JV-NITROSODIPHENYLAMINE
Agency for Toxic Substances and Disease Registry
U.S. Public Health Service
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ATSDR/TP-88/20
TOXICOLOGICAL PROFILE FOR
/V-NITROSODIPHENYLAMINE
Date Published — December 1988
Prepared by:
Syracuse Research Corporation
under Contract No. 68-C8-0004
for
Agency for Toxic Substances and Disease Registry (ATSDR)
U.S. Public Health Service
in collaboration with
U.S. Environmental Protection Agency (EPA)
Technical editing/document preparation by:
Oak Ridge National Laboratory
under
DOE Interagency Agreement No. I857-B026-A1
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DISCLAIMER
Mention of company name or product does not constitute endorsement by
the Agency for Toxic Substances and Disease Registry.
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FOREWORD
The Superfund Amendments and Reauthorization Act of 1986 (Public
Law 99-499) extended and amended the Comprehensive Environmental
Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund).
This public law (also known as SARA) directed the Agency for Toxic
Substances and Disease Registry (ATSDR) to prepare toxicological
profiles for hazardous substances which are most commonly found at
facilities on the CERCLA National Priorities List and which pose the
most significant potential threat to human health, as determined by
ATSDR and the Environmental Protection Agency (EPA). The list of the 100
most significant hazardous substances was published in the Federal
Register on April 17, 1987.
Section 110 (3) of SARA directs the Administrator of ATSDR to
prepare a toxicological profile for each substance on the list. Each
profile must include the following content:
"(A) An examination, summary, and interpretation of available
toxicological information and epidemiologic evaluations on a
hazardous substance in order to ascertain the levels of significant
human exposure for the substance and the associated acute,
subacute, and chronic health effects.
(B) A determination of whether adequate information on the health
effects of each substance is available or in the process of
development to determine levels of exposure which present a
significant risk to human health of acute, subacute, and chronic
health effects.
(C) Where appropriate, an identification of toxicological testing
needed to identify the types or levels of exposure that may present
significant risk of adverse health effects in humans."
This toxicological profile is prepared in accordance with
guidelines developed by ATSDR and EPA. The guidelines were published in
the Federal Register on April 17, 1987. Each profile will be revised and
republished as necessary, but no less often than every three years, as
required by SARA.
The ATSDR toxicological profile is intended to characterize
succinctly the toxicological and health effects information for the
hazardous substance being described. Each profile identifies and reviews
the key literature that describes a hazardous substance's toxicological
properties. Other literature is presented but described in less detail
than the key studies. The profile is not intended to be an exhaustive
document; however, more comprehensive sources of specialty information
are referenced.
Lit
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Foreword
Each coxicological profile begins with a public health statement,
which describes in nontechnical language a substance's relevant
toxicological properties. Following the statement is material that
presents levels of significant human exposure and, where known,
significant health effects. The adequacy of information to determine a
substance's health effects is described in a health effects summary.
Research gaps in toxicologic and health effects information are
described in the profile. Research gaps that are of significance to
protection of public health will be identified by ATSDR, the National
Toxicology Program of the Public Health Service, and EPA. The focus of
the profiles is on health and toxicological information; therefore, we
have included this information in the front of the document.
The principal audiences for the toxicological profiles are health
professionals at the federal, state, and local levels, interested
private sector organizations and groups, and members of the public. We
plan to revise these documents in response to public comments and as
additional data become available; therefore, we encourage comment that
will make the toxicological profile series of the greatest use.
This profile reflects our assessment of all relevant toxicological
testing and information that has been peer reviewed. It has been
reviewed by scientists from ATSDR, EPA, the Centers for Disease Control,
and the National Toxicology Program. It has also been reviewed by a
panel of nongovernment peer reviewers and was made available for public
review. Final responsibility for the contents and views expressed in
this toxicological profile resides with ATSDR.
James 0. Mason, M.D., Dr. P.H.
Assistant Surgeon General
Administrator, ATSDR
iv
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CONTENTS
FOREWORD iii
LIST OF FIGURES ix
LIST OF TABLES xi
1. PUBLIC HEALTH STATEMENT 1
1.1 WHAT IS tf-NITROSODIPHENYLAMINE? 1
1.2 HOW MIGHT I BE EXPOSED TO N-NITROSODIPHENYLAMINE? 1
1.3 HOW DOES N-NITROSODIPHENYLAMINE GET INTO MY BODY? 1
1.4 HOW CAN W-NITROSODIPHENYLAMINE AFFECT MY HEALTH? 2
1.5 IS THERE A MEDICAL TEST TO DETERMINE IF I HAVE BEEN
EXPOSED TO N-NITROSODIPHENYLAMINE? : 2
1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL
HEALTH EFFECTS? 2,
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE
TO PROTECT HUMAN HEALTH? 2
2. HEALTH EFFECTS SUMMARY 5
2.1 INTRODUCTION 5
2.2 LEVELS OF SIGNIFICANT EXPOSURE 6
2.2.1 Key Studies and Graphical Presentations 6
2.2.1.1 Inhalation 6
2.2.1.2 Oral 6
2.2.1.3 Dermal 12
2.2.2 Biological Monitoring as a Measure of
Exposure and Effects 12
2.2.3 Environmental Levels as Indicators of
Exposure and Effects 12
2.2.3.1 Levels found in the environment 12
2.2.3.2 Human exposure potential 12
2 . 3 ADEQUACY OF DATABASE 13
2.3.1 Introduction 13
2.3.2 Health Effect End Points 13
2.3.2.1 Introduction and graphic summary 13
2.3.2.2 Descriptions of highlights of graphs .... 16
2.3.2.3 Summary of relevant ongoing research .... 16
2.3.3 Other Information Needed for
Human Health Assessment 16
2.3.3.1 Pharmacokinetics and mechanisms
of action 16
2.3.3.2 Monitoring of human biological samples .. 17
2.3.3.3 Environmental considerations 17
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Contents
3. CHEMICAL AND PHYSICAL INFORMATION 19
3.1 CHEMICAL IDENTITY 19
3 . 2 PHYSICAL AND CHEMICAL PROPERTIES '.'.'. 19
4. TOXICOLOGICAL DATA 23
4. 1 OVERVIEW 23
4.2 TOXICOKINETICS '/_ 24
4.2.1 Absorption 24
4.2.1.1 Inhalation 24
4.2.1.2 Oral 24
4.2.1.3 Dermal 24
4.2.2 Distribution 25
4.2.3 Metabolism 25
4.2.3.1 Inhalation 25
4.2.3.2 Oral 25
4.2.4 Excretion 25
4.2.4.1 Inhalation 25
4.2.4.2 Oral 25
4.3 TOXICITY 26
4.3.1 Lethality and Decreased Longevity 26
4.3.1.1 Inhalation 26
4.3.1.2 Oral 26
4.3.1.3 Dermal 27
4.3.2 Systemic/Target Organ Toxicity 27
4.3.2.1 Bladder toxicity 27
4.3.2.2 End points of uncertain significance
in oral animal studies 28
4.3.3 Developmental Toxicity 29
4.3.4 Reproductive Toxicity 29
4.3.5 Genotoxicity 29
4.3.5.1 Human 29
4.3.5.2 Nonhuman 31
4.3.5.3 General discussion 31
4.3.6 Carcinogenicity 31
4.3.6.1 Inhalation 31
4.3.6.2 Oral 31
4.3.6.3 Dermal 35
4.3.6.4 General discussion 35
4.4 INTERACTIONS WITH OTHER CHEMICALS 35
5. MANUFACTURE, IMPORT, USE, AND DISPOSAL 37
5.1 OVERVIEW 37
5.2 PRODUCTION 37
5.3 IMPORT 38
5.4 USE '.'.'.'.'.'.'.'.'. 38
5.5 DISPOSAL 38
6. ENVIRONMENTAL FATE 39
6.1 OVERVIEW '..'"' 39
6 . 2 RELEASES TO THE ENVIRONMENT '..'... 39
6. 3 ENVIRONMENTAL FATE 39
7. POTENTIAL FOR HUMAN EXPOSURE 41
7.1 OVERVIEW 41
vi
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Contents
7.2 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 41
7.2.1 Air 41
7.2.2 Water 41
7.2.3 Soil 41
7.2.4 Other 41
7.3 OCCUPATIONAL EXPOSURES 42
7.4 POPULATIONS AT HIGH RISK 42
8. ANALYTICAL METHODS 43
8.1 ENVIRONMENTAL MEDIA '' 43
8.2 BIOMEDICAL SAMPLES 43
9. REGULATORY AND ADVISORY STATUS 47
9.1 INTERNATIONAL (WORLD HEALTH ORGANIZATION) 47
9.2 NATIONAL 47
9.2.1 Regulations 47
9.2.2 Advisory Guidance 47
9.2.2.1 Water 47
9.2.3 Data Analysis 47
9.2.3.1 Reference dose 47
9.2.3.2 Carcinogenic potency 47
9.3 STATE 48
10. REFERENCES 49
11. GLOSSARY 61
APPENDIX: PEER REVIEW 65
vii
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LIST OF FIGURES
1.1 Health effects from ingesting tf-nitrosodiphenylamine 3
2.1 Effects of N-nitrosodiphenylamine--oral exposure 8
2.2 Levels of significant exposure for W-nitroso-
diphenylamine--oral 9
2.3 Availability of information on health effects of
N-nitrosodiphenylamine (human data) 14
2.4 Availability of information on health effects of
N-nitrosodiphenylamine (animal data) 15
ix
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LIST OF TABLES
3.1 Chemical identity of tf-nitrosodiphenylamine 20
3.2 Physical and chemical properties of tf-nitrosodiphenylamine ... 21
4.1 Genotoxicity of W-nitrosodiphenylamine in vitro 30
4.2 Genotoxicity of tf-nitrosodiphenylamine in vivo 32
4.3 Incidences of tumors in F344 rats treated with
tf-nitrosodiphenylamine in the diet for 100 weeks 34
8.1 Analytical methods--environmental media 44
8.2 Analytical methods--biomedical samples 45
xi
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1. PUBLIC HEALTH STATEMENT
1.1 WHAT IS W-NITROSODIPHENYLAMINE?
N-Nitrosodiphenylamine is not a naturally occurring substance; it
is a man-made chemical that is no longer produced in the United States.
It was used to help control processes involved in making rubber products
such as tires and mechanical goods; however, in the early 1980s, the
U.S. manufacturers stopped producing tf-nitrosodiphenylamine because new
and more efficient chemicals were found to replace its uses. In
addition, the use of tf-nitrosodiphenylamine had several undesirable side
effects which do not occur with the replacement chemicals. N-
Nitrosodiphenylamine was imported from foreign countries in the 1970s
and early 1980s, but further information regarding importation since the
early 1980s was not found.
1.2 HOV MIGHT I BE EXPOSED TO W-NITROSODIPHENYLAMINE?
Under normal circumstances, the general population of the United
States is not exposed to any AT-nitrosodiphenylamine. There is no
available evidence to indicate that tf-nitrosodiphenylamine exists
naturally in soil, air, food, or water. It is unlikely that N-
nitrosodiphenylamine remains in finished rubber products. Workers who
were involved in the production or use of W-nitrosodiphenylamine may
have been exposed to the chemical. Current occupational exposure is
probably minimal, since N-nitrosodiphenylamine is no longer produced in
the United States. Current exposure also may include contact with N-
nitrosodiphenylamine wastes at various waste disposal sites from
disposal during past years.
1.3 HOW DOES tf-NITROSODIPHENYLAMINE GET INTO MY BODY?
Because N-nitrosodiphenylamine does not occur naturally in the
environment and is no longer being manufactured in the United States, it
is not likely to get into your body unless you come into contact with
wastes or soil from a waste disposal site where N-nitrosodiphenylamine
wastes were disposed. It is not known whether direct skin contact with
wastes or soil containing AT-nitrosodiphenylamine would allow this
chemical to enter the body. tf-Nitrosodiphenylamine is not likely to be
in most air, water, or soil, so you are not likely to breathe air, drink
water, or touch soil contaminated with this chemical. It can, however,
get into your body when you breathe airborne dust particles from
contaminated waste sites. Because it is unlikely that N-
nitrosodiphenylamine remains in finished rubber products, you should noc
be exposed by direct contact with rubber products that were made with
the chemical or from burning of these rubber products.
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2 Section 1
1.4 HOV CAN N-NITROSODIPHENYLAMINE AFFECT NT HEALTH?
Information is not available regarding effects of brief exposures
to N-nitrosodiphenylamine on human health. Very little is known about
the health effects of brief exposures to N-nitrosodiphenylamine in
experimental animals, other than that relatively high doses by ingestion
are required to produce death.
Long-term exposure of experimental animals to N-nitroso-
diphenylamine by ingestion produced inflammation and cancer of the
bladder. It is not known whether these effects or birth defects would
occur in humans if they were exposed to N-nitrosodiphenylamine.
It is not known if exposure to N-nitrosodiphenylamine by breathing
or skin contact can affect the health of humans or animals, but, because
ingestion of N-nitrosodiphenylamine has been shown to have adverse
health effects in animals, exposure of humans to N-nitrosodiphenylamine
should be minimized.
1.5 IS THERE A MEDICAL TEST TO DETERMINE IF I HAVE BEEN EXPOSED TO
N-NITROSODIPHENTLAMINE?
Although the presence of the c'r .aical in blood and urine can be
detected by chemical analysis, this analysis has not been used as a test
for human exposure or to predict potential health effects.
1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTS?
The graph on the following page shows the relationship between
exposure to N-nitrosodiphenylamine and known health effects. Exposure is
measured in milligrams of N-nitrosodiphenylamine per kilogram of body
weight per day (mgAg/day) , and effects in animals are shown on the left
side, effects in humans on the right. The level marked on the graph as
anticipated to be associated with minimal risk is based on information
that is currently available from animal experiments; therefore, some
uncertainty is associated with this estimate of minimal risk. Based on
studies in laboratory animals, the U.S. Environmental Protection Agency
(EPA) has estimated that ingestion of 1 mgAg/day for a lifetime would
result in 49 additional cases of cancer in a population of 10,000 people
and 49,000 additional cases of cancer in a population of 10,000,000
people. It should be noted that these risk values are plausible upper-
limit estimates. The actual risk levels are unlikely to be higher and
may be lower.
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT
HUMAN HEALTH?
Because N-nitrosodiphenylamine causes cancer in laboratory animals,
it is assumed that any exposure to the chemical involves some risk for
humans.
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Public Health Statement
SHORT-TERM EXPOSURE
(LESS THAN OR EQUAL TO 14 DAYS)
LONG-TERM EXPOSURE
(GREATER THAN 14 DAYS)
EFFECTS
IN
ANIMALS
nt-.fi i
DOSE
(mg/kg/day)
10.000
1000
100
10
10
01
001
EFFECTS EFFECTS
IN IN
HUMANS ANIMALS
QUANTITATIVE
DATA WERE
NOT
AVAILABLE DEATH
DECREASED
EFFECTS
DOSE
(mg/kg/day)
10.000
1000
100
10
10
01
->
0.01
EFFECTS
IN
HUMANS
QUANTITATIVE DATA
WERE NOT AVAILABLE
)
MINIMAL RISK FOR
> EFFECTS OTHER
THAN CANCER
0 0
Fig. 1.1. Health effects from ingesting JV-futrosodipnenylainine.
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4 Section I
The EPA has developed a guideline for the concentration of N-
nitrosodiphenylamine in ambient water (lakes, rivers, etc.) that is
associated with a risk of developing cancer. This guideline is a range,
490 to 49,000 nanograns of N-nitrosodiphenylamine per liter of water,
which reflects the increased risk of one person developing cancer in
populations of 10,000,000 to 100,000 people.
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2. HEALTH EFFECTS SUMMARY
2.1 INTRODUCTION
This section summarizes and graphs data on the health effects
concerning exposure to N-nitrosodiphenylamine. The purpose of this
section is to present levels of significant exposure for N-
nitrosodiphenylamine based on key toxicological studies, epidemiological
investigations, and environmental exposure data. The information
presented in this section is critically evaluated and discussed in Sect.
4, Toxicological Data, and Sect. 7, Potential for Human Exposure.
This Health Effects Summary section comprises two major parts.
Levels of Significant Exposure (Sect. 2.2) presents brief narratives and
graphics for key studies in a manner that provides public health
officials, physicians, and other interested individuals and groups with
(1) an overall perspective of the toxicology of N-nitrosodiphenylamine
and (2) a summarized depiction of significant exposure levels associated
with various adverse health effects. This section also includes
information on the levels of tf-nitrosodiphenylamine that have been
monitored in human fluids and tissues and information about levels of
tf-nitrosodiphenylamine found in environmental media and their
association with human exposures.
The significance of the exposure levels shown on the graphs may
differ depending on the user's perspective. For example, physicians
concerned with the interpretation of overt clinical findings in exposed
persons or with the identification of persons with the potential to
develop such disease may be interested in levels of exposure associated
with frank effects (Frank Effect Level, FEL). Public health officials
and project managers concerned with response actions at Superfund sites
may want information on levels of exposure associated with more subtle
effects in humans or animals (Lowest-Observed-Adverse-Effect Level,
LOAEL) or exposure levels below which no adverse effects (No-Observed-
Adverse-Effect Level, NOAEL) have been observed. Estimates of levels
posing minimal risk to humans (Minimal Risk Levels) are of interest to
health professionals and citizens alike.
Adequacy of Database (Sect. 2.3) highlights the availability of key
studies on exposure to N-nitrosodiphenylamine in the scientific
literature and displays these data in three-dimensional graphs
consistent with the format in Sect. 2.2. The purpose of this section is
to suggest where there might be insufficient information to establish
levels of significant human exposure. These areas will be considered by
the Agency for Toxic Substances and Disease Registry (ATSDR), EPA. and
the National Toxicology Program (NTP) of the U.S. Public Health Service
in order to develop a research agenda for tf-nitrosodiphenylamine.
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6 Section 2
2.2 LEVELS OF SIGNIFICANT EXPOSURE
To help public health professionals address the needs of persons
living or working near hazardous waste sites, the toxicology data
summarized in this section are organized first by route of exposure--
inhalation, ingestion, and dermal--and then by toxicological end points
that are categorized into six general areas--lethality, systemic/target
organ toxicity, developmental toxicity, reproductive toxicity, genetic
toxicity, and carcinogenicity. The data are discussed in terms of three
exposure periods--acute, intermediate, and chronic.
Two kinds of graphs are used to depict the data. The first type is
a "thermometer" graph. It provides a graphical summary of the human and
animal toxicological end points (and levels of exposure) for each
exposure route for which data are available. The ordering of effects
does not reflect the exposure duration or species of animal tested. The
second kind of graph shows Levels of Significant Exposure (LSE) for each
route and exposure duration. The points on the graph showing NOAELs and
LOAELs reflect the actual doses (levels of exposure) used in the key
studies. No adjustments for exposure duration or intermittent exposure
protocol were made.
Adjustments reflecting the uncertainty of extrapolating animal data
to man, intraspecies variations, and differences between experimental
versus actual human exposure conditions were considered when estimates
of levels posing minimal risk to human health were made for noncancer
end points. These minimal risk levels were derived for the most
sensitive noncancer end point for each exposure duration by applying
uncertainty factors. These levels are shown on the graphs as a broken
line starting from the actual dose (level of exposure) and ending with a
concave-curved line at its terminus. Although methods have been
established to derive these minimal risk levels (Barnes et al. 1987),
shortcomings exist in the techniques that reduce the confidence in the
projected estimates. Also shown on the graphs under the cancer end point
are low-level risk (10'4 to 10'7) reported by EPA. In addition, the
actual dose (level of exposure) associated with the tumor incidence is
plotted.
2.2.1 Key Studies and Graphical Presentations
2.2.1.1 Inhalation
No studies of the effects of inhalation exposure to N-nitroso-
diphenylaoine in humans or animals were found in the available
literature.
2.2.1.2 Oral
Human health effects data are not available for oral exposure to
tf-nitrosodiphenylamine. The animal data provide a limited
characterization of the lethality, systemic/target organ toxicity, and
carcinogenicity of N-nitrosodiphenylamine, but no information on
developmental or reproductive toxicity. The data on acute- and
intermediate-length exposure indicate that the chemical has a low order
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Health Effects Summary 7
of toxtclty. Chronic oral exposure to N-nitrosodiphenylamine is toxic
and carcinogenic to the bladders of rats, but does not appear to affect
the livers of rats or mice.
Dose-response-duration data for the oral toxicity and
carcinogenicity of N-nitrosodiphenylamine are displayed in two types of
graphs. These data are derived from the key studies described in the
following sections. The thermometer graph in Fig. 2.1 and the graph of
levels of significant exposure in Fig. 2.2 plot end point-specific
NOAELs and LOAELs and minimal levels of risk for acute (<14 days),
intermediate (15-364 days), and/or chronic (>36S days) exposure and also
show doses associated with individual lifetime upperbound increased
cancer risks of 1/10,000 through 1/10,000,000.
Lethality and decreased longevity. An acute oral LD50 of
3000 mg/kg was determined for N-nitrosodiphenylamine in rats (Druckrey
et al. 1967). This dose is plotted in Figs. 2.1 and 2.2.
Data from the subchronic range-finding and chronic studies of the
National Cancer Institute (NCI 1979) provide the best illustration of
dose response for lethality in rats and mice and indicate that rats are
more sensitive to N-nitrosodiphenylamine than are mice. In the
subchronic study, rats and mice were fed a wide range of N-nitroso-
diphenylamine concentrations in the diet for 8-11 weeks. All mice
survived at all dietary levels including the highest tested, 46,000 ppm.
Assuming that mice consume the equivalent of 13% of their body weight
daily as food (i.e., a food factor of 0.13) (EPA 1980a, 1986a),
46,000 ppm is equivalent to 5980 mgAg/day (NOAEL for lethality in mice
plotted for intermediate exposure on Figs. 2.1 and 2.2). All rats
survived at <10.000 ppm, two of five died at 16,000 ppm, and mortality
was 100% at dietary levels >16,000 ppm. Assuming that rats consume the
equivalent of 5% of their body weight daily as food (i.e., a food factor
of 0.05) (EPA 1980a, 1986a), 10,000 ppm corresponds to 500 mg/kg/day
(NOAEL for lethality in rats for intermediate exposure), and 16,000 ppm
corresponds to 800 mg/kg/day (FEL). These levels are plotted in Figs.
2.1 and 2.2.
In the chronic NCI (1979) study, rats and mice were fed N-nitroso-
diphenylamine in the diet for 100-101 weeks (-2 years). Survival was
affected in mice at 5741 ppm (711 mgAg/day) but not at 2315 ppm (301
ngAg/day) ; survival in rats was affected at 4000 ppm (200 mg/kg/day)
but not at 1000 ppm (50 mgAg/day). Dosages were estimated from dietary
concentrations using the above food factors. These no-effect and effect
levels for lethality and decreased survival are plotted in Figs. 2.1 and
2.2 as NOAELs and LOAELs for this particular end point, although it is
obvious that an exposure level which produces death is also a FEL and
one which does not produce death may produce adverse effects on other
end points.
Systemic/target organ toxicity. Acute- and intermediate-length
studies with mice showed mild effects in the liver that do not indicate
that the liver is a target of tf-nitrosodiphenylamine toxicity. Effects
on the liver were not described in intermediate.duration studies with
rats, the more sensitive of the two species.
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8 Section 2
ANIMALS
(mg/kg/day)
10.000 r
HUMANS
1000
100
10 >-
O MOUSE, UVER EFFECTS. DECREASED SURVIVAL 8 WEEKS
• RAT. LD... ACUTE
RAT. DECREASED SURVIVAL. 8-11 WEEKS
MOUSE. DECREASED SURVIVAL 2 YEARS
RAT. DECREASED SURVIVAL 8-11 WEEKS
MOUSE BLADDER TOXICITY, 2 YEARS
MOUSE. UVER EFFECTS. 4 DAYS. MOUSE DECREASED LONGEVITY. 2 YEARS
RAT. DEPRESSED WEIGHT GAIN. 8-11 WEEKS. BLADDER CANCER. DECREASED
SURVIVAL 2 YEARS
RAT. DEPRESSED WEIGHT GAIN. S-11 WEEKS
(• RAT. BLADDER TOXICITY. 2 YEARS
1 ° RAT. DECREASED LONGEVITY. 2 YEARS
QUANTITATIVE DATA
WERE NOT
AVAILABLE
• LOAEL
ONOAEL
Fig. 2.1. Effects of /V-nitrosodiphenylamine—oral exposure.
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Health Effects Siuamary 9
ACUTE
(SI 4 DAYS)
CHRONIC
(2365 DAYS)
TARGET
LETHALITY ORGAN
INTERMEDIATE
(15-364 DAYS)
TARGET DECREASED TARGET
LETHALITY ORGAN SURVIVAL ORGAN CANCER
(mg/kg/day)
10.000
1000
100
10
01
001
0001 -
00001 -
000001 L-
O m (LIVER)
om
r
o m (LJVER)
?r (DECREASED
BODY WEIGHT)
im
r
• m (BLADDER)
(BLADDER)
10-S-
,0-6-
10-7-"
ESTIMATED
UPPER-BOUND
HUMAN
CANCER
RISK LEVELS
; MINIMAL RISK LEVEL
; FOR EFFECTS OTHER
* THAN CANCER
• LOAEL
O NOAEL
r RAT
m MOUSE
I LOAEL AND NOAEL
IN THE SAME SPECIES
Fig. 2.2. Levels of significant exposure for ^V-nitrosodipbenylamine—oral.
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10 Section 2
In an acute study of hepatotoxicity (Nishie et al. 1972), mice
given 350 mg/kg/day of W-nitrosodiphenylamine for 4 consecutive days had
effects characteristic of enzyme induction (decreased pentobarbital
sleeping time and increased amounts of smooth endoplasmic reticulum in
the liver cells). This is considered an adaptive rather than an adverse
effect because light microscopic examination of the liver revealed no
lesions and liver lesions did not occur in mice in studies of
intermediate and chronic duration. This level of exposure is graphed as
a NOAEL for hepatic effects in Figs. 2.1 and 2.2 for acute exposure.
Because enzyme induction is a nonspecific effect that also may have
occurred in other organs and because there is no indication that the
enzyme induction is related to subsequent development of adverse liver
alterations, the effect does not indicate that the liver is a target of
toxicity. As shown in other experiments of intermediate and chronic
duration, rats are more sensitive than mice. As rats were not studied in
acute experiments and only the liver was examined in the acute study in
mice, the NOAEL in mice, which is plotted in Fig. 2.2, is not an
appropriate basis for a minimal risk level for acute exposure.
In an 8-week feeding study in mice (NCI 1979), the only gross or
histopathological effect observed during examination of unspecified
tissues was pigmentation of Kupffer's cells in the hepatic sinusoids in
mice that received the highest dietary concentration, 46,000 ppm (5980
mg/kg/day). The pigmentation is presumed to reflect phagocytic activity
by the Kupffer's cells and is not considered to be adverse because only
trace amounts occurred; there were no signs of toxicity or other
histological alterations, and survival was not affected. This level is
plotted as a NOAEL for hepatic effects in Figs. 2.1 and 2.2 for
intermediate exposure.
Although a target organ has not been demonstrated in rats for acute
or intermediate exposure, dose-response relationships for the systemic
toxicity of intermediate-length exposure in rats can be illustrated by
using a combination of lethality, body weight, and pathology data from
the NCI (1979) 8- to 11-week feeding study. No gross or
histopathological effects were seen in unspecified tissues in survivors,
including the two survivors in the group of five rats that received
16,000 ppm; rats that died during the study (at >16,000 ppm) were not
examined for target organ toxicity. A consistent decrease in body weight
gain (-14% decrease relative to control weight) occurred at >4000 ppm,
but the decrease in weight gain did not become more severe with
increasing dietary level until survival was also affected. Based on body
weight depression and the lack of pathological effects (or death), 3000
ppm (150 mg/kg/day) is the NOAEL, and 4000 ppm (200 mg/kg/day) is the
LOAEL for body weight depression and systemic toxicity. These levels
are shown for body weight depression in Fig. 2.1 and for intermediate
systemic toxicity in Fig. 2.2. The NOAEL is the basis for the minimal
risk level for intermediate exposure.
An -2-year feeding study identified the bladder as the target organ
for chronic exposure in rats and mice (NCI 1979, Cardy et al. 1979).
This is the only study that investigated the systemic toxicity of
chronic oral exposure to tf-nitrosodiphenylamine. Low, but dose-related,
incidences of bladder epithelial hyperplasia occurred in rats at both
the 1000- and the 4000-ppm dietary levels of N-nitrosodiphenylamine;
-------
Health Effects Summary 11
epithelial metaplasia (and bladder carcinomas) occurred at the higher
exposure only. The 1000-ppm level (50 mgAg/day) is therefore a LOAEL
for target organ toxicity and is graphed accordingly under chronic
exposure as the basis for the minimal risk level for chronic exposure in
Fig. 2.2; this level is graphed as a LOAEL for bladder toxicity in
Fig. 2.1.
In mice, high-dose-related incidences of bladder submucosal
inflammation occurred at 2315- and 5471-ppm dietary levels of N-
nitrosodiphenylamine (NCI 1979, Cardy et al. 1979). The 2315-ppm level
(300 mg/kg/day) constitutes a LOAEL for target organ toxicity in mice
and is graphed as such under chronic exposure in Fig. 2.2 and as a LOAEL
for bladder toxicity in Fig. 2.1. NOAELs for chronic systemic/target
organ toxicity are not defined for either rats or mice in this study or
in other oral studies, which are less adequate.
Dosages were calculated from dietary concentrations as described
previously in the section on lethality and decreased longevity.
Developmental toxicity. Pertinent data regarding developmental
toxicity of N-nitrosodiphenylamine were not found in the available
literature.
Reproductive tozicity. Pertinent data regarding reproductive
toxicity of N-nitrosodiphenylamine were not found in the available
literature.
Genotoxicity. Extensive testing in a variety of organisms and
cells has established that N-nitrosodiphenylamine does not produce gene
mutations in vitro, with or without metabolic activation (see Sect.
4.3.5). In vivo studies of mutation and other genotoxicity end points
have given negative results. Mixed results have been obtained in in
vitro studies of DNA damage or cell transformation.
Carcinogenicity. tf-Nitrosodiphenylamine was carcinogenic to rats
in the chronic feeding study discussed previously under lethality and
systemic/target organ toxicity. Rats fed 4000 ppm of tf-nitroso-
diphenylamine in the diet (200 mgAg/day) for -2 years had significantly
increased incidences of transitional cell carcinomas of the bladder;
controls and rats fed 1000 ppm had no bladder tumors (NCI 1979, Cardy et
al. 1979). The 4000-ppm level (200 mgAg/day) is graphed as a LOAEL for
bladder cancer in Figs. 2.1 and 2.2, although it is understood that a
level of exposure that causes cancer also constitutes a FEL.
Mice fed 2315 or 5471 ppm (females) and 5000 or 10,000 ppm (males)
for -2 years had no increases in tumor incidence (NCI 1979, Cardy et al.
1979). Negative results were also obtained for mice administered N-
nitrosodiphenylamine by gavage at 1000 mgAg/day from 7-28 days of age,
and subsequently in the diet at 3769 ppm until -82 weeks of age (BRL
1968). Two other oral carcinogenicity studies in rats (Druckrey et al.
1967, Argus and Hoch-Ligeti 1961), which reported negative results, were
not as adequate for the assessment of carcinogenicity.
EPA (1980b) calculated a carcinogenic potency factor for humans
(q1*) of 4.92 x 10'3 (mgAg/day)'1 based on dose-response data for the
incidence of bladder transitional cell carcinomas in female rats in the
study reported by NCI (1979) and Cardy et al. (1979). Based on this q *
-------
12 Section 2
estimated doses corresponding to individual lifetime upperbound limits
for increased risk of cancer in 1/10,000 to 1/10,000,000 people are
2 x 10*2 to 2 x 10'5 mg/kg/day. These levels are displayed graphically
in Fig. 2.2.
2.2.1.3 Dermal
No human health effects data are available for dermal exposure. The
only pertinent animal study is a carcinogenicity study. Hairless mice
treated with single weekly applications of a 1% solution of N-
nitrosodiphenylamine in acetone for 20 weeks had no local skin tumors
(Iverson 1980). Lung adenomas were detected in a few animals, but there
were no controls. This study is not adequate for the evaluation of the
carcinogenicity of N-nitrosodiphenylamine by the dermal route of
exposure because treatment duration and frequency were short, only one
exposure level was tested, histological examinations were limited, and
no controls were used.
2.2.2 Biological Monitoring as a Measure of Exposure and Effects
N-Nitrosodiphenylamine can be detected in blood, serum, and urine,
with detection limits in serum being the most sensitive (Pylyplw and
Harrington 1981), but monitoring data associating body fluid levels with
exposure and effects were not located. Therefore, no conclusion
regarding the usefulness of this test can be made.
2.2.3 Environmental Levels as Indicators of Exposure and Effects
2.2.3.1 Levels found in the environment
Data regarding the association between significant human exposure
or effects and levels of N-nitrosodiphenylamine found in the
environment, particularly food, soil, and water, were not encountered in
the available literature.
2.2.3.2 Human exposure potential
In limited monitoring studies, N-nitrosodiphenylamine was reported
to be present in contaminated soils. It has been predicted that N-
nitrosodiphenylamine will remain adsorbed in soils. The sorption will be
stronger as the organic carbon content of soils increases. As the
sorption becomes stronger, it will become less bioavailable to animals
and microorganisms. Conversely, factors that will help mobilize the
chemical from soil through solubilization or other mechanisms will also
increase its bioavailability for animals/microorganisms and possibly for
uptake by plants, although no data for either route of exposure are
available. The mobilization of the chemical in soils may also increase
the probability of its leaching into groundwater. If such uptake by
plants or leaching into groundwater occurs, it may increase the
potential of human exposure to it through consumption of foods or
possibly drinking water originating from groundwater; however, no
monitoring data are available to substantiate the above speculations.
-------
Health Effects Summary 13
2.3 ADEQUACY OF DATABASE
2.3.1 Introduction
Section 110 (3) of SARA directs the Administrator of ATSDR to
prepare a toxicological profile for each of the 100 most significant
hazardous substances found at facilities on the CERCLA National
Priorities List. Each profile must include the following content:
"(A) An examination, summary, and interpretation of available
toxicological information and epidemiologic evaluations on a
hazardous substance in order to ascertain the levels of
significant human exposure for the substance and the
associated acute, subacute, and chronic health effects.
(B) A determination of whether adequate information on the health
effects of each substance is available or in the process of
development to determine levels of exposure which present a
significant risk to human health of acute, subacute, and
chronic health effects.
(C) Where appropriate, an identification of toxicological testing
needed to identify the types or levels of exposure that may
present significant risk of adverse health effects in humans."
This section identifies gaps in current knowledge relevant to
developing levels of significant exposure for N-nitrosodiphenylamine.
Such gaps are identified for certain health effects end points
(lethality, system/target organ toxicity, developmental toxicity,
reproductive toxicity, and carcinogenicity) reviewed in Sect. 2.2 of
this profile in developing levels of significant exposure for N-
nitrosodiphenylamine, and for other areas such as human biological
monitoring and mechanisms of toxicity. The present section briefly
summarizes the availability of existing human and animal data,
identifies data gaps, and summarizes research in progress that may fill
such gaps.
Specific research programs for obtaining data needed to develop
levels of significant exposure for tf-nitrosodiphenylamine will be
developed by ATSDR, NTP, and EPA in the future.
2.3.2 Health Effect End Points
2.3.2.1 Introduction and graphic summary
The availability of data for health effects in humans and animals
is depicted on bar graphs in Figs. 2.3 and 2.4, respectively.
The bars of full height indicate that there are data to meet at
least one of the following criteria:
1. For noncancer health end points, one or more studies are available
that meet current scientific standards and are sufficient to define
a range of toxicity from no-effect levels (NOAELs) to levels that
cause effects (LOAELs or FELs).
-------
HUMAN DATA
V SUFFICIENT
^"INFORMATION*
SOME
INFORMATION
NO
INFORMATION
LETHALITY
ACUTE
INTERMEDIATE CHROMIC DEVELOPMENTAL REPRODUCTIVE CARCINOQENICITY
TOXICITV TOXICITV
SYSTEMIC TOXICITY
'Sufficient information exists to meet at least one of the criteria (or cancer or noncancer end points.
Fig. 2.3. Availability of information on health effects of JV-nitrosodiphenylamine (human data).
-------
ANIMAL DATA
SUFFICIENT
INFORMATION*
SOME
INFORMATION
NO
INFORMATION
DERMAL
LETHALITY ACUTE
Z
INTERMEDIATE CHRONIC DEVELOPMENTAL REPRODUCTIVE CAHCINOQENICITY
/ TOXICITY TOKICITV
3-
5
n
SYSTEMIC TOXICITY
Sufficient information exists to meet at least one of the criteria for cancer or noncancer end points.
Fig. 2.4. Availability of information on health effects of /V-nitrosodiphenylamioe (animal data).
-------
16 Section 2
2. For human carcinogenicicy, a substance is classified as either a
"known human carcinogen" or "probable human carcinogen" by both EPA
and the International Agency for Research on Cancer (IARC)
(qualitative), and the data are sufficient to derive a cancer
potency factor (quantitative).
3. For animal carcinogenicity, a substance causes a statistically
significant number of tumors in at least one species, and the data
are sufficient to derive a cancer potency factor.
4. There are studies which show that the chemical does not cause this
health effect via this exposure route.
Bars of half height indicate that "some" information for the end
point exists but does not meet any of these criteria.
The absence of a column indicates that no information exists for
that end point and route.
2.3.2.2 Descriptions of highlights of graphs
Human. Figure 2.3 indicates that there are no data regarding
effects of exposure for any duration by any route.
Animal. As seen from Fig. 2.4, data for inhalation exposure of
animals to N-nitrosodiphenylamine are lacking. Such studies may be less
important than oral and dermal studies because exposure to this chemical
is more likely to occur by the oral or dermal route. Virtually no data
on dermal exposure of animals are available, and dermal exposure may be
of concern in the environment. Data for oral exposure are adequate to
indicate that N-nitrosodiphenylamine is carcinogenic to animals. Oral
data are adequate to determine levels of significant exposure for
intermediate exposure. For acute exposure, levels resulting in systemic
toxicity are not known. Although a minimal risk level was determined for
chronic oral exposure based on a LOAEL, a NOAEL for chronic oral
exposure was not available; therefore, the bar for systemic toxicity of
chronic oral exposure indicates that only some data are available.
Pertinent data are not available for developmental and reproductive
effects.
2.3.2.3 Summary of relevant ongoing research
No pertinent ongoing research was identified.
2.3.3 Other Information Needed for Human Health Assessment
2.3.3.1 Pharmacokinetics and mechanisms of action
The mechanism of action of N-nitrosodiphenylamine is not known.
Pharmacokinetic data, which could be used in the understanding of
species differences in sensitivity and mechanism of toxicity to this
chemical, are lacking. No information is available to enable the
extrapolation of results of oral exposure to other routes. There are no
ongoing studies to fill these data gaps.
-------
Health Effects Summary 17
2.3.3.2 Monitoring of human biological samples
Although an analytical method for detecting and quantitating N-
nitrosodiphenylamine in human biological samples exists (see Sect. 8),
it does not appear to have been used to test for human exposurNo
ongoing studies of biological monitoring were found.
2.3.3.3 Environmental considerations
Analytical methods of reasonable sensitivities are available for
the determination of N-nitrosodiphenylamine in air, water, foods, and
biological samples. The methodologies for water analysis, however, may
not be sensitive enough to detect the ambient water quality criteria
concentrations. As toxic levels of this compound in the other media have
not been established, it is impossible to comment on whether the
available analytical methodologies will be sensitive enough to detect
this chemical down to these levels in a particular medium.
The database for environmental concentrations is very limited
because N-nitrosodiphenylamine is not naturally occurring, and
industrial production and use, which could lead to emissions into the
environment, has been discontinued in the United States since 1983.
Regarding human exposure, there are major data gaps in the
understanding of the bioavailability of N-nitrosodiphenylamine from soil
and foods. The bioavailability of a chemical is likely to depend on the
adsorption characteristics or conversely on the mobility of the chemical
in the medium of concern. Even a reliable experimental soil adsorption
coefficient value (Koc) for this chemical is not available.
The only data regarding the environmental fate of N-
nitrosodiphenylamine are studies on biodegradability and photolysis.
Other environmental fate and transport processes have been predicted
from its physical and chemical structure.
No studies are known to be available pertaining to interactions
between tf-nitrosodiphenylamine and other environmental pollutants.
There are no known ongoing experimental studies pertaining to the
environmental fate of N-nitrosodiphenylamine.
-------
19
3. CHEMICAL AND PHYSICAL INFORMATION
3.1 CHEMICAL IDENTITY
Data pertaining to the chemical identity of tf-nitrosodiphenylamine
are listed in Table 3.1. W-Nitrosodiphenylamine is commonly referred to
as diphenylnitrosamine in a significant percentage of the published
literature.
3.2 PHYSICAL AND CHEMICAL PROPERTIES
The physical and chemical properties of //-nitrosodiphenylamine are
presented in Table 3.2.
-------
20 Section 3
TaMe 3.1. Chemical ideality of /V-uJtroMdipbeayUmine
Chemical name
Synonyms
Trade names
Chemical formula
Wiswesser Line Notation
Chemical structure-
Identification numbers
CAS Registry No
NIOSH RTECS No
EPA Hazardous Waste No.
OHM-TADS No
DOT/UN/NA/INCO Shipping No
STCC No.
Hazardous Substances Data Bank No
National Cancer Institute No.
Benzenamme. JV-nuroso-/V-phenyl CAS* (IOth collective index)
Diphenylnitrosoamme SANSS 1987, IARC 1982a
/V-Nitroso-yV-phenylaniline
iV-Nitroso-yV-phenylbenzenamme
jV.jV-Diphenylnitrosoamuie
Nitrous diphenylamide
NDPA
NDPhA
Curetard A. Delac J. Naugard
TJB. Redax, Retarder J, TJB,
Vulcalent A, Vulcatard A.
Vulkalent A. Vultrol
C,jH10N20
ONNR&R
O
II
N
86-30-6
JJ9800000
Unknown
8300186
Unknown
Unknown
287 5
NC1-C02880
IARC I982a
SANSS 1987
SANSS 1987
SANSS 1987
SANSS 1987
SANSS 1987
EPA-NIH 1987
HSDB 1987
SANSS 1987
•Chemical Abstract Service.
-------
Chemical and Physical Information 21
Table 3.2. Physical ud chemical properties of /V-oitrosodipbeoylamioe
Property
Value
References
Molecular weight
Color
Physical state
Odor
Melting point
Boiling point
Autoignition temperature
Solubility
Water
Organic solvents
Density
Partition coefficients
Log octanol-water
Vapor pressure
Henry's law constant
Refractive index
Flash point
Flammability limits
Conversion factors
air
water
19823
Yellow
Orange-brown
Plates
Amorphous solid
Unknown
665"C
268 17°C (estimated)"
Unknown
35 mg/L at 25"C
Soluble in acetone, ethanol.
benzene, and ethylene dichlonde
I 23
3.13
6.69 X 10- mm Hg at 25°C (estimated)*
SOX 10'' atm-m'/mol at 258C (estimated)'
Unknown
Unknown
Unknown
I mg/m1 — 8.1 ppm
I ppm — 0 12 mg/m1
1 ppm (w/v) - I mg/L - 1
IARC 1982a
Weast I98S
IARC I982a
Weast 1985
IARC I982a
Weast 1985
EPA I987a
Banerjee et al 1980
(ARC I982a
Anonymous 1985
Hansch and Leo 1985
EPA I987a
'Average of the Meissner and Miller estimation methods, see Lyman et al (1982) for an
explanation of these estimation methods
'Estimated from the estimated boiling point and the Modified Watson estimation method, see
Lyman et al. (1982) for an explanation of this estimation method
'Estimated by dividing the estimated vapor pressure by the water solubility
-------
23
4. TOXICOLOGICAL DATA
A.1 OVERVIEW
No toxicokinetic data are available for humans. Limited data from a
study in rodents indicate that orally administered N-nitroso-
diphenylamine is absorbed and metabolized and that the metabolites are
excreted in the urine. The rate and extent of these processes have not
been investigated adequately.
Metabolism of N-nitrosodiphenylamine appears to proceed via
reductive processes in rodents. These include denitrosation to nitric
oxide and diphenylamine, with subsequent conversion of the nitric oxide
to nitrite and nitrate, and metabolism to the corresponding hydrazine.
N-Nitrosodiphenylamine has no oxidizable hydrogens on the carbon atoms
in alpha position to the N-nitroso function and therefore is not
susceptible to the generally accepted oxidative bioactivation pathway of
N-nitrosamines, which involves alpha-carbon hydroxylation followed by
N-dealkylation or ring opening to form an alkylating carbonium ion.
Data regarding the lethality of N-nitrosodiphenylamine are
available only for oral administration to animals. The acute oral LD50
in rats is 3000 mg/kg. Intermediate duration oral studies indicate that
rats are more sensitive to N-nitrosodiphenylamine than are mice, as
there was no effect on survival in the mice at exposure levels higher
than levels that produced 100% mortality in rats.
The only data available for the systemic/target organ toxicity of
N-nitrosodiphenylamine are from oral toxicity and carcinogenicity
studies in animals. The data are limited and do not clearly characterize
the toxicity of this compound. Acute and subchronic oral studies in rats
and mice indicate that N-nitrosodiphenylamine has a low order of
toxicity and produces enzyme induction and pigmentation of Kupffer's
cells in the liver. Chronic oral exposure to N-nitrosodiphenylamine is
toxic and carcinogenic to the bladder and does not appear to affect the
liver. The lack of liver toxicity in chronic studies indicates that the
enzyme induction reflects an adaptive process. Other findings in
subchronic and chronic oral studies include corneal opacity and kidney
and lung lesions, but, because of the lack of dose response or
inadequate experimental design and reporting, the association between
these findings and N-nitrosodiphenylamine treatment is uncertain.
A single dermal (skin painting) study has been performed, but it is
inadequate for the detection of systemic and target organ effects.
Information regarding developmental or reproductive toxicity of N-
nitrosodiphenylamine in humans or other mammals was not located in the
available literature.
-------
24 Section &
In vitro assays for DNA damage in human fibroblasts have given
mixed results. Additional gehotoxicity studies with human systems are
not available. In vitro studies of gene mutation and in vivo studies of
mutation and other end points in nonhuman systems have given negative
results. In vitro tests for DNA damage have given some positive results,
particularly in rodent hepatocytes. In vitro tests for cell
transformation have given positive results only in the presence of an
exogenous activating system.
Studies investigating the carcinogenicity of W-nitrosodiphenylamine
in humans are not available. Several oral studies, one dermal study, and
no inhalation carcinogenicity studies have been conducted with animals.
The best study of the carcinogenicity of N-nitrosodiphenylamine is
a long-term feeding study in rats and mice. In this study, N-
nitrosodiphenylamine caused bladder carcinomas in rats but was not
carcinogenic to mice. Another dietary study in mice also reported
negative results in this species. In rats, a drinking water study and a
gavage study, both of which reported negative results, may have been
inadequate to detect a carcinogenic response. Weekly dermal applications
to hairless mice produced a low incidence of lung adenomas that does not
appear to be treatment related, but the study was inadequate for the
assessment of the carcinogenity of dermal exposure to N-nitroso-
diphenylamine.
4.2 TOZICOKINETICS
4.2.1 Absorption
4.2.1.1 Inhalation
Pertinent human or animal data were not located in the available
literature.
4.2.1.2 Oral
Human. Pertinent data were not located in the available
literature.
Animal. Specific information on the rate and extent of absorption
is not available. Gastrointestinal absorption of W-nitrosodiphenylamine
by rats and guinea pigs is indicated by the appearance of metabolites in
the urine and blood, respectively, following oral administration (see
Sect. 4.2.3). In addition, the gastrointestinal absorption of N-
nitrosodiphenylamine by rats and mice is indicated by the occurrence of
systemic effects in these animals in oral carcinogenicity studies (see
Sect. 4.3.6).
4.2.1.3 Dermal
Human. Pertinent data were not located in the available
literature.
Animal. The results of a dermal carcinogenicity study with mice
(see Sect. 4.3.6) suggest that N-nitrosodiphenylamine may be absorbed
through the skin.
-------
Toxicological Data 25
4.2.2 Distribution
Pertinent data regarding the distribution of N-nitrosodiphenylamine
in humans or animals resulting from inhalation, oral, or dermal exposure
to the chemical were not located in the available literature.
4.2.3 Metabolism
4.2.3.1 Inhalation
Pertinent human or animal data were not located in the available
literature.
4.2.3.2 Oral
Human. Pertinent data were not located in the available
literature.
Animal. A single 1-g/kg dose of N-nitrosodiphenylamine in corn oil
was administered to rats by gavage (Appel et al. 1984). Nitrate was the
major urinary metabolite, but nitrite, diphenylamine, and
hydroxydiphenylamine were also identified as urinary metabolites.
Approximately 24.8 and 1.4% of the applied dose was excreted as nitrate
and nitrite, respectively, within 36 h. Denitrosation of N-nitroso-
diphenylamine also was demonstrated in in vitro studies conducted with
rat and mouse liver cytochrome P-4SO (Appel et al. 1979, Schrenk et al
1982, Uakabayashi et al. 1982).
Acetaldehyde diphenylhydrazone was identified in the plasma of
acetaldehyde-treated guinea pigs following administration of single
200-mg/kg oral doses of N-nitrosodiphenylamine (Tatsumi et al. 1983).
The acetaldehyde was used as an electron donor. These data and the
results of in vitro metabolism studies with guinea pig liver S-9
fractions (Tatsumi et al. 1983) indicate that N-nitrosodiphenylamine was
metabolized to 1,1-diphenylhydrazine.
Diphenylamine, the denitrosation product of N-nitrosodiphenylamine,
produced kidney lesions in rats and liver lesions and anemia in dogs
(EPA 1985a).
4.2.4 Excretion
4.2.4.1 Inhalation
Pertinent human or animal data were not located in the available
literature.
4.2.4.2 Oral
Human. Pertinent data were not located in the available
literature.
Animal. Appel et al. (1984) found that urinary excretion of
nitrate and nitrite by rats was greatest 24-48 h after a single 1-g/kg
oral dose of N-nitrosodiphenylamine. Urinary excretion of nitrate and
nitrite accounted for 25% of the administered dose at 96 h after dosing
-------
26 Section 4
Information regarding elimination of N-nitrosodiphenylamine by
routes other than urine is not available.
4.3 TOZICITT
4.3.1 Lethality and Decreased Longevity
4.3.1.1 Inhalation
Pertinent human or animal data were not located in the available
literature.
4.3.1.2 Oral
Human. Pertinent data were not located in the available
literature.
Animal. An acute oral LDSO of 3000 mg/kg was determined for N-
nitrosodiphenylamine in BD rats (Druckrey et al. 1967).
The subchronic range - finding study performed by the NCI (1979)
provides lethality data for intermediate exposure. Groups of five F344
rats of each sex and five B6C3F1 mice of each sex were used in these
studies. Male rats were fed diets containing 0, 1000, 2000, 3000, 4000,
6000, 8000, or 10,000 ppm of compound for 11 weeks, and female rats were
fed diets containing 0, 4000, 8000, 16,000, 24,000, 32,000, or 46,000
ppm of compound for 8 weeks. Hale and female mice were fed 0, 3160,
4640, 6800, 10,000, or 14,700 ppm for 8 weeks; additional groups of male
mice were fed 0, 4250, 7500, 8500, 9500, 11,000, 15,000, or 22,000 ppm
for 8 weeks; and additional groups of female mice were fed 22,000,
32,000, or 46,000 ppm for 8 weeks. Rat survival was not affected in
groups receiving <16,000 ppm. Survival in the rats (females) was 2/5 at
16,000 ppm and 0/5 in the higher concentration groups. Mouse survival
was not affected by treatment.
In another intermediate duration study, AT-nitrosodiphenylamine in
an aqueous methylcellulose vehicle was administered by gavage to 25 male
Wistar rats at a dose of 1070 mg per rat, 5 days/week for 45 weeks
(Argus and Hoch-Ligeti 1961). If the average weight of a rat is 0.35 kg.
the dose was 3057 mg/kg- All rats survived to the study termination at
53 weeks.
In a chronic study, F344 rats of both sexes were fed diets that
contained 1000 or 4000 ppm of the compound for 100 weeks, male B6C3F1
mice were fed diets that contained 10,000 or 20,000 ppm for 101 weeks,
and female B6C3F1 mice were fed diets that contained time-weighted
average (TWA) concentrations of 2315 and 5741 ppm for 98 of 101 weeks
(see Sect. 4.3.6.2 on carcinogenicity of oral exposure in animals for
experimental details) (NCI 1979. Cardy et al. 1979). There were no
significant treatment-related effects on survival in the male rats or
male mice. Survival was dose related in the female rats, with a marginal
reduction in survival at 1000 ppm and a more marked reduction at 4000
ppm. In female mice, survival in the low-dose group occasionally was
slightly better than in controls. Survival in the high-dose group,
however, was reduced compared with that in low-dose and control groups
of female mice.
-------
Toxicologies! Data 27
4.3.1.3 Dermal
Pertinent human or animal data were not located in the available
literature.
4.3.2 Systemic/Target Organ Toxicity
4.3.2.1 Bladder tozicity
Inhalation. Pertinent human or animal data were not located in the
available literature.
Oral, human studies. Pertinent data were not located in the
available literature.
Oral, animal studies. In the chronic portion of the NCI (1979)
study, epithelial hyperplasia of the urinary bladder occurred at low
incidences in rats at both treatment levels (1000 and 4000 ppm N-
nitrosodiphenylamine in the diet for 100 weeks). Incidences in the
control, low- and high-dose groups were 0/19, 2/46, and 6/45,
respectively, in the males and 0/18, 4/48, and 7/49, respectively, in
the females. Squamous metaplasia of the bladder occurred in 1/45 high-
dose males and 2/49 high-dose females and did not occur in controls or
low-dose animals. It is likely that the bladder hyperplasia and
metaplasia are preneoplastic effects, since transitional cell carcinoma
also occurred in the high-dose rats (see Sect. 4.3.6.2 on
carcinogenicity of oral exposure in animals).
Effects on the bladder also occurred in both sexes of mice at both
treatment levels in the chronic portion of the NCI (1979) study. Males
received 10,000 and 20,000 ppm N-nitrosodiphenylamine for 101 weeks, and
females received 2315 and 5741 ppm TWA in the diet for 98 of 101 weeks.
Incidences of submucosal inflammation of the urinary bladder in the
control, low-dose, and high-dose groups were 0/18, 12/49, and 31/46,
respectively, in the males and 0/18, 31/47, and 30/38, respectively, in
the females. The inflammatory response was associated with connective
tissue degeneration in the submucosa. Epithelial hyperplasia of the
bladder in the control, low-dose, and high-dose groups occurred in 0/18,
2/49, and 7/46 males and 0/18, 3/47, and 6/38 females, but incidences of
bladder neoplasms were not significantly increased. Since submucosal
inflammation of the bladder was clearly associated with low-dose
treatment in the mice, 2315 ppm represents a LOAEL.
Dermal. Pertinent human or animal data were not located in the
available literature.
General discussion. The chronic NCI (1979) study also included
measurements of body weight gain and comprehensive gross and
histopathological examinations. Decreased body weight gain occurred in
rats of both sexes that were treated with 1000 or 4000 ppm in the diet
for 100 weeks. The weight gain reductions were dose related in the males
throughout the study and in the females after about the first year.
Dose-related decreases in body weight gain occurred in the mice of both
sexes throughout the study, but were most pronounced in the females. The
significance of the decreased weight gain is uncertain because food
consumption was not reported. The only nonneoplastic effect, other than
-------
28 Section 4
bladder lesions, was corneal opacity in the high-dose male rats and
low-dose female rats (see Sect. 4.3.2.2 on other toxicity end points).
The data from two species indicate that the bladder is a target
organ for chronic oral exposure to N-nitrosodiphenylamine. In rats, the
predominant effect on the bladder was tumor development (see Sect.
4.3.6.2 on carcinogenicity of oral exposure); toxic effects were limited
to epithelial hyperplasla and metaplasia. In mice, the predominant
effect on the bladder involved submucosal inflammation and epithelial
hyperplasia; only a few tumors were found, and the incidences were not
statistically significant (P > 0.05). Acute and subchronic oral studies
have not shown evidence of bladder toxicity. Although corroboration from
other studies is lacking, prior to the publishing of the NCI (1979)
study, investigators had been concerned primarily with carcinogenicity,
had not routinely examined the bladder, had used smaller numbers of
animals, and, with the exception of the carcinogenicity study in mice
(BRL 1968, Innes et al. 1969), had used lower oral dosages (see Sect.
4.3.6.2 on carcinogenicity of oral exposure).
4.3.2.2 End points of uncertain significance in oral animal studies
Nishie et al.(1972) investigated hepatic effects in 10 Swiss-
Webster mice that were treated with N-nitrosodiphenylamine by gavage in
olive oil at a dose of 350 mg/kg/day on 4 consecutive days (Nishie et
al. 1972). A group of 10 controls was administered the vehicle alone.
Pentobarbital sleeping time was significantly shortened in the treated
mice. Examination of the livers of the treated mice by light microscopy
was unremarkable, but electron microscopy showed increased quantities of
smooth endoplasmic reticulum distributed among granules of glycogen, as
well as blebs, hypertrophy, and pleomorphism of the mitochondria. This
dosage represents a NOAEL, as the effects are indicative of adaptive
liver enzyme induction and adverse hepatic alterations were not
observed.
In the subchronic range-finding study performed by the NCI (1979)
(see Sect. 4.3.1.2 on lethality in animals exposed orally for protocol),
the only effect noted on gross and histopathologic examination of the
surviving mice was trace amounts of pigmentation of Kupffer's cells in
hepatic sinusoids in the female mice that received 46,000 ppm of N-
nitrosodiphenylamine in the diet for 8 weeks. No such effect was seen at
<32,000 ppm. Since the hepatic pigmentation does not appear to be
adverse because toxic and other histologic effects and decreased
survival did not occur, 46,000 ppm represents the highest NOAEL. No
gross or histopathological effects were reported for the rats in this
subchronic study (NCI 1979), but only the survivors were subjected to
necropsy and histopathologic evaluation (of unspecified tissues).
The NCI (1979) subchronic range - finding study also provided body
weight data (measured at week 11 for male rats or week 7 for female racs
and male and female mice). A consistent decrease in body weight (-14%
decrease relative to control weight) occurred at £4000 ppm in male and
female rats, but the depression in body weight did not become more
severe with increasing dietary level until survival was also affected
(at 16,000 ppm). Decreased body weight may not be indicative of an
adverse effect in rats because of the lack of dose-response relationship
-------
lexicological Data 29
and because the pathological examinations generally were unremarkable,
but full evaluation of the significance of the body weight depression is
precluded because of the lack of food consumption data. Based on body
weight depression and the lack of pathological effects (or death), the
concentration of 3000 ppm is the highest NOAEL, and 4000 ppm is the
LOAEL for systemic toxicity in rats in this study. Body weights in mice
were decreased (£14% depression) in a sporadic manner that does not
appear to be related to treatment.
In an intermediate-length gavage study, N-nitrosodiphenylamine in
an aqueous methylcellulose vehicle was administered to 25 male Vistar
rats at a dose of 1070 mg per rat (3057 mg/kg)• 5 days/week for 45 weeks
(Argus and Hoch-Ligeti 1961). The rats were killed after an additional
8-week observation period. Histological examination of the livers,
spleens, kidneys, and lungs revealed albuminous precipitation in the
tubules of "many" kidneys. Squamous metaplasia of the bronchial
epithelium, particularly in areas of bronchiectasis, occurred in "some"
of the lungs. The significance of the findings in the kidneys and lungs
is uncertain because incidences were not reported and control groups
were not tested.
In the chronic study, grossly observable corneal opacity occurred
at higher incidences in the high-dose male rats (15/50) and low-dose
female rats (16/50) than in the corresponding control males (0/20) and
control females (1/20) (NCI 1979, Cardy et al. 1979). It was concluded
that this effect may have been related to treatment, but incidences in
the low-dose males and high-dose females were not reported and no
histopathological findings were recorded for the cornea. (Experimental
details are provided in Sect. 4.3.6.2 on carcinogenicity of oral
exposure).
4.3.3 Developmental Toxicity
No information is available for humans, and AT-nitrosodiphenylamine
has not been tested for developmental toxicity in mammals. tf-Nitroso-
diphenylamine produced an increased incidence of malformed chicken
embryos when injected into the air chamber of eggs on day 3 of
development (Korhonen et al. 1983). These results do not necessarily
have implications for mammalian species, but indicate a need for
additional testing.
4.3.4 Reproductive Toxicity
Pertinent data regarding reproductive toxicity were not located in
the available literature.
4.3.5 Genotoxicity
4.3.5.1 Human
Some in vitro assays for DNA damage in human fibroblasts gave
positive results, while others gave negative results (Table 4.1). No
epidemiology studies of gentoxicity were available.
-------
30 Section 4
TaM* 4.1. Gcootoxicity of /Vniltrosodipbeoylmmine in ritro
End point
Species (test system)
Result with activation/
without activation'
References
Gene mutation Salmonella typhimurium
Eschenchia colt
Schizossaccharomyces pombe
Chinese hamster V79 cells
Rat embryo cells
Mouse lymphoma cells
DNA damage £ colt
Bacillus sublins
Saccharomyces cerevuiae
Rat hepatocytes
Mouse and hamster hepatocytes
Human fibroblaits
Chromosome effects Saccharomyces cerevisiae
Chinese hamster cells
(ovary, Don, fibroblasis)
Cell transformation Hamster cells
(kidney, embryo)
Rat embryo cells
Balb 3T3 cells
— /mixed
NT/mixed
NA/ +
NA/ +
Mixed/mixed
NT/-
Numerous studies as reviewed by EPA
1986c
Matsushima et al 1981, Probst et al 1981
Arakietal 1984
Lopneno 1981
Kurokietal 1977. Drevon et al 1978.
Jones and Huberman 1980, Jones et al
1980
Mishra et al. 1978
Chve et al. 1979. Jotz and Mitchell 1981.
Oberlyetal. 1984
McGregor et al 1980, Leifer et al 1981.
Rosenkranz et al. 1981, Ichmotsubo et al
1981. Mamber et al. 1983. Green 1981.
Tweats 1981
Kada 1981
Sharp and Parry 1981 a, Kassmova et al
1981
Becketal 1981. Althaus et al 1982.
Althaus and Petot 1983, Probst et al 1981.
IARC 1982a. Sma et al 1983, Bradley
et al. 1982
McQueen et al. 1983
Agrelo and Amos 1981, Snyder and
Matheson I98S, Martin and McDermid
1981. IARC 1982a
Jagannath et al. 1981, Zimmerman and
Scheel 1981. Sharp and Parry I98lb.
Simmon 1979, McGregor et al 1980.
Kassuiova et al. 1981
Ishidate and Odashima 1977, Abe and
Sasaki 1977. Perry and Thomson 1981,
Evans and Mitchell 1981
Daniel and Dchnel 1981, Pienta and
Kawalek 1981. IARC 1982a
Dunkel et al 1981. (ARC I982a
Dunkel et al 1981, Rundell et al. 1983
•NT - Not tested. NA = not applicable. + - positive result. - - negative result.
-------
Toxicologies! Data 31
4.3.5.2 Nonhuman
Studies on the in vitro genotoxicity of N-nitrosodiphenylamine in
prokaryotes, eukaryotes, and cultured mammalian cells are presented in
Table 4.1. Af-nitrosodiphenylamine has consistently given negative
results for gene mutations in a variety of organisms and cells,
regardless of the presence or absence of an exogenous activating system
Negative results were also obtained in assays for chromosome effects,
with or without an activating system. Assays for DNA damage in nonhuman
systems have given varying responses, and, because of the varieties of
end points and protocols employed, it is difficult to interpret these
findings. Cell transformation assays gave positive results with
exogenous activation and negative results without exogenous activation.
In vivo genotoxicity studies in Drosophlla and mice are shown in
Table 4.2. Results were negative.
4.3.5.3 General discussion
Many N-nitroso compounds are thought to exert their mutagenic and
carcinogenic effects through alpha-carbon hydroxylation to intermediates
that can alkylate DNA (Preussman and Stewart 1984, Schut and Castonguay
1984, Magee et al. 1976). N-Nitrosodiphenylamine, however, is not
susceptible to alpha-carbon oxidation and therefore is presumed to exert
its action by some mechanism other than direct alkylation. It is
speculated that the carcinogenicity of N-nitrosodiphenylamine may be due
to trans-nitrosation with formation of a carcinogenic N-nitroso
derivative(s) (Preussmann and Stewart 1984, Raineri et al. 1981, NCI
1979). Formation of nitrosamines by nitrosation of dietary amines is an
example of the reaction. There is evidence for trans-nitrosation by N-
nitrosodiphenylamine in vivo; trans-nitrosation by N-nitroso-
diphenylamine to proline occurred in rats when the compounds were
coadministered orally (Ohshima et al. 1982). The trans-nitrosation
mechanism is consistent with the negative results obtained for N-
nitrosodiphenylamine in assays for mutagenicity with or without
metabolic activation and the positive results obtained in the NCI (1979)
dietary study in rats.
4.3.6 Care inogenic ity
4.3.6.1 Inhalation
Pertinent human and animal data were not located in the available
literature.
4.3.6.2 Oral
Human. Pertinent data were not located in the available
literature.
Animal. In a chronic study, Af-nitrosodiphenylamine was
administered in the diet at two dose levels to groups of 50 F344 rats
and 50 B6C3F1 mice of each sex (NCI 1979. Cardy et al. 1979). Matched
control groups consisted of 20 untreated rats and mice of each sex.
Comprehensive gross and histopathological examinations were conducted on
-------
32 Section 4
Table 4.2. Genotoxicity of A'-nitrosodiphenylamine in vivo
End point
Species
Result"
References
Recessive lethal mutation Drosophila melanogaster
Abnormal sperm morphology Mouse
Micronucleus test Mouse
Depression of DNA
synthesis
Mouse
Vogelet al. 1981
Topham 1981
Salamone et al. 1981,
Tsuchimota and Matter 1981
Friedman and Staub 1976
a
negative results.
-------
Toxicological Data 33
animals dying during the study and on all animals surviving to the end
of the study.
The rats were fed diets that contained 1000 or 4000 ppm of N-
nitrosodiphenylamine for 100 weeks. Statistically increased incidences
of transitional cell carcinomas of the urinary bladder occurred in the
high-dose rats of both sexes (NCI 1979, Cardy et al. 1979) (Table 4.3).
Fibromas of the integumentary system (subcutis and skin) occurred in the
male rats at incidences that were dose related, but the incidences of
these tumors in the individual dosed groups were not significantly
higher than those in the control group in direct comparison (Table 4.3).
Because integumentary system fibromas are rare in historical controls at
the same laboratory (Table 4.3), the occurrence of the fibromas may have
been associated with the treatment. The bladder transitional cell
carcinoma data were sufficient to conclude that N-nitrosodiphenylamine
was carcinogenic to F344 rats of both sexes under the conditions of this
bioassay (NCI 1979, Cardy et al. 1979).
The male mice were fed diets that contained 10,000 or 20,000 ppm
for 101 weeks. The female mice initially received 5000 or 10,000 ppm for
38 weeks, but because mean weight gain was excessively reduced, dosing
was discontinued for 3 weeks and then continued at 1000 and 4000 ppm,
respectively, for 60 weeks. The TWA concentrations for the low- and
high-dose female mouse groups for weeks on treatment are 2315 and
5741 ppm. One low-dose male and one low-dose female had transitional
cell carcinomas of the bladder, and one high-dose male had a
transitional cell papilloma of the bladder; none of the controls had
bladder tumors. No statistically significant increases in tumor
incidences were seen in the treated mice, however, and it was concluded
that N-nitrosodiphenylamine was not carcinogenic to the mice (NCI 1979,
Cardy et al. 1979).
An earlier study in B6C3F1 and B6AKF1 mice also produced negative
results. Administration of N-nitrosodiphenylamine by gavage to groups
of 18 mice of each sex and strain at a dose of 1000 mg/kg/day from 7 to
28 days of age, and subsequently in the diet at a concentration of
3769 ppm until 81 or 83 weeks of age, did not result in increased
incidences of tumors relative to vehicle or untreated controls (BRL
1968, Innes et al. 1969). The histological examinations in this study
were usually limited to the chest contents, liver, spleen, kidneys,
adrenals, stomach, intestines, and genital organs. No increased
incidences of nonneoplastic lesions were reported.
Two earlier studies in rats reported negative results, but the
bladders were not routinely examined, smaller groups of rats were
studied, and doses were lower than those provided by the NCI (1979)
dietary levels. W-Nitrosodiphenylamine was administered to 20 BD rats of
unspecified sex in drinking water that provided a daily dose of
120 mg/kg and a total dose of 65 gAg (Druckrey et al. 1967). Pathologic
examinations, conducted after 700 days and consisting of gross
examination of the liver, brain, and unspecified organs, and
histological examination of gross abnormalities, did not detect tumors
Similarly, tumors were not observed in 25 male Uistar rats that were
treated with N-nitrosodiphenylamine in an aqueous methylcellulose
vehicle by gavage at a dose of 1070 jig/rac. 5 days/week for 45 weeks,
-------
34 Section 4
Table 4.3. Incidences of tumors in F344 rats treated with JV-nitrosodiphenylamine
in the diet for 100 weeks
Sex Target organ Tumor type
Diet concentration
(ppm)
Tumor incidence
(P value)8
Male
Female
Bladder
Integumentary
system
Bladder
Transitional cell
carcinoma
Fibroma
Transitional cell
carcinoma
0
1000
4000
0
1000
4000
0
1000
4000
O/ 19 (P< 0.001)
0/46 (NS)*
16/45 (/» = 0.001)
1/20 (P = 0.003)'
1/50 (NS)
10/50 (NS)
0/18(/»<0.001)
0/48 (NS)
40/49 (P< 0.001)
Source: NCI 1979; Cardy et al. 1979
The probability level for the Cochran-Armitage test for linear trend is given with the
incidence of tumors in the control groups. This test determines if the slope of the dose-
response curve is different from zero at the one-tailed 0.05 level of significance; the
direction of the significant trend for the data reported in this table is a positive dose
relationship. The probability level for the one-tailed Fisher Exact test is given with the
incidences of tumors in the dosed groups. This test compares the tumor incidence in each
dosed group with the control group when P < 0.05; otherwise, (NS) is indicated.
*NS = Not significant.
The incidence of integumentary system flbromas in historical male controls at the
same laboratory was 6/285.
-------
lexicological Data 35
and observed for 8 weeks (Argus and Hoch-Ligeti 1961) . Hlstological
examinations were limited to the liver, spleen, kidneys, lungs, and
organs with gross abnormalities.
4.3.6.3 Dermal
In the only dermal carcinogenicity study, Iverson (1980) treated
the intrascapular region of 16 male and 24 female hairless hr/hr Oslo
strain mice with single weekly 0.1-mL applications of a 1% solution of
A*-nitrosodiphenylamine in acetone for 20 weeks. Necropsies that included
histological examinations of the lungs and palpable lesions were
performed on surviving animals (14 males, 21 females) after 80*weeks of
observation. The only tumors detected were lung adenomas in three of the
males (there were no local tumors). Small ulcerations and scarrings
occurred on the skin; no other nonneoplastic findings were reported.
Vehicle or positive control groups were not used in this study, but it
was noted that historical experience indicated that lung adenomas were
observed in dermal studies only after treatment with a carcinogen. These
data are not adequate for evaluating the carcinogenicity (or systemic
toxicity) of dermal exposure to N-nitrosodiphenylamine, as treatment
duration and frequency were short, only one low-exposure level was
tested, histopathological examinations were limited, and control data
are not available.
4.3.6.4 General discussion
Additional studies have been conducted by parenteral routes of
administration. An increased incidence of reticulum cell sarcomas
occurred in male B6C3F1 mice (but not in females of that strain or in
male or female B6AKF1 mice) that were given a single 1000-mg
subcutaneous injection of tf-nitrosodiphenylamine at 28 days of age and
observed for -18 months (BRL 1968, Innes et al. 1969). Rats treated by
once weekly 2.5-mg intraperitoneal injections for 6 months with 18
months of observation did not have increased incidences of tumors
(Boyland et al. 1968).
The available animal data indicate that ingestion of N-
nitrosodiphenylamine is potentially carcinogenic for humans. The data
also indicate that there may be marked species differences in
sensitivity to ingestion of this chemical. The basis for the species
difference cannot be inferred from the available toxicokinetic data,
which are inadequate for rats and nonexistent for mice, or from the
postulated mechanism of action (see Sect. 4.3.5.3 on genotoxicity).
Bladder cancer is associated with occupational exposure to aromatic
amines in the rubber industry (IARC 1982b). Although tf-nitroso-
diphenylamine is an aromatic amine that produced bladder carcinoma in
rats, bladder cancer in rubber industry workers cannot be attributed
specifically to N-nitrosodiphenylamine or any other chemical because of
the diversity of potentially carcinogenic exposures.
4.4 INTERACTIONS WITH OTHER CHEMICALS
N-Nitrosodlphenylamine was mutagenic in strains TA98 and TA1535,
but not TA100, in preincubation assays with rat liver S-9 fractions only
in the presence of the comutagen norbarman (9H-pyrido[3,4-b]indole)
(Nagao and Takahashi 1981; Uakabayashi et al. 1981, 1982).
-------
37
5. MANUFACTURE, IMPORT, USE, AND DISPOSAL
5.1 OVERVIEW
Industrial production of N-nitrosodiphenylamine has been
discontinued in the United States. Current import data for N-
nitrosodiphenylamine are not available; therefore, it is not known
whether it is currently imported in significant quantities for
commercial use. If it is not imported in significant amounts, then it
can no longer be considered an industrially or commercially important
chemical.
5.2 PRODUCTION
W-Nitrosodiphenylamine has been manufactured in the United States
by reacting diphenylamine and sodium nitrite in water that has been
acidified with sulfuric acid (Rounbehler and Fajen 1983). The reaction
product from the aqueous solution was decanted, dried on hot rollers,
and packed into drums as the final product.
U.S. production volumes of N-nitrosodiphenylamine in recent years
have been reported as follows (USITC 1978a, 1979-1981):
Year Production (millions of pounds)
1980 0.405
1979 0.632
1978 1.614
1977 1.469
Production volumes are not available after 1980. The most recent year
for which any production was reported to the U.S. International Trade
Commission was 1983, when Goodyear Tire was the sole reporting
manufacturer (USITC 1984). N-Nitrosodiphenylamine was not listed as a
domestically produced chemical by the U.S. International Trade
Commission in 1984 or 1985 (USITC 1985, 1986). Barnhart (1982) reported
that the domestic commercial production of N-nitrosodiphenylaraine has
been discontinued. The decline in production of N-nitrosodiphenylaraine
was attributed to the availability of new and more efficient chemicals
for its applications (Taylor and Son 1982).
The following U.S. manufacturers (primarily tire manufacturing
companies) have produced tf-nitrosodiphenylamine (SRI 1986): The BF
Goodrich Company (Akron, Ohio); The Goodyear Tire and Rubber Co. (Akron.
Ohio); and Uniroyal, Inc. (Geismar, Louisiana).
-------
38 Section 5
5.3 IMPORT
Imports of N-nitrosodiphenylamine through principal U.S. customs
districts were last reported separately in 1982; in this year, they
amounted to 0.11 million pounds (USITC 1983). In 1977, 52 thousand
pounds were imported through principal U.S. custom districts (USITC
1978b). Current import data for N-nitrosodiphenylamine are not
available.
5.4 USE
N-Nitrosodiphenylamine was used as a retarder in rubber,compounding
(Barnhart 1982, Taylor and Son 1982). A retarder is a chemical that
prevents premature vulcanization of rubber compounds during mixing and
other processing operations. N-Nitrosodiphenylamine is an effective
retarder when used at levels of 0.5-1.0% (IARC 1982a) and was generally
used with sulfenamide accelerators in tire compounds and other
mechanical goods (Barnhart 1982, Taylor and Son 1982). Because of the
introduction of more efficient retarders and because of several
undesirable side effects of AT-nitrosodiphenylamine, the use of N-
nitrosodiphenylamine had declined significantly by 1980 (Taylor and Son
1982).
N-Nitrosodiphenylamine was reported also to have been used as an
intermediate in the manufacture of p-nitrosodiphenylamine, which was
subsequently used to produce W-phenyl-p-phenylenediamine and other
rubber-processing chemicals (IARC 1982a) No data were available to
indicate that N-nitrosodiphenylamine is . .rrently used in the United
States as an intermediate.
5.5 DISPOSAL
Product residues and sorbent media containing tf-nitroso-
diphenylamine may be packaged in 17H epoxy-lined drums and disposed of
at an EPA-approved site (EPA-NIH 1987). The compound can be destroyed by
high-temperature incineration with scrubbing equipment (NOx scrubber) or
acid hydrolysis.
-------
39
6. ENVIRONMENTAL FATE
6.I OVERVIEW
tf-Nitrosodiphenylamine is not expected to be a persistent
environmental contaminant. It appears to be susceptible to biological
degradation in both soil and water, although the rates at which
biodegradation may occur in the environment may vary considerably
depending upon local conditions. If released to the ambient atmosphere
in the vapor phase, it may be transformed rapidly (typical half-life of
7.1 h) by reaction with sunlight-produced hydroxyl radicals. In
addition, N-nitrosodiphenylamine appears to be susceptible to direct
photodegradation in the presence of sunlight. Extended periods of
persistence in soil or water may be possible if local microbial
populations are very low (or inactive) or the concentration of the
pollutants is high enough to be toxic to microbial populations.
6.2 RELEASES TO THE ENVIRONMENT
Release of N-nitrosodiphenylamine to the environment may result
from effluent discharges generated at sites of its production or use.
Industrial occurrences of tf-nitrosodiphenylamine in various wastewaters
are reported by EPA (EPA 1981a). Rhodes et al. (1980) also reported the
detection of N-nitrosodiphenylamine in industrial wastewaters.
Currently, N-nitrosodiphenylamine is not manufactured on an industrial
scale in the United States; therefore, releases from its production are
not occurring.
N-Nitrosamines may be formed inadvertently in industrial situations
when amines come in contact with nitrogen oxides, nitrous acid, or
nitrite salts or by trans-nitrosation via nitro or nitroso compounds
(Fajen et al. 1980). This suggests that under appropriate industrial
conditions where diphenylamine is present, tf-nitrosodiphenylamine could
be formed inadvertently and then released to the environment via
effluent discharges. No specific evidence to support this supposition
was found, however.
tf-Nitrosodiphenylamine has been used as a vulcanization retarder in
rubber compounds used to make tires. It has been suggested that N-
nitrosodiphenylamine could be released from tires as they are worn away;
however, it is not clear if tf-nitrosodiphenylamine even remains in the
final polymer products in which it was used as a retarder (EPA 1981b).
6.3 ENVIRONMENTAL FATE
From estimation equations appropriate for its chemical structure
(Karickhoff 1985, Lyman et al. 1982), the soil sorption coefficient
(Koc) for tf-nitrosodiphenylamine was estimated to be 830-1830. This Koc
range is indicative of low mobility in soil (Swann et al. 1983).
-------
40 Section 6
Therefore, significant leaching is not expected to occur in most types
of soil and soil conditions. In the aquatic environment, significant
partitioning from the water column to sediment and suspended particulace
organic matter may occur.
Organics having vapor pressures >10"^ mm Hg should exist almost
entirely in the vapor phase in the atmosphere (Eisenreich et al. 1981).
The estimated vapor pressure of tf-nitrosodiphenylamine [6.69 x 10'^ mm
Hg at 25°C (see Table 3.2)] indicates, therefore, that tf-nitroso-
diphenylamine should not partition from the vapor phase to particulates
in the atmosphere.
The Henry's law constant for W-nitrosodiphenylamine [5.0 x 10'6
atm-m3/mol (see Table 3.2)] indicates that volatilization from water
will be slow (Lyman et al. 1982). In addition, partitioning from the
water column to sediment will decrease the rate of volatilization.
The major environmental fate process for N-nitrosodiphenylamine in
water and soil is probably biodegradation. A static-culture flask-
screening biodegradability test found JV-nitrosodiphenylamine
significantly degradable with rapid microbial adaptation at
concentrations of 5 ppm and significantly degradable with gradual
adaption at 10 ppm (Tabak et al. 1981). In laboratory tests using a
sandy loam soil, 68% of added W-nitrosodiphenylamine was degraded after
30 days of incubation, but amending the soil with wheat straw (to
increase microbial activity) resulted in complete disappearance of added
ANnitrosodiphenylamine in 10 days (Hallik and Tesfai 1981).
N-Nitrosodiphenylamine strongly absorbs sunlight, suggesting a
potential for significant direct photolysis in the sunlit environment
(Callahan et al. 1979, Sadtler 1961). Irradiation experiments using
ethanolic and benzene solutions of N-nitrosodiphenylamine have shown
that N-nitrosodiphenylamine is photodecomposed at sunlight wavelengths
(Callahan et al. 1979, Sharma et al. 1986). The rate, however, at which
photolysis will occur in the environment cannot be predicted from the
available data. It is possible that photolysis may be important in
sunlit natural waters or on soil surfaces.
The dominant environmental fate process in the ambient atmosphere
is expected to be the vapor-phase reaction between W-nitroso-
diphenylamine and hydroxyl radicals (which are photochemically produced
by sunlight). The half-life for this reaction in a typical environmental
atmosphere has been estimated to be approximately 7.1 h (EPA 1987a).
Aquatic hydrolysis and oxidation are not environmentally important
fate processes with respect to N-nitrosodiphenylamine (Callahan et al.
1979, Mabey et al. 1981). A continuous 14-day exposure of bluegill
sunfish to a mean tf-nitrosodiphenylamine water concentration of 9.21 ppb
resulted in a maximum bioconcentration factor of 217 (Barrows et al.
1980). The depuration half-life of tf-nitrosodiphenylamine in the fish
was found to be <1 day when the fish were placed in pollutant-free water
after the exposure period.
-------
7. POTENTIAL FOR HUMAN EXPOSURE
7.1 OVERVIEW
The general population of the United States does not appear to be
exposed to any background levels of N-nitrosodiphenylamine. W-nitroso-
diphenylamine has not been reported to exist as a naturally occurring
product and has not been reported in drinking water, foodstuffs, or
ambient air. The industrial manufacture of N-nitrosodiphenylamine in the
United States has been discontinued, which effectively removes a major
potential point source of environmental and human exposure. At present.
there does not appear to be a major and continual source of N-
nitrosodiphenylamine release to the environment.
7.2 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT
7.2.1 Air
No report of W-nitrosodiphenylamine detection in the ambient
atmosphere was found in the available literature.
7.2.2 Water
No report of N-nitrosodiphenylamine detection in drinking water was
found in the available literature. Only one positive detection was found
for ambient surface waters. N-nitrosodiphenylamine was positively
detected (no concentration reported) in the Cuyahoga River, which feeds
Lake Erie (Great Lakes Water Quality Board 1983).
7.2.3 Soil
An tf-nitrosodiphenylamine concentration of 47 mg/kg was found in a
soil sample collected in 1978 immediately outside of a building used to
commercially manufacture the compound in the United States (Rounbehler
and Fajen 1983). It has also been detected (no concentration reported)
in the soil-sediment-water complex of the Love Canal near Niagara Falls
(Hauser and Bromberg 1982).
7.2.4 Other
No report of W-nitrosodiphenylamine detection in foodstuffs was
found in the available literature.
N-Nitrosodiphenylamine is formed during the aging of cellulose
nitrate explosives in which diphenylamine has been added as a stabilizer
(Layer and Kehe 1978). This formation results from the reaction of
nitrogen oxides with the diphenylamine.
-------
42 Section 7
7.3 OCCUPATIONAL EXPOSURES
A National Occupational Hazard Survey (NOHS) conducted between 1972
and 1974 estimated that 18,365 U.S. workers were potentially exposed to
tf-nitrosodiphenylamine (NIOSH 1984). Although tf-nitrosodiphenylamine was
included in the NOHS, it is not listed in the preliminary results of the
NIOSH National Occupational Exposure Survey (NOES), which was conducted
in the early 1980s. Current occupational exposure levels are not
available, because the industrial production and use of N-
nitrosodiphenylamine has been discontinued in the United States since
1983. Occupational monitoring data collected before cessation of the
domestic production of tf-nitrosodiphenylamine are presented below.
tf-Nitrosodiphenylamine concentrations ranging from 0 to 47 ^g/m3
were detected in the workplace air of an Ohio factory manufacturing the
compound during monitoring in the spring of 1978 (Fajen et al. 1979.
1980). Of the 12 air samples, 10 had detectable levels of tf-nitroso-
diphenylamine. A scraping from a staircase in the factory contained
15,000 mg/kg. ANnitrosodiphenylamine was not detected outdoors at the
production site. Additional monitoring conducted in Ohio during the
spring of 1978 found no detectable levels of tf-nitrosodiphenylamine in
the workplace air of an industrial rubber products factory, an aircraft
tire factory, a synthetic rubber and latex factory, or three tire
manufacturing factories (Fajen et al. 1979, 1980).
Workplace air samples of 6.7-13.1 /*g/m3 tf-nitrosodiphenylamine have
been detected at a Kelly-Springfield tire plant in the United States
(McGlothlin and Wilcox 1984). The high levels of JV-nitrosomorpholine
(1.4-248 /ig/m3), also found at the plant, were believed to have been due
to the transnitrosation of N-nitrosodiphenylamine, since levels of iV-
nitrosomorpholine dropped to 1-2 /ig/n3 after the NIOSH-recommended
ventilation improvements were made and Af-nitrosodiphenylamine was
removed from the rubber batch mixes. Levels ranging from below
detectable limits (5 ng per sample) to 0.158 A«g/n»3 were detected in the
breathing zone of curing press operators at a Uniroyal plant in
Mishawaka, Indiana (Hollett et al. 1982).
7.4 POPULATIONS AT HIGH RISK
No data identifying populations at higher risk of exposure or
effects were found in the available literature. Persons living near
waste sites where tf-nitrosodiphenylamine is present will have a higher
risk of exposure.
-------
8. ANALYTICAL METHODS
8.1 ENVIRONMENTAL MEDIA
Methods used for the analysis of tf-nitrosodiphenylamine in
environmental media are presented in Table 8.1. Methods 625 and 625.1
are required by the EPA Contract Laboratory Program for analysis of N-
nitrosodiphenylamine in water, soil, and sediment. A critique and
comparison of the three commonly used quantification methods (e.g., TEA.
Hall, and FTD) can be found in Rhodes et al. (1980). In spite of the
high specificity and selectivity of gas chromotography-thermal energy
analysis (GC-TEA), this method introduces uncertainties regarding the
origins of products, since tf-nitrosodiphenylamine may thermally
decompose to NO and diphenylamine in the injector of the GC-TEA system
Other authors, however, have used a temperature-programmed GC condition
that maintains lower GC operating temperature range (100-180°C) than the
original GC-TEA column temperature (210-220°C) to measure a mixture of
nonvolatile AT-nitrosoamines, including nitrosodiphenylamine, by
chemiluminesence detection (Spiegelhalder and Preussmann 1982).
A nondestructive diffuse reflectance Fourier transform infrared
spectroscopy (DRIFT) (Gurka et al. 1985) may allow specific
characterization of a given nitrosamine from its infrared spectra
(Pristera 1953) at the low-nanogram level.
8.2 BIOMEDICAL SAMPLES
Methods used for the analysis of N-nitrosodiphenylamine in
biomedical media are presented in Table 8.2. Spiked samples of blood,
serum, urine, and water were analyzed in the Pylyplw and Harrington
(1981) study. Although the differential pulse polarography (DPP) method
is relatively sensitive for the quantification of //-nitroso-
diphenylamine, Pylyplw and Harrington (1981) do not describe the details
of pretreatment methods for the separation and subsequent
characterization of the individual nitrosamines by this method.
-------
44 Section 8
Table 8.1. Analytical
Sample
matrix
Air
Sample
preparation
Absorption in
Therm osorb/N
cartridges; ex-
traction with
aqueous KOH
solution
Assay procedure
GC-TEA with carbowax
20 M/0 5% KOH column
HPLC-TEA with Lichro-
sorb column
Limit of
detection
<001 fig/m1
References
References
Fajen et al 1979. 1980
Water/soil
Wastewater
(municipal
and indus-
trial)
Foodstuffs
Vodka
Fish
Extract in methyl-
ene chloride;
and clean up ex-
tract by Floruil
or alumina column
chromatography if
required
Extract in methyl-
ene chloride; and
clean up extract
by Flonsil or
alumina column
chromatography if
required
Sample preparation
method not dis-
cussed
Extract with di-
chloromethane and
concentrate extract
Extract with i
tone/bexane; con-
centrates remove
lipids by gel per-
meation chromato-
graphy using ethyl
acetate
Fused silica capillary
column (SE-54) GC-MS,
packed SP-2250 column
GC-MS
GC/Hall or TEA detec-
tion with SP-2250 or
carbowax 20 M/2% KOH
column
GC-FTD on packed PEG
20 Ml 1% KOH column
HPLC-TEA on p-Pora-
sil column
GC/MS with SE-54 fused
silica capillary col-
10 ppb (water) Eichelberger et al. 1983
330 «tg/kg (EPA test method
(soil) 625 and 6251)
08lMg/L
EPA 1982
(test method 607)
1 ng
Fangetal. 1981
10 mg/kg Fine et al. 1976
NR
DeVault I98S
"NR - Not reported. FTD - flame thermionic detector. GC — gas chromatograpby, HLPC - high
performance liquid chromatography. MS - mass spectrometry, TEA - thermal energy analysis.
-------
Analytical Methods 45
TiMc8.2. Analytical methods—bioaedkal samples
Sample matrix Sample preparation Assay procedure
Limit of detection
Reference
Blood, serum.
unne, water
A phosphated buf-
fered solution
(pH 8) containing
the nitrosamue
was passed through
aSep-PakCIS
cartridge, cart-
ridge was then
washed with either
methanol or methyl-
ene chloride
Methanol eluate diluted
with HCKVNaClO..
and analyzed by DPP or
concentration extract
analyzed by TEA*
0 5 ppm (blood). Pylyplw and Harrington
0.05 ppm (serum). 1981
0 10 ppm (unne).
0 005 ppm (water) -
DPP: 001 ppm (blood).
001 ppm (serum).
0 001 ppm (water) -
TEA
'DPP - differential pulse polarography. TEA - thermal energy analysis.
-------
9. REGULATORY AND ADVISORY STATUS
9.1 INTERNATIONAL (WORLD HEALTH ORGANIZATION)
The World Health Organization has not advised a limit for N-
nitrosodiphenylamine in drinking water (IRPTC 1987).
9.2 NATIONAL
9.2.1 Regulations
The Occupational Safety and Health Administration (OSHA) has not
promulgated occupational exposure limits for tf-nitrosodiphenylamine.
The Reportable Quantity (RQ) for tf-nitrosodiphenylamine is 100
pounds or greater (EPA 1985b).
9.2.2 Advisory Guidance
9.2.2.1 Water
The EPA (1980b) has recommended criteria of 49,000 ng/L, 4900 ng/L
and 490 ng/L to protect human health from the potential carcinogenic
effects of exposure to JV-nitrosodiphenylamine through ingestion of
contaminated ambient water and contaminated aquatic organisms. These
criteria correspond to estimated incremental lifetime cancer risk levels
of 10'3, 10-°, and 10'7, respectively. The cancer risk levels provide
estimates of the additional incidence of cancer that may be expected in
an exposed population.
9.2.3 Data Analysis
9.2.3.1 Reference dose
EPA has not proposed a reference dose (RfD) for tf-nLtroso-
diphenylamine.
9.2.3.2 Carcinogenic potency
A qx* of 4.92 x 10'3 (mgAg/day)'I was calculated for tf-nitro-
sodiphenylamine from the incidence of bladder transitional cell
carcinomas in female rats in the NCI bioassay (EPA 1980a). This potency
factor was validated recently by the EPA (EPA 1987b). Other rat
bioassays and all mouse bioassays showed no carcinogenic effects, but
the mouse bioassay did show preneoplastic effects in the bladder; also.
ff-nitrosodiphenylamine is structurally related to other carcinogenic
nitrosamines. These data are sufficient to support an EPA cancer
-------
48 Section 9
classification of B2 (probable human carcinogen) for Af-nitrosodi-
phenylamine (EPA 1986b, Holder 1987). IARC (1982b) previously
categorized N-nitrosodiphenylamine in Group 3 (cannot be classified as
to its carcinogenicity in humans).
#-nitrosodiphenylamine has a LOU hazard ranking for carcinogenicity
under CERCLA (EPA 1986c).
9.3 STATE
No state regulations were available.
-------
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61
11. GLOSSARY
Acute Exposure--Exposure to a chemical for a duration of 14 days or
less, as specified in the Toxicological Profiles.
Bioconcentration Factor (BCP)--The quotient of the concentration of a
chemical in aquatic organisms at a specific time or during a discrete
time period of exposure divided by the concentration in the surrounding
water at the same time or during the same time period.
Carcinogen--A chemical capable of inducing cancer.
Ceiling value (CL)--A concentration of a substance that should not be
exceeded, even instantaneously.
Chronic Exposure--Exposure to a chemical for 365 days or more, as
specified in the Toxicological Profiles.
Developmental Toxicity--The occurrence of adverse effects on the
developing organism that may result from exposure to a chemical prior to
conception (either parent), during prenatal development, or postnatally
to the time of sexual maturation. Adverse developmental effects may be
detected at any point in the life span of the organism.
Embryotoxicity and Fetotoxicity--Any toxic effect on the conceptus as a
result of prenatal exposure to a chemical; the distinguishing feature
between the two terns is the stage of development during which the
insult occurred. The terms, as used here, include malformations and
variations, altered growth, and in utero death.
Frank Effect Level (FEL)--That level of exposure which produces a
statistically or biologically significant increase in frequency or
severity of unmistakable adverse effects, such as irreversible
functional impairment or mortality, in an exposed population when
compared with its appropriate control.
EPA Health Advisory--An estimate of acceptable drinking water levels for
a chemical substance based on health effects information. A health
advisory is not a legally enforceable federal standard, but serves as
technical guidance to assist federal, state, and local officials.
Immediately Dangerous to Life or Health (IDLE)--The maximum
environmental concentration of a contaminant from which one could escape
within 30 min without any escape-impairing symptoms or irreversible
health effects.
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62 Section 11
Intermediate Exposure--Exposure to a chemical for a duration of 15-364
days, as specified in the Toxicological Profiles.
Immunologic Toxiclty--The occurrence of adverse effects on the immune
system that may result from exposure to environmental agents such as
chemicals.
In vitro--Isolated from the living organism and artificially maintained.
as in a test tube.
In vivo--Occurring within the living organism.
Key Study--An animal or human toxicological study that best illustrates
the nature of the adverse effects produced and the doses associated with
those effects.
Lethal Concentration(LO) (LCLO)--The lowest concentration of a chemical
in air which has been reported to have caused death in humans or
animals.
Lethal Concentration(50) (LCSO)--A calculated concentration of a
chemical In air to which exposure for a specific length of time is
expected to cause death in 50% of a defined experimental animal
population.
Lethal Dose(LO) (LDLO)--The lowest dose of a chemical introduced by a
route other than inhalation that is expected to have caused death in
humans or animals.
Lethal Dose(5Q) (LDSO)--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.
Lowest-Observed-Effect Level (LOEL)--The lowest dose of chemical in a
study or group of studies which produces statistically or biologically
significant increases In frequency or severity of effects between the
exposed population and its appropriate control.
Malformations--Permanent structural changes that may adversely affect
survival, development, or function.
Minimal Risk Level—An estimate of daily human exposure to a chemical
that is likely to be without an appreciable risk of deleterious effects
(noncancerous) over a specified duration of exposure.
Mutagen--A substance that causes mutations. A mutation is a change in
the genetic ma arial In a body cell. Mutations can lead to birth
defects, miscarriages, or cancer.
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Glossary 63
Neurotoxlcity--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.
No-Observed-Effect Level (NOEL)--That dose of chemical at which there
are no statistically or biologically significant increases in frequency
or severity of effects seen between the exposed population and its
appropriate control.
Permissible Exposure Limit (PEL)--An allowable exposure level in
workplace air averaged over an 8-h shift.
q *--The upper-bound estimate of the low-dose slope of the dose-response
curve as determined by the multistage procedure. The qj^ can be used to
calculate an estimate of carcinogenic potency, the incremental excess
cancer risk per unit of exposure (usually /*g/L for water, mgAg/day for
food, and pg/m3 for air).
Reference Dose (RfD)--An estimate (with uncertainty spanning perhaps an
order of magnitude) of the daily exposure of the human population to a
potential hazard that is likely to be without risk of deleterious
effects during a lifetime. The RfD is operationally derived from the
NOAEL (from animal and human studies) by a consistent application of
uncertainty factors that reflect various types of data used to estimate
RfDs and an additional modifying factor, which is based on a
professional Judgment of the entire database on the chemical. The RfDs
are not applicable to nonthreshold effects such as cancer.
Reportable Quantity (RQ)--The quantity of a hazardous substance that is
considered reportable under CERCLA. Reportable quantities are: (1) 1 lb
or greater or (2) for selected substances, an amount established by
regulation either under CERCLA or under Sect. 311 of the Clean Water
Act. Quantities are measured over a 24-h period.
Reproductive Toxicity--The occurrence of adverse effects on the
reproductive system that may result from exposure to a chemical. The
toxicity may be directed to the reproductive organs and/or the related
endocrine system. The manifestation of such toxicity may be noted as
alterations in sexual behavior, fertility, pregnancy outcomes, or
modifications in other functions that are dependent on the integrity of
this system.
Short-Term Exposure Limit (STEL)--The maximum concentration to which
workers can be exposed for up to 15 min continually. No more than four
excursions are allowed per day, and there must be at least 60 min
between exposure periods. The daily TLV-TWA may not be exceeded.
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64 Section 11
Target Organ Toxlclty--Thls term covers a broad range of adverse effects
on target organs or physiological systems (e.g., renal, cardiovascular)
extending from those arising through a single limited exposure to those
assumed over a lifetime of exposure to a chemical.
Teratogen--A chemical that causes structural defects that affect the
development of an organism.
Threshold Limit Value (TLV)--A concentration of a substance to which
most workers can be exposed without adverse effect. The TLV may be
expressed as a TWA, as a STEL, or as a CL.
Time-weighted Average (TWA)--An allowable exposure concentration
averaged over a normal 8-h workday or 40-h workweek.
Uncertainty Factor (UF)--A factor used in operationally deriving the RED
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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65
APPENDIX: PEER REVIEW
A peer review panel was assembled for tf-nitrosodiphenylamine The
panel consisted of the following members: Dr. Rolf Hartung, Chairman
Toxicology Program, University of Michigan; Dr. Dietrich Hoffmann,
Associate Director and Chief, Division of Environmental Carcinogenesis,
American Health Foundation, Naylor Dana Institute for Disease
Prevention, Valhalla, New York; and Dr. Tsutomu Nakatsugawa, Professor
of Toxicology, SUNY School of Environmental Science and Forestry
Syracuse, New York. These experts collectively have knowledge of V
nitrosodiphenylamine's physical and chemical properties, toxicokinetics,
key health end points, mechanisms of action, human and animal exposure
and quantification of risk to humans. All reviewers were selected in '
conformity with the conditions for peer review specified in the
Superfund Amendments and Reauthorization Act of 1986, Section 110.
A joint panel of scientists from ATSDR and EPA has reviewed the
peer reviewers' comments and determined which comments will be included
in the profile. A listing of the peer reviewers' comments not
incorporated in the profile, with a brief explanation of the rationale
for their exclusion, exists as part of the administrative record for
this compound. A list of databases reviewed and a list of unpublished
documents cited are also included in the administrative record.
The citation of the peer review panel should not be understood to
imply their approval of the profile's final content. The responsibility
for the content of this profile lies with the Agency for Toxic
Substances and Disease Registry.
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