adequate data in experimental animals or humans to
assess the potential reproductive toxicity of p-DCB.
In a short-term inhalation study by Anderson and Hodge (1976, as
reported in Loeser and Litchfield 1983), no reduction in reproductive
performance (as measured by the percentage of males successfully
impregnating females) was observed when male mice were exposed to p-DCB
at levels up to 450 ppm for 5 days and then mated with virgin females.
In order to assess the potential effects of a compound on reproductive
performance, however, studies of this kind are usually carried out
during the entire period of spermatogenesis (approximately 9 weeks).
Therefore, the conditions of this study are not considered adequate to
test this effect.
Neither oral nor dermal studies have been conducted to assess this
effect in humans or in test animals.
2.2.1.5 Genotoxlcity
Based on the results of genotoxic studies in bacteria and mammalian
cells, p-DCB is generally viewed as nonmutagenic (NTP 1987). Genotoxic
effects have been observed in several studies of higher plants exposed
to p-DCB. Investigations using microbial, animal, and human systems and
cells have all been negative with two exceptions. One is a single study
in fungus (Prasad and Framer 1968, Prasad 1970). The other is an
unpublished study indicating that DNA replication is increased in the
liver tissue of male and female mice and in the kidney tissue of male
rats administered a single oral dose of p-DCB (Steinmetz and Spanggord
1987a,b).
-------
18 Section 2
2.2.1.6 Carcinogeniclty
Inhalation. There are no available data on the potential
carcinogenicity of p-DCB in humans exposed via inhalation for any
duration of exposure. Neither are data available on short-term or
intermediate exposures of test animals.
No evidence of carcinogenicity was observed by Riley et al. (1980,
as reported in Loeser and Litchfield 1983) in male or female SPF Alderly
Park Wistar-derived rats. SPF Alderly Park Swiss mice were also used in
this study, but, because of a high incidence of respiratory infections,
the results are not considered valid. Rats were exposed to p-DCB by
inhalation at 0, 75, or 500 ppm for 5 h/day, 5 days/week for 76 weeks.
As discussed in Sect. 4.2, Hawkins et al. (1980), using radiolabeled
p-DCB, showed that tissue levels of radioactivity are similar when
repeated oral doses of 250 mg/kg/day or repeated inhalation doses of
1000 ppm for 3 h/day are administered. However, the conditions of the
Riley et al. (1980) study may have resulted in considerably lower tissue
levels of p-DCB than those occurring in animals in the NTP (1987) gavage
study (dosed at 150 mg/kg/day and 300 mg/kg/day for male rats and 300
and 600 mg/kg/day for female rats and mice of both sexes). Another
consideration is that the maximum tolerated dose (MTD) was not achieved
in the inhalation study. Based on the dosage levels, as well as the
less-than-lifetime duration of dosing, the results of the Riley et al.
(1980) study cannot be viewed as providing definitive evidence of the
noncarcinogenieity of p-DCB via the inhalation route.
Oral. There are no available data on the potential carcinogenicity
of p-DCB in humans exposed by ingestion for any duration of exposure. In
animals, only data on chronic exposure are available.
p-DCB was carcinogenic in both rats and mice exposed to p-DCB for
2 years in the NTP (1987) carcinogenesis bioassay. p-DCB was
administered by gavage to F344/N rats and B6C3F1 mice in groups of 50
animals per sex per dosage group. Hale rats received doses of 150
mg/kg/day and 300 mg/kg/day; female rats and mice of both sexes received
doses of 300 mg/kg/day and 600 mg/kg/day.
In this study, p-DCB produced a dose-related increase in the
incidence of tubular cell adenocarcinomas of the kidney in male rats
[1/50 (2%); 3/50 (6%); 7/50 (14%)]. These malignant tumors are uncommon
in male F344/N rats; they have been diagnosed in only 4/1098 (0.4%) of
the corn oil gavage controls in previous NTP studies. In addition, one
tubular cell adenoma was observed in a high-dose male rat. There were no
tubular cell tumors in dosed or vehicle control female rats. There was a
marginal increase in the incidence of mononuclear cell leukemia in dosed
male rats compared with that in either vehicle controls or historical
controls. Based on this rat study, p-DCB was found to be carcinogenic in
male rats because of the finding of renal tumors.
In this study, p-DCB also increased the incidences of
hepatocellular carcinomas in high-dose male mice and of hepatocellular
adenomas in both high- and low-dose male and in high-dose female mice.
The increase in adenomas plus carcinomas was statistically significant
at the high dose but not at the low dose. Female control mice in this
bioassay had a substantially higher Incidence of liver tumors than did
-------
Healch Effects Summary 19
historical controls. Hepatoblastomas (a form of hepatocellular
carcinoma) were observed in four high-dose male mice with other
hepatocellular carcinomas but not in vehicle controls. This rare
malignant tumor had not previously occurred in 1091 male vehicle control
mice in NTP studies. An increase in thyroid gland follicular cell
hyperplasia was observed in dosed male mice, and there was a marginal
positive trend in the incidence of follicular cell adenomas of the
thyroid gland in female mice. Pheochromocytomas (tumors of chromaffin
tissue of the adrenal medulla or sympathetic preganglia) (benign and
malignant, combined) of the adrenal gland occurred with a positive trend
in dosed male mice, and the incidence in the high-dose group was
significantly greater than in vehicle controls. The incidences of
adrenal gland medullary hyperplasia and focal hyperplasia of the adrenal
gland capsule were also elevated in dosed male mice.
Further analysis of the results of the NTP (1987) bioassay has
raised certain questions as to the relevance of the observed renal
tumors in male rats and hepatic tumors in mice to the potential
carcinogenicity of p-DCB in humans. The observation that kidney tumors
are induced in male but not female rats in response to exposure to
certain chemicals has been the subject of current research.
Toxicologists at the Chemical Industry Institute of Toxicology (CUT)
have hypothesized that the male rat kidney is susceptible to the
induction of certain tumors because it contains the protein cr-2j»-
globulin, which has not been found at significant levels in female rats
or in mice or humans (Charbonneau et al. 1987a). They have demonstrated
that a-2/i-globulin in combination with certain components of petroleum
enhances the formation of hyaline droplets in the proximal convoluted
tubules of male rats. The resulting cellular damage and cell
proliferation are hypothesized to result in enhanced tumor formation.
This group is currently conducting studies to determine whether similar
events are observed during the induction of renal tumors in male rats
exposed to p-DCB (personal communication from J. Swenberg, CUT, June 9.
1987). Based on these considerations, it is not clear how to interpret
the renal tumors in evaluating the potential carcinogenicity of p-DCB in
humans. These tumors have not been used by EPA to estimate the
carcinogenic risk for p-DCB.
There has also been much discussion of the interpretation of the
finding of hepatocellular carcinomas and adenomas in mice in the NTP
(1987) study. There was a higher than usual rate of these tumors in
control female mice. Because p-DCB has not been demonstrated to be
mutagenic in any of the microbial or mammalian systems tested, NTP
(1987) has suggested that it may act as a tumor promotor. However, no
studies have been conducted to investigate this possibility.
The EPA Office of Drinking Water (EPA 1987a, 52FR25690 1987) has
placed p-DCB into Category C, possible human carcinogen. This category
is for substances with limited evidence of oncogenic potential in animal
studies in the absence of human data.
In an analysis of the NTP (1987) carcinogenicity data (available in
1986 as the galley draft), Battelle and Crump (1986) used the liver
tumors in male mice and the linearized multistage model to calculate a
-------
20 Section 2
q * of 2.2 x 10"2 (mg/kg/day)"1. Based on this calculation, oral doses
(ing/kg/day)'1 associated with upper-bound risks of 10"4, 10'5, 10'6. and
ID"' would be 4.5 x 10'3, 4.5 x 10'4, 4.5 x 10"5, and 4.5 x 10'6
mg/kg/day.
Using the male rat kidney tumor data in the NTP (1987) study with
p-DCB. Battelle and Crump (1986) report a q.* of 6 x 10'3 by the
linearized multistage model as well as by trie multistage-Weibull and
Crump's multistage models, taking time to death into account. This q *
is lower than the q.* of 2.2 x 10"2 obtained with the male mouse liver
tumor data from the NTP (1987) study and is, therefore, considered the
less conservative estimate of risk.
Dermal. There are no available data on the potential
carcinogenicity of p-DCB via the dermal route.
2.2.2 Biological Monitoring as a Measure of Exposure and Effects
As discussed in Sect. 4.1, Toxicokinetics, adipose tissue, kidneys,
and liver are the primary compartments into which p-DCB is deposited
after exposure by animals. As discussed in Sect. 4.3, Toxicity, the
major target organs of p-DCB appear to be the CNS, liver, and kidneys.
p-DCB and/or its metabolites can be measured in various biological
tissues in order to confirm prior recent exposure. Examples are:
1. measurement of p-DCB in blood;
2. measurement of p-DCB in adipose tissue; and
3. measurement of the p-DCB metabolite, 2,5-dichlorophenol, and/or
its conjugates in urine.
There are currently no data available to assess a potential
correlation between the values obtained with these measurements and the
toxic effects observed in humans or test species.
2.2.3 Environmental Levels as Indicators of Exposure and Effects
There are no available case studies or epidemiologic investigations
that suggest that levels of p-DCB found in environmental media are
associated with significant human exposure. The major route of exposure
for the general population is expected to be via inhalation, especially
in indoor air as a result of vapor released from commercial products.
The available data suggest that the levels of p-DCB in outside air are
relatively insignificant although the compound is widespread. Levels in
groundwater and surface water are also relatively low for the general
population. Therefore, exposure via drinking water does not pose a
significant health hazard for most individuals, but could be significant
in localized contaminated areas.
2.3 ADEQUACY OF DATABASE
2.3.1 Introduction
Section 110 (3) of SARA directs the Administrator of ATSDR to
prepare a toxicological profile for each of the 100 most significant
hazardous substances found at facilities on the CERCLA National
Priorities List. Each profile must include the following content:
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Healch Effaces Summary 21
"(A) An examination, summary, and interpretation of available
toxicological information and epidemiologic evaluations on a
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.
(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 section identifies gaps in current knowledge relevant to
developing levels of significant exposure for p-DCB. Such gaps are
identified for certain health effects'end points (lethality,
systemic/target organ toxicity, developmental toxicity, reproductive
toxicity, and carcinogenicity) reviewed in Sect. 2.2 of this profile in
developing levels of significant exposure for p-DCB and for other areas,
such as human biological monitoring and mechanisms of toxicity. The
present section briefly summarizes the availability of existing human
and animal data, identifies data gaps, and summarizes research in
progress that may fill such gaps.
Specific research programs for obtaining data needed to develop
levels of significant exposure for p-DCB will be developed by ATSDR,
NTP, and EPA in the future.
2.3.2 Health Effect End Points
2.3.2.1 Introduction and graphic summary
The availability of data for health effects in humans and animals
is depicted on bar graphs in Figs. 2.6 and 2.7, respectively.
The bars of full height indicate that there are data to meet at
least one of the following criteria:
1. For noncancer health end points, one or more studies are available
that meet current scientific standards and are sufficient to define
a range of toxicity from no effect levels (NOAELs) to levels that
cause effects (LOAELs or FELs).
2. For human carcinogenicity, a substance is classified as either a
"known human carcinogen" or "probable human carcinogen" by both EPA
and the International Agency for Research on Cancer (IARC)
(qualitative), and the data are sufficient to derive a cancer
potency factor (quantitative).
3. For animal carcinogenicity, a substance causes a statistically
significant number of tumors in at least one species, and the data
are sufficient to derive a cancer potency factor.
4. There are studies which show that the chemical does not cause this
health effect via this exposure route.
-------
HUMAN DATA
NJ
K>
SUFFICIENT
INFORMATION*
n
rt
No
V SOME
INFORMATION
J
NO
INFORMATION
INHALATION
DERMAL
LETHALITY
ACUTE INTERMEDIATE CHRONIC DEVELOPMENTAL REPRODUCTIVE CAHCINOGENICIIY
/ Toxicrrv TOXICITY
SYSTEMIC TOXICITV
'Sufficient Information exists to meat at least one of the criteria for cancer or noncancer end points.
Fig. 2.6. Availability of iBformatioa oa health effects ot f-DCB (human data).
-------
ANIMAL DATA
V SUFFICIENT
'INFORMATION*
V SOME
INFORMATION
J
NO
INFORMATION
ORAL
INHALATION
DERMAL
LETHALITY ACUTE INTERMEDIATE CHRONIC DEVELOPMENTAL REPRODUCTIVE CARCINOGENIC!!*
Z - - / TOXICITY TOXICITV
SYSTEMIC TOXICITV
"Sufficient Information exists to meet at least one of the criteria for cancer or noncancer end points.
8
»—
3-
n
in
0}
Fig. 2.7. Availability of information on health effects of p-DCB (animal data).
-------
24 Section 2
Bars of half height indicate that "some" information for the end
point exists, but does not meet any of these criteria.
The absence of a column indicates that no information exists for
that end point and route.
For systemic/target organ effects, data adequacy have been plotted
for the system/target organ which is most sensitive to p-DCB.
2.3.2.2 Descriptions of highlights of graphs
As shown in Fig. 2.6, human data for p-DCB are not considered
adequate in any of the categories presented. None of the available case
studies provided information on exposure levels associated with any of
the reported effects. In addition, exposure to p-DCB was not actually
verified in every report, nor was exposure to other possible causative
agents excluded. The case studies based on exposure in occupational
settings have provided some data for systemic toxicity resulting from
intermediate and short-term inhalation exposures to p-DCB.
In the data based on animal studies, as shown in Fig. 2.7, only
lethality data are available via the dermal route. In the few acceptable
studies conducted via inhalation, the levels tested were considered to
be below the MTD and may not have been high enough to assess the effects
(chronic toxicity, carcinogenicity, and developmental toxicity) that
were being tested. No inhalation data were available to assess
lethality, reproductive toxicity, or the systemic effects due to acute
or intermediate-duration exposures. In studies via the oral route, data
were considered adequate for systemic toxicity resulting from
intermediate and chronic exposures to p-DCB, with the liver found to be
the most sensitive target organ in most laboratory animals tested. The
carcinogenicity study is also considered to be adequate. Data on
lethality and developmental toxicity are not considered adequate. Oral
studies on developmental toxicity are considered adequate, but no oral
studies on reproductive toxicity have been located.
2.3.2.3 Summary of relevant ongoing research
A search of the National Institutes of Health (NIH) Computer
Retrieval of Information on Scientific Projects (CRISP) database gave no
indication that there is current research being conducted relevant to
the toxicity of p-DCB. The CUT, however, has been investigating the
relevance of renal tumors found in rats exposed to p-DCB in the NIP
(1987) bioassay (personal communication, J. Swenberg, CUT,
June 9, 1987). Recent information from the Chlorobenzene Producers
Association (CPA) submitted by Rautio (1988) indicates that current and
planned research activities for p-DCB include the following:
• The p-DCB manufacturers are sponsoring a reproductive effects study
in rats entitled "Two-generation reproductive sr dy of Inhaled
para-dichlorobenzene in Sprague-Dawley CD rats."
• CPA and several Japanese p-DCB manufacturers will soon initiate
further pharmacokinetic research regarding p-DCB. The object of
this research is to characterize the effects of route of
administration and exposure level on the distribution, metabolism.
and elimination of p-DCB in the rat and mouse.
-------
Health Effects Summary 25
• In response to a Federal Data Call-In issued pursuant to the
Federal Insecticide, Fungicide, and Rodenticide Act, 7 U.S.C.
Section 136 ec seq., the p-DCB manufacturers have agreed to sponsor
the following studies: a 21-day dermal toxicity study (rat),
chronic toxicity study (nonrodent), and a general metabolism study.
2.3.3 Other Information Needed for Human Health Assessment
2.3.3.1 Pharmacoki.netics and mechanisms of action
The mechanisms of carcinogenicity for p-DCB are currently in
question. There is speculation by NTP (1987) that it acts as a tumor
promoter rather than as an initiator of the carcinogenic process.
Studies to examine tumor promotion as an end point would be useful in
assessing the potential cancer risks from human exposure to p-DCB.
It appears that the exposure levels used in the Riley et al. (1980)
inhalation studies resulted in much lower tissue levels of p-DCB than
were achieved in the oral studies by NTP (1987). The generally negative
or very mild physiologic effects observed during this and other
inhalation studies provide indirect support for this observation.
These findings suggest that more detailed pharmacokinetic data
would be especially useful in assessing previous studies, and that any
further study via inhalation should probably be conducted at much higher
exposure levels, assuming that they are physically possible to achieve.
Based on available information, there are no ongoing studies being
conducted to resolve these issues.
2.3.3.2 Monitoring of human biological samples
There are at least three methods used to test for human exposure to
p-DCB. The method most commonly used in industry is analysis of urine
for the metabolite 2,5-dichlorophenol. The other two methods involve the
analysis of blood or adipose tissue for p-DCB itself. The utility of
these methods has not been clearly delineated. Measurement of urinary
2,5-dichlorophenol correlates approximately (correlation coefficient not
calculated) with the levels of exposure during certain p-DCB
manufacturing and packaging activities. There are no known ongoing
studies that would be useful in correlating levels in biological samples
with exposure levels.
2.3.3.3 Environmental considerations
Current methodologies to assess the levels of p-DCB in the
environment are satisfactory. The bioavailability of p-DCB present in
soil and water is not clearly understood. The consequences of its
adsorption to organic matter in these media may decrease its
bioavailability.
There have been few studies done or calculations made to predict
the degradation and movement of p-DCB in the environment over time. Mosc
predictions are based on available information on other chlorinated
benzenes. There are no known ongoing studies to address these
deficiencies.
-------
27
3. CHEMICAL AND PHYSICAL INFORMATION
3.1 CHEMICAL IDENTITY
The chemical formula, structure, synonyms, and identification
numbers for p-DCB are listed in Table 3.1.
3.2 CHEMICAL AND PHYSICAL PROPERTIES
Important physical and chemical properties of p-DCB are listed in
Table 3.2.
-------
28 Section 3
Table 3.1. fVaical Mntfty
Property
Chemical name
Synonyms
Trade names
Chemical formula
Wiswesser line Dotation
Chemical structure
Value
1.4,-Dichlorobenzene
1.4-Dichloorbenzeen (Dutch)
1,4-Dichlor-B (German)
1.4-Diclorobenzene (Italian)
Benzene. 1.4-Dichloro
Benzene. /j-Dichloro
Dichlorobenzene, para, solid
p-Chlorophenyl chlonde
p-DCB
p-Dichloorbenzeen (Dutch)
p-Dichlorbenzol (German)
p- Dichlorobenzene
p-Dicblorobeazol
p-Diclorobenzene (Italian)
Parazene
PDB
Paradichlorobenzene
Paradichlorooenzol
Parodi
Pema-perazoi
Santochtor
Para crystal!
Paracide
Paradow
Paramoth
Paranuggeu
Evola
C.H.C1,
GRDG
Identification numbers
CAS Rejtitry No.
NIOSH RTECS No.
EPA Hazardous Waste No.
OHM-TADS No.
DOT/UN/NA/IMCO Shipping No.
STCCNa
Hizudoos Subsunccs Data Bank Na
National Cancer Institute Na
106-46-7
CZ 4550000
U072
8200116
UN 1592. IMCO 6.1
49411 28
523
C54955
Sourct: HSDB 1987.
-------
Chemical and Physical Informacion
29
T»M*3.0. Physical and chemical propertie* of r-DCB
Propeny
Molecular weight
Color
Physical state
Odor
Odor threshold, ppm
Melting point, "C
Boiling point, °C
Autoignition temperature, °F
Solubility
Water. 20 to 30° C. mg/L
Organic solvents
Density at 20° C, g/mL
Vapor density, air - 1
Partition coefTicients
Octanol/water (£„) log
Organic carbon (Kx) mL/g
Vapor pressure 20 to 30° C. mm Hg
Henry's law constant, atm-m'/mol
Refractive index, 60° C
Flash point (closed cap). °C
Flammable limits. ft
Value
14701
White or colorless
Crystalline solid
Aromatic, penetrating
018 to 30
S3 1
174 (sublimes at room
temperature)
775
Practically insoluble (79 mg/L)
Soluble in alcohol, acetone,
ether, chloroform, carbon
duulfide, and benzene
1 2475
5.08
360
1700
1 18
2.89 X 10~3
15283
65.6
6.2 to 16
References
Weast 1985
Verschueren 1977
Weast 1985
Clayton and
Clayton 1981
Amoore and
Hautala 1983,
HSDB 1987
Weast 1985
Weast 198S
NFPA 1978"
Verschueren 1977
Weasl 1985
Weast 1985
Sax 1979"
EPA 1986a
EPA 1986a
EPA I986a
EPA I986a
Weast 1985
Sax 1979"
NFPA 1978"
"Cited in HSDB 1987.
-------
31
4. TOXICOLOGICAL DATA
4.1 OVERVIEW
p-DCB is highly lipid-soluble and is therefore assumed Co'be
absorbed by all exposure routes. Although quantitative absorption
studies are not available, p-DCB is assumed to be 100% absorbed when
administered orally, and about 30% absorbed via inhalation when exposure
persists from 1 to 3 h.
The major route of elimination appears to be the urine.
2,5-Dichlorophenol has been demonstrated to be the major urinary
metabolite of p-DCB in both animals and humans.
Laboratory studies on the toxicity of p-DCB have shown that the
major noncarcinogenic effects are CNS effects and hepatic and renal
toxicity. Developmental effects have also been demonstrated in both oral
and inhalation studies. There is evidence that p-DCB is carcinogenic in
rats and mice when administered by gavage, with liver and kidneys as the
target organs.
4.2 TOXICOKINETICS
4.2.1 Overview
Quantitative absorption studies are not available for p-DCB. This
compound is assumed, however, to possess absorption characteristics
similar to those of benzene and the smaller chlorinated aliphatics and,
as such, would be 100% absorbed when administered orally, and about 30%
absorbed via inhalation when exposure persists from 1 to 3 h. The
potential for dermal absorption has not been addressed.
Animal studies have demonstrated that p-DCB, once absorbed, is
highly concentrated in adipose tissue, with much lower levels in liver
and kidney. Detectable levels have also been reported in blood, lung,
heart, and brain. Levels in fat have been shown to persist at least five
days after exposure.
2,5-Dichlorophenol has been demonstrated to be the major urinary
metabolite of p-DCB in both animals and humans. This metabolite is
eliminated principally as conjugates of glucuronic or sulfuric acids.
Some elimination in feces and expired air has been observed, and there
is also evidence of reabsorption in the enterohepatic circulation and
excretion in bile.
-------
32 Section 4
4.2.2 Absorption
p-DCB is sparingly soluble in water but highly lipid soluble and
thus can be expected to cross most barrier membranes, including those of
the placenta and brain (EPA 1987a).
4.2.2.1 Inhalation
Human. No data are available on the absorption of p-DCB by humans
exposed via inhalation.
Animal. No studies have been located which determine the
percentage of a dose of p-DCB absorbed following inhalation exposure by
animals. The EPA (1987a) estimated that 30% of an inhaled dose of p-DCB
is absorbed when exposure continues for longer than 1 to 3 h. Hawkins et
al. (1980) estimated that tissue levels of p-DCB are similar when female
rats either receive ten repeated oral doses of 250 mg/kg/day or inhale
1000 ppm for 3 h/day for 10 days.
4.2.2.2 Oral
Human. No studies have been located which determine the amount of
p-DCB absorbed by humans following oral exposure.
Animal. No studies have been located which determine the amount of
p-DCB absorbed by animals following oral exposure.
Based on the absorption characteristics of benzene and the smaller
chlorinated aliphatics (Astrand 1975. Dallas et al. 1983). EPA (1987a)
has assumed that 100% of an oral dose of p-DCB is absorbed.
4.2.2.3 Dermal
Human. No studies have been located which determine the absorption
of p-DCB by humans following dermal exposure.
Animal. No studies have been located which determine the
absorption of p-DCB by animals following dermal exposure.
4.2.3 Distribution
p-DCB is lipophilic and tends to be most highly concentrated in
tissues with high fat content. Available data indicate that adipose
tissue is the main depot for p-DCB in laboratory animals, with much
lower levels in liver and kidney. p-DCB has also been found in human
breast milk and in human tissue high in fat content.
4.2.3.1 Inhalation
Human. There are no available studies which determine the tissue
distribution pattern of p-DCB in humans exposed via inhalation. The
compound has been found, however, in human blood, fatty tissue, and
breast milk, presumably as a result of exposure via inhalation.
p-DCB has been detected in human adipose tissue and blood. In a
study of Tokyo residents, detectable levels of p-DCB were found in all
of 34 adipose tissue samples and all of 16 blood samples tested (Morita
et al. 1975, Morita and Ohi 1975)
-------
Toxicologies! Data 33
EPA (1983b) presented the results of a database search for
information on several chemicals identified in human milk. For p-DCB,
samples were collected from 42 lactating women in five locations in the
eastern United States. Measured values ranged from 0.04 to 68 /ig/mL with
an average of 9.15
EPA (1986d) reported the results of a national survey of various
volatile organic compounds found in composites of human adipose tissue
samples collected from persons living in the nine geographic areas that
compose the United States (within this survey). The specimens
(subcutaneous, perirenal, or mesenteric tissue) were collected from
October 1981 through September 1982 (FY 1982) and were excised during
surgery or as part of postmortem examinations. For each geographic
location, three age groups were represented: 0 to 14 years, 15 to 44
years , and 45 or more years .
Positive results were detected for p-DCB in these composites in
every category of analysis, with levels ranging from 0.012 to 0.50 >ig/g
wet tissue.
Animal. Hawkins et al. (1980) investigated the tissue distribution
of p-DCB in adult female CFY rats following inhalation, oral, or
subcutaneous exposure. The inhalation exposure was ten consecutive daily
doses of 14C-p-DCB at 1000 ppm for 3 h/day. Distribution patterns for
all routes were similar to those observed by Kimura et al. (1979), as
described below, with highest concentrations measured in fat (up to 598
Mg/g via inhalation) and next highest levels in kidneys and liver.
Concentrations in kidney and liver were -8 and 5%, respectively, of that
found in adipose tissue irrespective of the route of exposure.
4.2.3.2 Oral
Human. There are no available data on the distribution of p-DCB in
humans following oral exposure.
Animal. Kimura et al. (1979) determined the distribution of p-DCB
in the tissues of fasted rats following a single oral dose of 200 mg/kg-
The highest concentration of p-DCB was found in adipose tissue at all
sampling intervals up to 120 h postexposure, and peak concentrations in
fat occurred at 12 h postexposure (>800 /*g/g tissue). Kidney and liver
showed the next highest levels of p-DCB, with peak concentrations of
32 i*g/g and 24 j*g/g occurring at 6 to 12 h. These concentrations were
-4 and 3%, respectively, of the concentrations found in adipose tissue.
Low levels of p-DCB were also found in blood, lung, heart, and brain.
Host of the p-DCB in all tissues except for adipose had disappeared
within 48 h after administration of the chemical. Low levels of p-DCB
were still detected in the adipose tissue after 120 h.
Hawkins et al. (1980) investigated the tissue distribution of p-DCB
in adult female CFY rats following oral administration of 50, 125, 250.
375, or 500 mg/kg/day by gavage for 10 days. Distribution patterns for
all routes of administration used (oral, inhalation, and subcutaneous)
were similar to those observed by Kimura et al. (1979), as described
above, with the highest concentrations measured in fat and next highest
(but much lower) levels in kidney and liver.
-------
34 Section 4
4.2.4 Metabolism
Following oral administration to rabbits, the p-DCB is oxidized
principally to the corresponding dichlorophenol, 2,5-dichlorophenol. A
very high percentage of this metabolite is eliminated as conjugates of
glucuronic or sulfuric acids (Azouz et al. 1955, Williams 1959).
Conjugated dichlorophenols also appear to be the principal metabolic
products of the DCB isomers in humans (Hallowell 1959, Pagnatto and
Walkley 1965).
The mechanism of p-DCB oxidation to 2,5-dichlorophenol has not yet
been thoroughly investigated. The metabolism of p-DCB could involve the
formation of an arene oxide intermediate, as has been proposed to occur
in the oxidative metabolism of many halogenated aromatic hydrocarbons
(Jerina and Daly 1974). Preston et. al. (1983) have reported that the
ring hydroxylation of 2,2,5,5-tetrachlorobiphenyl (a dimer of p-DCB)
takes place without the formation of an arene oxide intermediate. p-DCB
has not been shown to be mutagenic in microbial or mammalian systems, a
result that may be viewed as further suggestive evidence that an arene
oxide intermediate is not involved in its metabolism.
4.2.4.1 Inhalation
Human. The dichlorophenols appear to be the principal metabolic
product of the DCB isomers in humans. In a survey of persons
industrially exposed to p-DCB, Pagnatto and Walkley (1965) used the
urinary metabolite, 2,5-dichlorophenol, as a measure of exposure to
p-DCB.
Animal. There are no available data on the metabolism of p-DCB in
animals exposed via inhalation.
4.2.4.2 Oral
Human. In a case of accidental ingestion of an unknown quantity of
p-DCB crystals by a 3-year-old boy, analysis of urine specimens yielded
four unidentified phenols as well as 2,5-dichlorophenol. These were
shown to be conjugated with glucuronic and sulfuric acids (Hallowell
1959).
Animal. Kimura et al. (1979) identified two sulfur-containing
metabolites of p-DCB in Che tissues, blood, and urine of rats following
a single 200-mg/kg oral dose or a series of 800-mg/kg/day doses over a
week. These metabolites were identified as 2,5-dichlorophenyl methyl
sulfoxide and 2,5-dichlorophenyl methyl sulfone. Very small amounts of
these two compounds were found (never more than 2 Mg/g tissue). Based on
two peak blood levels of the latter compound, the authors postulated
that this substance might undergo enterohepatic reabsorption and
circulation.
4.2.4.3 Dermal
Human. There are no available data on the metabolism of p-DCB by
humans following dermal exposure.
Animal. There are no available data on the metabolism of p-DCB by
animals following dermal exposure.
-------
Toxicological Data. 35
4.2.5 Excretion
The limited data available indicate that urine is the major route
of excretion of p-DCB.
4.2.5.1 Inhalation
Human. No data are available on the excretion of p-DCB by humans
exposed via inhalation.
Animal. Hawkins et al. (1980) administered 14C-p-DCB to female CFY
rats for 10 days via inhalation at 1000 ppm for 3 h/day. The amount of
l^C excreted in the expired air during 45 h after the tenth dose
represented a small proportion of the total ^C excreted, and, to the
surprise of the authors, was lower after inhalation (0.2%) than after
oral doses (1.0%) .
In rats with cannulated bile ducts, no C was detected in the
feces up to 24 h after a single dose, whereas, of the total ^C
recovered, 97.4% was eliminated in the urine at 5 days post treatment.
4.2.5.2 Oral
Human. No data are available on the excretion of p-DCB orally
administered to humans.
Animal. Hawkins et al. (1980) administered 14C -p-DCB to female CFY
rats for 10 days orally in rats with cannulated bile ducts at 250
mg/kg/day. Nine percent of the recovered ^C was excreted in the feces
during the 24 h following the last dose and presumably represents
unabsorbed material. In noncannulated rats, 97% of the recovered I4C was
eliminated in the urine within 5 days posttreatment. Approximately 1%
was recovered in expired air.
4.2.5.3 Dermal
Human. No data are available on the excretion of p-DCB by dermal ly
exposed humans.
Animal. No data are available on the excretion of p-DCB by
dermally exposed animals.
4.2.6 Discussion
Experiments with laboratory animals show that p-DCB is absorbed via
oral or inhalation exposure and is distributed mainly to adipose tissue,
with some distribution to the liver and kidney and minor amounts found
in other organs. Absorbed p-DCB is metabolized mainly by oxidation to
the dichlorophenol , conjugated with glucuronic or sulfonic acid, and
rapidly eliminated, mainly in the urine. There are no data to indicate
that the route of exposure has any effect on the subsequent metabolism
and excretion of p-DCB.
A review of the existing database suggests that additional
metabolic and pharmacokinetic studies are required in order to actually
predict the rate of absorption of this compound when exposure occurs
orally, dermally, or via inhalation. (Current estimates are based on
data from benzene and the smaller chlorinated aliphatics.) Because p-DCB
-------
36 Section 6
is commonly used as an ingredient in mothballs and toilet deodorant
blocks, it may be handled or inhaled by a significant portion of the
population on a regular basis and also has a high potential for
accidental ingestion. Thus, there is potential for human exposure by all
three routes.
4.3 TOXICITY
4.3.1 Lethality and Decreased Longevity
4.3.1.1 Overview
Currently available data on the effects of p-DCB exposure by any
route on potential lethality or decreased longevity are extremely
limited. There are no epidemiological data for human exposure via
inhalation and no adequate laboratory data on animals via this route.
Data on lethality via oral exposure are not extensive but do
suggest that this is an area of concern for this compound.
4.3.1.2 Inhalation
Human. There are no acceptable data available on the effects of
inhalation of p-DCB on lethality or decreased longevity in humans.
Available data on case reports from human studies are summarized in
Table 4.1. It is important to note that case studies, such as the ones
reported here, are to be interpreted with caution, since they reflect
incidents in which an individual has apparently been exposed to p-DCB,
and they assume that there has been no other exposure to a potentially
toxic agent(s). There is usually little or no verification of these
assumptions. These studies are not scientifically equivalent to
carefully designed epidemiologic studies or carefully controlled and
monitored laboratory experiments; therefore, they are to be considered
only as providing suggestive evidence that p-DCB may cause the reported
effects.
Only one report of human death attributed to p-DCB exposure has
been located in the literature. A middle-aged couple died within months
of each other of acute yellow atrophy of the liver (confirmed at
autopsy) (Cotter 1953). Their home had been "saturated" with p-DCB
mothball vapor for a period of at least 3 to 4 months. Clinical symptoms
included severe headache, diarrhea, numbness, clumsiness, slurred
speech, weight loss (50 pounds in three months in the case of the
husband), and jaundice. The wife died within a year of the initial
exposure.
Animal. Acceptable lethality data are not available for animals
exposed to p-DCB by inhalation.
4.3.1.3 Oral
Human. There are no available data investigating the potential
lethality or decreased longevity associated with ingestion of p-DCB by
humans.
-------
Toxicological Data 37
Subject
62-year-old male
19-year-old female
60-year-old male
Wife of male
above
36-year-old female
34-year-old female
52-year-old mate
20-year-old mate
(+ 26 workmates)
52-year-old female
3-year^ld TIE Iff
19-year-old female
21-year-old
pregnant female
Exposure
p-DCB in bath-
room
Preparation of
p-DCB for 18
months
Heavy p-DCB
mothball vapor
10 home for
3 to 4 months
As above
p-DCB moth
killer ia house
Demonstnting
p-DCB-oontain-
ing products
p-DCB exposure
in fur storage
plant
p-DCB manufac-
ture, 1 to 7
months exposure
12- to 15-year
exposure to
p-DCB mothballs
ia house
Played with
p-DCB crystals
4-J pellets
of p-DCB
ingested daily
for 15 yean
Pica for p-DCB
toilet Mocka
first trimester
Tablt4.1. Resorts of sa
Symptoms
Asthenia, dizziness
Asthenia, dizziness.
weight lou
Headache, weight loss.
diarrhea, tarry
stools, numbness.
clumsiness
Headache, weight and
strength loss.
abdominal swelling.
jaundice
Periorbital swelling.
intense headaches.
profuse rhinitis
Tiredness, nausea.
headache, vomiting
Weakness, nausea.
blood, vomiting,
jaundice
Loss of weight.
ffuhmirtjoiii docrc&jc
of appetite
ff»tijhi piugusive
dyspnea, fatigue.
muooid sputnoi
black urine
Increased patchy
fijmmimhm Of Skin
None except those
commonly associated
with early pregnancy
SBU exposure to p-DCB
Clinical report
Light hyperchronuc
anemia, after 1
month, increase in
anemia and
bypogranulocytosis
Slight anemia.
reactional
hyperleukocytosis
Acute yellow
atrophy of the
liver (confirmed
by autopsy)
Acute yellow
atrophy of the
liver (confirmed
by autopsy),
splenomegaly
Exposure to p-DCB
Subacute yellow
atrophy and
cirrhosis of liver
Subacute yellow
atrophy of the
liver
MCtfiCOIOflODlACiDUl
and other blood
pathologies
Pulmonary
granalomatosis.
fjirml n • nsnn 11 • ftf
IOCW OtICPOIIi
-------
38 Section 4
Animal. One study on Che lethality of p-DCB administered by gavage
to rats (groups of 5 to 15, mixed sex) and guinea pigs (groups of 5,
mixed sex) was reported by Hollingsworth et al. (1956). In rats, a
single dose of 1000 mg/kg resulted in no lethality, whereas 4000 mg/kg
resulted in 100% lethality. In guinea pigs, 1600 mg/kg resulted in no
lethality, whereas 2800 mg/kg resulted in 100% lethality. Gaines and
Linder (1986) reported that oral LD50 values for p-DCB in adult rats
were 3900 and 3800 mg/kg for males and females, respectively.
4.3.1.4 Dermal
Human. There are no available data on the potential lethality or
decreased longevity associated with dermal exposure of humans to p-DCB.
Animal. Gaines and Linder (1986) reported that the dermal LDSO for
p-DCB in rats was greater than 6000 mg/kg in both sexes.
4.3.1.5 Discussion
The effects of p-DCB on longevity have not been addressed in any of
the available studies. Although the available data suggest that exposure
to high doses of p-DCB via inhalation can result in lethality in humans,
the data were not sufficient to establish this effect. However, in oral
studies in test animals, single doses of 2800 and 4000 mg/kg resulted in
100% lethality in guinea pigs and rats, respectively, whereas 1600 and
1000 mg/kg resulted in no lethality. Oral LDso values of 3900 and 3800
mg/kg have also been reported for rats.
4.3.2 Systemic/Target Organ Tozicity
4.3.2.1 Overview
The major target organs of p-DCB are the liver and kidneys and
probably the CNS. Adverse effects on these tissues are reported in most
of the available studies, in most species tested, and for various
durations of exposure. Acceptable data from human studies are lacking;
available suggestive data from case reports are summarized in Table 4.1.
CNS toxicity effects have been reported in several case studies in
humans who were exposed to p-DCB for periods ranging from a few months
to several years, and in a short-term study in animals. None of these
studies, however, provides quantitative data related to CNS effects.
Hepatic effects have been demonstrated in several animal studies
with exposures from 3 days to 2 years (lifetime studies). Observed
effects have ranged from porphyria and enzyme changes to liver
degeneration and necrosis. Effects in humans exposed for 3 months or
more included jaundice and yellow atrophy of the liver.
Renal effects have been reported in animal studies of 13 weeks or
longer and have ranged from increased kidney weights to epithelial
hyperplasia of the renal pelvis, focal hyperplasia of the renal tubular
epithelium, and mineralization of the collecting tubules in the renal
medulla. Renal effects were not reported in studies of shorter duration;
however, in most studies, renal effects were not being investigated.
(Levels of hepatic enzymes, for example, may have been the only study
parameter.)
-------
Toxicologies! Data 39
4.3.2.2 Central nervous system effects
Overview. The dichlorobenzenes in general are reported to produce
sedation and anesthesia in animals after acute oral or parenteral
administration. Relatively high doses are needed to produce these
effects. Acute poisoning is characterized by signs of disturbance of the
CNS including hyperexcitability, restlessness, and muscle spasms or
tremors. The most frequent cause of death is respiratory depression (EPA
1987a).
Acceptable data to support observation of CNS effects are limited
in the case of p-DCB. Although CNS effects have been reported in the
case studies of a few persons exposed to p-DCB in their homes or
workplaces, there are no available estimates of the levels to which they
were exposed. Also, as previously stated, there are various limitations
and deficiencies in these studies.
Inhalation, human. CNS effects have been reported in case studies
of humans exposed to p-DCB via inhalation. Neither duration nor
intensity of exposure is clearly known or stated in any of these
reports. In addition, it cannot be stated with certainty that each of
these persons was exposed to only p-DCB.
Perrin (1941) reported dizziness and asthenia (weakness) in a
60-year-old man exposed to p-DCB in the bathroom. Petit and Champeix
(1948) reported the same symptoms in a 19-year-old female who prepared
p-DCB crystals in a factory for 18 months. Cotter (1953) reported
intense headaches in a 36-year-old woman who used p-DCB as a moth killer
in her home; he also reported headaches, nausea, and vomiting in a 34-
year-old woman who demonstrated products containing p-DCB. Persistent
headaches were among the symptoms reported by Cotter (1953) in a 60-
year-old man and his wife whose home had been saturated with p-DCB
mothball vapor for 3 or 4 months. The man also complained of numbness,
clumsiness, and a burning sensation in the legs. The man and woman both
died within a year of the initial exposure, apparently as a result of
liver failure. It is important to note, however, that a definitive
association between the observed symptoms and results reported in these
case studies and p-DCB exposure has not been established.
Inhalation, animal. There are no acceptable data on CNS effects in
animals exposed to p-DCB by inhalation.
Oral, human. CNS effects in humans exposed to p-DCB via ingestion
have been reported in two case studies. Frank and Cohen (1961) reported
the case of a 19-year-old woman who ingested four or five p-DCB pellets
(p-DCB content unknown) daily for about 2.5 years with minor dermal
effects (patchiness). Upon ceasing consumption, she suffered tremors and
unsteadiness that were considered to be psychological rather than
physiological effects of withdrawal.
A 21-year-old woman reported by Campbell and Davidson (1970)
developed pica (a craving for unnatural substances) for p-DCB toilet
bowl deodorizer blocks, which she consumed at the rate of one or two per
week throughout pregnancy. Reported CNS effects included tiredness,
dizziness, and mild anorexia. These effects, however, were not different
from the common general symptoms observed during normal pregnancy.
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40 Section 4
These studies are not considered to provide adequate evidence that
ingestion of p-DCB by humans can result in CNS effects.
Oral, animal. There are no available studies which provide
evidence of CNS effects in animals exposed to p-DCB via oral exposure.
Dermal, human. There are no available studies which investigate
the potential CNS effects in humans dermally exposed to p-DCB.
Dermal, animal. There are no available studies which investigate
the potential CNS effects in animals dermally exposed to p-DCB.
General discussion. CNS effects have been reported in a number of
case studies of persons exposed to p-DCB via inhalation at unknown
levels. Although these data provide suggestive evidence that p-DCB can
cause CNS effects in humans exposed via inhalation, the information is
not sufficient to establish a defined dose-response relationship.
Currently, there are no adequate data in humans or animals to
indicate that ingestion of or dermal contact with p-DCB can result in
CNS effects.
4.3.2.3 Liver effects
Overview. Exposure to p-DCB has resulted in adverse hepatic
effects in both humans and test animals. Suggestive evidence of hepatic
effects in humans has been demonstrated only in case studies of persons
exposed via inhalation. In animals, these effects have been observed
following short-term, intermediate, and chronic exposure via oral and
inhalation routes and have been manifested as degeneration or necrosis,
sometimes coincident with porphyria. Effects on liver enzymes have also
been reported.
Inhalation, human. Hepatic effects have also been reported in
humans following long-term exposure to p-DCB via inhalation and possibly
via unverified dermal exposure. Cotter (1953) reported the cases of a
60-year-old man and his wife exposed to mothball vapor that "saturated"
their home for 3 to 4 months. Both of them died within a year of the
initial exposure, and acute yellow atrophy of the liver was confirmed at
autopsy. Subacute yellow atrophy and cirrhosis of the liver was the
diagnosis for a 34-year-old woman who demonstrated p-DCB products in a
department store; a 52-year-old man who used p-DCB in his job in a fur
storage plant was also diagnosed with subacute atrophy of the liver
(Cotter 1953). Duration of exposure was not estimated for either of the
latter two persons. No estimates of the p-DCB exposure levels have been
provided in any of the studies, nor was it verified that p-DCB exposure
was the only factor associated with the observed effects. Therefore,
available human case studies currently provide only qualitative evidence
that the liver is a target organ for p-DCB in humans.
Inhalation, animal. Hollingsworth et al. (1956) reported liver
effects in inhalation studies with p-DCB at various levels and durations
of exposure in rats and guinea pigs. Inhalation of p-DCB at levels of
158 ppm for 5 to 7 months by rats and guinea pigs for 7 h/day,
5 days/week caused cloudiness, swelling, and granular degeneration of
the liver, slight increases in the weights of the liver and kidneys, and
some interstitial edema and pulmonary congestion. Rats exposed to
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Toxicologies! Data k\.
341 ppm for 6 months showed evidence of a slight increase in the weight
of the liver and kidneys. Guinea pigs exposed to 341 ppm for 6 months
exhibited hepatic changes including slight cirrhosis, focal necrosis,
cloudiness, swelling, and fatty degeneration. Based on various clinical
and toxicological parameters, the authors found exposure to p-DCB at
96 ppm for 6 to 7 months to be without adverse effects in rats, guinea
pigs, mice, rabbits, or one monkey. It should be noted, however, that
this study was conducted with several inconsistent variables including
the species of animal at each dose level, the number of animals per
species exposed at each dose level, and the total number of exposures at
each dose level. Therefore, the usefulness of the resulting .data is
limited, and the observed NOAEL of 96 ppm serves only as supportive
evidence of the NOAEL of 75 ppm for hepatic effects reported by Riley et
al. (1980) in a 76-week study in rats as described below.
In a long-term inhalation study, Riley et al. (1980, as summarized
in Loeser and Litchfield 1983) exposed 76 to 79 male and female Alderly
Park Wistar-derived rats to p-DCB at 0, 75, or 500 ppm for 5 h/day,
5 days/week for 76 weeks with a subsequent 32- to 36-week observation
period. SPF Alderly Park Swiss mice were also used in this study, but,
due to the high incidence of respiratory infections in these animals,
the results are not considered valid. In rats at the high exposure
level, 500 ppm, there were reported increases in organ weights,
including the liver, and slight increases in urinary protein and
coproporphyrin output in the males. The NOAEL in rats was identified as
75 ppm.
Oral, human. There are no available data on the hepatic effects of
p-DCB in humans exposed by ingestion.
Oral, animal. Hepatic effects have been reported in several
studies in which p-DCB has been administered to test animals by gavage.
These effects have ranged from temporary effects on hepatic enzymes to
hepatic degeneration and necrosis.
Short-term exposure. p-DCB has been shown to produce disturbances
in porphyrin metabolism after short-term exposure. Increased excretion
of porphyrins, especially coproporphyrin and uroporphyrin, is considered
to be an indication of liver damage. Rimington and Ziegler (1963)
administered p-DCB to male albino rats at gradually increasing doses
until a dose level was reached (770 mg/kg/day for 5 days) which yielded
high porphyrin excretion but few fatalities. The first signs of
intoxication were increases in urinary coproporphyrin and
porphobilinogen followed later by an increase in aminolevulinic acid
excretion. Mean peak values of urinary coproporphyrin increased to about
62 pg/day. 10- to 15-fold when compared with controls. A nearly 100-fold
increase in urinary uroporphyrin levels occurred, and porphobilinogen
levels increased 200- to 530-fold when compared with controls. A 10-fold
increase (to 437 Mg/day) in A-ALA levels was also observed, and
protoporphyrin levels increased 6-fold. Similar effects were not
observed when p-DCB was administered to rats at lower levels for a
longer period of time by Carlson (1977), as discussed below.
Miranda et al. (1984) also reported that a single oral dose of
p-DCB at 800 rngAg administered to day-old white Leghorn chicks resulted
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42 Section 6
in significant increases (P < 0.05) in the porphyrin concentrations of
both the liver and bile.
Ariyoshi et al. (1975) investigated potential changes in certain
liver constituents, cytochrome P-450 levels, activities of some drug-
metabolizing enzymes (aminopyrine Af-demethylase and aniline
hydroxylase), and synthetase in rats treated with oral doses of p-DCB at
250 mg/kg/day for up to 3 days. Only A-ALA synthetase activity was
increased significantly by treatment with p-DCB (42%). The cytochrome
P-450 content did not change; however, the microsomal protein content of
liver preparations was increased.
Carlson and Tardiff (1976) studied the effects of several
halogenated benzenes, including p-DCB, on hepatic enzyme activities in
adult male rats. Groups of six rats were given p-DCB in corn oil by
gavage for 14 days. Significant decreases (P < 0.05) in hexobarbital
sleeping time were observed 24 h after cessation of a 14-day treatment
period at 650 mg/kg/day. In addition, when p-DCB was administered for 14
days at 20 or 40 mg/kg/day, increases were observed in hepatic
microsomal xenobiotic metabolism systems, including levels of glucuronyl
transferase and benzpyrene hydroxylase and EPN (0-ethyl 0-p-nitrophenyl
phenylphosphorothionate) detoxification to p-nitrophenol. At
10 mg/kg/day, other parameters measured, including cytochrome-c
reductase level, cytochrome P-450 content, and azoreductase levels, were
not affected. When these authors conducted a 90-day study at the same
dosage levels, significant increases were seen in EPN detoxification,
benzpyrene hydroxylase, and azoreductase levels. The former two were
still elevated at 30 days after the cessation of administration of the
compound. Most increases were noted at 20 mg/kg/day and above, as in the
14-day studies; however, azoreductase levels were elevated even at
10 mgAg/day.
Intermediate exposure. With administration of p-DCB to rats (two
per group) at 500 mg/kg/day by gavage for 4 weeks, marked hepatic
effects including cloudiness, swelling, and centrilobular necrosis were
observed (Hollingsworth et al. 1956). No adverse effects were observed
at 10 or 10Q mg/kg/day. The interpretation of this study is limited by
the size of the test groups and the fact that the use of controls was
not indicated.
The NTP (1987) conducted two 13-week pilot studies in which F344/N
rats and B6C3F1 mice were dosed with p-DCB by gavage. In the first
study, rats were dosed at 300, 600, 900, 1200, or 1500 mg/kg/day, and
histologic changes were seen in the kidneys of male rats at all dose
levels. Based on these observations, doses in the second study were
lowered Co 37.5, 75, 150, 300, or 600 mg/kg/day.
In the first study, doses of 1200 or 1500 mg/kg/day produced
degeneration and necrosis of hepatocytes, hypoplasia of the bone marrow,
lymphoid depletion of the spleen and thymus, and epithelial necrosis of
the nasal turbinates in male and female rats. Liver weight to brain
weight ratios were increased at dosage levels of 900 mg/kg/day or more
for both male and female rats. Serum cholesterol levels were increased
by doses of 600 mg/kg/day or more in male rats and 900 mg/kg/day or more
in female rats. Serum triglycerides and protein levels were reduced by
doses of 300 mg/kg/day or more in male rats. Urinary porphyrins were
-------
lexicological Data 43
increased in male rats administered 1200 or 1500 mg/kg/day and in female
rats receiving 1200 mg/kg/day. However, these increases were modest and
considered by the authors to indicate mild porphyrinuria rather than
hepatic porphyria. Liver porphyrins were not increased at any dose.
In the second 13-week study, hepatic effects were not reported in
rats. Based on renal effects in the second study and all observed
effects in the first, a NOAEL of 150 mg/kg/day was identified for rats
In the first NTP (1987) 13-week study in mice, p-DCB dose levels
were 600, 900, 1000, 1500, or 1800 mg/kg/day. Hepatocellular
degeneration was observed in both sexes at all doses, and the liver
weight to brain weight ratio was increased at doses of 900 mg/kg/day or
more. Serum cholesterol levels were increased in male mice at doses of
900 mg/kg/day or more, whereas serum protein and triglycerides were
increased at doses of 1500 mg/kg/day or more. These clinical chemistry
changes were thought by the authors to reflect the hepatic effects of
this compound. Hepatic porphyria was not found in mice at any dose in
this study.
Because renal effects were seen in rats in all dose groups in the
first 13-week study, a second 13-week study was conducted at doses of
85, 169, 338, 675, or 900 mg/kg/day. Hepatocellular cytomegaly was
observed in male and female mice at doses of 675 and 900 mg/kg/day.
Based on the results of both 13-week studies, a NOAEL of 338 mg/kg/day
for hepatotoxicity was identified for mice. The lowest level at which
hepatic effects were observed (LOAEL) was 600 mgAg/day in the first
study.
f
Hollingsworth et al. (1956) reported liver toxicity in oral studies
with p-DCB. Female rats (ten/group) were dosed with p-DCB at 0, 18.8,
188, or 376 mg/kg/day by gavage, 5 days per week for about 6 months. The
two higher doses resulted in an increase in the weights of the liver and
kidneys. At 376 mg/kg/day, decreased splenic weight and slight cirrhosis
and focal necrosis of the liver were also observed, as well as
cloudiness and swelling of the renal tubular epithelium. No adverse
effects were seen with the low dose. Therefore, 18.8 mg/kg/day was
identified as the NOAEL for the study, and 188 mg/kg/day was identified
as the LOAEL. This phase of the Hollingsworth et al. (1956) study, as
compared with other phases described elsewhere in this profile, was
apparently controlled and reported.
Data on the intermediate-term oral administration of p-DCB to
rabbits are also presented by Hollingsworth et al. (1956). However, the
level of administration was inconsistent and unclear (e.g., 263 doses of
500 mg/kg/day for 367 days to seven rabbits and "as many as" 92 doses of
1000 mg/kg in 219 days to five rabbits). The reported observations of
hepatic cloudy swelling and focal caseous necrosis are useful only as
supportive qualitative evidence of liver effects reported in other
studies.
Carlson (1977) investigated the ability of p-DCB to induce
porphyria in rats when orally administered at 50 to 200 mg/kg/day for
30 to 120 days. Results indicated that p-DCB had little potential for
causing porphyria at these doses in female rats. After 30 and 60 days,
dose-related liver weight increases were observed, but even after
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44 Section 4
120 days, only slight increases in liver porphyrins occurred. Urinary
excretion of A-ALA, porphobilinogen, or porphyrins was not increased
over control levels. Rimington and Ziegler (1963) had shown up to
100-fold increases in these parameters when p-DCB had been administered
at a higher level for a shorter period of time (i.e., 770 mg/kg/day for
5 days).
Chronic exposure. In the only study of lifetime oral exposure to
p-DCB, hepatic effects were seen in mice but not in rats (NTP 1987). In
this 2-year bioassay of p-DCB, male F344/N rats were dosed by gavage at
150 or 300 mg/kg/day and females at 300 or 600 mg/kg/day. Hepatic
effects were not observed in rats.
In the same study, male and female B6C3F1 mice were dosed by gavage
with p-DCB at 300 or 600 mg/kg/day. p-DCB increased the incidences of
nonneoplastic liver lesions in male and female mice, including
alteration in cell size (cytomegaly and karyomegaly), hepatocellular
degeneration, and individual cell necrosis. Therefore, the LOAEL is
identified as 300 mg/kg/day.
Dermal, human. There are no available studies of the
hepatotoxicity of p-DCB in dermally exposed humans.
Dermal, animal. There are no available studies of the
hepatotoxicity of p-DCB in dermally exposed animals.
General discussion. Most of the available data on p-DCB toxicity
indicate that the liver is a major target organ for this compound. In
case studies in humans, cirrhosis and subacute or acute yellow atrophy
of the liver have been diagnosed in individuals exposed to p-DCB via
inhalation at unknown levels and for uncertain durations. Data from
animal studies also demonstrated that p-DCB administered via inhalation
is hepatotoxic, with increased liver weights and increased porphyrin
excretion reported in one study and more severe changes, including
cirrhosis, focal necrosis, and fatty degeneration, in another.
In oral studies in animals, a broad spectrum of hepatic effects has
been reported, ranging from reversible effects on liver enzymes when low
levels were administered for brief durations (i.e., 20 mg/kg/day for
14 days) to hepatocellular degeneration and necrosis with chronic
administration of high levels (i.e., 300 mg/kg/day for 2 years).
Porphyria has also been demonstrated with oral administration of p-DCB
in animal studies.
4.3.2.4 Renal effects
Overview. Adverse renal effects have generally been observed in
the same subchronic and chronic studies in which hepatotoxicity has
occurred. Effects have ranged in severity from increased kidney weights
to degeneration, mineralization, and hyperplasia of renal tissue.
Inhalation, human. There are no data available on the renal
effects resulting from human exposure to p-DCB via inhalation.
Inhalation, animal. In a long-term inhalation study, Riley et al.
(1980, as summarized in Loeser and Litchfield 1983) exposed male and
female Alderly Park Vistar-derived rats to p-DCB at 0, 75, or 500 ppm
for 5 h/day, 5 days/week for 76 weeks. SPF Alderly Park Swiss mice were
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ToxicoLog Leal Daca 45
also exposed to p-DCB, but, due to the high incidence of respiratory
infections in these animals, the results are not considered valid. In
rats at the high exposure level, there were increases in organ weights,
including the kidneys. Based on these and other (hepatic) effects, the
NOAEL in rats was identified as 75 ppm.
Hollingsworth et al. (1956) reported that inhalation of p-DCB at
levels of 158 ppm for 5 to 7 months by rats and guinea pigs over
7 h/day, 5 days/week caused a slight increase in the weight of the
kidneys. Rats exposed to 341 ppm for 6 months showed evidence of a
slight increase in the weight of the kidneys. Based on various clinical
and toxicological parameters, the authors found exposure to p-DCB at
96 ppm for 6 to 7 months to be without adverse effects in rats, guinea
pigs, mice, rabbits, or one monkey. The limitations on the
interpretation of these data have been discussed, but the observed NOAEL
of 96 ppm is supportive of the NOAEL of 75 ppm for renal effects
reported by Riley et al. (1980) in a 76-week study in rats previously
described.
Oral, human. There are no data on the renal effects resulting from
human ingestion of p-DCB.
Oral, animal. In two NTP (1987) 13-week pilot studies, F344/N rats
and B6C3F1 mice were dosed with p-DCB by gavage, as discussed under
hepatic effects. In the first study, rats were dosed with 300 to 1500
mgAg/day. Because histologic changes were observed in the kidneys of
male rats at all doses, a second 13-week study was performed at doses of
38, 75, 150, 300, or 600 mg/kg/day. Renal tubular cell degeneration was
observed in male rats receiving 300 mg/kg/day or more in the first
study, but only slight changes were seen at 300 mg/kg/day in the second
study. The kidney weight to brain weight ratio was increased in male
rats receiving doses of 600 mg/kg/day or more. The blood urea nitrogen
level was increased slightly in male rats dosed with 900 mg/kg/day or
more. Based on the combined results of both studies, a NOAEL of 150
mg/kg/day was identified in rats.
In the two NTP (1987) 13-week studies in mice, dose levels were 600
to 1000 mg/kg/day and 80 to 900 mg/kg/day, respectively. Renal effects
in mice were not observed in either study.
Hollingsworth et al. (1956) observed renal toxicity in oral
studies with p-DCB. In rats, doses of 188 or 376 mg/kg/day by gavage,
5 days/week for about 6 months, increased the weights of the kidneys. At
376 mg/kg/day, cloudiness and swelling were observed in the renal
tubular epithelium. No adverse effects were seen at the 18.8-mg/kg/day
dose.
Charbonneau et al. (1987b) demonstrated that p-DCB administered by
gavage to F-344 rats at 7 daily doses of 120 or 300 mg/kg/day
significantly increased (P < 0.05) the level of protein droplet
formation in the kidneys of males but not in females. Administration of
a single dose of ^C-p-DCB by gavage at 500 mg/kg gave similar results.
An analysis of the renal tissue of animals administered radiolabeled p-
DCB indicated that it was reversibly associated with the protein a-2p-
globulin. Bombard and Luckhaus (undated) designed a study to correspond
to the experimental conditions of the 13-week NTP study with Fischer 344
-------
46 Section 4
rats. p-DCB was administered by gavage in corn oil at 0, 75, 150, 300,
or 600 mg/kg/day for 13 weeks. By 4 weeks, pronounced cortico-medullary
changes in the proximal convoluted tubules of the nephrons were evident
in most males at dosage levels of 150 mg/kg/day and higher. Cortical
tubuli showed hyaline droplets in the epithelia and large hyaline
droplets and sporadic desquamated epithelia in the lumina. At 13 weeks,
one male at 75 rag/kg/day and all males at 150 mg/kg/day and above were
observed to have an increased incidence of these changes. The female
animals showed no comparable findings.
Renal effects have also been observed in the only available study
of chronic oral exposure to p-DCB. In the NTP (1987) bioassay, described
above, male rats exposed to p-DCB at 150 and 300 mg/kg/day for 2 years
exhibited nephropathy, epithelial hyperplasia of the renal pelvis,
mineralization of the collecting tubules in the renal medulla, and focal
hyperplasia of the renal tubular epithelium. There were increased
incidences of nephropathy in female rats dosed with p-DCB at 300 and 600
mg/kg/day (64 and 84%, respectively), as compared with vehicle controls
(43%). Therefore, the LOAEL for renal effects in rats was 150 mg/kg/day,
the lowest level tested in this phase of the study.
p-DCB at 300 and 600 mg/kg/day in this study also increased the
incidence of nephropathy in male mice and renal tubular degeneration in
female mice. Therefore, 300 mg/kg/day was the LOAEL for renal effects in
mice.
Dermal, human. There are no available data on the renal toxicity
of p-DCB in dermally exposed humans.
Dermal, animal. There are no available data on the renal toxicity
of p-DCB in dermally exposed animals.
General discussion. Evidence that p-DCB administration can result
in renal damage comes only from intermediate and chronic animal studies.
In inhalation studies, increased renal weight has been reported. In oral
studies, adverse effects ranged from increased renal weight to
degeneration and mineralization of the collecting tubules and focal
hyperplasia of the renal tubular epithelium.
4.3.3 Developmental Toxicity
4.3.3.1 Overview
Limited data suggested that prenatal exposure to p-DCB results in
developmental toxicity at maternally toxic levels.
4.3.3.2 Inhalation
Human. There are no available data on the developmental toxicity
of p-DCB in humans exposed to p-DCB via inhalation.
Animal. Hodge et al. (1977, as summarized in Loeser and Litchfield
1983) conducted a teratogenicity study of p-DCB using pregnant SPF rats
exposed to p-DCB by inhalation at 0, 75. 200, or 500 ppm for 6 h/day on
days 6 to 15 of pregnancy. These exposures did not result in
developmentally toxic effects in the offspring. Therefore, 500 ppm is
identified as the NOAEL for these effects. (The terms NOEL and LOEL are
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lexicological Data ^7
more commonly used in evaluating developmental toxicity, since all
effects, whether adverse or not, are considered important. In this
document, however, the terms NOAEL and LOAEL are used instead).
Hayes et al. (1985) similarly exposed pregnant New Zealand white
rabbits (28 or 30 per group) to p-DCB by inhalation at 100, 300, or 800
ppm for 6 h/day on days 6 to 18 of gestation. The authors reported a
significant increase (P < 0.05) in the incidence of retroesophageal
right subclavian artery at 800 ppm. They concluded that it was a minor
variation in the circulatory system (seen in 2% of control litters in
their laboratory) and did not constitute a teratogenic response.
However, this effect was reported as an observed structural anomaly in
the development of these fetuses; therefore, 800 ppm is the LOAEL for
this study. Slight maternal toxicity was also observed at 800 ppm as
indicated by significantly decreased body weight gain during the first 3
days of exposure. Therefore, 300 ppm is the NOAEL for maternal and
developmental toxicity.
4.3.3.3 Oral
Human. There are no available data on the developmental toxicity
of p-DCB in orally exposed humans.
Animal. In the only oral study identified, Giavini et al. (1986)
administered p-DCB to pregnant rats (13 to 17 per group) by gavage on
days 6 through 15 of gestation at 0, 250, 500, 750, or 1000 mg/kg/day.
At doses of 500 mg/kg and above, there was a dose-related significant
increase in the incidence of an extra rib in the fetuses (17, 29, and
31% as compared to 6% of controls and 9% of 250 mg/kg/day dosage group;
P < 0.05, P < 0.01, and P < 0.01, respectively). A reduction in fetal
weights was observed at the 1000-mg/kg/day dose level, and maternal
weight gain was retarded at levels of 500 mg/kg/day and above.
Therefore, 250 mg/kg/day can be considered a NOAEL for maternal and
developmental toxicity, and 1000 mg/kg/day was identified as the NOAEL
for fetotoxicity. (The reduction in fetal weight gain at 1000 mg/kg/day
was not considered to be a fetotoxic effect since it was associated with
a decrease in maternal weight gain at the same dosage level.)
4.3.3.4 Dermal
Human. There are no available data on the developmental toxicity
of p-DCB in dennally exposed humans.
Animal. There are no available data on the developmental toxicity
of p-DCB in dermally exposed animals.
4.3.3.5 Discussion
The available studies are limited but suggest that p-DCB is
developmentally toxic at levels that result in maternal toxicity. From
these studies it cannot be determined whether the observed developmental
toxicity is a result of maternal toxicity.
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48 Section 4
4.3.4 Reproductive Toxicity
4.3.4.1 Overview
There are no appropriate data available to assess the potential
reproductive toxicity of p-DCB.
4.3.4.2 Inhalation
Human. There are no available data on the reproductive toxicity of
p-DCB in humans exposed via inhalation.
Animal. No reduction in reproductive performance (as measured by
the percentage of males successfully impregnating females) was observed
in an inhalation study by Anderson and Hodge (1976, as described by
Loeser and Litchfield 1983) in which male CD-I mice were exposed to
p-DCB at 75, 225, or 450 ppm for 6 h/day for 5 days before being mated
with virgin females. Studies to assess effects on male reproductive
performance, however, are usually conducted for the entire period of
spermatogenesis (about 9 weeks). Therefore, the conditions of this study
are not considered adequate to assess reproductive toxicity.
4.3.4.3 Oral
Human. There are no available data on the reproductive toxicity of
p-DCB in orally exposed humans.
Animal. There are no available data on the reproductive toxicity
of p-DCB in orally exposed animals.
4.3.4.4 Dermal
Human. There are no available data on the reproductive toxicity of
p-DCB in dermally exposed humans.
Animal. There are no available data on the reproductive toxicity
of p-DCB in dermally exposed animals.
4.3.4.5 Discussion
Only one study, Anderson and Hodge (1976), investigates the
potential reproductive toxicity of p-DCB. As described above, only male
mice were exposed, the duration of exposure was only 5 days, and only
the inhalation route was tested. No conclusions can be drawn as to the
potential of p-DCB to induce reproductive toxicity based on the limited
database.
4.3.5 GenotoxicIty
4.3.5.1 Overview
p-DCB is not mutagenic in most microbial and animal assay systems.
As indicated below, however, p-DCB is reported to be mutagenic in
plants. The results in microbial and mammalian systems are generally
considered to be more applicable to humans.
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ToxicoLogical Data i9
4.3.5.2 Mlcrobial systems
p-DCB was not mutagenic when tested with cultures of histidine-
requiring mutants of Salmonella cyphimuriua, in the Escherichia coli WP2
system, or in the Saccharomyces cecevisiae C3 test for chromosomal
aberrations in yeast (NTP 1987, Haworth et al. 1983, Anderson et al
1972, Anderson 1976, Simmon et al. 1979). However, p-DCB increased the
frequency of back mutation of the methionine-requiring locus in the
fungus Aspergillus nidulans (Prasad and Pramer 1968, Prasad 1970).
4.3.5.3 Higher plants
p-DCB has induced abnormal mitotic division in several species of
higher plants. Observed effects include shortening and thickening of
chromosomes, precocious separation of chromatids, tetraploid cells,
binucleated cells, chromosomal breaks, and chromosomal bridges
(c-mitosis) (Sharma and Battacharya 1956, Sharma and Sarkar 1957,
Srivastava 1966, Gupta 1972).
4.3.5.4 Mammalian systems
Unscheduled DNA synthesis was nqt induced by p-DCB in cultures of
human lymphocytes (Perocco et al. 1983) or in HeLa cells (Institute di
Ricerche Biomediche (1986a). Instituto di Ricerche Biomediche (1987)
reported that p-DCB at concentrations up to 100 jig/mL, in the presence
or absence of metabolic activation, did not increase the incidence of
chromosomal aberrations in cultured human lymphocytes.
Steinmetz and Spanggord (1987a,b) reported that gavage
administration of p-DCB at single doses of 300 to 1000 mg/kg to B6C3F1
mice and Fischer 344 rats did not result in unscheduled DNA synthesis in
the mouse hepatocytes or the renal tissue of the rats. However, p-DCB ac
the highest level did induce an increase in DNA replication (S-phase of
cell division) in the renal tissue of the male rats and in the
hepatocytes of the male mice. Based on a comparison with historical
controls, the authors concluded that levels of DNA replication were also
significantly elevated in the livers of female mice.
p-DCB did not induce chromosomal aberrations and sister-chromatid
exchange In Chinese hamster ovary cells at levels as high as ISO pg/mL
in the absence or presence of metabolic activation (S-9 from liver of
Aroclor 1254-induced male Sprague-Dawley rats) (NTP 1987). Negative
results using this test were also reported by Instituto di Ricerche
Biomediche (1986b) using p-DCB at levels up to 100 jig/mL without
metabolic activation or up to 200 pg/mL with metabolic activation. p-DCB
did not increase the mutation frequency of L5178Y/TK+/' mouse lymphoma
cells with or without metabolic activation (NTP 1987).
Cytogenetic studies have been conducted In rat bone marrow cells
following inhalation exposure of rats to p-DCB by Anderson and
Richardson (1976, as reported in Loeser and Litchfield 1983). Three
series of exposures were carried out: (1) one exposure at 299 or 682 ppm
for 2 h; (2) multiple exposures at 75 or 500 ppm, 5 h/day for 5 days;
and (3) multiple exposures to 75 or 500 ppm, 5 h/day, 5 days/week for
3 months. Benzene and vinyl chloride were used as the positive controls,
negative controls breathed fresh air alone. Bone marrow cells from both
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SO Section 4
femurs were examined for chromosome or chromatid gaps, chromatic! breaks,
fragments, or other complex abnormalities. In all three experiments,
exposure to p-DCB failed to induce any statistically significant effects
indicative of chromosomal damage when compared with the negative
controls.
Cytogenetic effects were not found in bone marrow cells from male
and female B6C3F1 mice treated with p-OCB at levels up to 1800 mg/kg/day
in a 13-week study by NTP (1987). No increase in micronucleated cells
occurred even at levels that were extremely toxic to the test animals
and resulted in liver toxicity and decreased survival. The NTP (1987)
study noted that the observed carcinogenic activity of this compound
cannot be adequately predicted on the basis of available genotoxicity
data, and that p-DCB may act as a tumor promoter rather than a mutagen.
Herbold (1986) also reported no evidence of a clastogenic effect in
mouse bone marrow erythroblasts after a single oral administration of
p-DCB at 2500 mg/kg.
Herbold (1986b) similarly found no evidence of clastogenic effects
in mouse bone erythroblasts after a single oral administration of 2,5-
dichlorophenol (the major metabolite of p-DCB) at 1500 mg/kg. Litton
Bionetics (1986) reported that 2,5-dichlorophenol with or without
metabolic activation did not induce an increase in mutagenic response in
the Chinese hamster ovary HGPRT forward mutation assay. This compound
was also inactive in the Balb/3T3 in vitro transformation assay (Litton
Bionetics 1985). This profile has not attempted to present a full
evaluation of the mutagenic potential or the potential of any other end
points of the toxicity of 2,5-dichlorophenol.
4.3.5.5 Discussion
The currently available data indicate that p-DCB is not mutagenic
in microbial or mammalian systems. The results of studies of higher
plants are of questionable significance in an evaluation of the health
effects of p-DCB in laboratory animals and humans. As mentioned above,
positive results in carcinogenicity testing of p-DCB combined with
negative results in mutagenicity testing suggest that p-DCB may act as a
tumor promoter rather than as an initiator in the carcinogenic process.
p-DCB has not been tested for its tumor promotion potential.
4.3.6 CareInogenlc1ty
4.3.6.1 Overview
p-DCB has been shown to be carcinogenic in animal studies when
orally administered, but not following long-term inhalation exposure. In
the NTP (1987) 2-year carcinogenesis bioassay of p-DCB. there was clear
evidence of carcinogenicity in male rats and in mice of both sexes. No
human data are available regarding the carcinogenicity of p-DCB.
4.3.6.2 Inhalation
Human. There are no available data on the potential
carcinogenicity of p-DCB in humans exposed via inhalation.
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lexicological Data 51
Animal. No evidence of carcinogenicity was observed in a long-term
inhalation study by Riley et al. (1980, as described by Loeser and
Litchfield 1983) using male and female SPF Alderly Park Wistar-derived
rats. SPS Alderly Park Swiss mice were also used in this study, but, due
to the high incidence of infections in these animals, the results are
not considered valid. Rats were exposed to p-DCB at 0, 75, or 500 ppm
for 5 h/day, 5 days/week for 76 weeks. As mentioned in Sect. 4.2,
Hawkins et al. (1980) has calculated that tissue levels of p-DCB are
similar when repeated oral doses of 250 mg/kg/day or repeated inhalation
doses of 1000 ppm for 3 h/day are administered. Based on the reported
lack of extensive organ toxicity, the conditions of the Riley et al.
(1980) study may have resulted in considerably lower tissue-levels of
p-DCB than those occurring in animals in the NTP (1987) gavage study
(150 and 300 mg/kg/day in male rats and 300 and 600 mg/kg/day in female
rats and mice of both sexes). In addition, the MTD was not achieved in
the Riley et al. (1980) study. Considering the presumed lower effective
dose in the rat-inhalation study, as well as the less-than-lifetime
duration of dosing, the Riley et al. (1980) study is not viewed as
providing conditions adequate for testing the potential carcinogenicity
of p-DCB via the inhalation route.
4.3.6.3 Oral
Human. There are no available data on the potential
carcinogenicity of p-DCB in humans exposed by ingestion.
Animal. p-DCB was carcinogenic in both rats and mice exposed to
p-DCB for two years in the NTP (1987) carcinogenesis bioassay. p-DCB was
administered in corn oil by gavage to F344/N rats and B6C3F1 mice in
groups of 50 animals per sex per dosage group. Male rats received doses
of 150 and 300 mg/kg/day; female rats and mice of both sexes received
doses of 300 and 600 mg/kg/day.
p-DCB produced a dose-related increase in the incidence of tubular
cell adenocarcinomas of the kidney in male rats [controls: 1/50 (2%);
low dose: 3/50 (6%); high dose: 7/50 (14%)]. These increases occurred
with a significant (P - 0.005) positive trend, and the incidence in the
high-dose group was significantly greater than that in the vehicle
controls by the life table test. [These malignant tumors are uncommon in
male F344/N rats; they have been diagnosed in only 4/1098 (0.4%) of the
corn oil gavage controls in previous NTP studies.) One tubular cell
adenoma was observed in a high-dose male rat. There were no tubular cell
tumors in dosed or vehicle control female rats. There was a marginal
increase in the incidence of mononuclear cell leukemia in dosed male
rats compared with that in vehicle controls [5/50 (10%); 7/50 (14%);
11/50 (22%)]. This was only slightly higher than the incidence in
historical controls from the same laboratory. The NTP concluded that
p-DCB was carcinogenic in male rats but not in female rats.
p-DCB increased the incidences of hepatocellular carcinomas in
high-dose male mice [14/50 (28%); 11/49 (22.5%); 32/50 (64%); ? < 0.01.
Fisher Exact Test] and high-dose female mice [5/50 (10%); 5/48 (10.4%);
19/50 (38%); P < 0.01, Fisher Exact Test] and of hepatocellular adenomas
in both high- and low-dose male mice [5/50 (10%); 13/49 (26.2%); 16/50
(32%); P - 0.006] and in high-dose female mice [10/50 (20%); 6/48
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52 Section 4
(12.5%); 21/50 (42%); P - 0.008). Female control mice in this bioassay
had a substantially higher incidence of liver tumors than did historical
controls. Hepatoblastomas (a form of hepatocellular carcinoma) were
observed in four high-dose male mice (? - 0.015), along with other
hepatocellular carcinomas, but not in vehicle controls. This rare
malignant tumor had not previously occurred in 1091 male vehicle control
mice in NTP studies. An increase in thyroid gland follicular cell
hyperplasia was observed in dosed male mice [1/47 (2%); 4/48 (2.3%);
10/47 (21.3%)], and there was a marginal positive trend in the incidence
of follicular cell adenomas of the thyroid gland in female mice [0/48
(0%); 0/45 (0%); 3/46 (6.5%)]. Pheochromocytomas (tumors of ehromaffin
tissue of the adrenal medulla or sympathetic preganglia) (benign and
malignant, combined) of the adrenal gland occurred with a positive trend
in dosed male mice, and the incidence in the high-dose group was
significantly greater than in the vehicle controls [0/47 (0%); 2/48
(4.2%); 4/49 (8.2%); P - 0.040]. The incidence of adrenal gland
medullary hyperplasia in male mice was 2/47 (4.3%), 4/48 (8.3%), and
4/49 (8.2%). Focal hyperplasia of the adrenal gland capsule was also
observed in male mice at 11/47 (23.4%), 21/48 (43.8%), and 28/49
(57.1%). (Unless otherwise stated, all P values presented for mice refer
to results derived using the Cochran-Armitage Trend Test. The results of
various other statistical tests have also been presented by the
authors.)
4.3.6.4 Dermal
Human. There are no available data on the potential
carcinogenicity of p-DCB to dermally exposed humans.
Animal. There are no available data on the potential
carcinogenicity of p-DCB to dermally exposed test animals.
4.3.6.5 Discussion
p-DCB was carcinogenic in male rats and in male and female mice
when administered orally. As mentioned previously, further analysis of
the results of the NTP (1987) bioassay has raised questions as to the
relevance of the observed renal tumors in male rats and hepatic tumors
in mice in evaluating the potential carcinogenicity of p-DCB in humans.
The observation that kidney tumors are induced in male (but not
female) rats in response to exposure to certain chemicals has been the
subject of recent research. Toxicologists at the CUT have hypothesized
that the male rat kidney is susceptible to the induction of certain
tumors because it contains the protein a-2/i-globulin, which has not been
found at significant levels in female rats or in mice or humans
(Charbonneau et al. 1987a). They have demonstrated that a-2ft-globulin in
combination with certain components of petroleum enhances the formation
of hyaline droplets in the proximal convoluted tubules of male rats.
They hypothesize that the resulting cellular damage and cell
proliferation results in enhanced tumor formation via a mechanism that
has not yet been elucidated. These investigators are currently
conducting studies to determine whether similar processes occur during
the induction of renal tumors in male rats exposed to p-DCB (personal
communication from J. Swenberg, CUT 1987). Kanerva et al. (1987) have
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Toxicological Daca 53
also demonstrated that the same effects can be elicited in male rats
orally administered either decalin (decahydronaphthalene) or d-liaonene
[l-methyl-4-(l-methylethenyl) cyclohexene] . Craig (1986) presented data
to show that a-2/j-globulin-associated nephropathy in male rats has been
observed in response to a broad range of chemicals (approximately 16 at
the time of his presentation). Based on these considerations, it is not
clear to what extent the rat kidney tumor results are relevant in
determining the cancer risk to humans from inhalation of p-DCB.
There has also been consideration of the interpretation of the
finding of hepatocellular carcinomas and adenomas in mice in the NTP
(1987) study. There was a high rate of these tumors in both male and
female control animals. Female control mice in this bioassay had a
substantially higher incidence of liver tumors than did historical
controls. Because p-DCB has not been demonstrated to be mutagenic in any
of the microbial or mammalian systems tested, NTP (1987) has speculated
that it may act as a tumor promotor.
4.4 INTERACTIONS WITH OTHER CHEMICALS
No studies have been identified which have investigated the effects
of p-DCB when administered with other chemicals.
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55
5. MANUFACTURE, IMPORT, USE, AND DISPOSAL
5.1 OVERVIEW
The three major production plants for p-DCB in the United
States are located in Illinois, West Virginia, and Delaware. The
major uses of p-DCB are as space deodorizers (primarily in bathrooms)
(20 million Ib), moth repellents (8 million Ib), and an intermediate in
the production of polyphenylene sulfide (PPS) resins (22 million Ib).
These three uses accounted for over 90% of the p-DCB used in the
United States in recent years. Of the total U.S. annual production of
75 million Ib, about one-third (or 25 million Ib) is exported.
Approximately 95% of the environmental releases of p-DCB occur during
its use, rather than during its manufacture or processing. Relatively
small amounts of p-DCB are disposed of in landfills from production
processes.
5.2 PRODUCTION
p-DCB is produced as a by-product of monochlorobenzene
manufacturing in a process involving direct chlorination of benzene in
continuous or batch reactors. The products include mono- and
dichlorobenzenes and insignificant amounts of higher chlorinated
benzenes. The p-DCB fraction is separated by distillation.
The batch chlorination process yields a higher proportion of
dichlorobenzenes than the continuous process and can be modified to
yield an even greater proportion of p-DCB (EPA 1981). p-DCB can also be
produced by the Sandmeyer procedure from the appropriate chloroaniline
(HSDB 1987).
p-DCBs can be manufactured in higher yields using a continuous
process by chlorinating benzene in the presence of aluminum chloride
(Lowenheim and Morgan 1975).
The total 1984 production of about 75 million Ib was produced
mostly by three companies in Illinois, West Virginia, and Delaware (ICF
1987).
5.3 IMPORT
Since 1980 virtually no p-DCB has been imported into the United
States. About one-third of the total production of p-DCB has been
exported in recent years (ICF 1987).
5.4 USE
One major consumptive use of p-DCB is as a space deodorizer for
toilet bowls, urinals, garbage cans, and diaper pails. These products
are usually 100% p-DCB blocks, sometimes with added perfume. A second
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56 Section 5
Important use of p-DCB Is moth control, in the form of mothballs or moth
repellent blocks. The third important use is as a chemical intermediate
in the production of PPS resins. Together, these three uses accounted
for over 90% of the p-DCB used in the United States in 1984 (ICF 1987).
p-DCB is also used in pesticides, dye synthesis, abrasives, floor waxes
and finishes, and agricultural chemicals (HSDB 1987, EPA 1981).
5.5 DISPOSAL
It is estimated that approximately 1,000,000 Ib, or 1.5% of total
p-DCB production during 1978, was released to the environment during
manufacture. Approximately 17,000 Ib, mainly in sludge from
fractionating towers (EPA 1981), was disposed of in landfills from
production processes in 1978. About 640,000 Ib of p-DCB was discharged
to water. Because p-DCB sublimes at room temperature (20°C), some of
this waste may also reach the air.
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57
6. ENVIRONMENTAL FATE
6. 1 OVERVIEW
p-DCB enters the environment primarily as a result of releases
during use. Manufacturing accounts for only -1.5% of the environmental
releases. There are no natural sources of p-DCB.
Relatively little information concerning the environmental fate of
p-DCB is available. p-DCB is expected to volatilize at a relatively
rapid rate, allowing atmospheric transport. It has an estimated half-
life of 9 h or less for removal from surface water via evaporation. The
dichlorobenzenes are reported to be reactive toward hydroxyl radicals in
air with a half-life of about 3 days, but indirect evidence suggests
that p-DCB does not hydrolyze at a significant rate under normal
environmental conditions. Other estimates indicate p-DCB residence time
in the atmosphere of more than 38 days. Its high log octanol/water
partition coefficient suggests that adsorption to organic matter in
aquatic systems and soil is probably an important environmental fate
process. Indirect evidence suggests that bioaccumulation, may also be an
important fate process. p-DCB appears to be initially resistant to
biodegradation in soil; however, it may be broken down to some degree by
pollutant-acclimatized microorganisms. Sorption, bioaccumulation, and
volatilization with subsequent atmospheric oxidation are likely to be
competing processes, with the dominant fate being determined by local
environmental conditions. If volatilization does not occur, p-DCB is
probably persistent in the environment (e.g., when in groundwater).
6.2 RELEASES TO THE ENVIRONMENT
6.2.1 Anthropogenic Sources
In 1984, almost 30 million Ib of p-DCB was used in the United
States in the form of space deodorants and moth repellents. All of the
20 million Ib used in space deodorants is assumed to be released to the
environment, with about 90% released to the air and the remainder to
land or water. Another major use of p-DCB, moth control, consumes 8 to
12 million Ib annually, all of which is assumed to be released to the
atmosphere. Minor uses of p-DCB and inadvertent sources contribute
little to the environmental releases of the compound (ICF 1987, EPA
1981). Taken together, the above information indicates that little p-DCB
enters the atmosphere from hazardous waste disposal sites. As summarized
in Sect. 7, use of consumer products accounts for the greatest source of
p-DCB in the atmosphere.
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58 Section 6
6.2.2 Natural Sources
There are no natural sources of p-DCB.
6.3 ENVIRONMENTAL FATE
6.3.1 Atmospheric Fate Processes
Atmospheric p-DCB may theoretically be degraded by chemical- or
sunlight-catalyzed reactions or may be adsorbed onto particles that
settle or are removed from the atmosphere by rain. One measure of the
effectiveness of these factors in removing p-DCB from the air is the
atmospheric residence time. The atmospheric residence time is the time
for removal of all of the chemical initially present in the atmosphere.
Singh et al. (1981. as cited in EPA 1985) reported that the atmospheric
residence time for p-DCB was 38.6 days. This estimate is based on a
daily average hydroxyl radical abundance of 106 mol-cm"^ in the boundary
layer of a polluted atmosphere, which is equivalent to a daytime (12 h)
hydroxyl radical abundance of 2 x 10" mol-cm"-* (typical of summer
months, but much higher than that expected during winter). These authors
also estimated a daily loss rate of 2.6% (assuming 12 h of sunlight per
day).
Dichlorobenzenes in general were reported by Ware and Weast (1977,
as cited in EPA 1979) to be reactive with hydroxyl radicals in the air
with a half-life of approximately 3 days. The half-life is the time
required for removal of one-half of the initial concentration of the
chemical. An estimate of the corresponding atmospheric residence time
was not provided in the cited reference. Thus, the relationship or
consistency between this half-life estimate and the residence time
estimate summarized above is not readily apparent. These authors also
reported that p-DCB is resistant to auto-oxidation by ozone in air.
Brunce et al. (1978) report that photolysis of chlorinated
biphenyls in iso-octane solution involves a triplet reactive state and
that excimers do not appear to play a role in the photodegradation.
Their study did not include p-DCB.
6.3.2 Surface Vater/Groundvater Fate Processes
The available data indicate that degradation of chlorobenzenes in
aquatic systems may be carried out by microbial communities in
wastewater treatment plants and in natural bodies of water (EPA 1985).
The degradation of p-DCB in aquatic systems is believed to be highly
variable and dependent upon specific microbial (and possibly other)
conditions. This is evidenced by a monitoring study in the Rhine River
that indicated the degradation half-life ranged from 1.1 to 25 days
based on a limited number of individual measurements from different
sampling locations (EPA 1985).
Ware and Weast (1977) indicate that p-DCB is resistant to auto-
oxidation by the peroxy radical (RO.•) in water. Indirect evidence
suggests that p-DCB does not hydrolyze at a significant rate under
normal environmental conditions. This is believed to be due to the
extreme difficulty with which the substance undergoes nucleophilic
substitution (EPA 1979).
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Envirorwencal Face 59
The available data also indicate that p-DCB probably volatilizes
from the water column to the atmosphere at a relatively rapid rate. EPA
(1979) used the data of Garrison and Hill (1972) to calculate an
approximate evaporative half-life of less than 30 min for aerated
solutions; the data for unaerated conditions correspond to a half-life
of less than 9 h.
Although no specific environment sorption studies were located, the
log P value of 3.39 (Leo et al. 1971, as cited in EPA 1979) indicates
that sorption processes may be significant at p-DCB concentrations
anticipated in natural waters. The adsorption of p-DCB to sedimentary
organic material may compete with volatilization processes to the
atmosphere (EPA 1979).
6.3.3 Soil Fate Processes
Studies of the fate of the dichlorobenzenes in soil indicate that
these compounds are somewhat resistant to microbial degradation.
Alexander and Lustigman (1966, as cited in EPA 1979) stated that the
presence of a chlorine atom on the benzene ring retarded the rate of
degradation; therefore, p-DCB, being more highly chlorinated than
chlorobenzene, would presumably biodegrade no faster than chlorobenzene
under similar environmental conditions (EPA 1979). Ware and Weast
(1977), Lu and Metcalf (1975), and Chiou et al. (1977. as cited in EPA
1979) present data which show chlorobenzene to be resistant to
biodegradation, unless microorganisms are already growing on another
hydrocarbon source in the medium.
Ballschmiter and Scholz (1980, as cited in EPA 1985) investigated
the metabolism of p-DCB by the soil microbe Pseudomonas and found that
this bacterium degraded the compound to dichlorophenols and
dichloropyrocatechols. Monsanto (1986) reported that p-DCB is moderately
to readily biodegradable under their assay conditions. Specifically,
primary degradation was greater than 95% in a 24-h, semicontinuous
activated sludge test. Using the Thompson-Duthie-Sturm assay method,
p-DCB yields a theoretical C02 evolution of approximately 58%. These
assay results probably are not representative of the biodegradation
levels likely Co occur under typical soil conditions; however, they do
represent fate under enrichment conditions.
6.3.4 Biotic Fata Processes
The log octanol/vater partition coefficient (log p - 3.39, Leo et
al. 1971, as cited in EPA 1979) suggests that p-DCB has a high potential
for bioaccumulation in aquatic organisms. The incorporation of chlorine
into an organic molecule generally increases its lipophilic character
and bioaccumulation potential (Kopperman et al. 1976, as cited in EPA
1979); therefore, p-DCB should be more lipophilic than benzene or
chlorobenzene.
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61
7. POTENTIAL FOR HUMAN EXPOSURE
7.1 OVERVIEW
p-DCB has been detected in air, water, soil, and foods. Potential
human exposure can result from inhalation or via ingestion of food or
water. Inhalation is likely to be the most significant route of human
exposure. There are no data which indicate that ingestion of
contaminated food is a significant exposure route. Additionally,
exposure to-substantial amounts of p-DCB from drinking contaminated
water appears to be low for the general population. However, the
potential for substantial, but localized, human exposures as the result
of contaminated groundwater near hazardous waste sites has been shown.
Human exposure to p-DCB is greatest in indoor air where higher
exposure potentials exist to vapors from p-DCB products used as
deodorizers and moth repellents. Various studies suggest that indoor air
concentrations are 8 to 100 times greater than outdoor ambient levels.
Specific measurements of indoor air concentrations for combined m-DCB
and p-DCB at several U.S. locations provide estimated mean values
ranging from 5.5 to 56 /ig/m3 (approximately 0.0009 to 0.009 ppm),
whereas estimated mean values for outdoor concentrations were
approximately an order of magnitude less (0.3 to 2.2 A»g/m3; 0.00005 to
0.0004 ppm). Median values ranged from 0.53 to 4.2 A»g/m3 (0.0001 to
0.0007 ppm) for indoor air and from 0.07 to 1.7 Mg/m" (0.00001 to 0 0003
ppm) for outdoor air.
Populations at elevated risk for exposure to high concentrations of
p-DCB include workers involved in the manufacture and processing of the
compounds and those individuals who may be transiently exposed to high
levels of p-DCB in moth repellents. Other occupational groups with
suspected elevated exposures to p-DCB include janitors, furriers, and
undertakers. No populations with above-average sensitivities to p-DCB
have been identified.
7.2 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT
7.2.1 Levels in Air
In discussing atmospheric levels of p-DCB, it is necessary to
distinguish between indoor air and outdoor (ambient) air. The
distinction is important because household consumer products can release
large amounts of p-DCB to the indoor air, and indoor air concentrations
may be much higher than outdoor concentrations.
The most comprehensive data on indoor air concentrations of p-DCB
in the United States comes from the EPA Total Exposure Assessment
Methodology (TEAM) study (Wallace et al. 1986). Using personal monitors.
combined concentrations of m-DCB and p-DCB were obtained for persons in
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62 Section 7
approximately 600 homes in New Jersey, North Carolina, North Dakota, and
California. (The combined measure was assumed to be almost entirely p-
DCB.) The highest mean nighttime personal exposures (taken as an
indication of concentrations in homes) were reported to be 49 to 56
pg/m3 (0.008 to 0.009 ppm) in the New Jersey study area, with a maximum
measured value of 1500 /ig/m3 (0.25 ppm). Mean personal exposure
concentrations for the other three areas ranged from 5.5 to 18 ^g/m3
(0.0009 to 0.003 ppm). By contrast, outdoor mean concentrations for the
four areas ranged from 0.3 to 2.2 pg/m3 (0.00005 to 0.0004 ppm). Median
concentrations from nighttime personal monitoring (indoor air) in the
four areas ranged from 0.53 to 4.2 Mg/m3 (0.0001 to 0.0007 ppm).
Other studies also document p-DCB in the indoor air environment.
Scuderi (1986) measured the rate of increase of air concentrations of
p-DCB after p-DCB blocks were placed in public bathrooms or p-DCB
crystals were placed in a wardrobe. The concentration in one of the
bathrooms exceeded 200 /ig/m3 (0.03 ppm). Lebret et al. (1986), in a
study of 300 Dutch homes, reported that indoor p-DCB concentrations
reached 300 ^g/m3 (0.05 ppm), whereas outdoor maximum and median
concentrations were less than 0.6 /*g/m3 (0.0001 ppm). Morita and Ohi
(1975) reported maximum outdoor p-DCB concentrations in Tokyo of 4 jjg/m3
(0.0007 ppm), whereas they observed that the p-DCB concentration in a
bedroom was more than 100 A»g/m3 (0.02 ppm).
Additional outdoor measurements in the United States also showed
generally lower levels than reported for some indoor environments.
Bozzelli and Kebbekus (1982) reported a mean concentration of 1.7 /jg/m3
(0.0003 ppm) from 330 outdoor samples taken in varied locations in New
Jersey in 1978. Brodzinsky and Singh (1982, as cited in EPA 1985)
reported a mean p-DCB concentration of 1.6 pg/m3 (0.0003 ppm) for 24
localities. Wallace et al. (1986) found that m-DCB and p-DCB were
ubiquitous; that is, they were detected in 80 to 100% of the samples at
each TEAM site.
The data presented above indicate that indoor air is a major source
of exposure to p-DCB. However, data needed to generate population
frequency distribution curves of exposure are limited.
7.2.2 Levels in Water
p-DCB has been detected in surface water and groundwater and in
municipal and industrial discharges. The EPA Storage and Retrieval
(STORET) database system contains monitoring data on this chemical. The
EPA (1975) presented the results of a survey of groundwater and surface
water at more than 1000 sites throughout New Jersey. Isomers of
dichlorobenzenes were found in about 3% of all groundwater samples and
in 4% of the surface water samples.
The TEAM study by Wallace et al. (1986) also reported on the
combined occurrence of m-DCB and p-DCB in drinking water in selected
cities in New Jersey, North Carolina, and North Dakota. These DCBs were
generally classified as "occasionally found," being detected in 3% of
samples in New Jersey, 2% of samples in North Dakota, and 0% of samples
in North Carolina. Coniglio et al. (1980, as cited in EPA 198S) reported
that 13% of the drinking water treatment plants in the United States
that use groundwater had drinking water samples that contained p-DCB.
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Potential for Human Exposure 63
The reported concentration range for all dichlorobenzene isomers was <1
to 100 Mg/L. Oliver and Nlcol (1982. as cited In EPA 1985) sampled
drinking water in three cities on Lake Ontario. p-DCB concentrations
ranged from 8 to 20 ng/L (mean - 13 ng/L) . The National Organics
Monitoring Survey (Symons et al. 1975, as cited in EPA 1981) found p-DCB
in 2/111. 20/113. and 29/110 samples (representing three different
sampling phases) of drinking water analyzed during the period March 1976
to January 1977. The mean concentration ranged from 0.07 to 2.0 ng/L,
and the median concentration was <1 Mg/L for all samples in all phases
of the survey. These data are generally consistent with the results of
an earlier EPA study (EPA 1975, as cited in EPA 1981), which indicated 1
Mg/L as the highest drinking water concentration found for p-DCB.
Chlorobenzenes have also been detected in wastewaters from
industrial processes and in influents and effluents at municipal sewage
treatment plants. Gaffney (1976, as cited in EPA 1985) sampled water at
four municipal facilities which handled sewage and wastewater from
carpet mills. Average dichlorobenzene (all isomers) concentrations in
the incoming and outgoing water ranged from 3 to 146 Mg/L and 0 to 268
Mg/L, respectively. The author concluded that the increases in effluent
dichlorobenzene levels resulted from chlorination (e.g., by reaction of
chlorine with precursor organics in the water). Neptune (1980, as cited
in EPA 1985) compiled data collected during several industrial
wastewater surveys conducted from September 1978 through October 1979.
p-DCB concentrations greater than 10 Mg/L were detected in 88 of 3268
samples (range - 10 to 410 Mg/L; median - 79
Significant localized contamination of drinking water may occur if
hazardous waste site leachate enters either surface water or groundwater
supplies. Several limited studies provide some information on this
exposure potential. Bramlett et al. (1986) performed priority pollutant
analyses of the leachate from 13 hazardous waste sites. Dichlorobenzenes
and monochlorobenzene accounted for 1.4% of the total mean mole fraction
of all organic chemicals detected in the leachates. The combined
chlorobenzenes were detected in the leachates from 6 of the 13 sites.
Ghassemi eC al. (1984) compiled a database on the constituents in
hazardous waste site leachates from 30 sets of analytical data collected
from 11 different sices. Dichlorobenzene was detected in one of eight
leachate samples of "mixed industrial wastes" collected above liners and
in five of seven leachate samples of "mixed industrial wastes" collected
below or between liners. The highest average concentrations of
dichlorobenzene in these samples were reported to be less than
0.311 mg/L for the sample collected above liners and 0.67 mg/L for the
samples collected below or between liners.
Wetzel et al. (1985) detected dichlorobenzene (detection limit of
0.001 mg/L) in one of seven groundwater wells in the vicinity of a waste
disposal site at Kelly Air Force Base, Texas.
The potential for water contamination depends on the quantity of
DCB disposed of at a particular site. The environmental fate data
presented earlier, however, indicate that p-DCB will be relatively
stable and persistent in water not exposed to air. Thus, the potential
exists for significant contamination of groundwater and/or surface water
-------
64 Section 7
at some waste sites. However, specific occurrences have not been
documented in the literature located for this report.
7.2.3 Levels in Soil
The available studies of soil contamination by chlorobenzenes have
focused on hexachlorobenzene with relatively few surveys including all
chlorobenzenes. Elder et al. (1981, as cited in EPA 1985) detected all
of the chlorobenzenes in the part-per-million range in the sediments of
streams draining the Love Canal area of Niagara Falls, New York. Oliver
and Nicol (1982, as cited in EPA 1985) detected all chlorobenzene
isomers in the sediments of Lakes Superior, Huron, Erie, and Ontario.
The most contaminated lake was Lake Ontario, with dichlorobenzene
sediment levels ranging from 11 to 94 ng/g.
Wetzel et al. (1985) detected dichlorobenzene in soil samples from
three of five boreholes in and around a waste disposal site at Kelly Air
Force Base, Texas. Concentrations ranged from 0.15 to 38.0 mg/L of soil.
These data further substantiate the potential for localized groundwater
contamination in the vicinity of some waste sites.
7.2.4 Levels in Food
Dichlorobenzenes may be present in food as a result of
contamination from uses of the chemical. Schmidt (1971, as cited in EPA
1980) reported the contamination of pork as a result of the use of p-DCB
in pig stalls as an odor-control product. Additionally, hens exposed to
p-DCB concentrations of 20 to 38 mg/m3 produced contaminated eggs within
3 days of exposure (Langner and Hillinger 1971, as cited in EPA 1980).
Morita et al. (1975, as cited in EPA 1980) reported detectable levels of
p-DCB in fish from Japanese coastal water; a species of mackerel
contained 0.05 mg/kg p-DCB. Oliver and Nicol (1982, as cited in EPA
1985) detected all dichlorobenzene isomers in trout from the Great
Lakes.
Limited data from 42 samples of human breast milk at five U.S.
locations .detected DCB (all isomers) at concentrations ranging from
0.04 to 68 ng/mL (Cone et al. 1983).
A measured steady-state bioconcentration factor of 60 (which
relates the concentration of a chemical in aquatic animals to the
concentration in the water they inhabit) was determined for p-DCB, using
bluegills (EPA 1978a,b. as cited in EPA 1980). When this factor is
adjusted for the percent lipid in bluegills compared with the weighted
average percent lipids in the edible portion of fish and shellfish
consumed in the United States, a weighted average bioconcentration
factor of 37.5 is derived for p-DCB in aquatic organisms consumed in the
United States (EPA 1980). For example, a concentration of 1 mg/L in
water would result in a concentration of 37.5 ppm (wet weight) in the
fish edible portion.
7.2.5 Resulting Exposure Levels
The monitoring studies discussed in the previous sections indicate
that p-DCB is present in the environment, and human exposure is more
likely to result from the Inhalation of contaminated air (indoor and
-------
Potential for Human Exposure 65
outdoor) than from the ingestion of contaminated water or food. The
compound is fairly ubiquitous in environmental media at low levels,
although substantial human exposure may occur from contact with certain
media (e.g., indoor air, localized contaminated water, and air in some
occupational environments). Evidence of widespread human exposure to
p-DCB is provided by data from EPA's National Human Adipose Tissue
Survey (NHATS) (EPA 1986c). Results from the NHATS FY 1982 repository
show that p-DCB was detected in all 46 composite samples of human
adipose tissue from all U.S. regions. Wet tissue concentrations ranged
from 0.012 to 0.50 Mg/g- No summary conclusions were drawn regarding the
human health significance of these levels.
Because the largest environmental releases of p-DCB are to the air,
and because volatilization is a major process for removing the substance
from aquatic media, inhalation is expected to be the major p-DCB
exposure route for the general population. In a recent estimate of human
exposure to p-DCB from the atmosphere by the EPA Office of Drinking
Water, the median concentration for outdoor urban/suburban environments
of 0.28 A»g/m3 (0.00005 ppm) was used (EPA 1987a). This is generally
consistent with the TEAM study findings in which the median outdoor air
concentrations of p-DCB ranged from 0.07 to 1.7 Mg/m3 (0.00001 to 0.0003
ppm) (Wallace et al. 1986). By contrast, the TEAM study reports median
indoor air concentrations of p-DCB in the range of 0.53 to 4.2 /ig/m3
(0.0001 to 0.0007 ppm) and mean concentrations in the range of 5.5 to 56
Mg/m3 (0.0009 to 0.009 ppm) (Wallace et al. 1986). When making human
exposure estimates for a 70-kg adult, a breathing rate of 20 m3/day is
typically used.
The most direct route of exposure for waterborne p-DCB is the
ingestion of drinking water. The EPA (1981) estimated human exposure to
p-DCB via contaminated water based on National Organics Monitoring
Survey data. These estimates, which assume daily water consumption of
2 L/day, are presented in Table 7.1. A recent exposure assessment of
p-DCB by the EPA Office of Drinking Water (EPA 1987a) estimated that
over 1.6 million persons (0.8% of the population served by public water
supplies) were exposed to p-DCB at drinking water concentrations at or
above 0.5 Mg/L, but that no individuals receive drinking water exposures
above 5 Mg/L. Surface water (53%) and groundwater (47%) contribute
nearly equally to these exposures. These estimates indicate the
potential for exposure to substantial amounts of p-DCB from drinking
water appears to be low. However, based on the limited soil and water
data from hazardous waste sites, localized contamination may result in
substantially increased water exposures for some populations.
Although p-DCB contamination of food occurs, there are no data
indicating that this is a significant route of human exposure (EPA
1981).
7.3 OCCUPATIONAL EXPOSURES
Levels of p-DCB may be much higher in certain workplace atmospheres
than in ambient air. Ware and Weast (1977, as cited in EPA 1985)
reported that in workplaces associated with the manufacture of p-DCB,
atmospheric concentrations of the chemical averaged 204 mg/m3 (34 ppm)
[range - 42 to 288 mg/m3 (7 to 48 ppm)] near shoveling and centrifuging
-------
66 Section 7
Table 7.1. Estimated hommn exposure to p-DCB
Maximum observed
Mean observed
Median concentration
Estimated
Concentration
(Mg/L)
2.0
0.07
<0.005
exposure
Exposure
(mg/day)
4 X 10~3
io-4
<10~5
Source: Adapted from EPA 1981.
-------
Potential for Human Exposure 67
operations and 150 mg/m3 (25 ppm) [range - 108 to 204 mg/m3 (18 co 34
ppm)] during pulverizing and packing. Generally, however, levels
throughout the manufacturing plant were detected at less than 48 mg/ra3
(8 ppm). Pagnatto and Walkley (1965, as cited in EPA 1981) reported
concentrations of 150 to 420 mg/m3 (25 to 70 ppm) in workplaces
associated with the manufacture of p-DCB. NIOSH (1980) reported that a
worker at a p-DCB drumming operation was exposed to -30 mg/m3 (5 ppra,
8-h TWA), and that some workers are exposed to levels up to 220 mg/m3
(37 ppra). Measurements made by the Occupational Safety and Health
Administration (OSHA 1986) between 1981 and 1986 show numerous instances
of workers exposed to greater than 66 mg/m3 (8 ppm).
7.4 POPULATIONS AT HIGH RISK
7.4.1 Above-Average Exposure
Subpopulations in the vicinity of production or industrial use
facilities may be exposed to transitory higher levels of p-DCB due to
accidental releases, but there are no data upon which to base an
estimate of this type of exposure (EPA 1981).
Workers involved in the production of p-DCB may be exposed to
concentrations significantly higher than those encountered by the
general population. A NIOSH survey reported by Hull and Co. (1980, as
cited in EPA 1981) projected that approximately one-half million workers
had nfull"-time (>4 h/week) or "parf-time (<4 h/week) exposure to p-
DCB. Hull and Co. estimated on the basis of their own survey that only
approximately 821 employees of manufacturers, processors, formulators,
and resellers of p-DCB would be potentially exposed.
High exposure levels may result from some consumer use of moth
repellents and room deodorizers. The indoor air measurements by Wallace
et al. (1986) suggest that consumers who use p-DCB deodorizers and moth
repellents will have higher exposures than persons who are not regularly
exposed to these products. Although the TEAM study provided no
information on the household use of products containing p-DCB, studies
now under way are expected to confirm that higher indoor air
concentrations of p-DCB are related to household uses of products
containing p-DCB.
7.4.2 Above-Average Sensitivity
No Information is available on populations with above-average
sensitivity to p-DCB.
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69
8. ANALYTICAL METHODS
Gas chromatography (GC) is the most common analytical method for
detecting and measuring p-DCB in environmental and biological samples.
High-performance liquid chromatography may also be used to measure p-DCB
in environmental samples (Bush et al. 1984).
Samples may be prepared by several methods, depending on the matrix
being sampled. The sample preparation procedures for analyzing
environmental samples for p-DCB include charcoal adsorption/desorption.
extraction with methylene chloride, purge and trap, and direct injection
(EPA 1983a, 1986b, APHA 1977). Sample preparation for biological samples
often involves extraction with hexane or carbon tetrachloride or a purge
and trap technique (Bristol et al. 1982, EPA 1986c, Stanley 1986
Langhorst and Nestrick 1979).
The GC separates complex mixtures of organics and allows individual
compounds to be identified and quantified.
Detectors used to identify p-DCB include the flame ionization
detector (FID), electron capture detector (BCD), halogen specific
detector (HSD), and photoionization detector (PID) (EPA 1983a, 1986b
Langhorst and Nestrick 1979, APHA 1977, Jan 1983, Bristol et al. 1982,
Mottram et al. 1982). When unequivocal identification is required, use
of a mass spectrometer (MS) coupled to the GC column (GC-MS) may be
employed (EPA 1983a).
8.1 ENVIRONMENTAL MEDIA
Representative methods appropriate for measuring p-DCB in
environmental media are listed in Table 8.1.
8.1.1 Air
The American Public Health Association (APHA) method for
measurement of organic solvent vapors in air (834) involves adsorption
of the organic vapors in the air onto an activated charcoal filter,
desorption. with carbon disulfide, and injection of an aliquot of the
desorbed sample Into a GC equipped with an FID. The resulting peaks are
measured and compared with standards.
Interference may be caused by high temperatures, high humidity,
high sampling flow rates, and other solvents with the same retention
times. Different GC column materials and temperatures may be employed to
resolve the interference of other solvents (APHA 1977).
-------
70 Section 8
Sod
Table 8.1. Antytfc*!
forf-DCBts
Sample
matnx
Sample
preparation
Analytical
method'
Sample
detection
limit
Accuracy*
References
Air Charcoal adsorption, GC/FID
desorption with
carbon disulfide
Water Extraction with GC/MS
methyiene chloride (EPA method 623)
Extraction with CC/ECD
methyiene chlonde (EPA method 612)
25ppbc 90-110%rf APHA 1977
4 4 «tg/L 63%
1 34 Mg/L 89%
Purge and trap GC/HISD 0 24 pg/L 97 5%
(EPA method 601)
Purge and trap or GC/HOSD
direct injection (EPA method 8010)
EPA 1983
EPA 1983
EPA 1983
2.4-300 ppb 42 to 143% EPA 1986b
Food Headspace GC/FID;
entrainment GC/MS
on Tenax GC
NO*
ND
Mottram et al. 1982
"GC, gas chromatography; FID. name lonization detector. MS. man spectrometry; ECD. electron cap-
ture detector. HISD. halide specific detector HOSD, halogen specific detector.
Average percent recovery.
'Lowest value for various detected compounds reported during collaborative testing.
Estimated accuracy of the sampling and analytical method when the personal sampling pump is cali-
brated with a charcoal tube in the line.
'Not determined; identified, but not quantified.
-------
Analytical Methods 71
8.1.2 Vater
The EPA approved several methods (601, 602, 612, 624, 625) for
analysis of wastewater samples for p-DCB. All of these methods employ
packed column GC for separation of the organic pollutants, but differ in
the sample preparation procedures and the detection instrumentation.
Measuring methods 601 and 612 are optimized for purgeable
halocarbons and chlorinated hydrocarbons, respectively, with detection
limits of about 0.2 to 1.5 Mg/L. Method 625, which employs MS for
detection and quantification, is more broadly applicable to a large
number of base/neutral and acid extractable organics.
8.1.3 Soil
Soil samples can be analyzed for p-DCB by GC with a halogen-
specific detector. Sample preparation is by purge and trap. This method
is approved by the EPA for analysis of halogenated volatile organics
(8010) in solid waste. The method detection limit for p-DCB ranges from
2.4 to 300 ppb, depending on the matrix (EPA 1986b).
8.1.4 Food
Analysis of p-DCB in meat is typically done by headspace sampling
and GC/FID or GC/MS analysis (Mottram et al. 1982).
8.2 BIOMEDICAL SAMPLES
Methods appropriate for measuring p-DCB in biological samples are
listed in Table 8.2.
8.2.1 Fluids and Exudates
Blood levels of p-DCB are measured using GC with either an ECD or
PID. The samples are prepared by extraction with hexane or carbon
tetrachloride (Bristol et al. 1982, Langhorst and Nestrick 1979).
Analysis of urine for p-DCB is by GC/PID, with sample extraction
with carbon tetrachloride (Langhorst and Nestrick 1979). As mentioned in
Sect. 2.2.2, the principal method of monitoring for recent p-DCB
exposure is the measurement of 2,5-dichlorophenol in the urine (Pagnatto
and Walkley 1965).
Human milk may be analyzed for p-DCB by GC/ECD with extraction by
hexane and concentrated sulfuric acid (Jan 1983) or by GC/MS (Erickson
et al. 1980).
8.2.2 Tissues
Adipose tissue levels of p-DCB may be determined by the same method
used for human milk (Jan 1983) or by a high-resolution gas
chromatography/mass spectroscopy method (Stanley 1986) which employs a
dynamic headspace purge and trap system for sample preparation.
-------
72 Section 8
Table U. Aaalytkil
for p-DCB (•
Sample
matru
Blood
Urine
Human
milk
Adipose
Sample
preparation
Extraction with
hexane
Extraction with
carbon tetrachloride
Extraction with
carbon tetrachloride
Extraction with
hexane/concemrated
sulfunc and
Extraction with
hexane
Dynamic headipace
purge and trap
Analytical
method'
GC/ECD
GC/PD
GC/PD
GLC/ECD
GC/MS
GLC/ECD
HRGC/MS
Sample
detection
limit
2ppb*
30og/g
0.75 ng/g
5Mg/kg*
004ng/mL*
146 Mg/kg'
0.012Mg/g*
Accuracy
82%
89%
81%
>80%
NRC
>80%
94%
Reference*
Bristol el aL 1982
Langhont and
Nestnck 1979
Langhont and
Nestnck 1979
Jan 1983
Enckson et aL 1980
Jan 1983
EPA 1986c
GC, gai chromatograpby: BCD. electron capture detector, PD. photownizstion detector GLC,
gas-liouid chramatography; MS, man ipectrometry; HRGC, high-resolution gas chromatography
Lowest level detected.
Not reported.
'Average level detected.
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73
9. REGULATORY AND ADVISORY STATUS
9.1 INTERNATIONAL
The World Health Organization (WHO) has not recommended a drinking
water guideline value for p-DCB based on health effects. The WHO
recommends 0.1 j*g/L p-DCB as a level "unlikely to give rise to taste and
odor problems. ..." (WHO 1984).
9.2 NATIONAL
9.2.1 Regulations
Regulations applicable to p-DCB address occupational exposure
concentrations, testing requirements, drinking water levels, spill
quantities, and presence in hazardous wastes. Regulations applicable to
p-DCB are summarized in Table 9.1.
OSHA sets permissible exposure limits (PELs) for occupational
exposures to chemicals based on the recommendations of the National
Institute for Occupational Safety and Health (NIOSH). The OSHA PEL for
p-DCB is 75 ppm (450 mg/m3) in workplace air for a TWA (8 h/day, 40
h/week).
The EPA Office of Drinking Water (ODW) has promulgated a Maximum
Contaminant Level (MCL) for p-DCB of 0.075 mg/L. The MCL is normally
based on analyses of health effects and other factors such as the best
available technology, analytical methods, treatment techniques, and
economic factors.
The Comprehensive Environmental Response, Compensation and
Liability Act of 1980 (CERCLA) requires that persons in charge of
facilities from which a hazardous substance has been released in
quantities equal to or greater than its reportable quantity (RQ)
immediately notify the National Response Center of the release. The RQ
for p-DCB set by the EPA Office of Emergency and Remedial Response
(OERR) is 100 Ib.
Chemicals are included on the Resource Conservation and Recovery
Act (RCRA) Appendix VIII list of hazardous constituents (40 CFR Part
261) if they have toxic, carcinogenic, mutagenic, or teratogenic effects
on humans or other life forms. p-DCB is included on this list, and
wastes containing p-DCB are subject to the RCRA regulations promulgated
by the EPA Office of Solid Waste (OSW).
The Office of Toxic Substances (OTS) promulgates test rules
requiring manufacturers and/or processors of chemicals which may present
an unreasonable risk to health or the environment to conduct tests of
those chemicals for health and/or environmental effects. Manufacturers
-------
74 Seccion 9
Tabfe 9.1.
Agency
OSHA
EPA ODW
EPAOERR
EPAOSW
EPAOTS
iPAOPP
Descnption
Permissible exposure limit (PEL) in
workplace air
Tune-weighted average (TWA)
8 h/day, 40 h/week
Maximum contaminant level (MCL)
Reportable quantity (RQ)
Hazardous Constituent List
Appendix VIII
Test rule— requirements for health
effects and chemical fate testing
Preliminary assessment information rate
Health and safety data reporting rule
Comprehensive assessment information
rule (proposed)
Registered pesticide; registration
standard in progress
Vall»e References
75 PP™ 29 CFR 1910
(450mg/mJ) (1971)
0075 mg/L 40 CFR 141 61
52 FR 25690
(07/08/87)
100 Ib 40 CFR 117 3
50 FR 13456
(04/04/85)
NAa 40 CFR 261
45 FR 33084
(05/19/80)
NA 40 CFR 799. 1052
51 FR 11728
(04/07/86)
51 FR 24657
(07/08/86)
NA 40 CFR 712
47 FR 26992
(06/22/82)
NA 40 CFR 716
47 FR 38780
(09/02/82)
NA 5| FR 35762
(10/07/86)
NA 32 FR 588
(01/07/87)
ACGIH Threshold limit value (TLV)
TWA
ACGIH 1986
(450 mg/m1)
NIOSH
NIOSH/OSHA
EPA ODW
EPAOWRS
Short-term exposure limit (STEL)
Immediately dangerous to life or health (IDLH)
Respiratory equipment required
Ambient water quality criteria for
prataetwM ft hnn»i| health
Ingesting water and organisms
110 ppm
(665 mg/m1)
1.000 ppm
75 ppm
sad above
0.075 mg/L
0.4 mg/L
2.6 mg/L
NIOSH 1983
NIOSH/OSHA 1981
40 CFR 141.50
52 FR 25690
(07/08/87)
EPA 1980
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Regulatory and Advisory Scacus 75
TtMe9.1 (coMtaed)
Agency
NAS
I ARC
EPA
EPA
Description
EPA ODW
Longer-term HA-child
Longer-term HA-adult
Lifetime HA
Suggested no advene response level (SNARL)
Cancer ranking
Cancer ranking
Carcinogenic potency (q,*)
Value
10.7 mg/L
37 5 mg/L
0075 mg/L
0094 mg/L
Group 2B
Group C
2.2 X I0~2
(mg/kg/day)-'
References
NAS 1977
IARC 1987
52 FR 25690
(07/08/87)
Battelle and
Crump 1986
"NA - not available.
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76 Section 9
and processors of p-DCB are required to conduct chemical face and
reproductive effects tests under current regulations.
Manufacturers of p-DCB are required to submit to EPA information on
the quantity of the chemical manufactured or imported, the amount
directed to certain uses, and the potential exposure and environmental
release of the chemical under the Preliminary Assessment Information
Rule. Unpublished health and safety studies on p-DCB must be submitted
to EPA by manufacturers or processors under the Health and Safety Data
Reporting Rule.
The OTS proposed a Comprehensive Assessment Information Rule (CAIR)
which would specify the reporting requirements for chemicals 'for which
EPA requires information. This rule is designed to streamline collection
of information to support chemical risk assessment/management
strategies. p-DCB is one of the 47 chemicals proposed to be included in
this rule.
The EPA Office of Pesticide Programs (OPP) is responsible for the
registration of all pesticide products sold in the United States. p-DCB
is currently a registered pesticide, and the OPP expects to require
additional data when it reviews p-DCB for reregistration. The OPP has
also included p-DCB on a list of inert ingredients of toxicological
concern in pesticide formulations (52 FR 13305).
9.2.2 Advisory Guidance
Advisory guidance levels are environmental concentrations
recommended by either regulatory agencies or other organizations which
are protective of human health or aquatic life. Although not
enforceable, these levels may be used as the basis for enforceable
standards. Advisory guidance for p-DCB is summarized in Table 9.1 and
includes the following: Immediately Dangerous to Life or Health (IDLH)
level for occupational exposure; a threshold limit value (TLV); the
drinking water Maximum Contaminant Level Goal (MCLG); ambient water
quality criteria; drinking water health advisories (HAs); and a chronic
Suggested No Adverse Response Level (SNARL) calculated by the National
Academy of Sciences.
The NIOSH IDLH for occupational exposure to p-DCB in air is 1000
ppm. This level represents a maximum concentration from which one could
escape within 30 min without any escape-impairing symptoms or
irreversible health effects. NIOSH/OSHA occupational health guidelines
require Che use of minimal respiratory equipment by workers exposed to
p-DCB at 75 ppm and above. At levels of 1000 ppm and above, more complex
and protective equipment is required.
The American Conference of Governmental Industrial Hygienists
(ACGIH) recommends a TLV TWA of 75 ppm and a Short-Term Exposure Limit
(STEL) of 110 ppm/15 min/8 h for p-DCB. This level is intended to be low
enough to prevent acute and chronic poisoning.
The EPA ODW MCLG for p-DCB, although not an enforceable standard,
is based on the health effects of p-DCB and is currently 0.075 mg/L.
based on chronic toxicity data and the classification of p-DCB in Group
C (possible human carcinogen) (52 FR 25690). The MCLG applies to
-------
Regulatory and Advisory Scacus 77
finished drinking water. The MCL (Maximum Contaminant Level) has also
been set at 0.075 mg/L.
The ODW prepared HAs for numerous drinking water contaminants The
HAs describe concentrations of contaminants in drinking water at which
adverse effects would not be anticipated to occur and include a margin
of safety to protect sensitive members of the population. The HAs are
calculated for 1-day, 10-day, longer-term, and lifetime exposures For
p-DCB the longer-term HA is 10.7 mg/L for a child and 37.5 mg/L for an
adult. The Lifetime HA is 0.075 mg/L. Adequate data were not available
to calculate a 1-day or 10-day HA, but the EPA recommends using the
longer-term HA for a child for this duration of exposure (EPA 1987b).
The ambient water quality criteria are guidelines set by the EPA
Office of Water Regulations and Standards (OWRS) to protect human health
from potential adverse effects from the ingestion of water and/or
organisms (fish or invertebrates) or from ingestion of organisms only
from surface water sources. The values for p-DCB are 0.4 mg/L for
ingesting water and organisms and 2.6 mg/L for ingesting only organisms
9.2.3 Data Analysis
Reference dose. A reference dose (RfD) of 0.1 mg/kg/day
(100 ^gAg/day) has been calculated for p-DCB in the final draft of the
Office of Drinking Water Health Advisory on p-DCB (EPA 1987b). This
value has not yet been verified by the Agency's RfD Workgroup. It is
based on the NOAEL of 150 mg/kg for rats in the 13-week NTP study, an
uncertainty factor of 1000, and a dosing regimen conversion factor of
5/7 (5 days dosing per week). For further information about the meaning
and calculation of RfDs, the reader should consult EPA 1987, Reference
Dose (RfD): Description and use in health risk assessments, Appendix A
of the Integrated Risk Information System (IRIS).
Carcinogenic potency, q.*. In an analysis of the NTP (1987)
carcinogenicity data (available in 1986 as the galley draft), Battelle
and Crump (1986) used the liver tumors in male mice and the linearized
multi-stage model to calculate a q * of 2.2 x 10'2 (mg/kg/day)"*• For a
more detailed explanation of how q * values are calculated, the reader
is referred to Anderson et al. (1983).
Therefore, as calculated by EPA (1987a), lifetime drinking water
exposure levels corresponding to 10'6, 10'5, and 10'4 excess risk (based
on 95% upper bound confidence limit to multistage model) would be 1.75,
17.5 and 175 Mg/L, respectively, for a 70-kg human consuming 2 L of
water per day. There were not enough distinct data points to allow fits
to other-models tried (Weibull, logit, probit) by the EPA's Office of
Drinking Vater.
Using the male rat kidney tumor data in the NTP (1987) study with
p-DCB, Battelle and Crump (1986) reports a q * of 6 x 10'3 by the
linearized multistage procedure as well as by the multistage-Weibull and
Crump's multistage models, taking time to death into account. This q *
is lower than the q * of 2.2 x 10'2 obtained with the male mouse liver
tumor data from the NTP (1987) study and is, therefore, considered the
less conservative estimate of risk. It should be noted that by using the
linearized multistage models, the lower limit of risk estimate is zero.
-------
78 Section 9
A quantitative assessment of risk using the NTP (1987) study has
also been carried out by the Office of Toxic Substances. The data sets
were modified slightly to eliminate animals that died early during
exposure. The linearized multistage extrapolation model was applied to
the adjusted data. An upper-bound risk of exposure to 1 mg/kg/day was
estimated to equal 2 x 10*2, based on male mouse liver tumors, and 6 x
10"3, based on male rat kidney tumors.
The Carcinogen Assessment Group (CAG) considers the model and the
data sets used for the quantitative risk estimates to be appropriate.
The upper-bound value of 2 x 10*2 derived from data on mouse liver
tumors is considered to be a reasonable estimate of risk. Since chere is
no good evidence to the contrary, when converting to an estimated human
risk from inhalation exposure, it is assumed that equivalent
administered doses will result in equivalent effects. Thus, the risk
from exposure to 1 mg/m3 p-DCB, assuming equivalent absorption
efficiency by either-route, would be estimated to equal 2 x 10~2
mgAg/day x 20 m3/day x 1 mg/m3 divided by 70 kg, or 5.7 x 10'3
mg/m3/day.
The EPA (1987a) has placed p-DCB in Category C, possible human
carcinogen. This category is for substances with limited evidence of
oncogenic potential in animal studies in the absence of human data.
Carcinogenic potency, other. No other estimates of the
carcinogenic potency of p-DCB as developed by other federal agencies
have been located.
9.3 STATE
9.3.1 Regulations
p-DCB is not specified in any state water quality standards.
However, this compound is included in the category "toxic substances" in
the water quality standards of most states in narrative form. Specific
narrative standards protect use of surface waters for public water
supply, contact recreation, etc.
9.3.2 Advisory Guidance
Advisory guidance from the states has not been located for p-DCB.
-------
79
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91
11. GLOSSARY
Acute Exposure-•Exposure to a chemical for a duration of 14 days or
less, as specified in the Toxicological Profiles.
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.
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.
Frank Efface Level (FEL)--That level of exposure which produces a
statistically or biologically significant increase in frequency or
severity of unmistakable adverse effects, such as irreversible
functional impairment or mortality, in an exposed population when
compared with its appropriate control.
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.
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.
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92 Section 11
Intermediate Exposure--Exposure to a chemical for a duration of 15-364
days, as specified in the Toxicological Profiles.
Immune-logic 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.
Key Study--An animal or human toxicological study that best illustrates
the nature of the adverse effects produced and the doses associated with
those effects.
Lethal Concentration(LO) (LCLO)--The lowest concentration of a chemical
in air which has been reported to have caused death in humans or
animals.
Lethal Concentration(SO) (LCso)--A calculated concentration of a
chemical in air to which exposure for a specific length of time is
expected to cause death in 50% of a defined experimental animal
population.
Lethal Dose(LO) (LDLO)--The lowest dose of a chemical introduced by a
route other than inhalation that 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.
Lovest-Observed-Adverae-Effect Level (LOAEL)--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.
Lowest-Observed-Effect Level (LOEL)--The lowest dose of chemical in a
study or group of studies which produces statistically or biologically
significant increases in frequency or severity of effects between the
exposed population and its appropriate control.
Malformations--Permanent structural changes that may adversely affect
survival, development, or function.
Minimal Risk Level--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.
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Glossary 93
Neurotoxicity- -The occurrence of adverse effects on Che 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.
No-Observed-Effect Level (NOEL) --That dose of chemical at which there
are no statistically or biologically significant increases in frequency
or severity of effects seen between the exposed population and its
appropriate control.
Permissible Exposure Limit (PEL) --An allowable exposure level in
workplace air averaged over an 8-h shift.
q *--The upper-bound estimate of the low-dose slope of the dose- response
curve as determined by the multistage procedure. The q.* can be used to
calculate an estimate of carcinogenic potency, the incremental excess
cancer risk per unit of exposure (usually /ig/L for water, mg/kg/day for
food, and pg/n^ 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 Ib
or greater or (2) for selected substances, an amount established by
regulation either under CERCLA or under Sect. HI of the Clean Water
Act. Quantities are measured over a 24-h period.
Reproductive Toxicity--The occurrence of adverse effects on the
reproductive system that may result from exposure to a chemical. The
toxicity may be directed to the reproductive organs and/or the related
endocrine- system. The manifestation of such toxicity may be noted as
alterations in sexual behavior, fertility, pregnancy outcomes, or
modifications in other functions that are dependent on the integrity of
this system.
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.
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Target Organ Toxlcity--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-h workday or 40-h workweek.
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 (4) 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 p-DCB. The panel consisted of
the following members: Dr. C. Klaassen, University of Kansas Medical
Center; Dr. S. Safe, Texas A&M University; and Mr. L. Skory (retired),
Dow Chemical Company. These experts collectively have knowledge of
p-DCB'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 the
Superfund Amendments and Reauthorization Act of 1986, Section 110.
A joint panel of scientists from ATSDR and EPA has 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 Agency for Toxic
Substances and Disease Registry.
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