Toxicological
Profile
for
3,3-DICHLOROBENZIDINE
Agency for Toxic Substances and Disease Registry
U.S. Public Health Service
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TOXICOLOGICAL PROFILE FOR
3,3'-DICHLOROBENZIDINE
Prepared by:
Life Systems, Inc.
Under Subcontract to:
Clement Associates, Inc.
Under Contract No. 205-88-0608
Prepared for:
Agency for Toxic Substances and Disease Registry
U.S. Public Health Service
In collaboration with:
U.S. Environmental Protection Agency
December 1989
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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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iii
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 lists
of the most significant hazardous substances were published in the Federal
Register on April 17, 1987, and on October 20, 1988.
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 epidemiological evaluations on the
hazardous substance in order to ascertain the levels of significant
human exposure for the substance and the associated acute, subacute,
and chronic health effects,
(B) A determination of whether adequate information on the health
effects of each substance is available or in the process of
development to determine levels of exposure which present a
significant risk to human health of acute, subacute, or chronic
health effects, and
(C) Where appropriate, an identification of toxicological testing
needed to identify the types or levels of exposure that may present
significant risk of adverse health effects in humans.
This toxicological profile is prepared in accordance with guidelines
developed by ATSDR and EPA. The original guidelines were published in the
Federal Register on April 17, 1987. Each profile will be revised and
republished as necessary, but no less often than every 3 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
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iv
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.
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. Data needs 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 as additional data become available.
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.
Wi >h.D.
Acting Administrator
Agency for Toxic Substances and
Disease Registry
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V
CONTENTS
FOREWORD iii
LIST OF FIGURES ix
LIST OF TABLES xi
1. PUBLIC HEALTH STATEMENT 1
1.1 WHAT IS DICHLOROBENZIDINE? 1
1.2 HOW MIGHT I BE EXPOSED TO 3,3'-DCB? 1
1.3 HOW CAN 3,3'-DCB ENTER AND LEAVE MY BODY? 1
1.4 HOW CAN 3,3'-DCB AFFECT MY HEALTH? 2
1.5 IS THERE A MEDICAL TEST TO DETERMINE IF I HAVE
BEEN EXPOSED TO 3,3'-DCB? 2
1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL
EFFECTS? 3
1.7 WHAT RECOMMENDATION HAS THE FEDERAL GOVERNMENT MADE
TO PROTECT HUMAN HEALTH? 3
1.8 WHERE CAN I GET MORE INFORMATION? 8
2. HEALTH EFFECTS 9
2.1 INTRODUCTION 9
2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 9
2.2.1 Inhalation Exposure 10
2.2.1.1 Death 10
2.2.1.2 Systemic Effects 10
2.2.1.3 Immunological Effects 11
2.2.1.4 Neurological Effects H
2.2.1.5 Developmental Effects 11
2.2.1.6 Reproductive Effects > H
2.2.1.7 Genetic Effects 11
2.2.1.8 Cancer 11
2.2.2 Oral Exposure H
2.2.2.1 Death 12
2.2.2.2 Systemic Effects 12
2.2.2.3 Immunological Effects ............. 15
2.2.2.4 Neurological Effects 15
2.2.2.5 Developmental Effects 15
2.2.2.6 Reproductive Effects 15
2.2.2.7 Genetic Effects 16
2.2.2.8 Cancer 16
2.2.3 Dermal Exposure 17
2.2.3.1 Death 17
2.2.3.2 Systemic Effects 17
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2.2.3.3 Immunological Effects 20
2.2.3.4 Neurological Effects 20
2.2.3.5 Developmental Effects 20
2.2.3.6 Reproductive Effects 20
2.2.3.7 Genetic Effects 20
2.2.3.8 Cancer 20
2.3 RELEVANCE TO PUBLIC HEALTH 21
2.4 LEVELS IN HUMAN TISSUES AND FLUIDS ASSOCIATED WITH
HEALTH EFFECTS 27
2.5 LEVELS IN THE ENVIRONMENT ASSOCIATED WITH LEVELS
IN HUMAN TISSUES AND/OR HEALTH EFFECTS 28
2.6 TOXICOKINETICS 28
2.6.1 Absorption 29
2.6.1.1 Inhalation Exposure 29
2.6.1.2 Oral Exposure 29
2.6.1.3 Dermal Exposure 29
2.6.2 Distribution 30
2.6.2.1 Inhalation Exposure 30
2.6.2.2 Oral Exposure 30
2.6.2.3 Dermal Exposure 30
2.6.3 Metabolism 31
2.6.3.1 Inhalation Exposure 31
2.6.3.2 Oral Exposure 31
2.6.3.3 Dermal Exposure 31
2.6.4 Excretion 31
2.6.4.1 Inhalation Exposure 31
2.6.4.2 Oral Exposure 32
2.6.4.3 Dermal Exposure 32
2.7 INTERACTIONS WITH OTHER CHEMICALS 32
2.8 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 33
2.9 ADEQUACY OF THE DATABASE 33
2.9.1 Existing Information On Health Effects of 3,3'-DCB ... 33
2.9.2 Data Needs 35
2.9.3 Ongoing Studies 38
3. CHEMICAL AND PHYSICAL INFORMATION 39
3.1 CHEMICAL IDENTITY 39
3.2 PHYSICAL AND CHEMICAL PROPERTIES 39
4. PRODUCTION, IMPORT, USE AND DISPOSAL 43
4.1 PRODUCTION 43
4.2 IMPORT 43
4.3 USE 43
4.4 DISPOSAL 43
4.5 ADEQUACY OF THE DATABASE 44
4.5.1 Data Needs 44
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5. POTENTIAL FOR HUMAN EXPOSURE 45
5.1 OVERVIEW 45
5.2 RELEASES TO THE ENVIRONMENT 45
5.2.1 Air 45
5.2.2 Water 46
5.2.3 Soil 46
5.3 ENVIRONMENTAL FATE 46
5.3.1 Transport and Partitioning 47
5.3.2 Transformation and Degradation 49
5.3.2.1 Air 49
5.3.2.2 Water 49
5.3.2.3 Soil 50
5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 51
5.4.1 Air 51
5.4.2 Water 52
5.4.3 Soil 52
5.4.4 Other Media 52
5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 53
5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 53
5.7 ADEQUACY OF THE DATABASE 54
5.7.1 Data Needs 54
5.7.2 Ongoing Studies 55
6. ANALYTICAL METHODS 57
6.1 BIOLOGICAL MATERIALS 57
6.2 ENVIRONMENTAL SAMPLES 57
6.3 ADEQUACY OF THE DATABASE 59
6.3.1 Data Needs 61
6.3.2 Ongoing Studies 62
7. REGULATIONS AND ADVISORIES 63
8. REFERENCES 67
9. GLOSSARY 81
APPENDIX 87
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ix
LIST OF FIGURES
2-1 Levels of Significant Exposure to 3,3'-DCB - Oral Exposure 14
2-2 Levels of Significant Exposure to 3,3'-DCB - Dermal Exposure .... 19
2-3 Existing Information on Health Effects of 3,3'-DCB 34
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LIST OF TABLES
1-1 Human Health Effects from Breathing 3,3'-DCB 4
1-2 Animal Health Effects from Breathing 3,3'-DCB 5
1-3 Human Health Effects from Eating or Drinking 3,3'-DCB 6
1-4 Animal Health Effects from Eating or Drinking 3,3'-DCB 7
2-1 Levels of Significant Exposure to 3,3'-DCB - Oral Exposure 13
2-2 Levels of Significant Exposure to 3,3'-DCB - Dermal Exposure .... 18
2-3 Geno toxicity of 3,3'-DCB - In Vitro 23
2-4 Genotoxicity of 3,3'-DCB - In Vivo 24
3-1 Chemical Identity of 3,3'-Dichlorobenzidine 40
3-2 Physical and Chemical Properties of 3,3'-Dichlorobenzidine 41
6-1 Analytical Methods for 3,3'-Dichlorobenzidine in
Biological Samples .... 58
6-2 Analytical Methods for 3,3'-Dichlorobenzidine in
Environmental Media 60
7-1 Regulations and Guidelines Applicable to 3,3'-Dichlorobenzidine . . 64
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1. PUBLIC HEALTH STATEMENT
1.1 WHAT IS DICHLOROBENZIDINE?
3,3'-Dichlorobenzldine (3,3'-DCB) salt, the major form in actual
use, is a stable, grey to purple crystalline solid that does not
evaporate. The compound does not occur naturally. It is manufactured
for use in the production of dyes and pigments for printing inks,
textiles, plastics and enamels, paint, leather, and rubber. 3,3'-DCB
breaks down rapidly in water exposed to natural sunlight and in air, but
lasts in soil for months. In air, it is estimated that half of the
chemical can breakdown within 2 hours. In water exposed to natural
sunlight, 3,3'-DCB is expected to breakdown rapidly with half being
removed in approximately 90 seconds. More information can be found in
Chapters 3 and 4.
1.2 HOW MIGHT I BE EXPOSED TO 3,3'-DCB?
3,3'-DCB does not occur naturally in air, soil, or water. Workers
who manufacture, process and package 3,3'-DCB are the major population
at risk from exposure to the chemical, which occurs primarily in the
workplace as dihydrochloride salt. Possible exposure in the workplace
involves both breathing of 3,3'-DCB suspended in air and skin contact
with the chemical. Current levels of 3,3'-DCB in workplace air in the
United States are not known. For the general population, exposure is
most likely to occur by drinking water from wells contaminated with
3,3'-DCB from industrial discharge and waste disposal sites. Also,
exposure may occur by eating soil contaminated with 3,3'-DCB. Available
information indicates that the levels of 3,3'-DCB in ground water
samples are generally very low. However, areas in the vicinity of
discharge from dye-manufacturing and other industrial plants may be
higher. 3,3'-DCB has been found in ground and surface water at 1% of
hazardous waste sites and in soil at about 4% of over 500 sites. The
chemical has no agricultural or food chemical uses; so exposure to
3,3'-DCB by eating contaminated food is not likely, except for possible
exposure from eating fish which could possibly store 3,3'-DCB in their
body fat. More information can be found in Chapter 5.
1.3 HOW CAN 3,3'-DCB ENTER AND LEAVE MY BODY?
In the workplace, 3,3'-DCB may possibly enter workers' bodies by
breathing 3,3'-DCB contaminated dust and through skin contact. For the
general population, the most likely route is by drinking contaminated
water. 3,3'-DCB can also enter the body through contact with soil
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1. PUBLIC HEALTH STATEMENT
containing the chemical. When 3,3'-DCB does enter the body very little
of it leaves the body unchanged. Most of it (over 90%) is changed to
related chemical substances, called metabolites which leave the body
mainly in feces and to a lesser extent in urine within 72 hours after
exposure. More information can be found in Chapter 2.
1.4 HOW CAN 3,3'-DCB AFFECT MY HEALTH?
Workers exposed to the salt form of 3,3'-DCB complained of sore
throat, respiratory infections and stomach upset. However, it is not
known if 3,3'-DCB salt causes these health effects because the workers
may also have been exposed at the same time to other chemicals.
Death has occurred in experimental animals after eating, for brief
periods of time, very high levels of DCB mixed in their food. In
studies in which pregnant mice were exposed to the chemical, the kidneys
of their offspring did not develop properly. The effects of 3,3'-DCB on
the growth of children of women exposed to the chemical while pregnant
have not been studied. Long-term exposure of experimental animals to
moderate levels of 3,3'-DCB mixed with food can cause mild injury to the
liver.
The major concern is that 3,3'-DCB may cause cancer In humans.
Studies show 3,3'-DCB causes cancer of the liver, skin, mammary gland,
bladder and blood forming tissues (leukemia) and other sites when eaten
with food by experimental animals. The ability of 3,3'-DCB to cause
cancer in humans has not been established; however, in view of available
animal data, 3,3'-DCB should be thought of as a probable cancer-
producing substance in humans. More information can be found In
Chapter 2.
1.5 IS THERE A MEDICAL TEST TO DETERMINE IF I HAVE BEEN EXPOSED TO
3,3'-DCB?
Exposure to 3,3'-DCB can be determined by finding the chemical or
Its metabolites in urine. The test is not commonly available to the
general population, but is available to workers, who may be exposed to
the chemical at potentially hazardous levels in the workplace. The test
is accurate and provides evidence that exposure has occurred. However,
since 3,3'-DCB does not remain in the body, the test must be performed
very soon after the possible exposure. Further, measured urine and
tissue levels of 3,3'-DCB or its metabolites do not predict adverse
health effects in man. More information can be found in Chapter 6.
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1. PUBLIC HEALTH STATEMENT
1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL EFFECTS?
Tables 1-1 and 1-3 show that no information is available on harmful
human health effects that result from breathing, eating or drinking food
or water containing specific levels of the chemical. 3,3'-DCB has a
mild odor, but no information was found about levels at which the
chemical is first smelled.
The relationship between oral exposure to 3,3'-DCB and known health
effects in animals is shown in Table 1-4. No information was found on
health effects in animals from breathing 3,3'-DCB for brief or long-term
exposure periods (Table 1-2).
1.7 WHAT RECOMMENDATION HAS THE FEDERAL GOVERNMENT MADE TO PROTECT
HUMAN HEALTH?
The U.S. Environmental Protection Agency (EPA) considers 3,3'-DCB
to be a probable human carcinogen, and has placed several limits on the
chemical in the environment in order to protect human health. Under the
Clean Water Act (1977), EPA controls discharges of 3,3'-DCB to
industrial wastewaters. The agency has listed 3,3*-DCB as a hazardous
waste and requires that any spill of one pound or more be reported to
the National Response Center.
The Food and Drug Administration (FDA) has classified 3,3'-DCB as a
cancer causing substance (carcinogen). Federal law does not allow the
use of any substance in food, food additives, coloring or drugs which
has been found by appropriate test to cause cancer.
The Occupational Safety and Health Administration (OSHA) classifies
3,3'-DCB as a cancer-suspect agent and controls 3,3'-DCB at the
workplace by making strict requirements to reduce 3,3'-DCB
concentrations in workplace air and protect the health of workers.
These include personal protective equipment, training, labeling, and
posting and engineering controls. OSHA also requires that initial
medical screening and regular medical examinations be made available to
any employee who is exposed to 3,3'-DCB at potentially hazardous levels.
The National Institute of Occupational Safety and Health (NIOSH)
considers 3,3'-DCB a suspect human carcinogen and recommends workplace
practices and controls to reduce exposures to the lowest possible limit.
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1. PUBLIC HEALTH STATEMENT
TABLE 1-1. Human Health Effects from Breathing 3,3'-DCB*
Short-term Exposure
(less than or equal to 14 days)
Levels in
Duration of
Air (dditO
Exposure Description of Effects
The health effects resulting from
short-term exposure of humans to
air containing specific levels
of 3,3'-DCB are not known.
Long-term Exposure
(greater than 14 days)
Levels in
Duration of
Air (ppm-)
Exposure Description of Effects
The health effects resulting from
long-term exposure of humans to
air containing specific levels
of 3,3'-DCB are not known.
*See Section 1.2 for a discussion of exposures encountered in daily life.
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1. PUBLIC HEALTH STATEMENT
TABLE 1-2.
Animal Health Effects from Breathing 3,3*-DCB
Short-term Exposure
(less than or equal to 14 days)
Levels in
Duration of
Air (ppm^
ExDosure Description of Effects
The health effects resulting from
short-term exposure of animals
to air containing specific
levels of 3,3'-DCB are not known.
Long-term Exposure
(greater than 14 days)
Levels in
Duration of
Air (Dpml
Exposure Description of Effects
The health effects resulting from
long-term exposure of animals to
air containing specific levels
of 3,3'-DCB are not known.
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1. PUBLIC HEALTH STATEMENT
TABLE 1-3. Human Health Effects from Eating or Drinking 3,3'-DCB*
Short-term Exposure
(less than or equal to 14 days)
Levels in
Food (ppm1)
Duration of
Exposure Description of Effects
Levels in
Water (ddiiO
The health effects resulting from
short-term exposure of humans to
food containing specific levels
of 3,3'-DCB are not known.
The health effects resulting from
short-term exposure of humans to
water containing specific levels
of 3,3'-DCB are not known.
Long-term Exposure
(greater than 14 days)
Levels in
Food fppm)
Duration of
Exposure Description of Effects
Levels in
Water (DDnO
The health effects resulting from
long-term exposure of humans to
food containing specific levels
of 3,3'-DCB are not known.
The health effects resulting from
long-term exposure of humans to
water containing specific levels
of 3,3*-DCB are not known.
*See Section 1.2 for a discussion of exposures encountered in daily life.
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1. PUBLIC HEALTH STATEMENT
TABLE 1-4. Animal Health Effects from Eating or Drinking 3,3'-DCB
Short-term Exposure
(less than or equal to 14 days)
Levels in
Food Cpcm")
Duration of
ExDosure
Descriotion of Effects*
76,000
Not Reported
Death in about half the exposed
rats.
Levels in
Water Cdditi')
The health effects resulting from
short-term exposure of animals
to water containing specific
levels of 3,3'-DCB are not known.
Long-term Exposure
(greater than 14 days)
Levels in
Food (ppm)
Duration of
Exposure
Descriotion of Effects*
320
Levels in
Water fppnt)
3.5 yr
Liver injury and convulsions
in dogs.
The health effects resulting from
long-term exposure of animals to
water containing specific levels
of 3,3'-DCB are not known.
*These effects are listed at the lowest level at which they were first
observed. They may also be seen at higher levels.
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1. PUBLIC HEALTH STATEMENT
1.8 WHERE CAN I GET MORE INFORMATION?
If you have further questions or concerns, please contact your
State Health or Environmental Department or:
Agency for Toxic Substances and Disease Registry
Division of Toxicology
1600 Clifton Road, E-29
Atlanta, Georgia 30333
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2. HEALTH EFFECTS
2.1 INTRODUCTION
This chapter contains descriptions and evaluations of studies and
interpretation of data on the health effects associated with exposure to
3,3'-DCB. Its purpose is to present levels of significant exposure for
3,3'-DCB based on toxicological studies, epidemiological investigations,
and environmental exposure data. This information is presented to
provide public health officials, physicians, toxicologists, and other
interested individuals and groups with (1) an overall perspective of the
toxicology of 3,3'-DCB and (2) a depiction of significant exposure
levels associated with various adverse health effects.
2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE
To help public health professionals address the needs of persons
living or working near hazardous waste sites, the data in this section
are organized first by route of exposure--inhalation, oral, and dermal--
and then by health effect--death, systemic, immunological, neurological,
developmental, reproductive, genotoxic, and carcinogenic effects. These
data are discussed in terms of three exposure periods--acute,
intermediate, and chronic.
Levels of significant exposure for each exposure route and duration
(for which data exist) are presented in tables and illustrated in
figures. The points in the figures showing no-observed-adverse-effect
levels (NOAELs) or lowest-observed-adverse-effect levels (LOAELs)
reflect the actual doses (levels of exposure) used in the studies.
LOAELs have been classified into "less serious" or "serious" effects.
These distinctions are intended to help the users of the document
identify the levels of exposure at which adverse health effects start to
appear, determine whether or not the intensity of the effects varies
with dose and/or duration, and place into perspective the possible
significance of these effects to human health.
The significance of the exposure levels shown on the tables and
graphs may differ depending on the user's perspective. For example,
physicians concerned with the interpretation of clinical findings in
exposed persons or with the identification of persons with the potential
to develop such disease may be interested in levels of exposure
associated with "serious effects". Public health officials and project
managers concerned with response actions at Superfund sites may want
information on levels of exposure associated with more subtle effects in
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2. HEALTH EFFECTS
humans or animals (LOAEL) or exposure levels below which no adverse
effects (NOAEL) have been observed. Estimates of levels posing minimal
risk to humans (Minimal Risk Levels, MRLs) are of interest to health
professionals and citizens alike.
For certain chemicals, levels of exposure associated with
carcinogenic effects may be indicated in the figures. These levels
reflect the actual doses associated with the tumor incidences reported
in the studies cited. Because cancer effects could occur at lower
exposure levels, the figures also show estimated excess risks, ranging
from a risk of one in 10,000 to one in 10,000,000 (10"* to 10"7) , as
developed by EPA.
Estimates of exposure levels posing minimal risk to humans (MRLs)
have been made, where data were believed reliable, for the most
sensitive noncancer end point for each exposure duration. MRLs include
adjustments to reflect human variability and, where appropriate, the
uncertainty of extrapolating from laboratory animal data to humans.
Although methods have been established to derive these levels (Barnes
et al. 1987; EPA 1980a), uncertainties are associated with the
techniques.
2.2.1 Inhalation Exposure
3,3'-DCB is not a volatile chemical. It exists in air attached to
dust particles or bound to particulate matter. The absorption of 3 3'-
DCB from such respirable particles depends in part on the size of the
particle. Large particles tend to deposit in the upper airways and are
subsequently cleared by ciliary action with little absorption across
lung tissues. Smaller particles can penetrate more deeply into the
respiratory tree where 3,3'-DCB absorption may be significant.
2.2.1.1 Death
No studies were located regarding lethal effects in humans or
animals after inhalation exposure to 3,3'-DCB. No fatalities were
observed in rats observed for 14 days following exposure for one hour to
an atmosphere containing an unspecified concentration of DCB
dihydrochloride dust (Gerade and Gerade 1974).
2.2.1.2 Systemic Effects
Respiratory. Gerarde and Gerarde (1974) listed upper respiratory
infection and sore throat among several principal reasons for frequent
visits to a company's medical clinic by workers handling 3,3'-DCB
dihydrochloride. It is possible that these effects were due to
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2. HEALTH EFFECTS
Inhalation of 3,3'-DCB dihydrochlorlde salt although the results are not
conclusive. No adverse health effects were observed in the respiratory
system in rats exposed by inhalation to DCB free base (25 mg/m3) two
hours per day for seven days (Gerarde and Gerarde 1974). In another
study, ten rats were exposed to an unspecified dose of DCB
dihydrochlorlde dust particles for one hour and then observed for
14 days. Slight to moderate pulmonary congestion and one pulmonary
abscess were observed upon autopsy (Gerarde and Gerarde 1974). Irritant
effects of HC1 from the chemical could have contributed to the observed
effects in this study.
Gastrointestinal. Gastrointestinal upset was one of the frequent
symptoms reported by employees who worked with DCB dihydrochloride
(Gerarde and Gerarde 1974). There is no conclusive evidence that the
gastrointestinal effects, or other symptoms reported by employees,
resulted from inhalation of 3,3'-DCB dihydrochloride salt. No studies
were located regarding gastrointestinal effects in animals following
inhalation exposure to 3,3'-DCB.
Other Systemic Effects. No studies were located regarding
cardiovascular, musculoskeletal, hepatic, renal or dermal/ocular effects
in humans or animals after inhalation exposure to 3,3'-DCB.
No studies were located regarding the following effects in humans
or animals after inhalation exposure to 3,3'-DCB.
2.2.1.3
Immunological Effects
2.2.1.4
Neurological Effects
2.2.1.5
Developmental Effects
2.2.1.6
Reproductive Effects
2.2.1.7
Genetic Effects
2.2.1.8 Cancer
2.2.2 Oral Exposure
Indirect gastrointestinal tract exposure may occur from breathing
contaminated airborne dust in the workplace. The deposition pattern of
inhaled 3,3'-DCB would depend primarily on the mass median aerodynamic
diameter (MMAD) of the particles. The mucociliary clearance mechanism
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2. HEALTH EFFECTS
moves most particulates with a MMAD of 1 to 5 flm out of the lungs and
into the gastrointestinal tract. Larger particles (> 5/im) impacting in
the nasopharyngeal region would also be eventually ingested. Oral
exposure may potentially occur in the general environment by drinking
contaminated groundwater, Occupational exposure by oral route is not
expected to be significant. Exposure through eating food is unlikely
since 3,3'-DCB has never had an application as an agricultural or food
chemical. However, fish have been reported to bioconcentrate 3,3'-DCB
(Appleton and Sikka 1980) under experimental conditions, raising the
potential for bioaccumulation and human exposure. Individuals, such as
children, consuming contaminated soil are at risk. All of the available
data on the effects of 3,3'-DCB following oral exposure are derived from
studies in experimental animals, Table 2-1 and Figure 2-1 summarize
available data.
2.2.2.1 Death
No studies were located regarding lethal effects in humans after
oral exposure to 3,3'-DCB. The acute oral LD50 of DCB in rats has been
estimated to be 7,100 mg/kg for the free base and 3,800 mg/kg for the
dihydrochloride salt (Gerarde and Gerarde 1974). Given this high LD
acute lethality in man following oral exposure is very unlikely. The
dose of 3,800 mg/kg/day has been converted to an equivalent
concentration (76,000 ppm) in food for presentation in Table 1-4.
2.2.2.2 Systemic Effects
Respiratory Effects. No studies were located regarding respiratory
effects in humans or animals after oral exposure to 3,3'-DCB,
Hepatic Effects. No studies were located regarding hepatic effects
in humans following oral exposure to 3,3'-DCB. Limited animal evidence
suggests that chronic oral exposure to 3,3'-DCB results in mild to
moderate liver injury. Six female dogs exposed to 3,3'-DCB
(-8 mg/kg/day) all had modestly elevated plasma glutamic-pyruvic
transaminase (GPT) during the first three years of a seven-year
treatment period (Stula et al. 1978). Thereafter, GPT levels returned
to normal in three of the experimental animals, but remained elevated in
two of the animals for the duration of the study. The significance of
this effect is unclear in the absence of pronounced histopathologic
effects. Further, enzyme levels may be altered by other conditions.
One of six dogs, sacrificed after 42 months on the test, showed a marked
fatty change in the liver. It should be noted that the study is limited
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13
2. HEALTH EFFECTS
TABLE 2-1. Levels of Significant Exposure to 3,3'-DCB - Oral Exposure
Graph
Key
Species
Route
Exposure
Duration/ Syst.
Frequency Effect
LOAEL (Effect 1
NOAEL Lass Serious Serious
(mg/kg/day) (mg/kg/day) (mg/kg/day)
Reference
ACUTE EXPOSURE
Lethality
1 rat (G) NR
Systemic
2
mouse (G) 1 dose
CHRONIC EXPOSURE
Systemic
U dog
3800 (LD50)
7100 (LD50)
(G) 1 dose Hepatic
Hematol
500 (UDS)
1000 (micronuclei
formation)
(C) 3.5-7 yr Hematol
3-5x/wk
Gerarde and
Gerarde 1974
Ashby and
Mohanmed 1988
Cihak and
Vontorvoka 1987
Stula et al.
1978
5 dog
Neurological
6 dog
Carcinogenic
7 rat
8
dog
-------
(mg/kg/d)
10,000 -
1,000 -
100 -
10 -
1.0 -
0.1 -
0.01 -
ACUTE CHRONIC
(<14 Days) (> 365 Pays)
___ Key
' rat ¦ LD5,
m mouse 9 LOAEL kx serious effects (animals)
d dog 3 LOAEL tor less serious effects (animats)
O NOAEL (animals)
~ CEL - Cancer Effect level
The number next to each point corresponds to entnes m the accompanying table
FIGURE 2-1. Levels of Significant Exposure to 3,3' DCB - Oral Exposure
-------
15
2. HEALTH EFFECTS
by the use of one dose level, precluding dose-response evaluations, and
the male dog was not evaluated. It is uncertain if these effects will
also occur in humans orally exposed to 3,3'-DCB. The dose of
8 mg/kg/day has been converted to an equivalent concentration (320 ppm)
in food for presentation in Table 1-4.
Hematological Effects. No studies were located regarding
hematological effects in humans after oral exposure to 3,3'-DCB.
Hematological variables (erythrocyte count, hemoglobin concentration,
hematocrit and leucocyte count) were found to be normal in dogs exposed
to 3,3'-DCB for seven years (Stula et al. 1978). Hematological effects
may not be sensitive indicators for 3,3'-DCB toxicity.
Other Systemic Effects. No studies were located regarding
cardiovascular, gastrointestinal, musculoskeletal, renal or
dermal/ocular effects in humans or animals after oral exposure to
3,3'-DCB.
2.2.2.3 Immunological Effects
No studies were located regarding immunological effects in humans
or animals after oral exposure to 3,3'-DCB.
2.2.2.4 Neurological Effects
No studies were located regarding neurological effects in humans
after oral exposure to 3,3'-DCB.
Stula et al. (1978) reported that one out of the six dogs in a
3,3'-DCB carcinogenicity study exhibited convulsions after 21, 28, and
42 months of treatment with 8 mg/kg/day (320 ppm) over a period of
3.5 years (total 3,3'-DCB intake - 86 g). On autopsy at 42 months,
slight neuronal degeneration was observed. In view of the fact that
only one dog developed the lesion, causality cannot be inferred.
2.2.2.5 Developmental Effects
No studies were located regarding developmental effects in humans
or animals after oral exposure to 3,3'-DCB.
2.2.2.6 Reproductive Effects
No studies were located regarding reproductive effects in humans or
animals after oral exposure to 3,3'-DCB.
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16
2. HEALTH EFFECTS
2.2.2.7 Genetic Effects
No studies were located regarding genetic effects in humans after
oral exposure to 3,3'-DCB; however, genotoxicity effects have been
reported in animals. Cihak and Vontorvoka (1987) reported that a single
dose of 3,3'-DCB (1000 mg/kg) administered to male and pregnant female
mice induced micronuclei in polychromatic erythrocytes in the bone
marrow of the males, in the liver of the fetuses, but not in bone marrow
of the dams. A micronucleus test is performed to detect a chemical's
ability to induce chromosomal aberrations. However, the relevance of
micronuclei formation to human health is not known. The lack of effect
of 3,3'-DCB on bone marrow micronuclei formation in the mothers is
unclear but may be related to deficiencies in the metabolic activation
of 3,3'-DCB peculiar to the pregnant state. The relative importance of
this differential effect is reduced since the study did not evaluate
nonpregnant females. In another study, Ashby and Mohammed (1988)
reported an increase in unscheduled DNA synthesis (UDS) in cultured
liver cells from male mice previously pretreated orally with single
doses of 3,3'-DCB of 500 mg/kg or higher; no response was observed at a
dose of 200 mg/kg or lower. The unscheduled DNA synthesis assay is used
to measure the repair that follows DNA damage. However, the relevance
of UDS to human health is not known. While results were positive in two
in vivo assay systems, sufficient data are not available from more
predictive indicator assays to adequately characterize the genotoxic
potential for 3,3'-DCB in humans.
2.2.2.8 Cancer
There are no epidemiological studies linking cancer in humans to
oral exposure to 3,3'-DCB. However, based on the findings of oral
studies in animals 3,3'-DCB may be regarded as a probable carcinogen in
humans. Stula et al. (1975) fed 50 male and 50 female ChRCD rats
1,000 ppm 3,3'-DCB in a standard diet for up to 16 months. Mammary
adenocarcinoma (16% incidence), malignant lymphoma (14%), granulocytic
leukemia (20%), carcinoma of the Zymbal gland (18%) in males, and
mammary adenocarcinoma (59%) in females were observed in rats fed
3,3'-DCB in the diet (1,000 ppm or 50 mg/kg/day) for a total duration of
349 (females) to 353 (males) days, respectively (Stula et al. 1975).
These tumors were either totally absent or occurred statistically less
frequently in untreated controls (Stula et al. 1975). Both sexes were
dosed orally and comprehensive histopathological evaluations were
-------
17
2. HEALTH EFFECTS
performed. While only one dose level was used and the purity of the
compound was not specified, these data are qualitatively significant.
In female dogs fed approximately 8 mg/kg/day (320 ppm) orally in gelatin
capsules over a period of 6.6 to 7.1 years (total 3,3'-DCB intake - 164
to 176 g), hepatocellular carcinomas and papillary transitional cell
carcinomas of the urinary bladder were observed (Stula et al. 1978).
These tumors were absent in untreated controls. It should be noted that
a small number of dogs (6) were evaluated and only one sex and one dose
were used. However, a sufficient number of animals survived to develop
tumors. The results are qualitatively significant. Existing animal
data show that 3,3'-DCB produces tumors in multiple organs in several
animal species. Although these data were derived from studies judged to
be limited in scope, they do suggest that 3,3'-DCB is a probable human
carcinogen. The doses observed to cause cancer in experimental animals
are presented in Table 2-1.
2.2.3 Dermal Exposure
Because of large particle size and increased usage of closed
systems and protective clothing, dermal absorption may be expected to be
minimal with the possible exception of conditions of high humidity and
high temperature. Extremely limited data (1 rabbit, 1 exposure) were
found regarding the effects of dermal exposure to 3,3'-DCB (Table 2-2
and Figure 2-2).
2.2.3.1 Death
No studies were located regarding lethal effects in humans after
dermal exposure to 3,3'-DCB. The dermal LD50 for DCB (free base) for
male and female New Zealand albino rats was reported to be greater than
8 g/kg bw (Gerarde and Gerarde 1974). The cause of death was not
reported and the dose causing the effect was similar by a different
route. Dermal exposure is not likely to cause death in humans.
2.2.3.2 Systemic Effects
Respiratory Effects. As mentioned in Section 2.2.1.2 on
"Respiratory Effects of Inhalation Exposure to 3,3'-DCB", upper
respiratory infection and sore throat were among the principal reasons
for frequent visits to a company's medical clinic by workers who handled
3,3'-DCB (Gerarde and Gerarde 1974). No studies were located regarding
respiratory effects in animals after dermal exposure to 3,3'-DCB.
-------
18
2. HEALTH EFFECTS
TABLE 2-2. Levels of Significant Exposure to 3,3'-DCB - Dermal
Exposure
Graph Duration/ Syat. ______
Key Species Frequency Effect NOAEL Less Serious Serious
(mg/kg/day) (mg/kg/day)
LQAEL (Effect)
Reference
ACUTE EXPOSURE
1 rabbit
1 hr
OC
5 (Corneal Gerarde and
opacity, Gerard* 1974
Irritation)
Syst - systemic* LOAEL « lovast-obsarved-adverse-effect levelj NOAEL - no-observed-adverse-effect levelj
hr * hour; oc ¦ ocular.
-------
ACUTE
(<14 Days)
(mg/kgAJay) &
10,000,-
1,000
100
10
1.0
h rabbit
LOA£L for serious effects (animals)
The number next to each point corresponds to entries in the
accompanying table.
FIGURE 2-2. Levels of Significant Exposure to 3,3'-DCB - Dermal Exposure
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20
2. HEALTH EFFECTS
Dermal/Ocular Effects. Dermatitis was cited as the only verified
health problem encountered by workers in contact with the free base of
3,3'-DCB in a DCB manufacturing plant (Gerarde and Gerarde 1974). There
was no discernable skin irritation when 3,3'-DCB dihydrochloride (at an
unstipulated dose) was applied to the intact and abraded skin of rabbits
(Gerarde and Gerarde 1974). Similarly, an aqueous suspension of DCB
instilled intradermally into rats at a dose of 700 rag/kg did not produce
adverse effects (Gerarde and Gerarde 1974). It is possible that
solubility limitations contributed to the failure of DCB to cause skin
irritation in the experimental animals examined. Alternatively, the
duration of observation may not have been of sufficient length. The
study did not specify the length of the observation periods. If,
however, DCB indeed causes no skin irritation in experimental animals,
dermatitis may be an effect of the chemical that is peculiar to humans.
No effects were reported in rabbits when 100 mg of DCB (free base)
was placed in the conjunctival sac of the eye (Cerarde and Gerarde
1974) . It should be noted that the authors did not report the duration
of exposure or the vehicle used. However, 20 mg of DCB dihydrochloride
(as 0.1 mL of 20% corn oil suspension) produced erythema, pus and
corneal opacity, giving a 76% score in the Draize test within an hour
when placed in the conjunctival sac of the eye of the rabbit (Gerarde
and Gerarde 1974).
Other Systemic Effects. No studies were located regarding
cardiovascular, gastrointestinal, hematological, musculoskeletal,
hepatic or renal effects in either humans or animals after dermal
exposure to 3,3'-DCB.
No studies were located regarding the following effects in humans
or animals after dermal exposure to 3,3'-DCB.
2.2.3.3
Immunological Effects
2.2.3.4
Neurological Effects
2.2.3.5
Developmental Effects
2.2.3.6
Reproductive Effects
2.2.3.7
Genetic Effects
2.2.3.8
Cancer
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21
2. HEALTH EFFECTS
2.3 RELEVANCE TO PUBLIC HEALTH
Existing data are considered inadequate to derive human Minimal
Risk Levels.
Systemic Effects. Dermatitis appears to be the only effect of
3,3'-DCB (free base) exposure for which evidence exists. However, a
dose-response relationship can not be determined from available
information. Gastrointestinal upset and upper respiratory tract
infections have also been reported by workers, but 3,3'-DCB exposure
conditions are unavailable. 3,3'-DCB has not been found to cause any of
these effects in experimental animals. The extent to which these, or
other effects of 3,3'-DCB exposure may occur predominantly in man is
unknown.
Hepatic. No studies were located regarding hepatic effects in
humans after exposure to 3,3'-DCB. Evidence suggestive of mild liver
injury has been reported in one chronic animal experiment. Stula et al.
(1978) reported that during a carcinogenicity study using six beagle
dogs, all of the animals showed modest elevation in serum transaminase
activity within one year of initiation of a regimen of oral DCB (total
dose, 24.8 g). On continuation of the DCB regimen (500 mg/week), the
serum transaminase levels returned to normal in three dogs. One dog,
sacrificed in extremis after 42 months of 3,3'-DCB exposure was found to
have a fatty liver. The interpretation of these data is complicated by
the fact that on eventual sacrifice, all of the surviving DCB treated
animals showed evidence of hepatocellular carcinoma, hepatic metastases
or other focal cell alterations. It is thus possible that the modest
elevations of serum transaminase activity reflects hyperplastic events
rather than hepatic necrosis or other frank cellular injury. Further,
since only one dose level was used in the study, dose response
relationships were not established. Collectively, while the data is
suggestive of mild hepatotoxicity, its significance for human toxicity
is not clear.
Iba and colleagues (Iba 1987b; Iba and Lang 1988; Iba and Thomas
1988) administered 3,3'-DCB to rats (20 mg/kg i.p.) and observed a
decrease in hepatic vitamin E levels in vivo, and an increase in lipid
peroxidative activity in In vitro assays using hepatic microsomes
isolated from DCB-treated rats. However, since the histology of the
liver and other indices of hepatotoxicity were not examined, no
conclusions can be drawn from these mechanistic studies as to the
capacity of 3,3'-DCB to cause frank hepatocellular injury in rats.
-------
22
2. HEALTH EFFECTS
Developmental Effects. No studies were located regarding
developmental effects of 3,3'-DCB in humans following brief or long-term
exposure. Abnormal growth was observed in kidneys explanted from
fetuses of pregnant mice treated sc daily during the last week of
pregnancy at an average daily dose of 257 mg/kg. This abnormal growth
was not observed in vehicle-treated controls (Shabad et al. 1972). It
should be noted that the authors did not provide data on maternal
effects; therefore, these findings should be interpreted with caution.
Similarly, in subcutaneous injection studies in BALB/C-mice,
hyperplastic foci and hyperchromic glomeruli were observed in kidneys of
offspring of dams administered 2 mg 3,3'-DCB throughout gestation.
(Golub 1970). No data were reported on maternal effects. These
observations suggest a potential for the chemical to act as a
developmental toxicant in experimental animals.
Genotoxic Effects. Studies in several test systems show 3,3'-DCB
to be genotoxic in vitro and in vivo (Tables 2-3 and 2-4) and suggest
that this effect most likely mediates the carcinogenicity of the
chemical. In vivo, micronuclei were induced in polychromatic
erythrocytes of the liver of fetal mice exposed transplacentally to the
chemical, and in liver cells of adult male mice treated orally with the
chemical at a maximum tolerated dose reported to be 1000 mg/kg (Cihak
and Vontorvoka 1987). A sex difference in the genotoxicity of the
chemical is suggested as adult male mice, but not pregnant females
developed erythrocyte micronuclei following 3,3'-DCB exposure. However,
whether this differential effect extends to carcinogenic effects is
unclear. Positive chromatid exchange findings in an in vitro test
system provide supportive evidence for 3,3'-DCB-induced cytogenetic
changes. Shiraishi (1986) reported 3,3'-DCB induced sister chromatid
exchanges (SCEs) in all types of Bloom Syndrome (BS) B-lymphoblastoid
cell lines. The induction of SCE was variable among the three types.
Exposure of BS type II and type III cells to 3,3'-DCB (1.7 x 10® to 1.3
x 10"3) caused an increase in SCEs (120 - 140/cell) over baseline levels
(70/cell) at the highest concentration (1.3 x 10"3). BS type II cells
required metabolic activation, while BS type III cells were sensitive
with and without activation. The frequency of SCEs in BS type I cells
was lower than in II and III.
The genotoxic effect of 3,3'-DCB is further supported by positive
responses in bacterial assays employing Salmonella tester strains TA1538
and TA98 In the absence of liver activating systems (Garner et al. 1975;
Iba 1987a; Iba and Thomas 1988; Lang and Iba 1987; Lazear et al. 1979;
Savard and Josephy 1986). This direct mutagenicity may be due to the
metabolic activation of the chemical by enzymes endogenous to the
-------
TABLE 2-3. Genotoxicity of 3,3'-DCB In Vitro
Results
Actlvation
Without
With
End Point
Test System
System
Activation
Activation
Reference
Gene mutation
Salmonella tYDhimurium
Rat S-9
+
+
Garner et al.
1975
Lazear et al.
1979
Savard and
Josephy 1986
Iba 1987a
Lang and Iba
1987
Unscheduled DNA synthesis
HELA cells
Rat S-9
-
+
Martin et al.
1978
Cell transformation
rat embryo cells
-
+
NA
Freeman et al
. 1973
Cell transformation
hamster kidney cells
Rat S-9
+
-
Styles 1978
Sister chromatid exchange
Lymphoblastoid cells
Rat S-9
-
+
Shiraishl 1986
-I- » positive result; - =* negative result; HA «* not available.
W
•n
m
o
H
CO
-------
TABLE 2-4. Genotoxiclty of 3,3'-DCB In Vivo
End Point Species Results Reference
Mlcronucleus test alee + Clhak and Vontorvoka 1987
Unscheduled DKA synthesis rat + Ashby and Mohamned 1988
+ » positive result.
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25
2. HEALTH EFFECTS
bacteria (Lang and Iba 1987), or the chemical may be a direct acting
genotoxic agent. The bacterial mutagenicity is highly enhanced in the
presence of liver activating systems indicating the importance of
metabolism in the genotoxicity of the chemical.
Based on mutagenicity findings, 3,3'-DCB is an effective inducer of
its own activation (Iba 1987a). The enhancing effect of 3,3'-DCB
pretreatment on the in vitro liver activation of the chemical to
mutagens has been associated with the induction of cytochrome P-450d
(Iba and Thomas 1988). This action may result in the chemical enhancing
its own genotoxicity and carcinogenicity. Iba and Sikka (1982) reported
that 3,3'-DCB is a potent inducer of hepatic microsomal enzymic
activities mediated by cytochrome-P-448. The authors noted that some of
the toxic properties as well as the carcinogenicity of compounds such as
the polycyclic aromatic hydrocarbons and the polyhalogenated aromatics
may be related to their ability to induce cytochrome P-448 mediated
monooxygenase activities. They therefore concluded that hepatocarcino-
genicity of 3,3'-DCB may thus be due, at least in part, to the induction
of hepatic cytochrome P-448.
Results of in vivo tests show 3,3'-DCB induced dose-dependent
unscheduled DNA synthesis in the liver of male rats treated orally
(Ashby and Mohammed 1988). In vitro evidence for the genotoxicity of
3,3'-DCB include the induction of unscheduled DNA synthesis in HeLa
cells at a concentration range of 10"7 to 10"4M (Martin et al. 1978), and
transformation of high passage rat embryo cells infected with the
Rauscher leukemia virus (Freeman et al. 1973). In the latter system, an
effect was observed at 2xlO~7M 3,3'-DCB but not at 4xlO"aM. Also,
3,3'-DCB transformed BHK21 cells (hamster kidney cells) in vitro in the
presence of metabolic activation (Styles 1978).
3,3'-DCB formed adducts with calf thymus DNA when incubated with
rat liver S9 (Bratcher and Sikka 1982), or horseradish peroxidase
(Tsuruta et al. 1985) in vitro. The relevance of DNA adduct formation
to the genotoxicity and carcinogenicity of the chemical is not yet
established.
Overall, there is convincing evidence that 3,3'-DCB is genotoxic in
animals. Results were positive in two in vivo (UDS, and micronucleus
formation) test systems. Supporting evidence was provided by one
bacterial assay ('Salmonella'). However, these in vivo and in vitro tests
are usually of limited predictive value in man. Therefore, the
genotoxicity potential of 3,3'-DCB in man, although a possibility,
remains uncertain.
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26
2. HEALTH EFFECTS
Cancer. 3,3'-DCB may cause tumors in multiple organs tri man as
suggested by findings in experimental animals. Epidemiological studies
of potential effects of occupational exposure to 3,3'-DCB have paid
particular attention to bladder tumors. To date, none of these studies
have found either bladder tumors or excess tumors at other sites that
are clearly attributable to exposure to 3,3'-DCB. Despite concerns of
the chemical's ability to induce bladder tumors, this form of cancer has
not been satisfactorily investigated in occupationally exposed workers
It has been speculated (IARC 1982a) that 3,3'-DCB may have
contributed to the incidence of bladder cancer attributed to benzidine
in dye industry workers who handled both benzidine and 3,3'-DCB (Gadian
1975), However, no bladder tumors were produced in another group of
workers who handled 3,3'-DCB exclusively within the same plant (Gadian
1975). The author reported a total exposure time of 68,505 hours
equivalent to nearly 140 full-time working years.
Cystodiagnostic tests produced no indication of tumors of the
bladder in an epidemiological study of 225 workers who had been exposed
for a total of less than 16 years to 3,3'-DCB (Maclntyre 1975).
In a retrospective epidemiological study, no bladder tumors were
observed in a cohort of 207 workers, most of whom had been exposed to
3,3'-DCB for up to 15 years (Gerarde and Gerarde 1974).
It should be pointed out that observations in two of the three
studies were made in workers who were exposed to 3,3'-DCB for less than
20 years. Since the average latency period for chemically induced
bladder cancer in man is 18 years, an adequate latency period for
3,3'-DCB-induced tumors may not have elapsed. Also, the number of
workers examined in the above three studies was relatively small thus
limiting the statistical power to detect significant (two-fold) increase
in bladder cancer mortality (incidence).
3,3'-DCB has been found to cause neoplasia in a variety of target
organs in several animal species. The chemical produces hepatocellular
carcinomas and urinary bladder carcinomas in dogs and hamsters. Liver
cell tumors were demonstrated in 3,3'-DCB exposed mice. In rats,
mammary gland tumors, Zymbal gland tumors and leukemias were
attributable to 3,3*-DCB exposure. (Pliss 1963; Stula et al. 1975,
1978), While concordance between tumor sites in experimental animals
and man cannot be assumed, the occurrence of multiple target organs in
experimental animals should be regarded as evidence for the potential
carcinogenicity of 3,3'-DCB to man.
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27
2. HEALTH EFFECTS
In subcutaneous injection studies, induction of tumors in progeny
of BALB/C-mice administered 2 mg 3,3'-DCB during the last week of
pregnancy suggest that the chemical may be a transplacental carcinogen
(Golub et al. 1975). There was an increased incidence of lymphatic
leukemias (7/24 or 29%), lung adenomas (5/24 or 20%) and adenocarcinomas
of the mammary gland (4/24 or 17%) in the treated group. Lung tumors
(3/30 or 10%) and mammary gland tumors (3/30 or 10%) were observed in
untreated controls.
The route of 3,3'-DCB exposure may be important in the
carcinogenicity of the chemical as suggested by the results of animal
studies. Following subcutaneous administration in rats, the compound
was found to cause tumors of the skin and intestines. These sites were
in addition to tumors of the mammary gland, hematopoietic organs and
Zymbal gland which predominate following oral exposure (Pliss 1963).
The results of industrial plant surveys suggest that the dermal
route is a minor source for exposure to 3,3'-DCB. Studies have not been
located which investigate the carcinogenic potential of 3,3'-DCB
following dermal exposure in laboratory animals.
Overall, there is convincing evidence that 3,3'-DCB is genotoxic
and carcinogenic in animals of various species and both sexes. One
cancer study of dogs which evaluated one sex and used one dose level,
precluding dose-response evaluation, shows a sufficient number of
animals survived to develop tumors.
2.4 LEVELS IN HUMAN TISSUES AND FLUIDS ASSOCIATED WITH HEALTH EFFECTS
No studies were located regarding levels of 3,3'-DCB in human
tissues and fluids associated with health effects.
Urinary excretion of 3,3'-DCB and/or metabolites may not persist in
man over long periods after initial exposure to the parent compound.
Monitoring of urine for 3,3'-DCB and/or metabolites would be useful only
if 3,3'-DCB exposure was continuous or, in the case of acute or
intermittent exposure, if monitoring was done very early after exposure.
Urinary cystology has been recommended by OSHA as a routine test
for 3,3'-DCB exposed workers for the early detection of incipient
bladder damage and/or cancer. However, Stula et al. (1978) in his
carcinogenicity study of 3,3'-DCB in dogs, reported that results from
the annual cystological examination of urine sediment did not provide
evidence of genitourinary tract neoplasia even though the bladder cancer
-------
28
2. HEALTH EFFECTS
incidence in the dogs surviving until termination of the study was 100%
These findings raise the consideration that urinary cystological
examinations alone may not be adequate to detect incipient danger in
3,3'-DCB exposed workers. Since 3,3'-DCB may cause lesions in systems
other than the bladder, reliance solely on indices of genitourinary
disturbances could be misleading.
2.5 LEVELS IN THE ENVIRONMENT ASSOCIATED WITH LEVELS IN HUMAN
TISSUES AND/OR HEALTH EFFECTS
There are no reports directly linking any level of 3,3'-DCB in the
environment with a biological effect. However, there appears to be a
positive correlation between detectable levels of the chemical in
occupational air and its presence in urine, as suggested by the finding
in epidemiological studies (Cherniack and Lewis 1984; Handke et al.
1986; London and Boiano 1986; Meigs et al. 1954), Existing data
indicate that urinary levels of 3,3'-DCB and/or its metabolites are an
indicator of human exposure to 3,3'-DCB. For example, in a survey of a
3,3'-DCB-handling plant, 3,3'-DCB was found in the urine of workers only
when their personal breathing-zone air concentrations contained
detectable levels of the chemical (London and Boiano 1986).
Insufficient information is available to assess the quantitative aspects
of the relationship.
2.6 TOXICOKINETICS
Very limited studies exist on the toxicokinetics of 3,3'-DCB in
humans. Most data focus on the urinary elimination of the chemical
following occupational exposure. Evidence from animal studies suggest
that 3,3'-DCB is rapidly absorbed from the gastrointestinal tract.
Animals administered a single oral dose of UC-labelled 3,3'-DCB showed
highest concentrations of radioactivity in the liver, kidney, lung,
spleen, heart, pancreas and testes. In rats, the major route of
elimination of 3,3'-DCB is by metabolism. N-acetyl metabolites (N-
acetyl- 3,3'-DCB and N, N'-diacetyl- 3,3'-DCB) have been detected in
urine of rats. N-acetyl metabolites are formed in vivo under the action
of hepatic N-acetyltransferase(s). In man, some isozyme(s) of N-
acetyltransferase show marked polymorphic differences; it is thus
possible that the proportion of the dose of 3,3'-DCB converted to its N-
acetyl metabolites in man may vary widely between individuals. The '
metabolites undergo rapid excretion primarily into feces and to a lesser
extent in urine. Unchanged 3,3'-DCB occurs as a minor urinary excretion
product.
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29
2. HEALTH EFFECTS
2.6.1 Absorption
2.6.1.1 Inhalation Exposure
3,3'-DCB has been detected In the urine of workers in 3,3'-DCB-
handling plants under conditions which favored inhalation of 3,3'-DCB
bound particulate (Meigs et al. 1954; Handke et al. 1986; London and
Boiano 1986). However, conditions in the plants were also conducive to
dermal exposure. Therefore, the extent to which 3,3'-DCB is absorbed
following inhalation exposure in man is inconclusive. It should be
noted that there is gastrointestinal exposure as well from breathing
dust. The mucociliary clearance mechanism moves most particulate out of
the lung and into the gastrointestinal tract. No information was
located on absorption in animals following 3,3'-DCB inhalation exposure.
2.6.1.2 Oral Exposure
No data were located on the absorption of 3,3'-DCB following oral
exposure in humans. The absorption of orally administered 3,3'-DCB in
rats was studied by Hsu and Sikka (1982). Following a dose of 40 mg/kg,
3,3'-DCB attained a peak plasma concentration of 1.25 tig/ml at 8 hr,
suggesting that 3,3'-DCB is rapidly absorbed following oral exposure.
Further, about 90% of the administered radioactivity was excreted in
feces and urine within 72 hours largely as metabolites, indicating a
high bioavailability, typical of primary arylamines. The elimination is
biphasic, with half-lives of 6 hrs and 14 hrs for the rapid and slow
phases (Hsu and Sikka 1982).
2.6.1.3 Dermal Exposure
No studies were located regarding absorption of 3,3'-DCB following
dermal exposure in humans. Because of large particle size and increased
usage of closed systems and protective clothing, dermal absorption is
minimized except under conditions of high humidity and high temperature.
In animal studies, Shah and Guthrie (1983) applied l4C-3,3'-DCB in
acetone to the shaved skin of rats. Based on the amount of
radioactivity remaining at the site of application, dermal absorption at
1, 8, and 24 hr following application was estimated to be 6%, 23% and
49%, respectively.
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30
2. HEALTH EFFECTS
2.6.2 Distribution
2.6.2.1 Inhalation Exposure
No studies were located regarding distribution in humans or animals
after inhalation exposure to 3,3'-DCB.
2.6.2.2 Oral Exposure
No studies were located regarding the distribution of 3,3'-DCB in
humans following oral exposure. Hsu and Sikka (1982) studied the
distribution of radioactivity in rat tissues after the oral
administration of I4C-3 , 3 '-DCB. Twenty-four hours after a single oral
dose, the highest levels of radioactivity were found in the liver,
followed by the kidney, lung, spleen, heart, pancreas and testes, in
that order. This pattern did not depend on dose. After 96 hours,
tissues that retained more than 0.02% of the administered radioactivity
were liver (1.48%), muscle (0.37%), kidney (0.19%) and lung (0.02%).
Erythrocytes retained more of the radioactivity than lung, but attention
was not paid to the hematopoietic system in this study. The effect of
repetitive 3,3'-DCB administration on tissue levels of the radioactivity
was also studied by Hsu and Sikka (1982). Radioactivity in tissues of
animals that received six daily doses of the chemical were generally
three to four times as high as the radioactivity in tissues of animals
that received a single dose. Similarly, the decline of radioactivity in
tissues was generally higher in animals that received a single dose than
in those treated with multiple doses of the chemical. The authors
concluded that repeated dosing with the chemical did not result in a
substantial retention of UC, and the chemical may be considered to have
a fairly low tendency to accumulate in tissues following repetitive
dosing.
2.6.2.3 Dermal Exposure
No studies were located regarding distribution of 3,3'-DCB in
humans following dermal exposure. The distribution of 14C-3,3'-DCB in
rat tissues following dermal application was studied by Shah and Guthrie
(1983). Tissues retaining >0.1% of the administered radioactivity
24 hours after application were liver (4.09%), blood (0.75), and lung
(0.45). The level in the lung was the same at the 8 and 24 hour time
points. Differences in the tissue distribution pattern of total
radioactivity between the oral and dermal routes of 3,3'-DCB
administration may be presumed to reflect differences in the rates of
absorption from these sites. These differences mean that the target
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31
2. HEALTH EFFECTS
organ in which 3,3'-DCB exerts an adverse effect may depend on the route
of exposure to the chemical. Organ toxicity can be better evaluated in
comparative studies designed to test tissue distribution and persistence
of the chemical using the oral, dermal and inhalation routes of
exposure.
2.6.3 Metabolism
2.6.3.1 Inhalation Exposure
No studies were located regarding metabolism in humans or animals
after inhalation exposure to 3,3'-DCJB.
2.6.3.2 Oral Exposure
No studies were located regarding metabolism of 3,3'-DCB in humans
following oral exposure. Studies in animals indicate 3,3'-DCB is
extensively metabolized. Hsu and Sikka (1982) reported that bile and
urine of rats given a single oral dose of uC-3,3'-DCB (40 rag/kg/day)
contained five metabolites in addition to 3,3'-DCB. None of the
metabolites were identified, but a majority were reported to be
conjugates. Tanaka (1981) reported that a 24 hr urine sample of rats
given a single oral dose of 3,3'-DCB (50 mg/kg/day) contained unchanged
3,3'-DCB, N, N'-diacetyl 3,3'-DCB and N-acetyl 3,3'-DCB in a ratio of
1:3:10.
2.6.3.3 Dermal Exposure
No studies were located regarding metabolism of 3,3'-DCB in humans
following dermal exposure. In a 24 hr urine sample of rats given a
single dermal application of 3,3'-DCB (50 mg/kg/day), N, N'-diacetyl
3,3'-DCB (but not N-acetyl 3,3'-DCB or the unchanged chemical) was
detected (Tanaka 1981). Since the mutagenicity of diacetylated product
is much less than either the monoacetylated or parent compound (Lazear
et al. 1979; Reid et al. 1984; Tanaka 1981), diacetylation may be a
detoxification reaction for 3,3'-DCB.
2.6.4 Excretion
2.6.4.1 Inhalat ion Exposure
Less than 0.2 ppb 3,3'-DCB was detected in urine samples of 36
workers exposed to 3,3'-DCB-derived pigments (Hatfield et al. 1982).
However, the authors did not clearly identify specific pigments. While
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32
2. HEALTH EFFECTS
the authors did not report exposure route, it was presumed to have been
by inhalation. Dermal exposure may have also occurred.
No studies were located regarding excretion in animals after
inhalation exposure to 3,3'-DCB.
2.6.A.2 Oral Exposure
No studies were located regarding the excretion of 3,3'-DCB in
humans following oral exposure. Studies on the fate of 3,3'-DCB-derived
pigments fail to provide conclusive evidence that these pigments are
broken down to release free 3,3'-DCB in humans. Results from animal
studies show that 3,3'-DCB is excreted primarily in feces and to a
lesser extent in urine. In rats administered a single oral dose of
3,3'-DCB (40 mg/kg), approximately 58 to 72% of the administered dose
was recovered in bile and feces and 23 to 33% in urine (Hsu and Sikka
1982) . Most of the material found in bile and feces consisted of
conjugated metabolites, while most of the material in urine consisted of
nonconjugated metabolites. The elimination appears to be biphasic, with
half-lives of about 6 hr and 14 hr for the rapid and slow phases,
respectively (Hsu and Sikka 1982). No detectable residues of 3,3'-DCB
were found in urine samples of hamsters administered a single dose of
100 mg/kg purified yellow 12 (NCTR 1979; Nony et al. 1980). Similarly,
3,3'-DCB was not detected in urine samples of mice and rats fed 3,3'-DCB
derived pigments (12, 16, and 83) in the diet at concentrations of 0.1%
(1,000 ppm) , 0.3% (3,000 ppm) and 0.9% (9,000 ppm) for 104 weeks
(Leuschner 1978).
2.6.4.3 Dermal Exposure
No studies were located regarding the excretion of 3,3'-DCB in
humans following dermal exposure. Fecal excretion in rats at 24 hours
following 3,3'-DCB exposure was 20% the administered dose, with
urinary excretion of 8% (Shah and Guthrie 1983).
2.7 INTERACTIONS WITH OTHER CHEMICALS
No data were found regarding the interactive effectg Q£ 3,3'-dcb
with other chemicals that would be re evant to its toxicity. 3,3'-DCB
enhances the carcinogenicity of 2"aC®^laminofluorene (2-AAF), and
butylhydroxybutyl nitrosamine (BBN) < to et al. 1983). Combined feeding
of BBN (0.001%) 2-AAF (0.005%) and *• -DCB (0.03%) produced urinary
bladder papillomas, but no carcino1®®3* Sequential administration of BBN
(0.01%), nitrofurylthiazolylformarnid6 (PANFT, 0.15%)( 2-AAF (0.025%) and
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33
2. HEALTH EFFECTS
3,3'-DCB (0.03%) produced papillomas and carcinomas (Ito et al. 1983;
Tatematsu et al. 1977). No tumors were produced in untreated controls
and when the chemicals were administered alone. In this situation with
a complex mix of four chemicals, no data are available to suggest
effects observed were due to 3,3'-DCB. It should be noted that
sequential administration of BBN, FANFT and 2-AAF produced papillomas
but no carcinomas. 3,3'-DCB may act as a promoter or enzyme inducer;
however additional data are needed.
2.8 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE
No information was located that identified any human population as
having above-normal susceptibility to 3,3'-DCB toxicities.
2.9 ADEQUACY OF THE DATABASE
Section 104(i)(5) of CERCLA, directs the Administrator of ATSDR (in
consultation with the Administrator of EPA and agencies and programs of
the Public Health Service) to assess whether adequate information on the
health effects of 3,3'-dichlorobenzidine is available. Where adequate
information is not available, ATSDR, in cooperation with the National
Toxicology Program (NTP), is required to assure the initiation of a
program of research designed to determine these health effects (and
techniques for developing methods to determine such health effects).
The following discussion highlights the availability, or absence, of
information on exposure and toxicity of 3,3'-DCB applicable to human
health assessment. A statement of the relevance of identified data
needs is also included. In a separate effort, ATSDR, in collaboration
with NTP and EPA, will prioritize data needs across chemicals that have
been profiled.
2.9.1 Existing Information On Health Effects of 3,3'-DCB
As shown in Figure 2-3, essentially no studies of human exposure to
3,3'-DCB were located by specific routes, except for occupational data
on direct dermal effects following dermal exposure. Although there are
studies of workers in the United States exposed to 3,3'-DCB, these
reports are limited by the fact that exposure potentially involved other
chemicals, and both the route and extent of exposure are largely
unknown. Dermal effects have also been investigated in experimental
animals as well as ocular irritant properties of 3,3'-DCB exposure.
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34
2. HEALTH EFFECTS
SYSTEMIC
Inhalation
Oral
Dermal
///
It
W///M
HUMAN
SYSTEMIC
ih 1L
Inhalation
Oral
Dermal
ANIMAL
Existing Studies
FIGURE 2-3. Existing Information on Health Effects of 3,3-Dichlorobenzldine
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35
2. HEALTH EFFECTS
Additional information on health effects following dermal exposure is
sparse. The majority of all animal studies of 3,3'-DCB have focused on
carcinogenic effects following oral exposure, data on noncarcinogenic
effects are limited.
2.9.2 Data Needs
Single Dose Exposure. Potential exposure to 3,3'-DCB may occur
through inhalation of contaminated airborne dust, ingestion of
contaminated water or skin contact. Studies regarding single dose
exposure showed the compound can cause eye damage following conjunctival
application and possibly respiratory effects when inhaled. The
significance of these findings is minor as conjunctival application is
not a typical route of exposure for the general population. 3,3'-DCB
can be lethal following oral and dermal exposure at high doses.
Comprehensive gross and histopathological evaluations have not been
conducted and clinical signs have not been monitored. Such studies may
provide insight into systemic toxicity and potential health threat
associated with one-time exposure.
Repeated Dose Exposure. Repeated dose inhalation studies have been
performed in rats without systemic effects, but these studies used only
one dose level and the number of animals tested was not specified. No
repeat oral or dermal dose studies were found. Animal studies
evaluating toxicological parameters at several dose levels would provide
dose response data which could prove more predictive when assessing
potential adverse effects in humans following repeated exposure.
Chronic Exposure and Carcinogenicity. Long-term exposure of humans
to 3,3'-DCB by inhalation and dermal contact may occur in occupational
settings and potential for oral exposure exists in areas near hazardous
waste sites. Available chronic oral studies provide information
regarding systemic and carcinogenic effects in rats and dogs. These
studies employed one dose level and toxicological parameters measured
were limited. No chronic animal inhalation or dermal exposure studies
were located. Well-conducted chronic inhalation, dermal and oral
studies involving low-dose exposure in animals might provide dose-
response data on potential systemic effects of exposure in humans.
Available data do not establish the relationship between the
concentration of 3,3'-DCB and/or its metabolites in the body and the
probability of cancer. Studies designed to establish urinary excretion
levels that are associated with disease may prove useful, but due to the
long latency of the possible carcinogenic effects, such studies are
difficult to perform.
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36
2. HEALTH EFFECTS
Genotoxicity. Available studies show that 3,3'-DCB does alter
genetic material. Studies involving more predictive indicator test
systems may allow a better assessment of genotoxic potential.
Reproductive Toxicity. No studies were found regarding
reproductive toxicity of 3,3'-DCB. Well-conducted multigenerational
reproductive studies in animals may provide some insight as to the
potential effects o£ 3,3'-DCB on human reproductive processes.
Developmental Toxicity. No studies were found regarding
developmental toxicity of 3,3'-DCB in humans. Animal studies have shown
that 3,3'-DCB crosses the placenta and can affect the growth of the
kidneys after parenteral exposure. The effects of the chemical on
development have not been studied following oral, inhalation or dermal
exposure. Well-conducted animal studies employing various dose levels
and relevant exposure routes during critical developmental periods may
provide information on potential fetotoxicity, embryotoxic and
teratogenic effects in humans. Further animal data may provide dose-
response information if studies are conducted to determine what dose of
3,3'-DCB, or its metabolites, reaches the fetus.
Immunotoxicity. No studies were located determining the role of
the immune system during 3,3'-DCB exposure. Investigations in animals
on the effects of 3,3'-DCB on the immune system may be valuable since
the immune system has been reported to be sensitive to chemical
toxicants.
Neurotoxicity. A chronic oral study in dogs examined organs and
tissues of the nervous system and reported signs of neuronal
degeneration. The confidence in the effect reported is reduced since
only one dose level was tested and the effect failed to appear in more
than one of the 6 test dogs. Additional studies may verify this finding
and document dose-response relationships between exposure by relevant
routes to low-dose concentrations and the potential neurotoxicity of
3,3'-DCB.
Epidemiological and Human Dosimetry Studies. The only known health
effect associated with DCB exposure in humans is dermatitis which was
attributed to a manufacturing process change resulting in exposure of
workers to DCB-free base. Epidemiological studies of people who live in
areas where 3,3'-DCB has been detected in groundwater, near industries
releasing 3,3'-DCB, or near hazardous waste sites, and of occupational
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37
2. HEALTH EFFECTS
exposure, could provide information on whether 3,3'-DCB exposure
produces effects in humans.
No studies were located that monitored human tissues for 3,3'-DCB
or its metabolites. 3,3'-DCB is excreted in urine. If 3,3'-DCB and
metabolites can be detected and correlated with exposure, it may be
possible to monitor humans for exposure. With monitoring, it may be
possible to correlate urinary levels of 3,3'-DCB or its metabolites,
with systemic effects.
Biomarkers of Disease. There are no disease states in humans that
can clearly be associated with exposure to 3,3'-DCB. If comprehensive
epidemiological studies are conducted, it may be possible to identify
subtle changes, such as altered blood chemistry indices, associated with
a particular disease state.
Disease Registries. The only reported health effects from human
3,3'-DCB exposure are skin, eye, nose and throat irritation. If
epidemiological studies identify particular diseases attributable to
3,3'-DCB exposure, it may be possible to determine the number of people
affected.
Bioavailability from Environmental Media. 3,3'-DCB is unstable in
air and water but persists in soil. No studies were located regarding
the bioavailability of 3,3'-DCB from these media. The lack of data do
not necessarily indicate a lack of bioavailability. 3,3'-DCB reportedly
bioconcentrates in the aquatic environment. Analysis of the body fluids
of those people who consume fish may allow a determination of exposure,
and estimation of the degree of exposure.
Food Chain Bloaccumulation. No studies were located regarding the
food chain bioaccumulation of 3,3'-DCB. Based on an assumed log Kow in
the range of 3.02 to 3.78, 3,3'-DCB is not likely to bioaccumulate
strongly.
Absorption, Distribution, Metabolism, and Excretion. Available
data are insufficient to allow accurate evaluation of absorption,
metabolism or persistence of 3,3'-DCB in human tissues. Additional
studies to identify and quantify metabolites of 3,3'-DCB in humans and
animals would be useful in establishing the relevance of animal studies
in predicting human health effects. Metabolic handling of 3,3'-DCB in
humans may need to be better characterized before urinary levels of the
chemical or its metabolites can be used to quantitate human exposure.
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38
2. HEALTH EFFECTS
Comparative Toxicokinetics. Pharmacokinetics studies have not been
performed under conditions analogous to those of the carcinogenicity
studies. Therefore, it is not possible to determine systemic levels of
the chemical associated with the reported effects. Pharmacokinetics
data concomitant with an identifiable biological effect would markedly
increase accuracy and improve species extrapolation when evaluating the
true potency of 3,3'-DCB in respect to that specific effect.
2.9.3 Ongoing Studies
Dr. M. Iba (Rutgers University) is performing research directed at
the identification of the in vivo and in vitro metabolites of DCB. No
other ongoing studies were located.
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39
3. CHEMICAL AND PHYSICAL INFORMATION
3.1 CHEMICAL IDENTITY
Table 3-1 lists common synonyms, trade names and other pertinent
identification information for 3,3'-DCB.
3.2 PHYSICAL AND CHEMICAL PROPERTIES
Table 3-2 lists important physical and chemical properties of
3,3'-DCB.
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40
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-1. Chemical Identity of 3,3'-Dichlorobenzidine
Value
References
Chemical. Name
Synonyms
Trade Name
Chemical Formula
Chemical Structure
Identification Numbers:
CAS Registry
NIOSH RTECS
EPA Hazardous Waste
OHM-TADS
DOT/UN/NA/IMCO
Shipping
HSDB
NCI
3,3'-Dichlorobenzidine
Dichlorobenzidine t 3,3'-Dlchloro-
4,4'-Diamlnobiphenyli 4,4'-Dlamlno-
3,3'-Dlchloroblphenyls o,o'-Dichlorobenzidine
curlthane
H jN
91-94-1
DD0525000
U073
8100004
ND
1632
ND
NH,
NLM 1988
IARC 1982a
EPA 1983
NLM 1988
HSDB 1988
NLM 1988
HSDB 1988
HSDB 1988
NLM 1988
NLM - National Library of Medicine i I ARC - International Agency for Research on Cancer; EPA -
Environmental Protection Agencyi CAS - Chemical Abstracts Service) NIOSH - National Institute
for Occupational Safety and Healthi RTECS - Registry of Toxic Effects of Chemical Substancesi
HSDB - Hazardous Substances Data Banki OHM-TADS - Oil and Hazardous Materials/Technical Assistance
Data System! DOT/UN/NA/IMCO - Department of Transportation/United Nations/North America/International
Maritime Dangerous Goods Code; ND - No datai NCI - National Cancer Institute.
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41
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-2. Physical and Chemical Properties of 3,3'-Dichlorobenztdine
Property
Value
Referenced
Molecular Weight
Color
Physical State
Melting Point, °C
Boiling Point, °C
Density
Odor
Odor Threshold
Water
Air, ppm
Solubility in dlst
Water, mg/L
Organic Solvents
Partition coefficients
Log octanol/water
Log k(organic carbon/water)
Vapor Pressure, nm Hg
Henry's law constant,
atra-m /mol
Ignition
temperature, °C
Flash point
Flammabillty limits
Conversion factors
ppm (Wv) to mg/m
in air (20°C)
mg/ra3 to ppm (v/v)
in air (20°C)
253.13
grey to purple
crystalLlne
solid
132 (up to 136)
368 (estimate)
ND
mild
ND
3.11
soluble in
alcohol, benzene
3.5
3.2
4.51-09 at 20°C
JE-10
350
>200
ND
1 ppm -10.4 mg/m^
1 mg/ra1 > 0.10 ppm
Verschueren
1977
HSDB 1988
BSDB 1988
Mabey et al.
1982 t DCMA 1989
PCGEHS 19BB
HSDB 1988
HSDB 1988
HSDB 1988
DCMA 1989
BSDB 1988
Mabey et al.
1982i DCMA 1989
Mabey et al.
1982
DCMA 1989
DCMA 1989
DCMA 1989
DCMA 1989
HSDB 1988
HSDB - Hazardous Substances Data Bank; PCGEMS - Personal Computer Conversion of Graphical Exposure
Modeling System) DCMA - Dry Color Manufacturers' Assoclationi KD - no datai dlst - distilled.
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43
4. PRODUCTION, IMPORT, USE AND DISPOSAL
4.1 PRODUCTION
3,3'-DCB Is commercially produced through various reduction
procedures of o-nitrochlorobenzene to form a hydrazo compound which Is
rearranged in the presence of mineral acids to form 3,3'-DCB (DCMA 1989;
Sax 1987). Commercial supplies are usually provided in the form of the
dihydrochlorlde salt because of its greater stability.
A small number of domestic companies are listed as manufacturers.
Current production volumes of 3,3'-DCB are considered confidential
business information and cannot be reported. The United States
International Trade Commission (USITC 1984a) reported a 1983 production
volume of 3,3'-DCB-based dyes of over 18 million pounds. Consumption of
3,3'-DCB in the United States amounted to 9,900,000 pounds in 1987
(Hopmeier 1988).
4.2 IMPORT
Imports of 3,3'-DCB base and salts were 1.1 million pounds in 1983,
while pigments were about 129,000 pounds in 1983 (USITC 1984b).
4.3 USE
3,3'-DCB is used primarily in the production of yellow, and some
red and orange pigments for the printing ink, textile, paper, paint,
rubber, plastic and related industries (EPA 1979). As of 1983, 7
specific pigments were commercially available. Little, if any, dye is
prepared from this compound. The chemical also has application as a
compounding Ingredient for rubber and plastics, and can be used to test
for the presence of gold (Searle Chemical Carcinogens 1976). 3,3'-DCB
is used in the formulation of the raw material tetraminobiphenyl which
is used to produce polybenzimidazole (PBI). PBI fiber is used in many
protective clothing applications, such as fireman's apparel, welder's
garments, high temperature gloves and crash rescue garments (Celanese
1985).
4.4 DISPOSAL
3,3'-DCB is treated in the workplace as a controlled substance
under OSHA. Therefore, strict requirements have been made to minimize
exposure to the chemical in the workplace air and contact with the skin
and eye. Nonetheless, some releases may occur in wastewater effluents.
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44
4. PRODUCTION, IMPORT, USE AND DISPOSAL
A report by London and Boiano (1986) indicates that one company which
purchases 3,3'-dichlorobenzidine as the dihydrochloride salt in sealed
fiber in drums rinses the empty drums with water, adds the rinse water
to the product stream, then sprays the drums with a sodium hypochlorite
bleach solution (converting 3,3'-DCB to a quinone-type compound), and
places them in polyethylene bags for disposal.
4.5 ADEQUACY OF THE DATABASE
Section 104(i)(5) of CERCLA, directs the Administrator of ATSDR (in
consultation with the Administrator of EPA and agencies and programs of
the Public Health Service) to assess whether adequate information on the
health effects of 3,3'-dichlorobenzidine is available. Where adequate
information is not available, ATSDR, in cooperation with the National
Toxicology Program (NTP), is required to assure the initiation of a
program of research designed to determine these health effects (and
techniques for developing methods to determine such health effects).
The following discussion highlights the availability, or absence, of
exposure and toxicity information applicable to human health assessment.
A statement of the relevance of Identified data needs Is also Included.
In a separate effort, ATSDR, in collaboration with NTP and EPA, will
prioritize data needs across chemicals that have been profiled.
4.5.1 Data Needs
According to the Emergency Planning and Community Right to Know Act
of 1986 (EPCRTKA), (§313), (Pub. L. 99-499, Title III, §313), industries
are required to submit release information to the EPA. The Toxic
Release Inventory (TRI), which contains release information for 1987,
became available in May of 1989. This database will be updated yearly
and should provide a more reliable estimate of industrial production and
emission.
Production, Use, Release and Disposal. Recent USITC data do not
give current production volumes specifically for 3,3'-DCB. If one can
infer from production data for specific pigments, production is only
slightly elevated from a decade ago. Import figures from the late 1970s
show wide fluctuation. It is possible that the basis of the figures
used varies.
Use data appear adequate, as 3,3'-DCB is largely a single-purpose
compound. Regulated disposal practices were not specified, although an
example of current disposal practice was obtained.
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45
5. POTENTIAL FOR HUMAN EXPOSURE
5.1 OVERVIEW
Major release routes of 3,3'-DCB to the environment appear to be
wastewaters, sludges, and solid wastes where emissions are not properly
controlled during the production and use of 3,3'-DCB and benzidine-based
dyes. The chemical was detected in ground and surface water at less
than one percent of a sample of hazardous waste sites but in the soil of
4.4% (CLPSD 1988). Relatively high concentrations have been found in
the vicinity of industrial sources such as those resulting from the
improper land disposal of 3,3'-DCB solid wastes.
Concern for human health is primarily for inhalation of airborne
dust, drinking of contaminated well water by persons living in the
proximity of hazardous waste sites, and skin contact by workers in
occupational settings. However, occupational case reports suggest that
risk to workers exposed to 3,3'-DCB through the use of benzidine-based
dyes may be minimal. No adverse health effects were reported in an
average of 20 workers engaged in the manufacture and handling of
3,3'-DCB alone (concentration not specified) in a Japanese facility
(DCMA 1989). Less than 0.2 ppb 3,3'-DCB was detected in urine samples
of 36 workers exposed to 3,3'-DCB-derived pigments (specific pigments
not specified) (Hatfield et al. 1982). While these data suggest that
3,3'-DCB derived pigments are not metabolized in humans, limitations in
the existing evidence do not allow a conclusive decision about the human
health implications.
3,3'-DCB readily photolyzes in water exposed to light, but may not
readily biodegrade in soil and acclimated sludges. It has a strong
tendency to partition to soils and sediments which reduces the potential
for human exposure (Boyd et al. 1984; Chung and Boyd 1987; Sikka et al.
1978). It does not volatilize or hydrolyze in solution, but it may
slowly oxidize (Banerjee et al. 1978; Callahan et al. 1979). 3,3'-DCB
may be bioconcentrated by aquatic organisms (Appleton and Sikka 1980),
but it is not certain if it is biomagnified by transfer through the food
chain.
5.2 RELEASES TO THE ENVIRONMENT
5.2.1 Air
3,3'-DCB is handled by industry primarily as a powder or a paste
(NIOSH 1980). 3,3'-DCB is not a volatile chemical. A vapor pressure of
4.5 x 10"9 mmHg has been reported (DCMA 1989). Prior to OSHA 1974
regulations, benzidine and 3,3'-DCB were manufactured in open systems
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46
5. POTENTIAL FOR HUMAN EXPOSURE
that permitted atmospheric releases of suspended particles at the work
site (Shriner et al. 1978), but no data were located specifically for
3,3'-DCB emissions (atmospheric or in water). The absence of data may
be attributed to then-used analytical methods that could not distinguish
benzidine from its derivatives or many other aromatic amines (Shriner
et al. 1978). Under OSHA regulations adopted in 1974, only closed
systems are permitted, and atmospheric emissions are presumably reduced
because of this regulation. Aggregate annual releases of DCB to the air
in the United States are estimated to be far less than 22 pounds, and
possibly lower than one pound (DCMA 1989).
5.2.2 Water
The base form of 3,3'-DCB is sparingly soluble in water. Banerjee
et al. (1978) measured the solubility of 3,3'-DCB*2HC1 in water as
4 mg/L (pH 6.9). 3,3'-DCB may be released into the environment in
wastewaters generated by the production of dyes and pigments.
Preliminary data from the Contract Laboratory Program Statistical Data
Base (CLPSD 1988) indicated that 3,3'-DCB was detected in ground and
surface water samples collected at hazardous waste sites. The frequency
of detection was only 0.6% and 0.3%, respectively, at over 500 sites.
Median concentrations were not available.
5.2.3 Soil
Soils and other unconsolidated materials may be contaminated with
3,3'-DCB by atmospheric transport of dust particles, industrial
discharges, or by 3,3'-DCB-contaminated wastewater sludge. However,
there is a paucity of data to show how frequently contamination occurs.
Boyd et al. (1984) reported that the improper disposal of industrial
waste sludges containing 3,3'-DCB resulted in soil, groundwater and
surface water contamination. The sludges had been placed into earthen
pits. Soil, groundwater and surface water contamination at other
hazardous waste sites has also been detected. Preliminary data from the
Contract Laboratory Program Statistical Data Base (CLPSD 1988) indicated
that 3,3'-DCB was detected in solid phases collected at hazardous waste
sites. The frequency of detection was 4.4% at over 500 sites.
5.3 ENVIRONMENTAL FATE
Because 3,3'-DCB stays attached to airborne dust particles or is
bound to particulate matter, it is subject to dispersion, gravitational
settling, and wash out by rain. In water, 3,3'-DCB is sparingly
soluble, does not volatilize or hydrolyze, and may slowly oxidize in
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47
5. POTENTIAL FOR HUMAN EXPOSURE
solution (Banerjee et al. 1978; Callahan et al. 1979; Mabey et al.
1982). 3,3'-DCB may be strongly adsorbed by soils, clays, and
sediments, depending on the pH of the soil-water system. It may be
strongly bound by soil organic matter (Boyd et al. 1984; Chung and Boyd
1987; Sikka et al. 1978). It does not appear to be readily
biodegradable in soil or wastewater sludges. 3,3'-DCB may be
bioconcentrated by aquatic organisms under experimental conditions
(Appleton and Sikka 1980), but it is not certain if it is bioaccumulated
or transferred through the food chain.
5.3.1 Transport and Partitioning
In the atmosphere, 3,3'-DCB stays attached to dust particles or
bound to particulate matter. As such, suspended 3,3'-DCB is subject to
atmospheric convection, dispersion, gravitational settling, and wash-out
by rain.
The Henry's Law constant (KH) for a compound is useful in
estimating the partitioning of the compound between its vapor phase and
aqueous media. A value of 5 x 10~10 atm-m3/niole has been estimated (DCMA
1989). This very low value suggests that 3,3'-DCB essentially remains
dissolved in water, and does not migrate from water into air.
3,3'-DCB in solution has a strong tendency to be adsorbed onto
soils and sediments. The extent of adsorption of hydrophobic
(sparingly-water soluble) compounds has been shown to be highly
correlated with the organic carbon content of the adsorbents (Hassett
et al. 1983). When adsorption is expressed as a function of organic
carbon content, an organic carbon-water partition coefficient (Koc) is
generated which is a unique property of the compound and may be used to
rank the relative mobility of organic contaminants in saturated soil-
water systems. Mabey et al. (1982) calculated a Koc value for 3,3'-DCB
of 1553, based on an octanol-water partition coefficient (Kow) of 3236.
This relatively high value implies that 3,3'-DCB would exhibit "low
mobility" in soil (see Roy and Griffin 1985). However, 3,3'-DCB is not
strictly a hydrophobic compound but can exist as a weak base in water,
and exists in both neutral and cationic forms. Written as a hydrolysis
reaction, the amine groups may be protonated as follows:
3,3'-DCB + H20 «-» 3,3'-DCBH+ + OH"
3,3' -DCBH+ + H20 «-» 3,3' -DCBH22+ + OH"
The PKa's of the conjugate acids (DCBH+ and DCBH22+) are apparently
not known accurately; Sikka et al. (1978) and Boyd et al. (1984)
-------
48
5. POTENTIAL FOR HUMAN EXPOSURE
reported that they are less than 4. In the pH range of most
environmental situations (pH 6 to 8), the dominant state of 3,3'-DCB in
water is as the non-ionic form. As pH increases, the proportion of
cationic 3,3'-DCB decreases, and the extent of adsorption to sediments
via Coulombic interactions would also decrease and 3,3'-DCB adsorption
would be dominated by hydrophobic processes. This expectation was
demonstrated by Sikka et al. (1978), who found that the adsorption
constant (Kf) decreased with increasing pH, especially in the range of
pH 7 to 9. The adsorption data conformed to the Freundlich equation,
viz. C, - K£Cf1/n where Ca is the concentration of DCB adsorbed per mass
of adsorbent, and C, is the equilibrium concentration of 3,3'-DCB in
solution Kfd and 1/n are empirically-derived constants. Sikka et al.
(1978) and Boyd et al. (1984) found no correlation between Kf and the
organic carbon content of the sediments. In the same regard, the extent
of benzidine adsorption does not correlate to the organic carbon content
of soils and sediments (Graveel et al. 1986; Zierath et al. 1980). Boyd
et al. (1984) concluded that nonionized 3,3'-DCB is subject to
hydrophobic bonding to some extent. It is clear from these studies that
adsorption constants for 3,3'-DCB cannot be accurately predicted for a
given soil based only on a Koe value.
The adsorption of 3,3'-DCB by soils and sediments may not be
reversible (Boyd et al. 1984; Chung and Boyd 1987; Sikka et al. 1978).
The extent of 3,3'-DCB desorption decreased with an Increase in the age
of the sample. Also, the adsorbed 3,3'-DCB was resistant to extraction;
after 24 hours of 3,3'-DCB-sediment contact, only 36% of the parent
compound could be extracted by methanol. Both Sikka et al. (1978) and
Boyd et al. (1984) speculated that 3,3'-DCB forms covalent bonds with
soil humic components. Experiments have indicated that covalent binding
of ring-substituted anilines to humates is not a readily reversible
reaction (Parris 1980). 3,3'-DCB was highly immobile in soil column
experiments (Chung and Boyd 1987). Water was passed through sandy soil
(Entic Haplorthod), and a 3,3'-DCB-contaminated sewage sludge samples.
Most of the 3,3'-DCB was bound by the soil, while sludge and leachate
samples collected from the columns contained low concentrations of
3,3'-DCB. This information suggests that DCB would migrate from
contaminated sludge to soil.
Since 3,3'-DCB is lipophilic, it may be concentrated from solution
by aquatic organisms. Bluegill sunfish were exposed to radiolabeled
3,3'-DCB in dynamic flow experiments for 120 to 168 hours by Appleton
and Sikka (1980). Moderately low bioconcentration factors (BCF) of 495
to 507 were calculated for the whole fish. Freitag et al. (1984, 1985)
reported a bioconcentration factor in fish (golden Ide) of 610 and in
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49
5. POTENTIAL FOR HUMAN EXPOSURE
green algae of 940. EPA (1980b) reported a bloconcentratlon factor in
edible portions of bluegill sunfish of 114-170. Bioaccumulation by
plants or animals has not been studied. Assuming a Log Kow in the range
3.02 to 3.78 (DCMA 1989; Mabey et al. 1982), 3,3'-DCB is not likely to
bioaccumulate strongly.
5.3.2 Transformation and Degradation
5.3.2.1 Air
3,3'-DCB in the atmosphere may be photooxidized with hydroxyl
radicals and ozone, but there were no quantitative data on reaction
rates. Radding et al. (1977) estimated the persistence of "all
benzidines" in the atmosphere by assuming a hydroxyl radical
concentration of 8 x 10"15 mole/liter (an average value in a 24-hour
day-night cycle). Treating the photooxidation process as a first-order
reaction, the rate constant was 7.2 x 1012/®ole-hr and the corresponding
half-life was 12 hours. This approach was based on data on the rates of
reaction of hydroxyl radicals with olefins, aromatics, and alkanes in
the atmosphere. The estimated half-life of 3,3'-DCB in air has ranged
from 1 to 60 days (Shriner et al. 1978; EPA 1980b). Based on the
reaction rate constant of photodegradation in the atmosphere, the
half-life may be as little as two hours (DCMA 1989). There was no other
information on the fate of atmospheric 3,3'-DCB.
5.3.2.2 Water
The limited information that is available suggest that 3,3'-DCB may
photolyze yielding benzidine which is more photostable. It does not
appear that the chemical is susceptible to other transformations in
water.
There are no data to suggest that the hydrolysis of 3,3'-DCB is
significant (Callahan et al. 1979). Mabey et al. (1982) proposed a
hydrolysis-rate constant of 0/mole-hour for 3,3'-DCB.
It has been speculated that aromatic amines can be oxidized in
solution by organic radicals, but there are no actual data on reaction
rates. Based on structural analogs, Radding et al. (1977) estimated
that the half-life of such compounds in water is approximately 100 days,
assuming a peroxy concentration of 10~10 mole/L in sunlit, oxygenated
water. Based on the oxidation rates with similar compounds, Mabey
et al. (1982) treated the direct oxidation of 3,3'-DCB by oxygen in
solution as a first-order reaction, and estimated a reaction rate
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50
5. POTENTIAL FOR HUMAN EXPOSURE
constant of less than 4 x 107/mole-hour. The oxidation rate constant
with peroxy radicals was estimated to be approximately 4 x 107/mole-
hour. However, no information was located that demonstrates that
3,3'-DCB is significantly oxidized in water.
In a study reported by Sikka et al. (1978) and Banerjee et al.
(1978), 3,3'-DCB was found to be extremely photolabile in water.
3,3'-DCB photolyzed yielding monochlorobenzidine, benzidine, and a
number of colored, water-insoluble products. In natural sunlight, the
half-life of 3,3'-DCB in water was approximately 90 seconds. While
3,3'-DCB is very rapidly photolyzed under environmental conditions, the
process may yield benzidine, a relatively photostable carcinogen
(Banerjee et al. 1978).
3,3'-DCB was not metabolized by microorganisms over a four-week
period in lake water samples (Sikka et al. 1978). The sample from one
of two reservoirs studied contained approximately 5 x 106 cells/mL, but
the composition of the biological community was not described. Minor
decreases in 3,3'-DCB concentrations were attributed to adsorption onto
suspended sediment.
5.3.2.3 Soil
It does not appear that 3,3'-DCB is significantly degraded in soil
nor that it is transformed to other forms.
Unsubstituted benzidine may be oxidized at clay surfaces when mixed
with some types of clay minerals (Tennakoon et al. 1974; Theng 1971).
Benzidine is oxidized to a monovalent radical cation by iron (III) in
the silicate lattice and by aluminum at crystal edges. However, there
is no experimental evidence that demonstrates that 3,3'-DCB is subject
to the same type of surface oxidation at solid-liquid interfaces.
Activated sludge did not degrade 3,3'-DCB after weekly
subculturing. The sludge was not described or chemically characterized.
Observed decreases in 3,3'-DCB concentration were attributed to
adsorption by the sludge.
Brown and Laboureur (1983) summarized the results of seven
laboratories conducting aerobic biodegradation experiments with
3,3'-DCB. There was a clear dependence of the extent of degradation on
the concentration of yeast extract added to the batch containers. The
role of the extract was uncertain, but without it, no degradation was
detected. Brown and Laboureur (1983) felt that these results showed the
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51
5. POTENTIAL FOR HUMAN EXPOSURE
"inherent biodegradability" of 3,3'-DCB, but that it would not be
classified as "readily biodegradable." Possible degradation mechanisms,
and degradation by-products were not discussed.
3,3'-DCB degraded very little when incubated with soil. In a stud}
by Boyd et al. (1984), a Brookston clay loam soil (a typic Argiaquoll)
was incubated aerobically and anaerobically in batch experiments. Under
aerobic conditions, 3,3'-DCB degradation occurred at a very slow rate;
accumulative 14C02 production was approximately 2% after 32 weeks.
Under anaerobic conditions, no gas evolution was detected after one year
of incubation. Boyd et al. (1984) did not comment on the population or
type of microorganisms in the soil sample. Additional studies by Chung
and Boyd (1987) indicated that 3,3'-DCB was very persistent in soil and
sludge-amended soil. Biodegradation of 1AC-labeled 3,3'-DCB was
evaluated during a 182-day incubation period in a sandy soil (Entic
Haplorthod) amended with sewage sludge. The total amount of 14C-
3,3'-DCB recovered as 14C02 was less than 2%. It should be noted that
biodegradation when measured by 14C02 evolution may be a conservative
estimate of the extent of decomposition. This technique does not
account for carbon that is incorporated into the biomass or into soil
organic matter, or if the compound is only partially metabolized
(Graveel et al. 1986).
5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT
3,3'-DCB was not detected in ambient air at production facilities
at detection limits of 0.1-5.0 ng/m3 (Narang et al. 1982; Riggin et al.
1983). The median concentration of 3,3'-DCB in waste effluents (< 10
ppb), groundwater (< 10 ppb), surface water (< 10 ppb), and soils (< 1
ppb) is very low, although significant contamination may be associated
with hazardous waste sites (Staples et al. 1985). Moreover, the
production and utilization of benzidine-based dyes has decreased in the
last 30 years, while environmental and health regulations have been
implemented to reduce the release of 3,3'-DCB to the environment.
However, the inability to determine very low concentrations in water
creates some uncertainty in estimating levels in the environment.
5.4.1 Air
3,3'-DCB does not naturally occur in the environment (IARC 1982a).
3,3'-DCB was not detected in ambient air of two dyestuff production
plants at detection limits of 5 (Narang et al. 1982) and 0.1 ng/m3
(Riggin et al. 1983). Current data on occupational exposure levels
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52
5. POTENTIAL FOR HUMAN EXPOSURE
indicate levels < 0.6 - 2.5 Mg/m3 in 3,3'-DCB production and pigment
manufacturing plants in Germany (DCMA 1989).
5.4.2 Water
Staples et al. (1985) used EPA's computerized water quality data
base (STORET) to determine the median concentration of 3,3'-DCB in
surface water, groundwater, and in municipal and industrial inflow and
outflow. The median concentration of 3,3'-DCB in 1,239 samples of waste
effluent, collected from about 1980 to 1984, was reported to be less
than 10 ppb. 3,3'-DCB was detected in only 12 samples. The median
concentration of 3,3'-DCB in both surface and groundwater was also
reported to be less than 10 ppb. The EPA (1980b) reported that water
samples collected from drinking water wells near a waste disposal lagoon
that contained 3,3'-DCB-manufacturing wastes had concentrations of the
chemical ranging from 0.13 to 0.27 ppm. EPA (1983) indicated that
3,3'-DCB concentrations in wastewaters from metal finishing operations
were 0.07 ppb or less. Discharge concentrations from other industrial
sources were at most 10 ppb.
5.4.3 Soil
Staples et al, (1985) reported that the median concentration of
3,3'-DCB in sediments in the United States was estimated to be less than
1 ppm dry sediment. In 347 measurements recorded in the STORET data
base, none of the samples contained detectable concentrations of
3,3'-DCB.
5.4.4 Other Media
There is a potential for 3,3'-DCB to occur in wastewater sludges
and industrial solid wastes. A 3,3'-DCB concentration in sludge of
16 ppm has been reported (Chung and Boyd 1987). 3,3'-DCB (3.13 mg/kg of
sewage sludge, dry weight) was detected in two cases out of a total of
253 sewage treatment plants (Fricke et al. 1985). Concentrations up to
535 /Jg/L were detected in communal sewage treatment plant (Lopez-Avila
et al. 1981). The chemical was detected at 8.55 mg/kg in sewage sludge
of an aeration basin (Demirjian et al. 1984). It is very unlikely that
3,3'-DCB occurs in food in general, since the chemical has no
agricultural or food chemical application. However, the chemical has
been detected in fish in an experimental exposure study. 3,3'-DCB (UC)
was found to rapidly accumulate in bluegill sunfish as a result of
exposure to water containing 5 ppb or 0.1 ppm of the chemical. Residues
were distributed in both the edible and nonedible portions (Appleton and
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53
5. POTENTIAL FOR HUMAN EXPOSURE
Sikka 1980). However, 3,3'-DCB was not detected in fish samples
obtained from rivers near nine textile and dyestuff manufacturers known
to use 3,3'-DCB (Diachenko 1979).
5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE
In most cases, benzidine and its congeners such as 3,3'-DCB are
potential hazards only in the vicinity of dye and pigment plants where
wastes may escape or be discharged (EPA 1980b; Shriner et al. 1978).
The risk to the general population from 3,3'-DCB is unknown, but based
on available data, the potential for nonindustrial exposure via air,
soil, or water is expected to be negligible. However, the greatest risk
of exposure to the general public is from the improper land disposal of
industrial wastes generated by the synthesis and use of 3,3'-DCB
compounds. The significance of this risk can only be evaluated on a
site by site basis.
A potential source of exposure to 3,3'-DCB by the general public
may be by the use of pressurized spray containers of paints, lacquers,
and enamels containing traces of benzidine yellow, an azo dye derived
from 3,3'-DCB (Shriner et al. 1978). No quantitative data were located
regarding use of 3,3'-DCB in consumer products.
The most likely occupational health risks exist in the processing
of 3,3'-DCB in the synthesis of azo dyes, and for workers in the
garment, leather, printing, paper, and homecraft industries where
benzidine-based dyes are used. However, there appears to be no
information available on current levels of occupational exposure in the
United States. While there is no evidence for in vivo cleavage of
3,3'-DCB-derived pigments to free DCB in animals, it cannot be concluded
that 3,3'-DCB-derived pigments are not metabolized in humans.
5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES
NIOSH (1980) concluded that during the use of benzidine-based dyes,
the greatest potential for exposure would be expected to be by dermal
absorption or inhalation by personnel who routinely handle dry powders.
However, EPA (1980b) has generalized that dermal absorption in the
workplace was probably a minor route of 3,3'-DCB exposure, although
dermatitis has occurred in plants where 3,3'-DCB and 3,3'-DCB-based
pigments were manufactured. It may be that health risks with regard to
3,3'-DCB exposure depend on the specific operations of the individual
plant, and extent of personal protective practices of the individual
operator.
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54
5. POTENTIAL FOR HUMAN EXPOSURE
5.7 ADEQUACY OF THE DATABASE
Section 104(i)(5) of CERCLA, directs the Administrator of ATSDR (in
consultation with the Administrator of EPA and agencies and programs of
the Public Health Service) to assess whether adequate information on the
health effects of 3,3'-dichlorobenzidine is available. Where adequate
information is not available, ATSDR, in cooperation with the National
Toxicology Program (NTP), is required to assure the initiation of a
program of research designed to determine these health effects (and
techniques for developing methods to determine such health effects).
The following discussion highlights the availability, or absence, of
exposure and toxicity information applicable to human health assessment.
A statement of the relevance of identified data needs is also included.
In a separate effort, ATSDR, in collaboration with NTP and EPA, will
prioritize data needs across chemicals that have been profiled.
5.7.1 Data Needs
Physical and Chemical Properties. It has been demonstrated that
3,3'-DCB is strongly adsorbed by soils and sediments, and that it may
not readily desorb. Adsorption can not be accurately predicted g
priori: such data are soil-system specific and must be determined
experimentally for each system under study.
Environmental Fate. It is not known if 3,3'-DCB, like benzidine,
is oxidized by clay minerals or If cations In water can have the same
effect. 3,3'-DCB does not appear to easily biodegrade, but the few
studies in this area did not state the type(s) or concentrations of
microorganisms used in each study. More systematic studies with other
organisms may prove useful.
Exposure Levels In Environmental Media. There were no data on
current levels of atmospheric emissions of 3,3'-DCB or its potential to
act as a surface contaminant of soil environments. It is difficult to
determine 3,3'-DCB levels in the aquatic environment because the
concentrations tend to be at or below analytical detection limits. In
general, it may only be possible to fully ascertain the environmental
fate of 3,3'-DCB with analytical advances that permit the routine
determination of very low concentrations. Moreover, it would help to
determine the nature and environmental fate of breakdown products of
3,3'-DCB.
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55
5. POTENTIAL FOR HUMAN EXPOSURE
Exposure Levels in Humans. It has been speculated that the 1974
OSHA regulations have reduced workplace air levels of 3,3'-DCB. It
would be helpful to conduct exposure studies to monitor air levels in
the workplace. It would be beneficial to assess how chemical spills are
handled. There is a lack of information on the extent of air, water,
and soil contamination by industrial wastes containing 3,3'-DCB.
Exposure Registries. An exposure registry for 3,3'-DCB was not
located.
5.7.2 Ongoing Studies
No information was located regarding on-going studies.
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57
6, ANALYTICAL METHODS
6.1 BIOLOGICAL MATERIALS
The major ways of determining 3,3'-DCB and its congeners have been
summarized by Fishbein (1984), and means for the derivatization of
3,3'-DCB and its metabolites in biological materials and determination
by GC and HPLC have been described by Bowman and Nony (1981), Nony and
Bowman (1980) and Nony et al. (1980). Most studies of the analysis of
3,3'-DCB in biological materials have concentrated upon urine as a means
of monitoring human exposure. In addition to 3,3'-DCB itself, its
metabolites have been determined in biological samples. These include
monoacetylated metabolites and diacetylated metabolites (Bowman and
Nony 1981). The analytical methods used to measure 3,3'-DCB and its
metabolites in biological materials include gas chromatography
(NIOSH 1985) and liquid chromatography with ultraviolet absorption or
electrochemical detection (Trippel-Schulte et al. 1986). 3,3'-DCB can
be extracted from urine with a solvent such as benzene and may be
converted to volatile derivatives such as heptachlorobutyl
dichlorobenzidine (Bowman and Nony 1981) for gas chromatographic
determination.
Methods for the determination of 3,3'-DCB in biological materials
are summarized in Table 6-1,
6.2 ENVIRONMENTAL SAMPLES
Analysis of 3,3'-DCB in environmental samples is most commonly
achieved by gas chromatography/mass spectrometry (GC/MS) (EPA 1986a),
capillary column gas chromatography/fourier transform infrared
(GC/FT-IR) spectrometry (EPA 1986a), and high performance liquid
chromatography (HPLC) (EPA 1982a). The GC/MS determination of 3,3'-DCB
involves extraction into a methylene chloride or chloroform solvent,
followed by separation without derivatization. Separation may be
achieved on a gas chromatographic fused-silica capillary column coated
with a slightly polar silicone material and detection with a mass
spectrometer or electron capture detector.
For the HPLC determination of 3,3'-DCB in water, a relatively
complicated procedure may be used (EPA 1982a) in which the analyte is
extracted into chloroform, back-extracted with acid, neutralized and
extracted with chloroform. The chloroform is exchanged to methanol and
concentrated using a rotary evaporator and nitrogen blowdown, then
brought to a 5 mL volume with an acetate buffer. Conditions are used
that permit the separation of 3,3'-DCB compound by HPLC and measurement
with an electrochemical detector, which is now currently favored over
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58
6. ANALYTICAL METHODS
TABLE 6-1. Analytical Methods for 3,3'-Dichlorobenzidine
in Biological Samples
Sample type
Extract ion/cleanup
Detection
Limit of
Detection
References
Animal chow
Fish tissue
Urine
(hamster)
Urine
Urine
Urine
Urine
(for 3,3'-DCB
and metabolites)
NR
Digest NaOH, extract
benzene cleanup,
concentration
Extract with benzene,
heptafluorbutyryl
derivative
Extract with benzene
Extract with benzene, penta
fluoropropyl derivative
NR
Extract vlth benzene,
heptafluorbutyryl
derivative
GC
GC/NPD/HCD
CC/ECD
HPLC/Spec
HPLC/UV
GC
Spec
GC/ECD
NR
<20 ppb
8 Uft/L
523 ilga
Zl *«/L
<1 (t»/L
<100 lull.
Bowman and
Rushing 1981
Dlachenko
1979
Bowman and
Nony 1981)
Nony and Bowman
1980i Nony
at al. 1980
Bowman and
Nony 1981;
Natty and Bowman
1980i Nony
at al. 1980
Bowman and
Rushing 1981
Aobe rt s and
Rosaand 1982
Bowman and
Nony 1981
NR m not reported: GC • gas chromatography) NPD ¦ nitrogen-phosphorus detectori BCD ¦ Ball conductivity
detector; ECD ¦ electron capture detector; HPLC ¦ high performance liquid chromatography; Spec ¦
spectrophotometry; LTV - ultraviolet absorption.
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59
6. ANALYTICAL METHODS
spectrophotometry measurement (Trippel-Schulte et al. 1986). The
method detection limit with HPLC separation and electrochemical
detection is reported to be 0.13 tig/1, and single operator accuracy and
precision for 30 analytes of 5 different types of water samples over a
spike range of 1.0 to 5.0 (Mg/L gave an average percent recovery of 65%
and a standard deviation of 9.6% (EPA 1982a).
HPLC separation with ultraviolet absorption (UV) detection is used
for the determination of 3,3'-DCB in air (NIOSH 1985). The analyte at
levels in a range from 0.2 to 7 ug per sample can be collected in a
silica gel collection tube for up to 100 L of air at a flow rate of
0.2 L/min. The estimated limit of detection is 0.05 jig/sample.
The most important methods for measuring 3,3'-DCB levels in air,
water, food and urine are GC and HPLC procedures. For both methods, the
most difficult step in the procedure is the extraction of the chemical
from its matrix. While extraction of the chemical from collected air
samples poses little difficulty, its extraction from a more complex
matrix such as urine is more difficult. The extraction steps in
themselves often result in poor recovery and have the potential for
increasing assay variability. When extremely high sensitivity is
required (< 1 Hg/L), GC - coupled with the preparation of derivatized
3,3'-DCB is the method of choice. However, as with extractions, the
derivatization process introduces another step which may decrease
analytical precision. If extreme sensitivity is not required, HPLC
would be preferred to GC because of the simplicity of the HPLC
procedure. The two types of detectors currently used in conjunction
with HPLC are ultraviolet (UV) and electrochemical (EC). EC detectors
are generally 20 times more sensitive than UV detectors.
Methods for the determination of 3,3'-DCB in environmental samples
are summarized in Table 6-2.
6.3 ADEQUACY OF THE DATABASE
Section 104(i)(5) of CERCLA, directs the Administrator of ATSDR (in
consultation with the Administrator of EPA and agencies and programs of
the Public Health Service) to assess whether adequate information on the
health effects of 3,3'-dichlorobenzidine is available. Where adequate
information is not available, ATSDR, in cooperation with the National
Toxicology Program (NTP), is required to assure the initiation of a
program of research designed to determine these health effects (and
techniques for developing methods to determine such health effects).
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60
6. ANALYTICAL METHODS
TABLE 6-2. Analytical Methods for 3,3'-Dichlorobenzidine
in Environmental Media
Sample type
Extract ion/oLeanup
Detection
Lim11 of
Detection References
Air
Air
Water
Water
Water
Wastewater
Wastewater
Wastewater
Soil, sediment,
solid waste
Soil, sediment,
solid waste
Collect, extract with
chloroform
Glass fiber filter, silica
gel, extract
Glass fiber filter and
silica gel, extract with
t r1e t hy1amlne-me thano1
Filter, elute with
triethylamine in methanol
Chloroform, exchange to
methanol, evaporate
Dichloromethane, dry,
evaporate
Dichlororoethane, dry,
concentrate by evaporation
NR
Extract, convert to
pentafluoropropionamldes
NR
Dtchloromethane, dry,
evaporate
Dlchlororaathane, dry,
HPLC
GC/MS
HPLC
HPLC
HPLCIUV
HPLC/ELCD
GC/MS
GC/IDMS
HPLC/UV
HPLC/ELCD
HPLC/ELCD
HPLC
GC/MS
GC/FT-IR
3
3 llg/m3
NR
0.13 UilL
16.5 Hg.1 L
50 HtlL
<3 Ha.ll.
0.2 pg
HR
NR
NR
Sittig 1985
Versehueren
1983
Morales
et al. 1981
Sittig 1985
EPA 1982a
EPA 1982b
EPA 1984
Armentrout
and Cutle 1980
Kavahara
et al. 1982
Riggin et al.
1979
EPA 1986a
EPA 1986b
HPLC - high performance liquid chromatography! NR « not reported! GC » gas chromatography! MS - mass
spectrometry! UV — ultraviolet absorption! ELCD m electrochemical detcctori ZDMS - isotope dilution mass
spectrometry! FT-IR « fourier transform infrared.
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6. ANALYTICAL METHODS
The following discussion highlights the availability, or absence, of
exposure and toxicity information applicable to human health assessment.
A statement of the relevance of identified data needs is also included.
In a separate effort, ATSDR, in collaboration with NTP and EPA, will
prioritize data needs across chemicals that have been profiled.
6.3.1 Data Needs
Method for Determining Parent Compounds and Metabolites in
Biological Materials. Methods for the determination of parent 3,3'-DCB
in biological materials are adequate. Although obviously specific for
the occurrence of 3,3'-DCB exposure, the sensitivity of urinary 3,3'-DCE
measurement as an index of severity of 3,3'-DCB exposure needs to be
established.
Methods for Biomarkers of Exposure. Adducts are reported to occur
between 3,3'-DCB and nucleic acid; however, the relevance to effects,
genotoxicity and carcinogenicity, are not known.
Methods for Determining Parent Compounds and Degradation Products
in Environmental Media. With the exception of aquatic samples, the
database for the determination of 3,3'-DCB in environmental media is
adequate.
There exists an ongoing effort to develop a "Master Analytical
Scheme" for organic compounds in water (Michael et al. 1988). The
overall goal is to detect and quantitatively measure organic compounds
at 0.1 jUg/L in drinking water, 1 /Xg/L in surface waters, and 10 Hg/~L in
effluent waters. Analytes are to include numerous semivolatile
compounds and some compounds that are only "semi-soluble" in water, as
well as volatile compounds (bp <150°C). A comprehensive review of the
literature leading up to these efforts has been published (Pellizzari
et al. 1985).
Studies designed to improve the determination of environmental
semivolatile compounds will continue to yield refinements and
improvements in the environmental determination of 3,3'-DCB. The
current high level of activity in supercritical fluid extraction of
solid and semisolid samples should yield improved recoveries and
sensitivities for the determination of 3,3'-DCB in solid wastes and the
-------
62
6. ANALYTICAL METHODS
compound should be amenable to supercritical fluid chromatographic
analysis. Immunoassay analysis Vanderlaan et al. 1988) is an area of
intense current activity from which substantial advances in the
determination of 3,3'-DCB in environmental samples can be anticipated.
6.3.2 Ongoing Studies
Supercritical fluid extraction/chromatography and immunoassay
analysis are two areas of intense current activity from which
substantial advances in the determination of 3,3'-DCB and its
metabolites in biological samples can be anticipated. The two
techniques are complementary in that supercritical fluid extraction is
especially promising for the removal of analytes from sample material
(Hawthorne 1988) and immunoassay analysis is very analyte-selective and
sensitive (Vanderlaan et al. 1988).
An especially promising approach to the determination of 3,3'-DCB
in biological samples is supercritical fluid extraction coupled with
supercritical fluid chromatography. This combination has been described
for the determination of sulfonylurea herbicides and their metabolites
in complex matrices, including soil, plant materials, and a cell culture
medium (McNally and Wheeler 1988). The approach described in this work
should be applicable to many other toxicologically and environmentally
significant analytes including 3,3'-DCB.
Thermospray techniques interfaced with mass spectrometry, with or
without high performance liquid chromatographic separation, are proving
useful for the determination of thermally labile compounds such as
toxicant metabolites (Korfmacher et al. 1987) and should be applicable
to the determination of 3,3'-DCB in biological materials (see also
Betowski et al. 1987).
-------
63
7. REGULATIONS AND ADVISORIES
Because of its potential to cause adverse health effects in exposed
people, a number of regulations and advisory values have been
established for 3,3'-DCB by various international, national and state
agencies. These values are summarized in Table 7-1.
-------
64
REGULATIONS AND ADVISORIES
TABLE 7-1. Regulations and Advisories Applicable to 3,3'-Dichlorobenzidine
Agency
Description
Value
References
I ARC
Intnut loul
Carcinogenic classification
Croup 2B
IARC 1982b
¦at loul
Regulations
a. Air
OSHA
b. Water
EPA OWRS
c. Non-specific Media
EPA OERR
EPA OSU
Guidelines
a. Air
ACGIB
NIOSB
Cancer-suspect agenti
Specific regulations
General permits under the
National Pollutant Discharge
Elimination System (KPDES)
General Pretreatment Regulations
for Existing and New Sources
of Pollution
Reportable quantity
Reportable quantity (proposed)
Hazardous Haste Constituent
(Appendix VIII)
Ground-water Monitoring List
(Appendix IX)
Threshold limit value (TLV)
Suspected Human Carcinogen
Recommended Exposure Limit for
Occupational Exposure
Stringent
workplace
controls,
record keeping
and medical
surveillance
NA"
NA
1 lb
1 lb
NA
NA
None
Potential
human
carcinogen.
Use 29 CFR
1910.1007.
29 CPR
1910.1007
*0 era 122
Appendix D
Table II
*0 CFR *03
40 era 302.4
EPA 1985
EPA 1987a
40 CFR 261
EPA 1980c
40 era 264
EPA 1987b
ACGIH 19B6
NIOSH 19B6
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65
REGULATIONS AND ADVISORIES
TABLE 7-1 (continued)
Agency
Description
Value
Reference*
b. Hater
EPA OURS
e. Other
EPA
Ambient Water Quality Criteria to
Protect Human Health'*
Ingesting Hater and Organisms
10"5
10
10
-6
-7
Ingesting Organisms Only
10
10
10"
-6
Carcinogenic Clarification
luta K«|ulat lau
EPA 19804
1.03E-* mg/L
1.03E-S mg/L
1.03E-6 B*/L
2.04E-* ag/L
2.04E-5 mg/L
2.06E-6 ng/L
B2
EPA l»86c
and Cuidaline*
State
Environmental
Agencies
State
Environmental
Agenciea
Drinking Water Standard*
and Guideline*
Kan* as
Minnesota
Acceptable Ambient
Culdelinea or Standards
FSTRAC 1988
Hev York
Rhode Island
Virginia
0.21 ug/L
0.21 ug/L
Air Concentration RATICH 1987
0.1 ug/m (1 yr)
0.002 ugtm (annual)
0 ug/m3 (24 hr)
*KA - not applicable.
"Because of its carcinogenic potential, the EPA-recoemeruled value for 3,3'-DCB In ambient water 1s aero.
However, because attainment of this Igvel may not be possible, levels which correspond to upper-bound
incremental cancer risks of 10 , 10~6 and 10~7 are estimated.
I ARC ¦ International Agency for Research en Cancan OSHA - Occupational Safety and Health Administration!
CFR - Code of Federal Regulation] EPA » Environmental Protection Ageneyi OURS - Office of Hatar Regulations
and Standardsi OERR « Office of Emergency and Remedial Responsei OSH - Office of Solid Hastei ACGIH -
American Conference of Governmental Industrial Hyglenlstsi HIOSH » Rational Institute for Occupational
Safety and Health) FSTRAC - Federal-State Toxicology and Regulatory Alliance Committee) RATICH - National
Air Toxic* Information Clesrlnghousa.
-------
67
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Shiraishi Y. 1986. Hypersensitive character of Bloom syndrome B-
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Sittig M. 1985. Handbook of Toxic Hazardous Chemicals and
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9. GLOSSARY
Acute Exposure -- Exposure to a chemical for a duration of 14 days or
less, as specified in the Toxicological Profiles.
Adsorption Coefficient (Koc) -- The ratio of the amount of a chemical
adsorbed per unit weight of organic carbon in the soil or sediment to
the concentration of the chemical in solution at equilibrium.
Adsorption Ratio (kd) -- The amount of a chemical adsorbed by a sediment
or soil (i.e., the solid phase) divided by the amount of chemical in the
solution phase, which is in equilibrium with the solid phase, at a fixed
solid/solution ratio. It is generally expressed in micrograms of
chemical sorbed per gram of soil or sediment.
Bioconcentration Factor (BCF) -- The quotient of the concentration of a
chemical in aquatic organisms at a specific time or during a discrete
time period of exposure divided by the concentration in the surrounding
water at the same time or during the same time period.
Cancer Effect Level (CEL) -- The lowest dose of chemical in a study or
group of studies which produces significant increases in incidence of
cancer (or tumors) between the exposed population and its appropriate
control.
Carcinogen -- A chemical capable of inducing cancer.
Ceiling value (CL) -- A concentration of a substance that should not be
exceeded, even instantaneously.
Chronic Exposure -- Exposure to a chemical for 365 days or more, as
specified in the Toxicological Profiles.
Developmental Toxicity -- The occurrence of adverse effects on the
developing organism that may result from exposure to a chemical prior to
conception (either parent), during prenatal development, or postnatally
to the time of sexual maturation. Adverse developmental effects may be
detected at any point in the life span of the organism.
Embryotoxicity and Fetotoxicity -- Any toxic effect on the conceptus as
a result of prenatal exposure to a chemical; the distinguishing feature
between the two terms is the stage of development during which the
insult occurred. The terms, as used here, include malformations and
variations, altered growth, and in utero death.
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9. GLOSSARY
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.
Intermediate Exposure -- Exposure to a chemical for a duration of 15-364
days, as specified in the Toxicological Profiles.
Immunologic Toxicity -- The occurrence of adverse effects on the immune
system that may result from exposure to environmental agents such as
chemicals.
In vitro -- Isolated from the living organism and artificially
maintained, as in a test tube,
In vivo -- Occurring within the living organism.
Lethal Concentration (L0) (LC) -- The lowest concentration of a chemical
in air which has been reported to have caused death in humans or
animals.
Lethal Concentration (50) (LCS0) - - 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 (L0) (LD^) -- The lowest dose of a chemical introduced by a
route other than inhalation that is expected to have caused death in
humans or animals.
Lethal Dose (50) (LD50) -- The dose of a chemical which has been
calculated to cause death in 50% of a defined experimental animal
population.
Lowest-Observed-Adverse-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.
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9. GLOSSARY
LT50 (lethal time) -- A calculated period of time within which a
specific concentration of a chemical is expected to cause death in 50%
of a defined experimental animal population.
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.
Neurotoxicity -- The occurrence of adverse effects on the nervous system
following exposure to a chemical.
No-Observed-Adverse-Effect Level (NOAEL) -- That dose of chemical at
which there are no statistically or biologically significant increases
in frequency or severity of adverse effects seen between the exposed
population and its appropriate control. Effects may be produced at this
dose, but they are not considered to be adverse.
Octanol-Water Partition Coefficient (Kow) -- The equilibrium ratio of
the concentrations of a chemical in n-octanol and water, in dilute
solution.
Permissible Exposure Limit (PEL) -- An allowable exposure level in
workplace air averaged over an 8-h shift.
q1* -- The upper-bound estimate of the low-dose slope of the dose-
response curve as determined by the multistage procedure. The q1* can
be used to calculate an estimate of carcinogenic potency, the
incremental excess cancer risk per unit of exposure (usually Mg/L for
water, mg/kg/day for food, and /ig/m3 for air).
Reference Dose (RfD) -- An estimate (with uncertainty spanning perhaps
an order of magnitude) of the daily exposure of the human population to
a potential hazard that is likely to be without risk of deleterious
effects during a lifetime. The RfD is operationally derived from the
NOAEL (from animal and human studies) by a consistent application of
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9. GLOSSARY
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) l
lb or greater or (2) for selected substances, an amount established by
regulation either under CERCLA or under Sect. 311 of the Clean Water
Act. Quantities are measured over a 24-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.
Target Organ Toxicity -- This term covers a broad range of adverse
effects on target organs or physiological systems (e.g., renal,
cardiovascular) extending from those arising through a single limited
exposure to those assumed over a lifetime of exposure to a chemical.
TD50 (toxic dose) -- A calculated dose of a chemical, introduced by a
route other than inhalation, which is expected to cause a specific toxic
effect in 50% of a defined experimental animal population.
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.
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9. GLOSSARY
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 3,3'-DCB. The panel
consisted of the following members: Dr. Paul Mushak, Private
Consultant, Durham, North Carolina; Dr. David Jollow, Professor, Medical
University of South Carolina; Dr. T.J. Kneip, Professor, New York
University Medical Center. These experts collectively have knowledge of
3,3'-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.
a U.S. GOVERNMENT PRINTING OFFICE !
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