Toxicological
Profile
for
N-NITROSODIMETHYL AMINE
Agency for Toxic Substances and Disease Registry
U.S. Public Health Service
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TOXICOLOGICAL PROFILE FOR
N-NITROSODIMETHYLAMINE
Prepared by:
Syracuse Research Corporation
Under Subcontract to:
Clement Associates, Inc.
Under Contract No. 205-88-0608
Prepared for:
Agency for Toxic Substances and Disease Registry (ATSDR)
U.S. Public Health Service
In collaboration with
U.S. Environmental Protection Agency (EPA)
December 1989
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ii
DISCLAIMER
Mention of company name or product does not constitute endorsement by the
Agency for Toxic Substances and Disease Registry.
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iii
FOREWORD
The Superfund Amendments and Reauthorization Act of 1986 (Public
Law 99-499) extended and amended the Comprehensive Environmental Response,
Compensation, and Liability Act of 1980 (CERCLA or Superfund). This public
law (also known as SARA) directed the Agency for Toxic Substances and Disease
Registry (ATSDR) to prepare toxicological profiles for hazardous substances
which are most commonly found at facilities on the CERCLA National Priorities
List and which pose the most significant potential threat to human health, as
determined by ATSDR and the Environmental Protection Agency (EPA). The lists
of the most significant hazardous substances were published in the Federal
Register on April 17, 1987, and on October 20, 1988.
Section 110 (3) of SARA directs the Administrator of ATSDR to prepare a
toxicological profile for each substance on the list. Each profile must
include the following content:
(A) An examination, summary and interpretation of available
toxicological information and epidemiological evaluations on the
hazardous substance in order to ascertain the levels of significant
human exposure for the substance and the associated acute, subacute,
and chronic health effects,
(B) A determination of whether adequate information on the health
effects of each substance is available or in the process of
development to determine levels of exposure which present a
significant risk to human health of acute, subacute, or chronic
health effects, and
(C) Where appropriate, an identification of toxicological testing
needed to identify the types or levels of exposure that may present
significant risk of adverse health effects in humans.
This toxicological profile is prepared in accordance with guidelines
developed by ATSDR and EPA. The original guidelines were published in the
Federal Register on April 17, 1987. Each profile will be revised and
republished as necessary, but no less often than every 3 years, as required
by SARA.
The ATSDR toxicological profile is intended to characterize succinctly
the toxicological and health effects information for the hazardous substance
being described. Each profile identifies and reviews the key literature that
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iv
describes a hazardous substance's toxicological properties. Other literature
is presented but described in less detail than the key studies. The profile
is not intended to be an exhaustive document; however, more comprehensive
sources of specialty information are referenced.
Each toxicological profile begins with a public health statement, which
describes in nontechnical language a substance's relevant toxicological
properties. Following the statement is material that presents levels of
significant human exposure and, where known, significant health effects. The
adequacy of information to determine a substance's health effects is described
in a health effects summary. Data needs that are of significance to
protection of public health will be identified by ATSDR, the National
Toxicology Program of the Public Health Service, and EPA. The focus of the
profiles is on health and toxicological information; therefore, we have
included this information in the front of the document.
The principal audiences for the toxicological profiles are health
professionals at the federal, state, and local levels, interested private
sector organizations and groups, and members of the public. We plan to revise
these documents as additional data become available.
This profile reflects our assessment of all relevant toxicological
testing and information that has been peer reviewed. It has been reviewed by
scientists from ATSDR, EPA, the Centers for Disease Control, and the National
Toxicology Program. It has also been reviewed by a panel of nongovernment
peer reviewers and was made available for public review. Final responsibility
for the contents and views expressed in this toxicological profile resides
with ATSDR.
Wi >h.D.
Acting Administrator
Agency for Toxic Substances and
Disease Registry
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V
CONTENTS
FOREWORD iii
LIST OF FIGURES ix
LIST OF TABLES xi
1. PUBLIC HEALTH STATEMENT 1
1.1 WHAT IS N-NITROSODIMETHYLAMINE? 1
1.2 HOW MIGHT I BE EXPOSED TO N-NITROSODIMETHYLAMINE? 1
1.3 HOW CAN N-NITROSODIMETHYLAMINE ENTER AND LEAVE MY BODY?. ... 2
1.4 HOW CAN N-NITROSODIMETHYLAMINE AFFECT MY HEALTH? 2
1.5 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN
EXPOSED TO N-NITROSODIMETHYLAMINE? 3
1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH
EFFECTS? 3
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO
PROTECT HUMAN HEALTH? 3
1.8 WHERE CAN I GET MORE INFORMATION? 3
2. HEALTH EFFECTS 9
2.1 INTRODUCTION 9
2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 9
2.2.1 Inhalation Exposure 10
2.2.1.1 Death 10
2.2.1.2 Systemic Effects 13
2.2.1.3 Immunological Effects 14
2.2.1.4 Neurological Effects 14
2.2.1.5 Developmental Effects 14
2.2.1.6 Reproductive Effects 14
2.2.1.7 Genotoxic Effects 15
2.2.1.8 Cancer ..... 15
2.2.2 Oral Exposure 16
2.2.2.1 Death 16
2.2.2.2 Systemic Effects 29
2.2.2.3 Immunological Effects 33
2.2.2.4 Neurological Effects 34
2.2.2.5 Developmental Effects 34
2.2.2.6 Reproductive Effects 35
2.2.2.7 Genotoxic Effects 35
2.2.2.8 Cancer 36
2.2.3 Dermal Exposure 38
2.2.3.1 Death 38
2.2.3.2 Systemic Effects 38
2.2.3.3 Immunological Effects 39
2.2.3.4 Neurological Effects 39
2.2.3.5 Developmental Effects 39
2.2.3.6 Reproductive Effects . . 39
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vi
2.2.3.7 Genotoxic Effects 39
2.2.3.8 Cancer 39
2.3 RELEVANCE TO PUBLIC HEALTH 39
2.4 LEVELS IN HUMAN TISSUES AND FLUIDS ASSOCIATED WITH HEALTH
EFFECTS 46
2.5 LEVELS IN THE ENVIRONMENT ASSOCIATED WITH LEVELS IN HUMAN
TISSUES AND/OR HEALTH EFFECTS 47
2.6 TOXICOKINETICS 47
2.6.1 Absorption 47
2.6.1.1 Inhalation Exposure 47
2.6.1.2 Oral Exposure 47
2.6.1.3 Dermal Exposure 48
2.6.2 Distribution 48
2.6.2.1 Inhalation Exposure 48
2.6.2.2 Oral Exposure 48
2.6.2.3 Dermal Exposure 49
2.6.3 Metabolism 49
2.6.3.1 Inhalation Exposure 49
2.6.3.2 Oral Exposure 49
2.6.3.3 Dermal Exposure 51
2.6.4 Excretion 51
2.6.4.1 Inhalation Exposure 51
2.6.4.2 Oral Exposure 51
2.6.4.3 Dermal Exposure 51
2.7 INTERACTIONS WITH OTHER CHEMICALS 51
2.8 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 52
2.9 ADEQUACY OF THE DATABASE 52
2.9.1 Existing Information on Health Effects of
N-Nitrosodimethylamine 53
2.9.2 Data Needs 53
2.9.3 On-going Studies 58
3. CHEMICAL AND PHYSICAL INFORMATION 59
3.1 CHEMICAL IDENTITY 59
3.2 PHYSICAL AND CHEMICAL PROPERTIES 59
4. PRODUCTION, IMPORT, USE, AND DISPOSAL 63
4.1 PRODUCTION 63
4.2 IMPORT 63
4.3 USE 63
4.4 DISPOSAL 63
4.5 ADEQUACY OF THE DATA BASE 64
4.5.1 Data Needs 64
5. POTENTIAL FOR HUMAN EXPOSURE 65
5.1 OVERVIEW 65
5.2 RELEASES TO THE ENVIRONMENT 66
5.2.1 Air 66
5.2.2 Water 66
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vii
5.2.3 Soil 67
5.3 ENVIRONMENTAL FATE 67
5.3.1 Transport and Partitioning 67
5.3.2 Transformation and Degradation 68
5.3.2.1 Air 68
5.3.2.2 Water 68
5.3.2.3 Soil 68
5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 69
5.4.1 Air 69
5.4.2 Water 69
5.4.3 Soil 70
5.4.4 Other Media 70
5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 73
5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURE 74
5.7 ADEQUACY OF THE DATABASE 74
5.7.1 Data Needs 75
5.7.2 On-going Studies 76
6. ANALYTICAL METHODS 77
6.1 BIOLOGICAL MATERIALS 77
6.2 ENVIRONMENTAL SAMPLES 77
6.3 ADEQUACY OF THE DATABASE 81
6.3.1 Data Needs 81
6.3.2 On-going Studies 82
7. REGULATIONS AND ADVISORIES 83
8. REFERENCES 87
9. GLOSSARY 115
APPENDIX 119
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ix
LIST OF FIGURES
2-1. Levels of Significant Exposure to N-Nitrosodimethylamine -
Inhalation 12
2-2. Levels of Significant Exposure to N-Nitrosodimethylamine - Oral. . 25
2-3. Metabolism of N-Nitrosodimethylamine 50
2-4. Existing Information on Health Effects of N-Nitrosodimethylamine . 54
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xi
LIST OF TABLES
1-1. Human Health Effects from Breathing N-Nitrosodimethylamine .... 4
1-2. Animal Health Effects from Breathing N-Nitrosodimethylamine. ... 5
1-3. Human Health Effects from Eating or Drinking N-Nitroso-
dimethylamine 6
1-4. Animal Health Effects from Eating or Drinking N-Nitroso-
dimethylamine 7
2-1. Levels of Significant Exposure to N-Nitrosodimethylamine -
Inhalation 11
2-2. Levels of Significant Exposure to N-Nitrosodimethylamine - Oral. . 17
2-3. Genotoxicity of N-Nitrosodimethylamine In Vitro 43
2-4. Genotoxicity of N-Nitrosodimethylamine In Vivo 45
3-1. Chemical Identity of N-Nitrosodimethylamine 60
3-2. Physical and Chemical Properties of N-Nitrosodimethylamine .... 61
5-1. Detection of N-Nitrosodimethylamine in Food 71
6-1. Analytical Methods for Determining N-Nitrosodimethylamine in
Biological Samples 78
6-2. Analytical Methods for Determining N-Nitrosodimethylamine in
Environmental Samples 79
7-1. Regulations and Guidelines Applicable to N-Nitrosodi-
methylamine 84
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1
1. PUBLIC HEALTH STATEMENT
1.1 WHAT IS N-NITROSODIMETHYIAMINE?
N-Nitrosodimethylamine is commonly known as NDMA. It is a yellow
liquid which has no distinct odor. It is produced in the U.S. only for use
as a research chemical. NDMA was used to make rocket fuel, but this use
was stopped after unusually high levels of this compound were found in air,
water, and soil samples collected near a rocket fuel manufacturing plant.
NDMA is, however, unintentionally formed during various manufacturing
processes at many industrial sites and in air, water and soil from reactions
involving other chemicals called alkylamines. Alkylamines are both natural
and man-made compounds which are found widely distributed throughout the
environment.
NDMA does not persist in the environment. When NDMA is released into
the atmosphere, it breaks down in sunlight in a matter of minutes. When
released to soil surfaces, NDMA may evaporate into air, break down upon
exposure to sunlight, or sink into deeper soil. NDMA should break down
within a few months in deep soil. When NDMA is released into water, it may
break down upon exposure to sunlight or break down by natural biological
processes. The rate of breakdown in water is not known. More information
can be found in Chapters 3, 4 and 5.
1.2 HOW MIGHT I BE EXPOSED TO N-NITROSODIMETHYLAMINE?
Information suggests that the general population may be exposed to NDMA
from a wide variety of sources, including environmental, consumer, and
occupational sources. At this time, NDMA has been found in at least 1 out
of 1177 hazardous waste sites on the National Priorities List (NPL) in the
United States. Under certain conditions, NDMA may be found in outdoor air,
surface waters (rivers and lakes, for example), and soil. The primary
sources of human exposure to NDMA are tobapco smoke, chewing tobacco, diet
[cured meats (particularly bacon), beer, fish, cheese, and other food
items], toiletry and cosmetic products (for example, shampoos and
cleansers), interior air of cars, and various other household goods, such as
detergents and pesticides. In addition, NDMA can form in the stomach during
digestion of alkylamine-containing foods. Alkylamines are naturally
occurring compounds which are found in some drugs and in a variety of foods.
Infants may be exposed to NDMA from the use of rubber baby bottle nipples
and pacifiers which may contain very small amounts of NDMA, from ingestion
of contaminated infant formulas, and from breast milk of some nursing
mothers. Very low levels of NDMA have been found in some samples of human
breast milk. Occupational exposure may happen in a large number of places
including industries such as tanneries, pesticide manufacturing plants,
rubber and tire manufacturing plants, alkylamine manufacture/use industries,
fish processing industries, foundries, and dye manufacturing plants.
Researchers making or handling NDMA may also be exposed to this compound if
it passes through the rubber gloves they wear during laboratory work. NDMA
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2
1. PUBLIC HEALTH STATEMENT
has been found in groundwater samples, in amounts of 10 parts NDMA per
billion parts of water, at one or more hazardous waste sites on the
National Priorities List (NPL). No information is available about
contamination of soil, drinking water, irrigation water, sewers, storm
drains, or the human food chain with NDMA near NPL sites. For more
information, refer to Chapter 5.
1.3 HOW CAN N-NITROSODIMETHYLAMINE ENTER AND LEAVE MY BODY?
NDMA can enter the body when a person breathes air that contains NDMA
or when a person eats food or drinks water contaminated with NDMA. NDMA can
also enter the body through the skin after contact with rubber articles that
contain NDMA. Experiments in animals have shown that after being given by
mouth, NDMA enters the bloodstream and goes to many organs of the body in a
matter of minutes. In the liver, NDMA is broken down into other substances,
most of which leave the body within 24 hours in air exhaled from the lungs
and in urine, along with the NDMA that is not broken down. Little is known
about what happens to NDMA that enters the body through the skin or through
contaminated air. Although vapors of NDMA are broken down within minutes
after exposure to sunlight, if NDMA is spilled at a waste site and
evaporates, a person nearby can be exposed to NDMA before it disappears from
the air. The most important and probably the most harmful way of coming
into contact with NDMA seems to be by eating contaminated food or drinking
contaminated water. Further information on how NDMA can enter and leave the
body can be found in Chapter 2.
1.4 HOW CAN N-NITROSODIMETHYLAMINE AFFECT MY HEALTH?
NDMA is very harmful to the liver of animals and humans. People who
were intentionally poisoned on one or several occasions with unknown levels
of NDMA in beverage or food died of severe liver damage accompanied by
internal bleeding. Animals that ate food, drank water, or breathed air
containing high levels of NDMA over a period of days or several weeks also
developed serious, non-cancerous, liver disease. When rats, mice, hamsters,
and other animals ate food, drank water, or breathed air containing lower
levels of NDMA for periods more than several weeks, liver cancer and lung
cancer as well non-cancerous liver damage occurred. The high level short-
term and low level long-term exposures that caused non-cancerous liver
damage and/or cancer in animals also usually resulted in internal bleeding
and death. Although there are no reports of NDMA causing cancer in humans,
it is reasonable to expect that exposure to NDMA by eating, drinking, or
breathing could cause cancer in humans. Mice that were fed NDMA during
pregnancy had offspring that were born dead or died shortly after birth.
However, it is not known whether NDMA could cause the death of human babies
whose mothers are exposed during pregnancy. It should be realized that
exposure to NDMA does not mean that any effect on health will definitely
occur.
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3
1. PUBLIC HEALTH STATEMENT
1.5 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO
N-NITROSODIMETHYLAMINE?
The presence of NDMA can be detected in blood and urine by a test, but
this test is not usually available and has not been used as a test for
human exposure or to predict possible health effects.
1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTS?
The amounts of N-nitrosodimethylamine in air, drinking water, and food
that cause known health effects other than cancer in humans and animals are
summarized in Tables 1-1, 1-2, 1-3, and 1-4. These amounts are expressed as
parts of NDMA per million parts of air, water, or food (ppm). As seen in
Tables 1-1 and 1-3, the amounts of NDMA in air, water, or food that result
in health effects in humans are unknown. As seen in Table 1-2, short-term
exposure of animals to air containing NDMA produces liver damage and death.
Toxic effects of long-term exposures of animals to air containing NDMA are
unknown. As seen in Table 1-4, short-term or long-term exposure of animals
to water or food containing NDMA is also associated with serious effects,
such as liver disease and death. More information on levels of NDMA that
cause harmful effects in animals is presented in Chapter 2.
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN
HEALTH?
The Federal government has issued guidelines and rules to protect human
health from exposure to NDMA in water and in food. The U.S. Environmental
Protection Agency (EPA) has set limits on the amounts of NDMA in water such
as lakes and streams. The EPA controls the release of NDMA. Releases or
spills of one pound or more of NDMA must be reported to the National
Response Center. The Food and Drug Administration (FDA) has set a limit of
10 parts of NDMA per billion parts of barley malt (ppb). Further
information on Federal and state regulations can be found in Chapter 7.
1.8 WHERE CAN I GET MORE INFORMATION?
If you have more questions or concerns, please contact your State
Health or Environmental Department or:
Agency for Toxic Substances and Disease Registry
Division of Toxicology
1600 Clifton Road, E-29
Atlanta, Georgia 30333
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4
1. PUBLIC HEALTH STATEMENT
TABLE 1-1. Human Health Effects from Breathing
N-Nitrosodimethylamine*
Short-term Exposure
(less than or equal to 14 days)
Levels
in Air
fpprn)
Length of Exposure Description of Effects
The health effects resulting
from short-term human
exposure to air containing
specific levels of NDMA
are not known.
Long-term Exposure
(greater than 14 days)
Levels
in Air
(Dpm)
Length of Exposure Description of Effects
The health effects resulting
from long-term human
exposure to air containing
specific levels of NDMA
are not known.
*See Section 1.2 for a discussion of exposures encountered in daily
life.
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1. PUBLIC HEALTH STATEMENT
TABLE 1-2. Animal Health Effects from Breathing
N-Nitrosodimethylamine
Short-term Exposure
(less than or equal to 14 days)
Levels
in Air
fDt>nO
Leneth of ExDosure DescriDtion of Effects*
16
4 hour Liver damage and death in
dogs.
Long-term Exposure
(greater than 14 days)
Levels
in Air
(ppm)
Leneth of Exposure DescriDtion of Effects
The health effects resulting
from long-term animal
exposure to air containing
specific levels of NDMA
are not known.
*These effects are listed at the lowest level at which they were first
observed. They may also be seen at higher levels.
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1. PUBLIC HEALTH STATEMENT
TABLE 1-3. Human Health Effects from Eating or Drinking
N-Nitrosodimethylamine*
Short-term Exposure
(less than or equal to 14 days)
Levels in Food (ppm) Length of Exposure Description of Effects
The health effects resulting
from short-term human
exposure to food containing
specific levels of NDMA
are not known.
Levels in Water (ppnO The health effects resulting
from short-term human
exposure to water containing
specific levels of NDMA
are not known.
Long-term Exposure
(greater than 14 days)
Levels in Food (ppm) Length of Exposure Description of Effects
The health effects resulting
from long-term human
exposure to food containing
specific levels of NDMA
are not known.
Levels in Water (ppm) The health effects resulting
from long-term human
exposure to water containing
specific levels of NDMA
are not known.
*See Section 1.2 for a discussion of exposures encountered in daily
life.
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1. PUBLIC HEALTH STATEMENT
TABLE 1-4. Animal Health Effects from Eating or Drinking
N-Nitrosodimethylamine
Short-term Exposure
(less than or equal to 14 days)
Levels
in Food
(ppm)
Length of Exposure
Description of Effects*
75
1 week
Liver damage in rats.
Levels
in Water
(¦DDItl)
20
50
1 day
1 week
Liver damage in hamsters.
Death in mice.
Long-term Exposure
(greater than 14 days)
Levels
in Food
(ppm)
Leneth of Exposure
Description of Effects*
50
100
5 months
62-93 days
Liver damage in mice.
Death in rats.
Levels
in Water
(r»om)
5.5
20
30 weeks
28 days
Death in rats.
Liver damage in hamsters.
*These effects are listed at the lowest level at which they were first
observed. They may also be seen at higher levels.
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2. HEALTH EFFECTS
2.1 INTRODUCTION
This chapter contains descriptions and evaluations of studies and
interpretation of data on the health effects associated with exposure to
NDMA. Its purpose is to present levels of significant exposure for NDMA
based on toxicological studies, epidemiological investigations, and
environmental exposure data. This information is presented to provide
public health officials, physicians, toxicologists, and other interested
individuals and groups with (1) an overall perspective of the toxicology of
NDMA and (2) a depiction of significant exposure levels associated with
various adverse health effects.
2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE
To help public health professionals address the needs of persons
living or working near hazardous waste sites, the data in this section are
organized first by route of exposure -- inhalation, oral, and dermal -- and
then by health effect -- death, systemic, immunological, neurological,
developmental, reproductive, genotoxic, and carcinogenic effects. These
data are discussed in terms of three exposure periods -- acute,
intermediate, and chronic.
Levels of significant exposure for each exposure route and duration
(for which data exist) are presented in tables and illustrated in figures.
The points in the figures showing no-observed-adverse-effect levels (NOAELs)
or lowest-observed-adverse-effect levels (LOAELs) reflect the actual doses
(levels of exposure) used in the studies. LOAELs have been classified into
"less serious" or "serious" effects. These distinctions are intended to
help the users of the document identify the levels of exposure at which
adverse health effects start to appear, determine whether or not the
intensity of the effects varies with dose and/or duration, and place into
perspective the possible significance of these effects to human health.
The significance of the exposure levels shown on the tables and graphs
may differ depending on the user's perspective. For example, physicians
concerned with the interpretation of clinical findings in exposed persons or
with the identification of persons with the potential to develop such
disease may be interested in levels of exposure associated with "serious"
effects. Public health officials and project managers concerned with
response actions at Superfund sites may want information on levels of
exposure associated with more subtle effects in humans or animals (LOAEL) or
exposure levels below which no adverse effects (NOAEL) have been observed.
Estimates of levels posing minimal risk to humans (minimal risk levels,
MRLs) are of interest to health professionals and citizens alike.
For certain chemicals, levels of exposure associated with carcinogenic
effects may be indicated in the figures. These levels reflect the actual
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2. HEALTH EFFECTS
doses associated with the tumor incidences reported in the studies cited.
Because cancer effects could occur at lower exposure levels, the figures
also show estimated excess risks, ranging from a risk of one in 10,000 to
one in 10,000,000 (10"^ to 10"'), as developed by EPA.
Estimates of exposure levels posing minimal risk to humans (MRLs) have
been made, where data were believed reliable, for the most sensitive
noncancer end point for each exposure duration. MRLs include adjustments to
reflect human variability and, where appropriate, the uncertainty of
extrapolating from laboratory animal data to humans. Although methods have
been established to derive these levels (Barnes et al. 1987; EPA 1980a),
uncertainties are associated with the techniques.
2.2.1 Inhalation Exposure
2.2.1.1 Death
At least two human deaths following inhalation of NDMA have been
reported in the literature. One was a male chemist who was involved in the
production of NDMA and was exposed to an unknown level of fumes for about
two weeks, and subsequently to an unknown level of fumes during cleanup of a
spilled flask (Freund 1937). The subject became ill 6 days later, showed
abdominal distention, large amounts of yellow ascitic fluid, a tender and
enlarged liver and enlarged spleen, and died 6 weeks after the last
exposure, The other death was that of a male worker who was exposed to
unknown concentrations of NDMA in an automobile factory. Autopsy of this
subject showed a cirrhotic liver with areas of regeneration (Hamilton and
Hardy 1974).
The lethality of inhaled NDMA has been evaluated in several acute
duration studies with animals. Four-hour single exposure LC50 values of 78
ppm (95% confidence limits of 68 and 90 ppm) and 57 ppm (95% confidence
limits of 51 and 64 ppm) were determined for rats and mice, respectively
(Jacobson et al. 1955). The observation time in these assays was 14 days.
The cause of death was not specified but liver damage and hemorrhage in
various abdominal tissues were predominant pathologic findings. Druckrey
(1967) reported that the "LD50" for rats exposed to NDMA by inhalation for
one hour is 37 mg/kg. The air concentration corresponding to this dose is
not reported but a value of 925 ppm can be calculated from information
provided in the report", confidence in this value is low, however, because
this information is ambiguously reported. Two of three dogs that were
exposed to 16 ppm NDMA for 4 hours died or were moribund by the second day
(Jacobson et al. 1955). All dogs that were similarly exposed to 43-144 ppm
died or were moribund after 1-3 days. The 57 ppra mouse and 78 ppm rat LC50
values are presented in the acute duration category in Table 2-1 and Figure
2-1. The Druckrey (1967) rat value is not included in Table 2-1 and Figure
2-1 due to uncertainty regarding its validity. The 16 ppm concentration
represents a LOAEL for lethality in dogs due to acute duration inhalation
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TABLE 2-1. Levels of Significant Exposure to N-Nitrosodimethylamine - Inhalation
Exposure
Graph Frequency/
Key Species Duration
Effect NQAEL Less Serious
(ppra) (ppm)
LOAEL8 (Effect)
Serious
Reference
ACUTE EXPOSURE
Death
1 rat
2 mouse
3 dog
Systemic
4 rat
5 mouse
6 dog
7 dog
CHRONIC EXPOSURE
Cancer
8 rat
9 rat
10 mouse
4 hr,
once
4 hr,
once
4 hr,
once
4 hr,
once
4 hr,
once
4 hr,
once
4 hr,
once
life,
2 d**,
30 ain/d
25 mo,
continuous
17 mo,
continuous
Hepatic
Hepatic
llcmato
Hepatic
78 (LCjj,))
57
16 (death)
Jacobsan et al. 1955
Jacobs on et al. 1955
Jacobson et al. 1955
78 (hemorrhagic necrosis) Jacobsan et al. 1955
57 (hemorrhagic necrosis) Jacobson et al. 1955
16 (increased clotting time) Jacobson et al. 1055
16 (hemorrhagic necrosis) Jacobson et al. 1955
50 (CELc) (nasal tumors) Druckrey et al. 1967
0.07 (CEL) (liver, luig,
kidney tumors)
0.07 (CEL) (liver, lung,
kidney tumrs)
Noiseev and Benemanski
1975
Moiseev and Benemanski
1975
ro
K
>
r*
H
33
w
PJ
o
H
10
?NQAEL - No Observed Adverse Effect Level
T.OAEL - Lowest Observed Adverse Effect Level
cCEL - Cancer Effect Level
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12
2. HEALTH EFFECTS
(PPm)
100
10
1
0.1
0.01
0.001
0.0001
0.00001
0.000001
0.0000001
0.00000001
0.000000001
3d
»r 2m
ACUTE
(< 14 Days)
&
td
/
~W
4i
7d
5m
CHRONIC
far 365 Days)
~
to
to 10m
~ ~
10 < _
10 S
10*
10 -? J
Estimated
Upper-Bound
Human Cancer
Risk Levels
Key
r Rat
¦
LCS0
m Mouaa
•
LOAEL tor Mrtout aflacti (animate)
4 Dog
LOAEl tor Km aarioua aftacti (animate)
o
~
NOAEL (anlmalt)
CEl • Canear Eftact Laval
Tha numbar naxi to aaeh point
ccnvaponda to antriat in tha
accompanying labia.
FIGURE 2-1. Levels of Significant Exposure to N-Nltrosodimethylamine -
Inhalation
-------
13
2. HEALTH EFFECTS
exposure (Table 2-1 and Figure 2-1). The concentration of 16 ppm in air
(Jacobson et al. 1955) is presented in Table 1-2.
2.2.1.2 Systemic Effects
No studies were located regarding musculoskeletal or renal effects in
humans or animals following inhalation exposure to NOMA.
Respiratory Effects. Freund (1937) observed small hemorrhages in the
bronchi and trachea of a person who died from accidental exposure to vapors
of NDMA (Section 2.2.1.1).
No studies were located regarding respiratory effects in animals
following inhalation exposure to NDMA.
Cardiovascular Effects. Subpericardial hemorrhage was observed in a
person who died from accidental exposure to vapors of NDMA (Freund 1937)
(Section 2.2.1.1).
No studies were located regarding cardiovascular effects in animals
following inhalation exposure to NDMA.
Gastrointestinal Effects. Gastrointestinal hemorrhage was observed in
a person who died from accidental exposure to vapors of NDMA (Freund 1937)
(Section 2.2.1.1).
No studies were located regarding gastrointestinal effects in animals
following inhalation exposure to NDMA.
Hematological Effects. No studies were located regarding hematological
effects in humans following inhalation exposure to NDMA.
Hematological determinations were performed in dogs that were exposed
to 16-144 ppm NDMA for 4 hours (Jacobson et al. 1955). Increased coagulation
time, increased prothrombin time, increased plasma cholinesterase levels and
leukopenia occurred following exposure to all concentrations. There was no
evidence of intravascular hemolysis. As indicated in Section 2.2.1.1, the
concentrations producing these effects were lethal. Pathologic examination
of the dogs showed bloody ascites and hemorrhage in the liver and other
abdominal tissues. Due to the clinical evidence of impaired blood
coagulation and the possibility that the hemorrhagic effects were related to
impaired coagulation, 16 ppm is a LOAEL for hematological effects due to
acute inhalation exposure (Table 2-1 and Figure 2-1).
Hepatic Effects. Four cases of liver disease in humans resulting from
inhalation exposure to NDMA have been described in the literature. Two of
the subjects died; these cases are discussed in Section 2.2.1.1. Of the
subjects who did not die, one was a chemist who was exposed to unknown
concentrations of fumes and experienced exhaustion, headache, cramps in the
-------
14
2. HEALTH EFFECTS
abdomen, soreness on the left side, nausea and vomiting for at least two
years (Freund, 1937). The second case was an automobile factory worker who
was exposed to unknown levels of NDMA and became violently ill with jaundice
and ascites (Hamilton and Hardy 1974).
Hepatotoxicity is a predominant effect of high concentrations of
inhaled NDMA in animals. Pathologic examination of dogs following exposure
to 16-144 ppm NDMA for 4 hours showed marked necrosis and varying degrees of
hemorrhage in the liver (Jacobson et al. 1955). Related effects at all
concentrations included increased bilirubin levels and increased
sulfobromophthalein retention. As indicated in Section 2.2.1,1, the
concentrations producing these effects were lethal. Jacobson et al. (1955)
also indicated that necrosis and hemorrhage occurred in the liver of rats
and mice that were exposed to lethal concentrations of NDMA for 4 hours; as
indicated in Section 2.2.1.1, LC50 values for the rats and mice are 78 and
57 ppm, respectively. The 16 ppm, 57 and 78 ppm concentrations represent
LOAELs for hepatic effects due to acute inhalation exposure and are
presented in Table 2-1 and Figure 2-1. The concentration of 16 ppm in air
(Jacobson et al. 1955) is presented in Table 1-2.
Dermal/Ocular Effects. No studies were located regarding dermal or
ocular effects in humans following inhalation exposure to NDMA.
Limited information is available regarding dermal or ocular effects of
inhaled NDMA. Doolittle et al. (1984) reported that the only toxic signs
observed in rats exposed to 500 or 1000 ppm for 4 hours were reddened eyes
and piloerection. The only additional information reported in this study
pertained to genotoxic effects. Although high concentrations of NDMA vapor
are likely to be irritating, the significance of the reddened eyes and
piloerection cannot be determined because it is not specified if the effects
occurred at both concentrations and prevalence is not indicated. As
indicated in Section 2.2.1.1, acute exposure to much lower concentrations of
NDMA was lethal for rats, mice and dogs. The lack of mortality in rats at
the higher concentrations in the Doolittle et al. (1984) study may be
attributable to the fact that the animals were killed immediately following
exposure and consequently not observed for subsequent death.
No studies were located regarding the following effects in humans or
animals following inhalation exposure to NDMA;
2.2.1.3 Immunological Effects
2.2.1.4 Neurological Effects
2.2.1.5 Developmental Effects
2.2.1.6 Reproductive Effects
-------
15
2. HEALTH EFFECTS
2.2.1.7 Genotoxic Effects
No studies were located regarding genotoxic effects in humans following
inhalation exposure to NDMA.
Rats exposed to 500 or 1000 ppm of NDMA in the air for 4 hours showed
chemically induced DNA repair in epithelial cells in the nasal turbinates
and trachea. DNA repair was also evident in hepatocytes, indicating that the
substance entered the general circulation. No DNA repair was seen in the
pachytene spermatocytes, indicating that NDMA either did not reach the
testes in high enough concentrations, or that the testes could not
metabolically activate the compound (Doolittle et al. 1984). It should be
noted that the exposures in this study are likely to have been lethal if the
rats had been observed following treatment; as indicated in Section 2.2.1.1,
4-hour exposure to much lower concentrations of NDMA was lethal for rats,
mice and dogs in other studies.
2.2.1.8 Cancer
No studies were located regarding carcinogenic effects in humans
following inhalation exposure to NDMA.
The carcinogenicity of inhaled NDMA has been evaluated in two studies.
Twice weekly 30-minute exposures to 50 or 100 ppm NDMA vapor for life
produced malignant nasal cavity tumors in rats (Druckrey et al. 1967). The
incidence of tumors was 67% in each group, and the time to induce tumors in
50% of the rats was 400 days. Group sizes were small (12 and 6 animals at 50
and 100 ppm, respectively), control data were not reported, and additional
information regarding longevity was not provided. The 50 ppm concentration
is included in Table 2-1 and Figure 2-1 as an effect level for cancer
(cancer effect level, CEL.) in rats due to intermittent inhalation exposure
of chronic duration.
Rats and mice that were continuously exposed to 0.07 ppm NDMA for 25
and 17 months, respectively, developed significantly increased incidences of
lung, liver and kidney tumors (Moiseev and Benemanski 1975). Tumor types
included various adenomas, carcinomas, and sarcomas in the lung, liver and
kidneys, and hemangiomas in the liver, but the types were not tabulated
according to species or concentration. Induction of nasal tumors was not
reported. Exposure to 0.002 ppm NDMA according to the same schedule did not
produce significantly increased incidences of tumors in either species.
Since the tumors associated with exposure to 0.07 ppm NDMA are consistent
with those produced by NDMA in oral ana injection studies and the study is
reported adequately otherwise, 0.07 ppm is considered to be a CEL for rats
and mice due to continuous inhalation exposure of chronic duration (Table
2-1, Figure 2-1).
EPA has adopted the oral carcinogenicity slope factor (Bh) of 51
(mg/kg/day)(see Section 2.2.2.8) as the slope factor for inhalation (EPA
-------
16
2. HEALTH EFFECTS
1988a). The oral slope factor was converted to a unit risk for inhalation of
1.4 x 10"^ which is equivalent to 42.4 (ppm)"^. Using this unit
risk, the concentrations associated with upper bound lifetime cancer risk
levels of 10"^ to 10"? are calculated to be 2.36 x 10"^ to 2.36 x 10"® ppm,
respectively. The cancer risk levels are plotted in Figure 2-1.
2.2.2 Oral Exposure
2.2.2.1 Death
At least three human deaths following oral exposure to NOMA have been
reported in the literature. One of the fatalities was a woman who was
apparently poisoned over a two-year period by her husband (Fussgaenger and
Ditschuneit 1980, Pedal et al. 1982). It was estimated by the authors that
she received at least 4 doses as high as 250-300 mg each, for a total dose
of less than 1.5 gram; the mean daily dose was estimated to be 50 /xg/kg.
Both clinical and autopsy findings indicated that she died of hepatic
failure. Two other people (an adult male and a 1-year-old boy) died within
days after consuming lemonade tainted with unknown quantities of NDMA
(Kimbrough 1982, Cooper and Kimbrough 1980). Based on animal studies, the
authors estimated that the adult might have received about 1.3 gm, and the
boy might have received about 300 mg. In both cases, clinical and autopsy
findings primarily showed liver failure and cerebral hemorrhage.
Single dose lethality studies have been conducted in which NDMA was
administered to rats and cats by gavage. Druckrey et al. (1967) determined a
LD50 of 40 mg/kg for rats. This value was determined using an unspecified
graphic technique, and confidence limits and specific mortality data were
not reported. All of 12 rats that were treated with 40 mg/kg in a skin
grafting (immunology) experiment died by day 21, but the stress of skin
graft rejection may have contributed to mortality (Waynforth and Magee
1974). Jenkins et al. (1985) reported that single 25 mg doses of NDMA
resulted in 100% mortality in an unspecified number of rats, but it is
unclear if this is dose per kg body weight or dose per total body weight.
Single doses of 15 and 20 mg/kg were not lethal for nonpregnant rats but 23
mg/kg was estimated to be the LD50 for pregnant rats (Nishie 1983). The LD50
for the pregnant rats was extrapolated using mortality of 18-day pregnant
rats given single oral doses of 15 or 20 mg NDMA/kg. A dose of 10 mg/kg did
not produce deaths in rats within 48 hours (Sumi and Miyakawa 1983). Two of
6 cats died when treated with 50 mg NDMA/kg (Maduagwu and Basir 1980). The
NOAEL and appropriate LOAEL values for lethality from these single dose
studies are included in the acute duration category in Table 2-2 and Figure
2-2. The 40 mg/kg and 23 mg/kg rat LD50S are also presented in Table 2-2 and
Figure 2-2.
Rats, guinea pigs, cats and monkeys that were treated with NDMA by
gavage at a dose of 5 mg/kg/day for 11 days experienced 30-40% mortality;
-------
TABLE 2-2. Levels of Significant Exposure to N-Nitrosodimethylamine - Oral
Exposure
Graph Frequency/
Key Species Route8 Duration Effect
NOAEL
(mg/kg/day)
Less Serious
LOAELc (Effect)
Serious
Reference
ACUTE EXPOSURE
Death
1 rat
2, 3 rat
4
5
6
7
8
9
10
11
12
(6)
CO)
rat CG)
rat (G)
rat (G>
¦ouse (U>
gn pig (G>
haaster (U)
cat (G>
cat (G>
once
once
5-11 days,
daily
once
6 days,
daily
1 wk
dai ly
5-11 days,
daily
1, 2. 4, 7
or 14 d,
daily
5-11 days,
daily
once
20
(non-pregnant rats)
10
4.0
aonkey (G) 5-11 days,
daily
40 (LDM)
23
-------
TABLE 2-2 (continued)
Exposure
Graph Frequency/
Key Species Route8 Duration Effect
NOAEL
(mg/kg/day)
LOAEL (Effect)
Less Serious
Serious
Reference
Systemic
13 rat
14
15
16
rat
rat
rat
rat
17
18. 19 rat
20
21
22
23
24
rat
(G)
(G)
(G)
(G)
(F)
(G)
(G)
gn pig (G)
hamster (U)
cat
(G)
monkey (G)
I itmunological
25 rat (G)
once
once
once
once
1 or 2
wk, daily
5-11 d,
dai ly
5-11 d,
daily
5-11 d,
dai ly
5-11 d,
daily
once
Hepatic
Hepatic
Other
(thyroid)
Hepatic
Hepatic
Hepatic
Hepatic
Hepatic
1, 2, 4, 7 Hepatic
or 14 d,
daily
Hepatic
Hepatic
20
0.7
2.5 (degeneration)
1.9 (vacuolation)
4.0 (portal venopathy)
20 (necrosis)
8 (necrosis)
3.75 (necrosis)
5 (necrosis)
5 (necrosis)
5 (necrosis)
5 (necrosis)
40
Jenkins et al.
1985
Nishie 1983
Nishie 1983
Suni and Miuakawa
1983
Khama and Puri
1966
Korsrud et al.
1973
Maduagwu and
Bassir 1980
Maduagwu and
Bassir 1980
(Jngar 1984
Maduagwu and
Bassir 1980
Maduagwu and
Bassir 1980
Waynforth and
Magee 1974
N>
EC
Pi
>
t"1
H
X
m
*1
n
o
H
w
oo
-------
TABLE 2-2 (continued)
Exposure
Graph Frequency/
Key Species Route0 Duration Effect
NOAEL
(wg/kg/day)
Less Serious
LOAELc (Effect)
Serious
Reference
Developmental
26 rat
(G)
once,
G d 15,
or 20
20 (decreased
fetal weight)
Nishie 1983
Cancer
27 aouse (W)
INTERMEDIATE EXPOSURE
Death
28 rat (G)
29, 30 rat (F)
31
rat
32 rat
33
rat
35
(F)
(U)
(G)
34 mouse (U)
¦ouse (F)
36 nouse (U)
1 wk,
daily
30 d.
daily
24-110 d
daily
40 wk,
daily
30 wk,
5 d/wk
30 wk,
2 d/wk
49 d,
daily
5 no,
dai ly
13 wk,
daily
2.5
9.5 (CEL ) (kidney, Terracini et al.
lung)
5.0 (death)
3.9 (decreased
survival)
0.32 (decreased
survival)
6.0 (decreased
survival)
1.8 (decreased
survival)
5.26 (decreased
survival)
1.9 (decreased
survival)
1966
Haduagwu and
Bassir 1980
Barnes and Magee
1954
Magee and Barnes
1956
Lijinsky and
Reuber 1984
Lijinsky et al.
1987
Clapp and Toya
1970
Takayana and
Oota 1965
Den Engelse
et al. 1974
X
m
>
5
EC
m
*3
M
O
H
CO
VD
-------
TABLE 2-2 (continued)
Exposure
Graph Frequency/
Key Species Route8 Duration Effect
MOAEL
(mg/kg/day)
Less Serious
LOAELc (Effect)
Serious
Reference
37 mouse (U)
38
(U)
224 d,
dai ly
38 wk,
dai ly
0.4
1.19 (decreased
survival)
Clapp and Toya
1970
Terracini et al.
1966
39 gn pig (6)
30 d,
dai ly
Maduagwu and
Bassir 1980
40
41
42
43
haMster (G)
booster (G)
toaster (U)
hamter (U)
4 wk,
1 d/wk
20 wk,
1 d/wk
8, 12 or
16 wk,
daily
28 d,
daily
10.7 (decreased
survival)
5.4 (decreased
survival
4.0 (death)
4.0
Lijinsky et al.
1987
Lijinsky et al.
1987
Ungar 1986
Urtgar 1984
X
M
5
sc
pi
•»!
PI
O
H
u
IO
o
44
cat
(G)
30 d,
daily
1 (decreased
survival)
Bassir 1980
45
46
anrkey (G)
mink (F)
30 d,
daily
32-34 d.
daily
0.32 (decreased
survival)
Maduagwu and
Bassir 1980
Carter et al.
1969
System c
47 rat
CF)
40 ufc,
daily
Hepatic
3.9 (necrosis) Nagee and Barnes
1956
48, 49 rat
-------
TABLE 2-2 (continued)
Exposure
Graph Frequency/
Key Species Route3 Duration Effect
NOAEL
(mg/kg/day)
LOAEL (Effect)
Less Serious
Serious
Reference
50
51
52
53
54
55
56
57
58
59
60
61
62
rat
rat
mouse
mouse
mouse
9n pig
rabbit
hamster
hamster
dog
cat
monkey
mink
(F)
(G)
(F)
(W)
(F)
(G)
(F)
(W)
(U)
(C)
(G)
(G)
(F)
4,8 or 12
wk, daily
30 d,
dai ly
16-92d,
daily
1-4 wk,
daily
5 mo,
daily
30 d,
dai ly
22 Hk,
dai ly
8, 12 or
16 uk,
daily
28 d,
dai ly
3 uk, 2 d/w
(consec)
30 d,
dai ly
30 d,
daily
122 d,
dai ly
Hepatic
Hepatic
Hepatic
Hepatic
Hepatic
Hepatic
Hepatic
Hepatic
Hepatic
Hepatic
Hepatic
Hepatic
Hepatic
1 (vacuolation)
1.6 (fibrosis)
4.0 (portal venopathy)
4.0 (portal venopathy)
3.75 (necrosis)
13 (hemorrhage/
necrosis)
5.0 (hemorrhage)
5.26 (hemorrhage/
necrosis)
1 (necrosis)
2.5 (necrosis)
1 (necrosis)
1 (necrosis)
0.13 (venopathy)
Khama and Puri
1966
Maduagwu and
Bassir 1980
Otsuka and
Kuwahara 1971
Anderson et al.
1986
Takayama and
Oota 1965
Maduagwu and
Bassir 1980
Nagee and Barnes
1956
Ungar 1986
Ungar 1984
Strcmbeck et al.
1983
Maduagwu and
Bassir 1980
Maduagwu and
Bassir 1980
Koppang and
Rimeslatten 1976
ac
m
>
f
H
X
m
w
o
H
to
S3
-------
TABLE 2-2 (continued)
Exposure
Graph Frequency/
Key Species Route® Duration Effect
NOAEL
ro
71 mouse (U)
224 d,
daily
0.4 (CEL ) (liver) Clapp and Toya
1970
72
73
mouse (F)
mouse (F)
10 mo,
dai ly
16-92 d,
daily
9.04 (CEL ) (liver, Takayaoa and
ling) Oota 1965
13 (CELd) (ling) Otsuka and
ICuwahara 1971
74 mouse (G)
50 wk,
2 d/wk
1 (CEL ) (liver) Griciute et al.
1981
-------
TABLE 2-2 (continued)
Exposure
Graph Frequency/
Key Species Route8 Duration Effect
NQAEL
(mg/kg/day)
less Serious
L0AELc (Effect)
Serious
Reference
75 mouse (F)
76
77
78
79
hamster (G)
hamster (G)
hamster (G)
hamster (W)
CHRONIC EXPOSURE
Death
80 rat (F)
5 mo,
dai ly
20 wk,
1 d/uk
6.5 uk,
2 d/wk
4 uk,
1 d/wk
12 or
16 uk,
daily
54 wk
S.26 (CEL**) (liver, Takayaaa and
lung, kidney) Oota 1965
5.4 (CELd) (liver) Lijinsky et at.
1987
5.4 (CEL**) (liver) Lijinsky et al.
1987
10.7 (CELd) (liver) Lijinsky et al.
1987
4.0 (CELd) (liver) Ungar 1986
0.5
Terao et al.
1978
to
£
t"1
H
EC
m
•n
o
H
CO
ro
UJ
81
82
mouse (W)
¦ink (F)
406 d,
daily
321-670 d
dai ly
0.43 (decreased
survival)
0.1 (decreased
survival)
Clapp and Toya
1970
Koppang and
Rineslatten 1976
Systemic
83 rat
84
rat
(F)
(F)
54 uk
96 uk.
daily
Hepatic
Hepatic
0.5
0.5
Terao et al.
1978
Arai et al. 1979
85
mink (F)
321-670 d Hepatic
dai ly
0.1 (venopathy, Koppang and
focal necrosis)Rimmeslatten 1976
-------
TABLE 2-2 (continued)
Exposure
Graph Frequency/
Key Species Route8 Duration Effect
NOAEL
(mg/tcg/day)
Less Serious
LOAELc {Effect)
Serious
Reference
Cancer
86 rat
87
88
89
91
rat
rat
rat
(F)
(F)
(F)
(U)
90 Mouse (U)
¦ink (F)
54 uk
dai ly
96 uk,
daily
96 uk,
daily
life,
daily
life,
daily
321-607 d
dai ly
0.5 (CELd) (testes) Terao et al.
1978
0.05 (CELd) (liver) Arai et al. 1979
10 (CELd) (liver) Ito et al. 1982
0.02 (CELd) (liver) Peto et al. 1984
0.43 (CELd) (liver, Clapp and Toya
ling)
1970
0.1 (CELd) (liver) Koppang and
Rimeslatten 1976
?G - gavage, F - diet, W - drinking water, C - capsule
TIOAEL - No Observed Adverse Effect Level
^LOAEL - Lowest Observed Adverse Effect Level
CEL. - Cancer Effect Level
a:
m
>
x
pi
pj
o
C/i
ro
-------
25
2. HEALTH EFFECTS
ACUTE
(s 14 Days)
(mg/kg/day)
100 -
10
tie
Ur
' 2r
L O
I 7m
10c 12*
• o##
•*
17r I
1*
i*3
1*0
i*0
21g 23c
3 24k
22%
/
/
J
2b
o
o
15»
Mr
27m
~
0.1
r
fUt
¦
LD50
m
•
a
f
k
Moum
Hamatar
Girinaaplg
Cat
Monkay
•
<*
0
~
IOAEL tor Mriout aflac* (animal*)
IOAEL tor laa* aarloua affact* (animal*)
NOAEl (animal*)
CEl • Canear Effact luaval
Thanumbar nan to aaeh point
corraapondtloantrlaatntha
accompanying labia.
FIGURE 2-2. Levels of Significant Exposure to N-Nitrosodlmethylamine -
Oral
-------
26
2. HEALTH EFFECTS
INTERMEDIATE
(15 - 364 Days)
(mg/kg/day)
100 r-
/
10
0.1
Sim
33f
40>
35m 41*
4«r
84m
73m
~
72m ~ 7*
~
t *
D
JOr
31 r
2Sr
h o mo
2Sr 3am
43§
o
47r
SOr
57. Mi
O _
34m | Mg
4Sk
o
1 „
Sir 69g
Mr ^ 75m
5M
•5r
37m
O
32r
46o
60c «1K
•3n
•2n
~ **
A Mm
• 70m
76,77*
7*«
l
Mr
0.01 >-
K#y
i
Rat
•
LOAEL tor aartoua aflat* (animal*)
m
Moum
O
LOAEL tor laaa aarioua alfaeli (artmata)
h
RabbH
0
NOAEL (animate)
•
0
d
Ha malar
Oulnaa PI9
Dog
~
CEL • Canear Eftact Laval
Tha numbar nait to aach point
correspond* 10 ontrlaa In via
accompanying taWa.
e
k
n
Cat
Monday
Mtnk
FIGURE 2-2 (continued)
-------
27
2. HEALTH EFFECTS
(mg/kg/day)
10
1
0.1
0.01
0.001 ¦
0.0001 ¦
0.00001 -
0.000001 -
0.0000001 -
0.00000001 -
0.000000001 -
CHRONIC
(* 365 Days)
M-
_ atm
CJ A *2n
63, Mr
O BSn
~
•7r
t
•ftr
Mm
^ tin
10 *
10#
10-*
10-7
Estimated
Upper-Bound
Human Cancer
Risk Levels
Kev
r Rat
•
LOAEL lor Mflou* «f1»cti (animal*)
m Moum
0
LOAEL tor la*a aarloua affactt (anhnala)
n Mink
0
NOAEl (animal*)
~
CEl • Canoar Effect Laval
TIm numbar naxt to aaeh point
eorraapond* to onirla* In via
accompanying taMa.
FIGURE 2-2 (continued)
-------
28
2. HEALTH EFFECTS
mean survival times were 5-11 days (Maduagwu and Bassir 1980). Rats treated
by gavage daily with 8 mg/kg NDMA for 6 days experienced 10% mortality
within one month (McGiven and Ireton 1972). Administration of NDMA in the
drinking water at a daily dose of 9.5 mg/kg for one week resulted in
decreased survival in mice (Terracini et al. 1966). Administration of a
daily dose of 4 mg/kg/day in the drinking water of hamsters for 1, 2, 4, 7
or 14 days did not result in mortality (Ungar 1984). The hamster NOAEL value
and all LOAEL values for lethality from these repeated exposure studies are
recorded in Table 2-2 and plotted in Figure 2-2. The mouse dose of 9.5
mg/kg/day was calculated from the administered concentration of 50 ppm in
water (Terracini et al. 1966); this concentration is presented in Table 1-4
for short-term exposure.
Numerous oral studies in which NDMA was administered for intermediate
durations (15-365 days) have been conducted. Deaths resulting from
intermediate duration exposure to NDMA were usually attributed to liver
toxicity or carcinogenicity. Representative lethal and nonlethal
intermediate duration exposures in various species are presented below.
In rats, decreased survival resulted when 0.32 mg NDMA/kg was given in
the drinking water for 5 days/week for 30 weeks (Lijinsky and Reuber 1984),
and when 6 mg/kg was administered by gavage for 2 days/week for 30 weeks
(Lijinsky et al. 1987). Control groups were not included in the latter study
but there was 100% mortality by 40 weeks after cessation of treatment.
Barnes and Magee (1954) administered NDMA in the diet to small numbers of
rats (6/group); 2.5 mg/kg/day produced no deaths, 5 mg/kg/day produced 100%
mortality after 62-93 days, and 10 mg/kg/day produced 100% mortality after
34-37 days. Rats treated with 3.9 mg/kg/day in the diet for 40 weeks also
had high mortality (Magee and Barnes 1956). Daily exposure to 1 mg/kg/day by
gavage for 30 days had no effect on survival of rats (Maduagwu and Bassir
1980). Jenkins et al. (1985) observed mortality in rats that received 2.5 mg
doses of NDMA by gavage for 4 days/week for 9 weeks, but it is unclear if
this is dose per kg body weight or dose per total body weight. The NOAEL
values and all reliable LOAEL values for lethality in rats from these
intermediate duration studies are recorded in Table 2-2 and plotted in
Figure 2-2. The rat dose of 5 mg/kg/day was calculated from the administered
concentration of 100 ppm in diet (Barnes and Magee 1954); this concentration
is presented in Table 1-4 for long-term exposure. The rat dose of 0.32
mg/kg/day was calculated from the administered concentration of 5.5 ppm in
water (Lijinsky and Reuber 1984); this concentration is also presented in
Table 1-4 for long-term exposure.
In intermediate duration studies with mice, decreased survival resulted
from treatment with doses of 1.8 mg/kg/day via drinking water for 49 days
(Clapp and Toya 1970), 1.9 mg/kg/day via drinking water for 13 weeks (Den
Engelse et al. 1974), 1.19 mg/kg/day via drinking water for 38 weeks
(Terracini et al. 1966) and 5.26 mg/kg/day via diet for 5 months (Takayama
and Oota 1965). Mice that received 0.4 mg/kg/day in drinking water for 224
days did not experience significantly decreased survival (Clapp and Toya
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29
2. HEALTH EFFECTS
1970). The NOAEL value and all LOAEL values for lethality in mice from these
intermediate duration studies are recorded in Table 2-2 and plotted in
Figure 2-2.
Survival data for intermediate oral exposure to NDMA are available for
species other than rat and mouse. Daily gavage exposure to 1 mg NDMA/kg for
30 days caused decreased survival in cats but not guinea pigs or monkeys
(Maduagwu and Bassir 1980). In hamsters, daily administration of 4 mg/kg/day
in the drinking water for 8, 12, or 16 weeks resulted in occasional
moribundity (Ungar 1986), while no lethality resulted from daily
administration of the same dose for 28 days (Ungar 1984); this dose is a
NOAEL or LOAEL for lethality depending on duration of exposure. Once weekly
gavage treatment with a dose of 10.7 mg/kg for 4 weeks or 5.4 mg/kg for 20
weeks was lethal for hamsters (Lijinsky et al. 1987). Mink that were given
doses of 0.32 or 0,63 mg/kg/day in the diet died after 23-34 days of
treatment (Carter et al. 1969), but low numbers of animals were tested
(three per dose). Mink fed a contaminated diet that provided approximately
0.18 mg NDMA/kg/day died (Martino et al. 1988), but there is uncertainty
about the dietary concentration of NDMA used to calculate the dose. The mink
that were examined in this study were from a commercial breeding colony that
died during a 2 month period; durations of exposure were not specified. The
NOAEL values and all reliable LOAEL values for lethality in these
intermediate duration studies are recorded in Table 2-2 and plotted in
Figure 2-2.
Chronic lethality data are available for NDMA-exposed rats, mice and
mink. Survival of rats that received 0.5 mg/kg/day of NDMA in the diet for
54 weeks (Terao et al. 1978) was not affected. Decreased survival occurred
in mice that were exposed to 0.43 mg/kg/day in the drinking water for life
(average 406 days) (Clapp and Toya 1970). Mink appear to be particularly
sensitive to NDMA as mortality resulted from ingestion of 0.1 mg/kg/day in
the diet for 321-670 days (Koppang and Rimeslatten 1976). The NOAEL value
and LOAEL values for lethality in these chronic duration studies are
recorded in Table 2-2 and plotted in Figure 2-2.
2.2.2.2 Systemic Effects
No studies were located regarding hematological, musculoskeletal or
dermal/ocular effects in humans or animals following oral exposure to NDMA.
Respiratory Effects. Petechial and larger hemorrhages were observed in
the lungs of two people following lethal poisoning with NDMA (Kimbrough
1982) (Section 2.2.2.1).
Macroscopic congestion was noted in the lungs of rats that were
administered 3.75 mg/kg/day doses of NDMA in the diet for 1-12 weeks (Khanna
and Puri 1966). The adversity of the congestion cannot be determined because
results of lung histological examinations were not reported. No studies were
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30
2. HEALTH EFFECTS
located regarding respiratory effects in animals due to chronic duration
oral exposure.
Cardiovascular Effects. Myocardial and endocardial bleeding was
observed in a person following lethal poisoning with NDMA (Kimbrough 1982)
(Section 2.2.2.1).
Macroscopic congestion was noted in the myocardium of rats that were
administered 3.75 mg/kg/day doses of NDMA in the diet for 1-12 weeks (Khanna
and Puri 1966). The adversity of the congestion cannot be determined because
results of heart histological examinations were not reported. No studies
were located regarding cardiovascular effects in animals due to chronic
duration exposure.
Gastrointestinal Effects. Gastrointestinal hemorrhage occurred in
humans following lethal poisoning with NDMA (Kimbrough 1982, Pedal et al.
1982) (Section 2.2.2.1).
NDMA produced similar gastrointestinal effects in animals. Barnes and
Magee (1954) observed occasional hemorrhage into the gastrointestinal tract
in rats that died from treatment with a single 50 mg/kg dose of NDMA by
gavage, or with 10 mg/kg/day doses in the diet for 34-37 days. The numbers
of animals examined were unspecified (single dose study) or small (6 in the
diet study), and frequency of occurrence was not indicated. Gastrointestinal
hemorrhages were also observed in mink that ingested 0.32 or 0.63 mg
NDMA/kg/day via diet for 23-34 days (Carter et al. 1969). Only three mink
per dose were treated, the hemorrhages occurred in a total of three mink,
and the dose(s) that the affected mink received was not specified. The cause
of the hemorrhages in the mink was attributed to gastric and duodenal
erosions. No studies were located regarding gastrointestinal effects in
animals due to chronic duration exposure.
Hepatic Effects. Five members of a family who consumed unknown
quantities of NDMA in lemonade became ill with nausea and vomiting
associated with acute liver disease, generalized bleeding and low platelet
counts (Kimbrough 1982, Cooper and Kimbrough 1980). As indicated in Section
2.2.2,1, two of these people died; the other three were released from a
hospital 4-21 days after admission. Another fatality due to ingestion of
NDMA was attributed to liver failure (Fussgaenger and Ditschuneit 1980,
Pedal et al. 1982) (Section 2.2.2.1). Autopsies of the subjects described
above showed that the primary effects were hemorrhagic and cirrhotic changes
in the liver and necrosis and hemorrhage in other internal organs.
Hepatotoxicity of NDMA has been described and investigated in numerous
oral studies of acute, intermediate and chronic duration in several animal
species. Hepatotoxicity is the most prominent and characteristic systemic
effect of NDMA, resulting in centrilobular necrosis and hemorrhage often
leading to hemorrhagic ascites.
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2. HEALTH EFFECTS
In acute studies, characteristic hepatotoxic alterations, as indicated
above, occurred in rats following single gavage doses as low as 20 and 8
mg/kg (Nishie 1983, Surai and Miyakawa 1983), and following daily doses of
3.75 mg/kg in the diet for 1 or 2 weeks (Khanna and Puri 1966). These doses
therefore are LOAELs for serious hepatic effects. Jenkins et al. (1985)
observed degenerative alterations in the livers of rats following a single
2.5 mg/kg gavage dose of NDMA. As these alterations (collapse of reticulum
network in the centrilobular areas followed by regeneration) were
nonnecrotic and did not result in loss of the lobular architecture, the 2.5
mg/kg dose is a LOAEL for less serious hepatic effects. Single gavage doses
of 1.9 mg/kg and 0.7 mg/kg are a LOAEL for less serious hepatic effects and
a NOAEL, respectively, for rats, as nonnecrotic histologic alterations
(clumping and slight vacuolation of cells in the central vein area) occurred
at 1.9 mg/kg and no alterations occurred at 0.7 mg/kg (Korsrud et al. 1973).
Daily gavage exposure to 5 mg/kg for 5-11 days produced hemorrhagic necrosis
in rats, guinea pigs, cats and monkeys (Maduagwu and Bassir 1980). Hamsters
that ingested daily doses of 4 mg/kg/day in the drinking water for 1, 2, 4,
7 or 14 days showed portal venopathy, a less serious hepatic effect (Ungar
1984). The NOAEL value and LOAEL values for hepatic effects in these acute
duration studies are recorded in Table 2-2 and plotted in Figure 2-2. The
rat diet dose of 3.75 mg/kg/day was calculated from the administered
concentration of 75 ppm in food (Khanna and Puri 1966) ; this concentration
is presented in Table 1-4 for short-term exposure. The hamster drinking
water dose of 4 mg/kg/day was calculated from the administered concentration
of 20 ppm in water (Ungar 1984); this concentration is also presented in
Table 1-4 for short-term exposure.
In intermediate duration studies with rats, characteristic hepatic
effects (described previously) were produced by treatment with NDMA doses of
3.75 mg/kg/day In the diet for 4-12 weeks (Khanna and Puri 1966), 5
mg/kg/day in the diet for 62-95 days (Barnes and Magee 1954), and 3.9
mg/kg/day in the diet for 40 weeks (Magee and Barnes 1956). Jenkins et al.
(1985) observed cirrhosis in rats that received 2.5 mg doses of NDMA by
gavage for 4 days/week for 9 weeks, but it is unclear if this is dose per kg
body weight or dose per total body weight. A dose of 1 mg/kg/day
administered by gavage for 30 days produced centrilobular congestion and
vacuolation of hepatocytes without necrosis in rats (Maduagwu and Bassir
1980), indicating that this dose is a LOAEL for less serious hepatic
effects. Hepatic alterations were not observed in rats treated with 2.5
mg/kg/day in the diet for 110 days (Barnes and Magee 1954). The NOAEL and
all LOAEL values for hepatic effects in rats from these intermediate
duration studies are recorded in Table 2-2 and plotted in Figure 2-2.
Characteristic liver alterations (described previously) occurred in
mice that were treated with NDMA doses of 5.0 mg/kg/day in the drinking
water for 1-4 weeks (Anderson et al. 1986), 13 mg/kg/day in the diet for 16-
92 days (Otsuka and Kuwahara 1971) and 5.26 mg/kg/day in the diet for 5
months (Takayama and Oota 1965). These LOAELs for hepatic effects in mice
due to intermediate duration exposure are included In Table 2-2 and plotted
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32
2. HEALTH EFFECTS
in Figure 2-2. The mouse dose of 5.26 mg/kg/day was calculated from the
administered concentration of 50 ppm in food (Takayama and Oota 1965); this
concentration is presented in Table 1-4 for long-term exposure.
Liver effects resulting from intermediate duration oral exposure have
been observed in species other than rat and mouse. Treatment with 1
mg/kg/day by gavage for 30 days was hepatotoxic for guinea pigs, cats and
monkeys (Maduagwa and Basir 1980). Necrotic alterations occurred in dogs
treated with 2.5 mg/kg by capsule on 2 days/week for 3 weeks (Strombeck et
al. 1983). Fibrotic and proliferative alterations without necrosis or
hemorrhage were observed in rabbits treated with an average NDMA dose of 1.6
mg/kg/day in the diet for 22 weeks (Magee and Barnes 1956), indicating that
this dose is a less serious LOAEL for hepatic effects. Occlusive alterations
in the portal veins developed in hamsters that received daily 4 mg/kg doses
in the drinking water for 28 days or 8, 12 or 16 weeks (Ungar 1984, 1986),
indicating that this dose is also a less serious LOAEL for hepatic effects.
Similar hepatic venopathy occurred in mink exposed to 0.13-0.15 mg/kg/day in
the diet for 122 days (Koppang and Rimeslatten 1976). Mink that were given
doses of 0.32 or 0.63 mg/kg/day in the diet for 23-34 days had widespread
liver necrosis (Carter et al. 1969), but low numbers of animals were tested
(three per dose). Liver necrosis was also observed in mink that ingested
0.18 mg/kg/day via diet (Martino et al. 1988); limitations of this study,
discussed in Section 2.2.2.1, include uncertainty regarding exposure
duration and concentration. All reliable LOAEL values for hepatic effects
due to intermediate duration exposure in these studies are recorded in
Table 2-2 and plotted in Figure 2-2. The hamster drinking water dose of 4
mg/kg/day was calculated from the administered concentration of 20 ppm in
water (Ungar 1984, 1986); this concentration is presented in Table 1-4 for
long-term exposure. It should be noted that this water concentration (20
ppm) is higher than the water concentration associated with death (5.5 ppm)
due to long-term exposure reported in Table 1-4. The apparent discrepancy in
these values is attributable to differences in species sensitivity and
length of exposure (rats exposed for 30 weeks, hamsters exposed for 28
days).
In chronic duration studies, characteristic hepatotoxic alterations
(described previously) were not observed in rats that were treated with 0.5
mg/kg/day NDMA in the diet for 54 weeks (Terao et al. 1978) or 96 weeks
(Arai et al. 1979). Alterations in mink that ingested 0.1 mg/kg/day doses of
NDMA in the diet for 321-670 days included occlusive changes in the hepatic
veins with focal necrosis (Koppang and Rimeslatten 1976). Data regarding
hepatic effects of chronic oral NDMA exposure in other species were not
found in the available literature. The N0AEL values and LOAEL value for
hepatic effects due to chronic exposure in these studies are recorded in
Table 2-2 and plotted in Figure 2-2.
Although hepatotoxicity is the primary effect of NDMA and has been
demonstrated in all tested species, calculation of MRLs for NDMA is
precluded by insufficient data defining the threshold region (i.e., NOAELs)
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33
2. HEALTH EFFECTS
for intermediate and chronic exposures, particularly for species which
appear to be particularly sensitive (e.g., mink) and because serious effects
(perinatal death) occurred in a developmental study (see Section 2.2.2.5) at
a dose lower than any NOAELs for liver effects.
Renal Effects. No studies were located regarding renal effects in
humans following oral exposure to NDMA.
Limited information is available regarding renal effects of orally-
administered NDMA in animals. In a study by Nishie (1983), pregnant and
nonpregnant rats were treated with a single NDMA dose of 15 or 20 mg/kg/day
by gavage. An unspecified number of deceased animals (dose and pregnancy
state not indicated) had distal tubule necrosis two days following
treatment, and surviving rats had normal kidneys. Macroscopic congestion was
noted in kidneys of rats that were administered 3.75 mg/kg/day doses of NDMA
in the diet for 1-12 weeks (Khanna and Puri 1966). The adversity of the
congestion cannot be determined because results of kidney histological
examinations were not reported. Moderate tubule congestion with other
effects (glomerulus dilatation, slightly thickened Bowman's capsule) were
observed in mink that ingested 0.18 mg/kg/day via diet (Martino et al.
1988); limitations of this study, discussed in Section 2.2.2.1, include
uncertainty regarding exposure duration and concentration.
Other Systemic Effects. Adrenal relative weight and mitotic count were
increased in rats following a single 20 mg/kg gavage dose of NDMA (Nishie et
al. 1983). Other results of the adrenal histological examinations were not
described, precluding assessment of adversity of the increased adrenal
weight. There was no effect on thyroid weight or histology in the same
study. It therefore is appropriate to regard 20 mg/kg as a NOAEL for
thyroid effects in rats due to acute oral exposure (Table 2-2 and Figure
2-2). Macroscopic congestion was noted in spleens of rats that were
administered 3.75 mgAg/day doses of NDMA in the diet for 1-12 weeks (Khanna
and Puri 1966). The adversity of the congestion cannot be determined because
results of spleen histological examinations were not reported.
2.2.2.3 Immunological Effects
No studies were located regarding immunological effects in humans
following oral exposure to NDMA.
Limited information is available regarding immunological effects of
orally-administered NDMA in animals. Skin graft survival time and white
blood cell count were not reduced in rats that received a single 40 mg/kg
dose of NDMA by gavage, indicating that treatment was not immunosuppressive
(Waynforth and Magee 1974). The dose reported was near the LD50 for rats,
but all of the animals died by day 21; it is indicated that the high
mortality may partially reflect the stress of skin graft rejection. Although
treatment resulted in 1003! mortality, this dose represents a NOAEL for
immunological effects due to acute duration oral exposure (Table 2-2 and
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34
2. HEALTH EFFECTS
Figure 2-2). No studies were located regarding immunological effects in
animals following intermediate or chronic duration exposure to NDMA.
2.2.2.4 Neurological Effects
No studies were located regarding neurological effects in humans
following oral exposure to NDMA.
Dogs treated with 2.5 mg NDMA/kg/day by capsule on 2 consecutive
days/week for 3 weeks experienced marked central nervous system (CNS)
depression (Strombeck et al. 1983). The significance of this observation
cannot be ascertained since it was not characterized further. As these dogs
developed liver necrosis and hepatic insufficiency, it is possible that the
CNS depression is secondary to liver damage rather than a direct
neurological effect of NDMA.
2.2.2.5 Developmental Effects
No studies were located regarding developmental effects in humans
following oral exposure to NDMA.
Evidence indicates that orally-administered NDMA is a developmental
toxicant in animals. Fetuses of rats that received single 20 mg/kg doses of
NDMA by gavage on days 15 or 20 of gestation had significantly decreased
body weights, but fetal survival data were not reported (Nishie 1983). This
dose was also toxic to the dams as indicated by reduced body weight,
hepatotoxicity and mortality. Other investigators have reported fetal
mortality in rats that were treated with a single 30 mg/kg dose of NDMA by
gavage on various days during the first 12 days (Aleksandrov 1974) or 15
days (Napalkov and Alexandrov 1968) of gestation. In other studies, NDMA
reportedly caused fetal deaths in rats when administered in the diet at a
dose of 5 mg/kg/day from an unspecified day in early pregnancy (treatment
duration not indicated) (Bhattacharyya 1965), by gavage at a dose of 2.9
mg/kg/day during the first or second weeks of gestation (Napalkov and
Alekandrov 1968), or by gavage at a dose of 1.4 mg/kg/day throughout
gestation until days 17-21 (not specified) (Napalkov and Alekandrov 1968).
Teratogenic effects were not observed in the studies of Aleksandrov (1974)
and Napalkov and Alekandrov (1968), and not evaluated in the studies of
Nishie (1983) and Bhattacharyya (1965). Evaluation of the studies of
Bhattacharyya (1965), Napalkov and Alekandrov (1968) and Aleksandrov (1974)
is complicated by insufficient information regarding experimental design and
results; deficiencies include lack of control data, lack of maternal
toxicity data, use of pooled data and/or uncertain treatment schedule. Due
to these limitations, there is low confidence in the doses associated with
fetotoxicity in these studies. As Nishie (1983) is the only adequately
reported fetotoxicity study, 20 mg/kg is presented as a LOAEL for
developmental effects in rats due to acute exposure to NDMA in Table 2-2 and
Figure 2-2.
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35
2. HEALTH EFFECTS
In another experiment conducted by Aleksandrov (1974), a single dose of
30 mg NDMA/kg was administered by gavage to rats on day 21 of gestation,
Histological examination of the offspring at the time of natural death (>274
days after exposure) reportedly showed tumors in 5 of 20 animals. Although
this is possibly a manifestation of transplacental carcinogenesis,
evaluation of this finding is precluded by limitations including a lack of
control data and inadequate reporting of tumor types.
Increased perinatal mortality (stillbirths and newborn deaths) occurred
in mice as a consequence of maternal treatment with 0.02 mg NDMA/kg/day in
the drinking water (Anderson et al. 1978). The mice were treated for 75 days
prior to mating and throughout pregnancy and lactation. Histological
examinations of the stillborn fetuses and dead neonates showed no
abnormalities. The 0.02 mg/kg/day dose represents a L0AEL for developmental
effects due to intermediate duration exposure (Table 2-2 and Figure 2-2).
2.2.2.6 Reproductive Effects
No studies were located regarding reproductive effects in humans
following oral exposure to NDMA.
There was no significant increase in time-to-conception in mice that
were exposed to 0.02 mg NDMA/kg/day via drinking water for 75 days prior to
mating (Anderson et al. 1978). Other reproductive indices were not
evaluated.
2.2.2.7 Genotoxic Effects
Methylated DNA (7-methylguanine and 0*>- methyl guanine) was detected in
the liver of a victim of suspected NDMA poisoning (Herron and Shank 1980).
Additional studies regarding genotoxic effects in humans following oral
exposure to NDMA were not located.
Oral studies with rats indicate that the liver is sensitive to the
genotoxic effects of NDMA. When administered by gavage at a dose of 5.2
mg/kg, NDMA induced damage in rat liver DNA as measured by increased
alkaline elution (Brambilla et al. 1981). When administered to rats via
diet at a dose of 2.5 mg/kg/day, NDMA induced DNA damage in the liver as
measured by a slow sedimentation in alkaline sucrose gradients (Abanobi et
al. 1979). The effect was first observed after 2 days of feeding, and
became progressively worse during the next 8 weeks of feeding; no
proportionate increases in damage occurred when the feedings were continued
for 15 or 31 weeks. DNA synthesis and repair was detected In the liver of
rats treated with single 10 or 50 mg/kg doses by gavage (Bermudez et al.
1982). Radiolabeled thymidine uptake during mouse testicular DNA synthesis
was inhibited by a single gavage dose of 50 mg NDMA/kg (Friedman and Staub
1976).
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2. HEALTH EFFECTS
Administration of NDMA to hamsters by gavage at doses of 50, 100, or
200 mg/kg on the 11th or 12th day of pregnancy caused micronucleus formation
and chromosomal aberrations in the embryonic fibroblasts (Inui et al. 1979).
NDMA did not induce significant increases in sister chromatid exchanges in
bone marrow cells of Chinese hamsters following gavage administration of
12.5-400 mg/kg (Neal and Probst 1983).
2.2.2.8 Cancer
No studies were located regarding carcinogenic effects in humans
following oral exposure to NDMA.
The carcinogenicity of orally-administered NDMA has been demonstrated
unequivocally in acute, intermediate and chronic duration studies with rats,
mice, hamsters and mink. The liver and lungs are the primary targets for
NDMA carcinogenesis but tumors of the kidneys and testes can also occur.
Incidences of liver and lung tumors are generally very high (often 50-100%),
but liver tumors appear to occur most frequently in rats and hamsters and
lung tumors appear to occur most frequently in mice. The liver tumors are
usually hemangiosarcomas and hepatocellular carcinomas, and lung tumors are
usually adenomas and liver tumor metastases.
Low incidences of epithelial tumors (8.6%) and mesenchymal tumors
(14.5%) developed in the kidneys of rats following treatment with 8 mg
NDMA/kg/day for 6 days (McGiven and Ireton 1972, Ireton et al. 1972).
Evaluation of these data is complicated by the lack of a control group.
Daily diet treatment with 9.5 mg/kg for one week produced kidney and lung
adenomas in mice (Terracini et al. 1966). No other acute duration oral
carcinogenicity studies were found in the reviewed literature. The CEL from
the mouse study is presented in the acute duration category in Table 2-2 and
in Figure 2-2.
Numerous oral carcinogenicity studies of NDMA of intermediate duration
have been conducted. Treatment durations were often in the range of 20-40
weeks, frequency of treatment ranged from once weekly to daily, and
carcinogenicity was observed in all studies. Studies representing various
treatment durations and various methods of oral treatment (drinking water,
diet and gavage) for the lowest doses in different species are identified
below.
Rats administered NDMA in the drinking water at doses of 0.3
mg/kg/day, 5 days/week for 30 weeks, developed malignant liver tumors
(Keefer et al. 1973, Lijinsky and Reuber 1984). Lijinsky et al. (1987)
observed high incidences of liver, lung and kidney tumors in rats that were
treated by gavage with 6 mg NDMA/kg twice weekly for 30 weeks; controls were
not used in this study. In an intermediate duration diet study with rats,
daily treatment with a dose of 3.9 mg/kg for 40 weeks resulted in a 95%
incidence of hepatic tumors (Magee and Barnes 1956). The CELs from these
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37
2. HEALTH EFFECTS
intermediate duration studies with rats are recorded in Table 2-2 and
plotted in Figure 2-2.
Liver, lung and/or kidney tumors developed in mice that were exposed to
NDMA daily via drinking water at doses of 1.8 mg/kg for 49 days (Clapp and
Toya 1970), 1.19 mg/kg for 38 weeks (Terracini et al. 1966) and 0.4 mg/kg
for 224 days (Clapp and Toya 1970). Daily administration of NDMA via diet at
doses of 13 mg/kg for 16-92 days (Otsuka and Kuwahara 1971), 5.26 mg/kg for
5 months (Takayama and Oota 1965) and 9.04 mg/kg for 10 months (Takayama and
Oota 1965) also induced liver, lung and/or kidney tumors in mice. In the
only intermediate duration gavage study with mice, twice weekly doses of 1
mg/kg for 50 weeks resulted in high (37-53%) incidences of malignant liver
tumors (Griciute et al. 1981). The CELs from these intermediate duration
studies with mice are recorded in Table 2-2 and plotted in Figure 2-2.
Hamsters that were treated with NDMA by gavage twice weekly with a dose
of 5.4 mg/kg for 6.5 weeks, once weekly with a dose of 10.7 mg/kg for 4
weeks, or once weekly with a dose of 5.4 mg/kg for 20 weeks developed high
(60-79%) incidences of liver tumors (Lijinsky et al. 1987). However, control
groups were not included in the study of Lijinsky et al. (1987). Daily
administration of 4 mg/kg in the drinking water to hamsters for 12 or 16
weeks resulted in high incidences of cholangiocellular adenocarcinomas
(Ungar 1986). The CELs from these intermediate duration studies with
hamsters are recorded in Table 2-2 and plotted in Figure 2-2. Hemangiomatous
liver tumors occurred in 55% of deceased mink that received NDMA in the diet
at an estimated dose of 0.18 mg/kg/day (Martino et al. 1988); limitations of
this study, discussed in Section 2.2.2.1, include uncertainty regarding
exposure duration and concentration, examination only of animals that died
and use of historical controls. Due to the limitations of this study, it is
inappropriate to present a CEL for mink due to intermediate duration
exposure in Table 2-2 and Figure 2-2.
Chronic oral carcinogenicity studies of NDMA have been conducted with
rats, mice and mink. Tumors at sites other than the liver and testis have
not been associated with chronic treatment. Terao et al. (1978) observed a
47% increase in the incidence of testicular Leydig-cell tumors, but no
tumors in the liver or other tissues, in rats that were treated with 0.5
mg/kg daily doses of NDMA in the diet for 54 weeks. Increased incidences of
liver tumors, but not testicular interstitial cell tumors, occurred in rats
that received 0.05 or 0.5 mg/kg/day doses of NDMA in the diet for 96 weeks
(Arai et al. 1979). In this study, liver tumor incidences were generally
higher in female rats than in male rats. Increased incidences of liver
tumors also occurred in rats that were treated with NDMA in the diet for 96
weeks at a dose of 10,0 mg/kg/day (Ito et al. 1982); similar treatment with
doses of 0.1 or 1.0 mg/kg/day did not produce increased incidences of liver
tumors. It should be noted that Wistar rats were tested in both the Ito et
al. (1982) and Arai et al. (1979) studies. The reason for the lack of liver
tumors at doses below the relatively high 10 mg/kg/day dose in the Ito et
al. (1979) study is not clear, but may be related to low susceptibility of
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2. HEALTH EFFECTS
male rats. In a lifetime drinking water study, Peto et al. (1984)
administered doses of 0.001-1.2 mg/kg/day to rats and observed that
incidences of liver tumors were significantly increased at >0.02 mg/kg/day;
median survival time at the lowest tumorigenic doses was in the range of 28-
31 months. Crampton (1980) administered NDMA to rats in the drinking water
at doses ranging from 0.002-1.5 mg/kg/day for life and observed increased
liver tumor incidences at >0.008 mg/kg/day; median survival time at 0.008
mg/kg day was >900 days. The results reported by Crampton (1980) were
preliminary and there is uncertainty regarding the dosages; ppm
concentrations in water and mg/kg/day equivalency were reported, but the
basis for the equivalency is not indicated and the conversion cannot be
verified using standard methodology. Clapp and Toya (1970) administered NDMA
to mice via drinking water at daily doses of 0.43 and 0.91 mg/kg/day for
life and observed that incidences of lung tumors and liver hemangiosarcomas
were significantly increased at both doses; mean survival time at the low
and high doses were 12 and 17 months, respectively. Hemangiomatous liver
tumors developed in mink exposed to 0.1 mg/kg/day NDMA in the diet for 321-
607 days (Koppang and Rimeslatten 1976). The CELs for rats, mice and mink
from these chronic studies, except the uncertain value from the Crampton
(1980) study, are recorded in Table 2-2 and plotted in Figure 2-2.
The EPA (1988a) has derived and verified an oral slope factor (BH) of
51 (mg/kg/day)"1 for NDMA based on the liver tumor response in the Peto et
al. (1984) study. Using this slope factor, the doses associated with upper
bound lifetime cancer risk levels of 10 ^ to 10 are calculated to be 1.96
x 10"6 to 1.96 x 10"9 mg/kg/day, respectively. The cancer risk levels are
plotted in Figure 2-2.
2.2.3 Dermal Exposure
2.2.3.1 Death
No studies were located regarding lethality in humans or animals
following dermal exposure to NDMA.
2.2.3.2 Systemic Effects
No studies were located regarding systemic effects in humans following
dermal exposure to NDMA. Limited information was located regarding systemic
effects in animals following dermal exposure; no animal studies provided
information on respiratory, cardiovascular, gastrointestinal, hematological,
musculoskeletal, hepatic or renal effects.
Dermal/Ocular Effects. Small ulcerations and scarring of the skin were
observed in hairless mice that were treated once weekly with topical doses
of 33.3 mg NDMA/kg for 20 weeks (Iversen 1980). No studies were located
regarding NDMA-related ocular effects in animals.
-------
39
2. HEALTH EFFECTS
Other Systemic Effects. Barnes arid Magee (1954) noted that daily
application of 100 mg NDMA/kg to rats for 4 days had no effect on general
condition.
No studies were located regarding the following effects in humans or
animals following dermal exposure to NDMA:
2.2.3.3
Immunological Effects
2.2.3.4
Neurological Effects
2.2.3.5
Developmental Effects
2.2.3.6
Reproductive Effects
2.2.3.7
Genotoxic Effects
2.2.3.8
Cancer
No studies were located regarding carcinogenic effects in humans
following dermal exposure to NDMA.
A low incidence of lung adenomas (13%), but no skin tumors, developed
in hairless mice that were treated once weekly with 33.3 mg/kg topical doses
of NDMA for 20 weeks (Iversen 1980). Lung and skin tumors were not observed
in historical control groups. Although Iversen (1980) concluded that the
lung cancers were related to the topical applications of NDMA, it should be
noted that the mice were housed 8 to a cage and could have licked the NDMA
off each other or inhaled the compound due to its volatility.
2.3 RELEVANCE TO PUBLIC HEALTH
Death. Oral LD50 values of 23 and 40 mg NDMA/kg have been reported for
pregnant and nonpregnant rats, respectively (Nishie 1983, Druckrey 1967).
Oral LD50S have not been determined for NDMA in other species. LD50S for
single doses of NDMA administered by intraperitoneal injection have also
been reported; these values are consistent with the oral LD50S and include
26.5 mg/kg in rats (Barnes and Magee 1954), 42.7 mg/kg in rats (Heath 1962)
and 19 mg/kg in mice (Friedman and Sanders 1976). Repeated oral exposure to
NDMA resulted in decreased survival in rats, mice and all other species that
have been tested. In general, doses ranging from approximately 0.1-5
mg/kg/day have produced death in animals after several days to several
months of exposure. Variations in lethal doses appear to be attributable
more to intraspecies differences than differences in frequency or method of
oral treatment. With the exception of mink, there do not appear to be marked
differences in sensitivity among the species that have been tested. Deaths
resulting from a single exposure or repeated exposures for several days or
several weeks are generally attributed to liver toxicity; deaths associated
-------
40
2. HEALTH EFFECTS
with longer duration (e.g., 20-40 weeks) exposures are due to liver tumor
development.
In general, lethal doses of NDMA and causes of death are similar among
animal species. Human fatalities due to ingestion or inhalation of NDMA were
also attributed to liver toxicity but adequate dose information is not
available.
Systemic Effects. Hepatotoxicity is the primary systemic effect of
NDMA. Hepatotoxicity has been demonstrated in all animal species that have
been tested, and has been observed in humans who were exposed to NDMA by
ingestion or inhalation. The characteristic hemorrhagic necrosis caused by
NDMA are particularly prevalent following exposure to acutely toxic single
doses or repeated doses for short durations. Liver tumors are the
predominant effect of longer duration exposures. The mechanism of NDMA-
induced liver toxicity is not clearly understood but may be related to
alkylation of cellular protein (Barnes and Magee 1954, Magee et al. 1976,
Diaz Gomez et al. 1981, 1983, Martino et al. 1988).
Although the hepatotoxicity of NDMA has been established unequivocally
in numerous acute, intermediate and chronic duration oral studies with
animals, relatively few of the studies delineate dose-response relationships
and appropriate information regarding thresholds for this effect is not
available. As noted for lethality, reported hepatotoxic doses for all
species occur in the same general range with variations attributable more to
intraspecies differences than treatment schedule or method. Human fatalities
due to oral and inhalation exposure to NDMA have been reported in which
hemorrhagic, necrotic and cirrhotic alterations in the liver were observed,
indicating that NDMA produces similar hepatic effects in humans and animals.
Therefore it is reasonable to expect that NDMA also will be hepatotoxic in
humans at sublethal doses.
Limited information is available regarding nonhepatic systemic effects
of NDMA in humans. This information has been obtained from autopsies of
victims accidentally exposed to NDMA vapors or poisoned after ingestion of
NDMA. The effects can be described as a general bleeding tendency.
Hemorrhages have been noticed in the gastrointestinal tract, heart,
respiratory system and brain (Freund 1937; Kimbrough 1982). The mechanism by
which NDMA could induce bleeding is not known, but the bleeding tendency
could be a consequence of decreased formation of clotting factors resulting
from liver damage, impairment of the clotting mechanism or decreased number
or function of platelets. Jacobson et al. (1955), for example, showed that
NDMA greatly increases prothrombin time in dogs exposed to NDMA by
inhalation. It is also possible that hemorrhagic effects could be caused by
effects of NDMA on tissues. Because of its irritant properties, it is not
difficult to explain the occurrence of hemorrhages in tissues that have
direct contact with NDMA (gastrointestinal bleeding after oral ingestion, or
bleeding of the bronchi and trachea after inhalation). However, it remains
unknown why gastrointestinal bleeding can occur following inhalation
-------
41
2. HEALTH EFFECTS
exposure. An alternative explanation could be that NDMA has a direct effect
on the blood vessels. In fact, Ungar (1984, 1986) showed that oral treatment
of hamsters with NDMA induced fragmentation of elastic fibers in portal
vessels as well as denudation of the portal endothelium. Furthermore,
autopsy of a victim of acute NDMA poisoning showed that "the central hepatic
veins had lost their endothelial lining cells" (Kimbrough 1982).
There is a relative paucity of information for nonhepatic systemic
effects in animals because the emphasis of most studies was on
hepatotoxicity or cancer, for which the liver is the primary target organ.
Nonhepatic systemic effects that have been reported include gastrointestinal
hemorrhage and congestion of several organs (kidney, lung, heart, spleen) in
rats and/or mink, but the prevalence of these effects cannot be determined
because these sites were examined infrequently.
Immunological Effects. A single oral dose of NDMA near the oral LD5Q
did not reduce humoral immune response in rats, but a single intraperitoneal
dose near the intraperitoneal LD50 reduced humoral immune response in mice
(Waynforth and Magee 1974). A number of other recent studies have found that
NDMA given by intraperitoneal injection alters humoral immunity and
antibody-mediated host defense mechanisms (Kaminski et al. 1989; Thomas
et al. 1985, Myers et al. 1986, 1987, Scherf and Schmahl 1975, Holsapple et
al. 1983, 1984, 1985, Johnson et al. 1987a,b). Immunosuppression resulting
from NDMA exposure is not believed to be a result of direct interaction
between the reactive intermediaries of NDMA and splenic lymphocytes, thereby
indicating a difference between the mechanisms of immunotoxicity and
carcinogenicity/genotoxicity (Holsapple et al. 1984). In vivo studies have
shown that NDMA modulates the cellular immune response by altering the
production and/or maturation/differentiation of bone marrow stem cells into
functional macrophages (Myers et al. 1986, 1987). In vitro tests identify
the primary cell target of NDMA as the B-lymphocyte (Holsapple et al. 1984,
1985). Thus, it is likely that NDMA decreases the overall reactivity of both
T- and B-lymphocytes. It is not known whether NDMA is likely to be
immunosuppressive in humans.
Developmental Effects. NDMA was fetotoxic to rats at oral doses that
were toxic to the mother. Limited data indicate that these doses were not
teratogenic for the rats. Oral administration of NDMA to mice resulted in
increased perinatal deaths without histological abnormalities. It is not
known whether NDMA could cause developmental effects in humans, but it could
be a potential developmental toxicant at doses which are toxic to pregnant
women.
Reproductive Effects. Mice that were exposed to NDMA in drinking water
prior to mating and during pregnancy and lactation showed an increase in the
frequency of perinatal death among their offspring. Based on these data,
NDMA could be considered a potential human reproductive toxicant.
-------
42
2. HEALTH EFFECTS
Genotoxic Effects. Several in vitro studies have examined genotoxic
effects of NDMA in human cells. As indicated in Table 2-3, NDMA induced DNA
repair and synthesis in human lymphoblasts, and sister chromatid exchange
in human lymphocytes and fibroblasts.
Genotoxicity of NDMA has been demonstrated consistently in numerous in
vitro studies with non-human systems. As indicated in Table 2-3, NDMA was
mutagenic in bacteria (Salmonella tvphimurium. Escherichia coli), yeast
(Saccharomvces cerevislae), and mammalian cells (Chinese hamster V79 and
ovary cells and mouse lymphoma L5178Y cells). NDMA induced unscheduled DNA
synthesis and DNA repair and synthesis in rat, mouse and hamster
hepatocytes. Treatment-related DNA fragmentation occurred in rat and human
hepatocytes. Chromosomal aberrations occurred in Chinese hamster primary
lung cells, rat ascites hepatoma cells, and rat esophageal tumor cells.
Sister chromatid exchanges occurred in Chinese hamster ovary cells, Chinese
hamster primary lung cells, human lymphoblasts and fibroblasts, and rat
esophageal tumor and ascites hepatoma cells.
In vivo studies (Table 2-4) have shown that NDMA methylates DNA, causes
DNA fragmentation and induces DNA synthesis and repair in liver and other
tissues of various species (e.g., rat, mouse, hamster, gerbil). NDMA
induced chromosomal aberrations in hamster embryonic fibrolasts, sister
chromatid exchanges in mouse bone marrow cells, and micronuclei in rat
hepatocytes and rat and mouse bone marrow cells. The genotoxic effects
indicated above occurred after inhalation, oral or intraperitoneal
administration of NDMA. Sperm abnormalities were not seen in mice following
intraperitoneal administration of NDMA. Sex linked recessive lethal
mutations occurred in Drosophila melanogaster. which indicates potential
heritable mutagenicity of NDMA.
The weight of evidence indicates that NDMA is genotoxic in mammalian
cells. In vitro studies with human cells, as well as in vitro and in vivo
studies with animals and microbes, support this conclusion. Given the type
and weight of genotoxicity evidence, it is appropriate to predict that NDMA
poses a genotoxic threat to humans.
Cancer. The oral carcinogenicity of NDMA has been demonstrated in
numerous studies with various species of animals. Inhalation exposure to
NDMA has been reported to be carcinogenic to rats and mice in two studies.
The carcinogenicity of NDMA is also documented in numerous single and or
weekly subcutaneous and intraperitoneal injection studies, and in studies in
which NDMA was administered prenatally and to newborn animals. Many of the
carcinogenicity studies of NDMA were conducted specifically to induce cancer
for various purposes, such as investigations of structure-activity
relationships and pathogenesis. Tumors in tissues other than the liver and
respiratory system (e.g., kidney, testis) have not been observed often in
many of the carcinogenicity studies; this appears to be attributable in part
to limited examination of nonhepatic tissues.
-------
TABLE 2-3. Genotoxicity of N-Nitrosodimethylamine In Vitro
Result
Species With Uithout
Encfcioint (Test System) Activation Activation References
Gene mutation
DMA fragmentation
Chromosomal
aberrations
Salmonella typhimuriim
Escherichia coli
Saccharoayces cerevi sae
Chinese Hamster V79 and
ovary cells
Mouse lymphana L5178Y cells
Rat hepatocytes
Hunan hepatocytes
Chinese hamster lung cells
Rat ascites hepatoma (AH668) and
rat esophageal (R1, R3) tumor cells
NT
NT
+
NT
+ Araki et al. 1984,
Bartsch et al. 1980, langenbach et al. 1986,
DeFlora et al. 1984, Prival and Mitchell 1981,
Ishidate and Yoshikawa 1980
NT Araki et al. 1984, DeFlora et al. 1984
NT Jagamath et al. 1981, Frezza et al. 1983
Kuroki et al. 1977, Adair and Carver 1983,
O'Neill et al. 1982, Carver et al. 1981,
Dickins et al. 1985, Bartsch et al. 1980,
Katoh et al. 1982, Langenbach 1986,
Hsie et al. 1978
Amacher and Paillet 1983, Clive et al. 1979
+ Bradley et al. 1982
+ Kartelli et al. 1985
NT Matsuoka et al. 1979, 1986,
Ishidate and Yoshikaua 1980
+ Ikeuchi and Sasaki 1981
M
tc
PJ
>
r
H
a
m
•n
w
o
H
w
•P-
UJ
-------
TABLE 2-3 (continued)
Result
Endpoint
Species
(Test System)
With Without
Activation Activation
References
Sister-chromatid
exchange
Rat esophageal tunor, ascites hepatoma
Hunan lymphocytes
NT
+
+
Abe and Sasaki 1982, Ikeuchi and Sasaki 1981
Inoue et al. 1983, Hadle et al. 1987,
Human fibroblasts
+
NT
Tomkins et al. 1982
Chinese hamster ovary cells
+
NT/-
Tomkins et al. 1982, Okinaka et al. 1981
Blazak et al. 1985
Chinese hamster V79 cells
+
-
Hadle et al. 1987, Siriami and Huang 1987
Blazak et al. 1985
Chinese hamster primary lisig cells
+
-
Shimizu et at. 1984
DNA Damage
Rat hepatocytes
NT
+
Bermudez et al. 1982
DNA repair/
synthesis
Rat hepatocytes
Hunan tynphoblasts
+
+
+
NT
Andrae and Schwarz 1981,
Andrae et al. 1979
Mice hepatocytes
NT
+
McQueen et al. 1983
Hamster hepatocytes
NT
+
McQueen et al. 1983
Rat pancreatic cells
NT
-
Steinmetz and Mirsalis 1984
EC
PI
>
r
H
IX
M
PJ
O
H
00
4>
NT = Not tested
-------
TABLE 2-4. Genotoxicity of N-Nitrosodi methyl ami ne In Vivo
Endpoint
Species
(Test System)
Result
References
DNA methylation
DMA fragmentation
DNA synthesis
and repair
Sex-linked recessive lethal
mutations
Sperm abnormalities
Sister chromatid exchange
Rat, mouse, hamster
and/or gerbil liver
Hunan liver
Rat liver and kidney elution
Mouse liver and kidney elution
Fetal mouse kidney and liver
Mouse testes
Rat liver
Rat respiratory cells
Rat spermatocytes
Drosodi ila melanogaster
Mouse
Chinese hamster bone marrow
Mouse bone marrow
+ O'Connor et al. 1982, Bamborschke et al. 1983,
Pegg et al. 1981, Pegg and Hui 1978, Sturopf et al.
1979
+ Herron and Shank 1980
+ Brambilla et at. 1981, Petzold and Swenberg 1978,
Abanobi et al. 1979, Bermudez et al. 1982
+ Cesarone et al. 1982
+ Bolognesi et al. 1988
+ Friednan and Staub 1976, Cesarone et al. 1979
+ Bakke and Mirsalis 1984, tCornbrust and Dietz 1985,
Doolittle et al. 1984
+ Doolittle et al. 1984
Doolittle et al. 1984
+ Brodberg et al. 1987, Blount et al. 1985,
Lee et al. 1983
Wyrobek and Bruce 1975
+/- Meal and Probst 1983
+ Sharma et al. 1983, Bauknecht et al. 1977
K
PJ
>
f
H
ac
m
m
o
H
CO
-p-
U1
Chromosome aberrations
Micronucleus
Hamster enbryonic fibroblasts
Rat bone marrow
Rat hepatocytes
Mouse bone marrow
Hamster embryonic fibroblasts
+ Inui et al. 1979
+/- Trzos et al. 1978
+ Mehta et al. 1987, Tates et al. 1980
+ Odagiri et al. 1986, Bauknecht et al. 1977
+ Inui et al. 1983
-------
46
2. HEALTH EFFECTS
There is increasing evidence, derived from in vitro and in vivo
metabolic studies, indicating that the carcinogenic effects of NDMA are due
to a metabolite rather than the compound itself (Singer 1979) . NDMA is
converted into an alkylating (methylating) agent after metabolism by
microsomal mixed-function oxidases. This process occurs principally in the
liver and to a lesser extent in kidney and lungs, and results in the
methylation of cellular macromolecules such as DNA, RNA and other proteins.
Methylation occurs at several positions in DNA including N-l, N-3 or N-7 of
deoxyadenosine; N-3, N-7 or 0^ of deoxyguanosine; N-3 of deoxycytidine; and
02 or 0^ of thymidine. Experimental evidence indicates that methylation at
the 0®-position of guanine may be responsible for the carcinogenic activity
of nitrosamines in general, however, the carcinogenic potential of other
methylated products cannot be ruled out. The methylation of DNA by NDMA has
been studied extensively (e.g., Bamborschke et al. 1983, O'Connor et al.
1982, Pegg et al. 1981, Pegg and Hui 1978, Stumpf et al. 1979.).
The carcinogenic properties of NDMA, and nitrosamines in general, have
been extensively studied. It is of considerable interest that, despite its
ubiquitous distribution, NDMA induces tumors in a limited number of organs
and tissues and that there are marked differences in this response among
animal species. Differences in pharmacokinetics properties seem to play an
important role in the carcinogenic action of NDMA (Pegg 1980, Lijinsky
1987). For example, the degree of hepatic extraction from the portal blood
seems to determine whether tumors develop in extrahepatic sites. Therefore,
large doses of NDMA tend to induce extrahepatic tumors (spill-over effect).
In addition, metabolic activating systems and repair mechanisms may not
operate at the same rates in different organs and different species. Route
of administration also seems to be a factor in NDMA carcinogenesis since
different responses are seen in a particular species when different routes
of exposure are used. This suggests that rates of absorption can determine
the site of tumor development.
Based on the unequivocal evidence of carcinogenicity in animals, it is
reasonable to anticipate that NDMA will be carcinogenic in humans. It is
important to recognize that this evidence also indicates that oral exposures
of acute and intermediate duration are sufficient to induce cancer.
2.4 LEVELS IN HUMAN TISSUES AND FLUIDS ASSOCIATED WITH HEALTH EFFECTS
A considerable amount of DNA methylation in the liver of a suspected
NDMA poisoning case was reported by Herron and Shank (1980). Based on
studies in rats, in which the amount of DNA alkylation could be correlated
with known amount of orally administered NDMA, the authors estimated that
the victim had been exposed to a dose of 20 mg/kg or more of NDMA. No other
studies were located regarding levels of NDMA or its metabolites in human
tissues and fluids associated with effects. Several analytical methods have
been developed to determine levels of NDMA in human tissues and fluids.
These methods are described in Chapter 6.
-------
47
2. HEALTH EFFECTS
2.5 LEVELS IN THE ENVIRONMENT ASSOCIATED WITH LEVELS IN HUMAN TISSUES
AND/OR HEALTH EFFECTS
Although data relating specific amounts of NDMA in the environment
with levels in human tissues and/or health effects have not been reported,
some qualitative information is available. This information, given below,
has to be interpreted with caution since results were not always rigorously
reported or evaluated, and endogenous formation of NDMA was not quantitated.
A high incidence of nasopharyngeal carcinoma was found in Tunisia
(North Africa), Southern China and Greenland among populations who consume
foods with a high content of volatile nitrosamines (Poirier et al. 1987). Lu
et al. (1987) found a positive correlation between the amount of NDMA and
other nitrosamines in the gastric juice of Chinese with a. high incidence of
esophageal carcinoma. Wild et al. (1987) observed a positive relationship
between levels of O^-methyldeoxyguanosine (implicated in the initiating
process of nitrosamine-induced cancer) and incidences of esophageal and
stomach cancer in the province of Lin-xian, China. Yu and Henderson (1987)
reported finding a high incidence of nasopharyngeal carcinoma in individuals
from Hong Kong, who are known to consume from early in life considerable
amounts of Cantonese-style salted fish, which has a high content of NDMA and
other nitrosamines.
2.6 TOXICOKINETICS
2.6.1 Absorption
2.6.1.1 Inhalation Exposure
No studies were located regarding the rate and extent of absorption of
NDMA following inhalation exposure of humans or animals to NDMA. However, it
can be inferred that NDMA is absorbed from the air since it can be detected
in the urine of rats (Klein and Schmezer 1984) and dogs (Raabe 1986) after
inhalation exposure. Absorption is also indicated by reports of human
deaths following inhalation of NDMA (see Section 2.2.1.1).
2.6.1.2 Oral Exposure
No studies were located regarding the absorption of NDMA following
oral exposure of humans.
The absorption of NDMA from the gastrointestinal tract of animals is
fast. Less than 2% of the labelled compound could be recovered from the
gastrointestinal tract 15 minutes after oral administration of ^C-NDMA to
rats (Diaz Gomez et al. 1977). Absorption seems to be independent of the
dose administered (Diaz Gomez et al. 1977). In the rat, NDMA is absorbed
much faster from the small intestine than from the stomach, in isolated
preparations (Heading et al. 1974) and in vivo (Pegg and Perry 1981).
-------
48
2. HEALTH EFFECTS
Ishiwata et al. (1977) reported that the disappearance curve of NDMA from
isolated guinea pig stomach and small intestine follows first order
kinetics.
2.6.1.3 Dermal Exposure
No studies were located regarding the absorption of NDMA following
dermal exposure of humans.
Indirect evidence indicating that NDMA may be absorbed through the
skin was found in a study published by Iversen (1980) in which topical
application of NDMA induced lung adenomas in mice. The results from
Iversen, however, should be interpreted with caution since the mice were
housed 8 to a cage and could have licked the NDMA from each other and also
could have inhaled this volatile compound.
2.6.2 Distribution
Unmetabolized NDMA was found to be evenly distributed among the main
organs of mice and rats shortly after i.v. injection to animals in which the
metabolism of NDMA had been inhibited (Magee 1956; Johansson and Tjalve
1978). Wishnok et al. (1978) reported a similar finding in rats following
i.p. injections. Johnson et al. (1987a) reported that one hour after a dose
of 6 mg 14C-NDMA/kg was administered by intraperitoneal injection to mice,
the liver contained two times as much radioactivity as the kidney, spleen
and thymus.
2.6.2.1 Inhalation Exposure
No studies were located regarding the distribution of NDMA following
inhalation exposure of humans or animals.
2.6.2.2 Oral Exposure
No studies were located regarding the distribution of NDMA following
oral exposure of humans.
Daugherty and Clapp (1976) reported that 15 minutes after oral
administration of ^C-NDMA to mice, the relative amounts of radioactivity in
the homogenates of heart, forestomach, esophagus, liver and lung were 1, 2,
3, 10 and 70, respectively. The differences could be attributed to different
tissue affinity, transport and/or metabolism. Measurable amounts of NDMA
were reported in blood, liver, kidney, lungs and brain of mice exposed to 5
mg NDMA/kg/day in drinking water for up to 4 weeks (Anderson et al. 1986).
NDMA has been detected in maternal blood, placenta, fetus and amniotic
fluid of pregnant Syrian hamsters for up to 2 hours after a single
subcutaneous dose of 12.5 mg/kg of the chemical (Althoff et al. 1977).
-------
49
2. HEALTH EFFECTS
Liver and kidney DNA from 14-day-old rats became labelled after treating the
nursing mothers with ^C-NDMA by gavage (Diaz Gomez et al. 1986).
2.6.2.3 Dermal Exposure
No studies were located regarding the distribution of NDMA following
dermal exposure of humans.
The study by Iversen (1980), in which lung adenomas were noticed in
mice after skin application of NDMA, indicates that this chemical (or a
metabolite) was distributed to the lungs.
2.6.3 Metabolism
Evidence from in vitro and in vivo studies with rodents indicates that
NDMA is metabolized by hydroxylation of the ot-carbon, followed by formation
of formaldehyde, molecular nitrogen and a methylating agent, which is
considered to be the carcinogenic form (Lotlikar et al. 1975; Czygan et al.
1973). Recent evidence suggests that a significant proportion of NDMA is
metabolized via a denitrosation mechanism. The latter mechanism takes place
in rats in vivo, as indicated by the urinary excretion of labelled
methylamine after i.v. administration of 14C-NDMA (Keefer et al. 1987), and
in human liver microsomes (Yoo et al. 1988). The metabolism of NDMA is
summarized in Figure 2-3.
Metabolism of NDMA varies among species (Prassana et al. 1985;
Montesano et al. 1982). Age of the animal and route of administration can
also influence the rate of metabolism of NDMA (Phillips et al. 1975). In
addition, at varying doses, different forms of enzymes appear to be
responsible for NDMA metabolism (Kroeger-Koepke and Michejda 1979; Lotlikar
et al. 1978).
2.6.3.1 Inhalation Exposure
No studies were located regarding the metabolism of NDMA following
inhalation exposure of humans or animals.
2.6.3.2 Oral Exposure
No studies were located regarding the metabolism of NDMA following
oral exposure of humans.
Phillips et al. (1975) demonstrated that NDMA is metabolized at a
lower rate when given orally to rats than when administered by parenteral
routes,
-------
50
2. HEALTH EFFECTS
NO
CHj-N-CHj
N-ni Ir osod ima t hyIomi n«
d • n I troiol ion
a-hydroiylotion
P 4 50
Is o•n zymi
H-N-CHj + N02" + (H-C-0)
nolhylomu. „ 1 t r I . . formoIdoh,d.
(peilulalid)
NO
I
H0-CH2-N-CHj
a-hydroxy N-niIroiomini
NO
I
H-CHO + H-N-CH
Io rmaId•h y d• H-n I t »¦ o « omi I h y I om I n •
11 I on
CHj-N-N-OH
dlazehydroxId*
C H 3-N*N + OH"
oIkyIdI 0 I on I urn Ion (molhylollng «g«nl lor twkolrato X)
X:
CHjX + N2 mtrojor
Figure 2-3. Metabolism of N-Nitrosodinethylamiiie
Source: Crygan et al. 1973; Keefer et al., 1987;
Lotikar et al. 1975; Yoo et al. 1988
-------
51
2. HEALTH EFFECTS
2.6.3.3 Dermal Exposure
No studies were located regarding the metabolism of NDMA following
dermal exposure of humans or animals.
2.6.4 Excretion
Labelled C0£ can be detected in the exhaled air 1 hour after i.p.
administration of ^C-NDMA to rats (Phillips et al. 1975). Hemminki (1982)
administered labelled NDMA by intraperitoneal injection to rats and was able
to detect three main radioactive fractions in the urine over a period of 5
days. Fraction I was composed of radioactive aminoacids, fraction II of
allantoin and a metabolite of thiazolidine-4-carboxylic acid, and fraction
III of 7-methylguanine.
2.6.4.1 Inhalation Exposure
Klein and Schmezer (1984) reported that 10-30% of NDMA is excreted by
exhalation after exposing rats to the chemical during 10 minutes by
endotracheal intubation. In beagle dogs, 23% of the administered
radioactive label is exhaled in 30 minutes after a 3 hour inhalation
exposure (Raabe 1986).
2.6.4.2 Oral Exposure
Spiegelhalder et al. (1982) reported that, in a 24 hour period, human
volunteers excreted in the urine between 0.5 and 2.4% of an ingested dose of
12-30 /ig of NDMA added to drinking fluids containing ethanol.
Unchanged NDMA was recovered in the urine and feces of rats up to 24
hours after a single oral dose of 50 mg (Magee 1956). Swann et al. (1984)
did not detect labelled NDMA in the urine of rats after oral administration
of 30 ng/Kg of C-NDMA in water. Phillips et al. (1975) determined that
after administration of a single oral dose of 5 mg of ^C-NDMA to female
rats the maximum rate of CO2 production was 12.4% of the dose/hour, and
that 48% of the dose could be recovered as ^C02 in the exhaled air in 7
hours and 5.7% as C (total label) in a 24 hour urine sample.
2.6.4.3 Dermal Exposure
No studies were located regarding the excretion of NDMA following
dermal exposure of humans or animals.
2.7 INTERACTIONS WITH OTHER CHEMICALS
NDMA is normally formed by bacteria in the human stomach and small
intestine, but not in the large intestine (Archer et al 1982; Spiegelhalder
and Preussmann 1985; Zeisel et al. 1988). Also, rats and guinea pigs have
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52
2. HEALTH EFFECTS
been shown to make NDMA in their stomachs (Hashimoto et al. 1976; Omori et
al. 1979). Small amounts of NDMA are formed in the saliva of humans;
concentrations can vary from 4 to 10 fig/mL depending on pH and type of food
in the mouth (Rao et al. 1982). NDMA formation in the saliva can be
increased by chemicals such as chlorogenic acid, which is found in coffee,
and decreased by a number of synthetic additives, as well as caffeic acid,
tannic acid and ascorbic acid, which are found in coffee, tea, and citrus
fruits, respectively.
Consumption of alcohol has been shown to have complicated effects on
the toxicity of NDMA. Rats that received alcohol (ethanol or isopropanol)
by gavage for 2 days before receiving NDMA had more liver damage with the
alcohol than without it (Lorr et al. 1984; Maling et al. 1975). Increased
levels of plasma glutamic pyruvate transaminase were monitored and used as a
sign of liver damage. Another study showed that 4 weeks of ethanol
pretreatment in rats worsened the effects on DNA repair that occurred
following DNA alkylation induced by NDMA (Mufti et al. 1988). There is at
least one other study in rats, however, that showed that 23 days of
pretreatment with ethanol decreased the hepatotoxicity of NDMA (Gellert et
al. 1980).
Other substances to which people are exposed have been shown to alter
the toxic effects of NDMA in rats. Vitamin E and calcium channel blocking
agents have been shown to decrease the hepatotoxicity associated with NDMA
(Landon et al. 1986; Skaare and Nafstad 1978). Selenium increased the toxic
effect of NDMA on the liver (Skaare and Nafstad 1978) and cadmium increased
the carcinogenic effect of NDMA in the kidney (Wade et al. 1987). NDMA
induced higher incidences of stomach cancer in rats fed diets low in zinc
than in those fed normal diets (Ng et al. 1984). Rats fed diets low in
copper developed more kidney tumors from NDMA than rats fed normal diets
(Carlton and Price 1973). In contrast, rats given NDMA and cupric acetate
had fewer tumors than rats given NDMA (Yamane et al. 1984). Although these
data indicate that simultaneous administration of other chemicals may
augment NDMA toxicity in animals, it not clear how these simultaneous
exposures may occur in humans.
2.8 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE
People with chronic renal failure produce more NDMA in their small
intestines due to increased levels of bacterial growth than normal people do
(Lele et al. 1983). This increase in NDMA can be blocked by injections of
ascorbic acid or antibiotics, but is potentiated by alcohol (Lele et al.
1987). People who consume alcohol may be unusually susceptible to NDMA for
reasons discussed in Section 2.7.
2.9 ADEQUACY OF THE DATABASE
Section 104 (i) (5) of CERCLA, directs the Administrator of ATSDR (in
consultation with the Administrator of EPA and agencies and programs of the
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53
2. HEALTH EFFECTS
Public Health Service) to assess whether adequate information on the health
effects of NDMA is available. Where adequate information is not available,
ATSDR, in cooperation with the National Toxicology Program (NTP), is
required to assure the initiation of a program of research designed to
determine these health effects (and techniques for developing methods to
determine such health effects). The following discussion highlights the
availability, or absence, of exposure arid toxicity information applicable to
human health assessment. A statement of the relevance of identified data
needs is also included. In a separate effort, ATSDR, in collaboration with
NTP and EPA, will prioritize data needs across chemicals that have been
profiled.
2.9.1 Existing Information on Health Effects of
N-Nitrosodimethylamine
Information regarding health effects of NDMA in humans is limited to
case reports of fatalities due to hepatotoxicity following ingestion or
inhalation. Health effects of NDMA in animals have been investigated in
numerous oral studies and several inhalation and dermal studies. As
indicated in Figure 2-4, animal oral data are available for lethality,
systemic toxicity, immunological effects, neurological effects,
developmental effects, reproductive effects, genotoxic effects and cancer.
These data indicate that hepatotoxicity and cancer are the most prominent
NDMA-related effects.
2.9.2 Data Needs
Single Dose Exposure. Information on lethality In rats following
single oral doses, including two LD50 values, are available. Information on
hepatic effects in rats due to single oral exposures are also available.
Additional single dose oral studies with rats would provide more Information
on thresholds for lethality and hepatotoxicity, and on nonhepatic effects.
Studies on species other than the rat would provide data on interspecies
differences. Single-exposure inhalation experiments provide limited
information on lethality in rats, mice and dogs, and dermal/ocular effects
in rats; additional studies could corroborate these data as well as provide
NOAELs. Single application dermal studies would provide information on
lethality and skin and eye irritation.
Repeated Dose Exposure. Numerous repeated dose studies of
intermediate duration have been conducted with rats, mice and other species.
These studies provide extensive Information on doses and treatment schedules
that are lethal and hepatotoxic but do not adequately identify thresholds
for these effects, particularly in species that may be more sensitive (e.g.,
mink). Additional repeated dose oral studies designed to examine tissues
other than the liver could provide useful information on nonhepatic systemic
effects of NDMA. Oral studies conducted over periods longer than 20-30 weeks
may not be necessary as sufficient evidence indicates that cancer will be
the predominant effect. Repeated exposure inhalation studies could provide
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54
2. HEALTH EFFECTS
Inhalation
Oral
Dermal
HUMAN
SYSTEMIC
Inhalation
Oral
Dermal
ANIMAL
^ Existing Studies
FIGURE 2-4. Existing Information on Health Effects of
N-Nitrosodinethylamine
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55
2. HEALTH EFFECTS
information on concentrations associated with lethality and systemic
effects.
Chronic Exposure and Carcinogenicity. Chronic oral and inhalation
studies of NDMA have been conducted with rats and mice. These studies
indicate that the predominant effect of chronic exposure to NDMA is cancer.
As low doses of NDMA have been tested in chronic oral studies and it is
established that intermediate duration exposure to NDMA is sufficient to
induce cancer, additional chronic studies may not be needed.
Genotoxicity. The genotoxic potential of NDMA is established
unequivocally. Only several studies, however, evaluated genotoxic effects in
animals following oral or inhalation exposure to NDMA, and only several in
vitro studies evaluated human cells. Additional studies, particularly assays
with human cells and assays providing information on the potential for
heritable mutations, would add to the data base on genotoxicity.
Reproductive Toxicity. Oral exposure to NDMA for 75 days prior to
mating had no significant effect on time-to-conception in mice. Other
reproductive indices or species have not been evaluated. Histological
examinations of reproductive organs of animals exposed in subchronic and
chronic studies would provide relevant data. Multigenerational or
continuous breeding studies would provide further information regarding
reproductive effects of NDMA in animals, which may be related to possible
reproductive effects in human.
Developmental Toxicity. Evidence indicates that NDMA is fetotoxic to
rats and mice, but NOAELs have not been defined. Well-conducted
developmental studies using several exposure levels and environmentally
relevant routes of exposure could provide the dose-response information
necessary to determine the threshold for fetotoxicity and to determine the
possible relevance and risk for humans. Additional studies also could
determine if NDMA is a transplacental carcinogen.
Innnunotoxicity. Information regarding immunological effects of NDMA in
humans is not available. Immunosuppression by NDMA has been demonstrated in
a number of intraperitoneal injection studies, but not in an oral study,
with mice. Specific immunotoxicity tests or a battery of immunotoxicity
tests in which NDMA is administered by the oral route would provide a better
assessment of possible immunotoxic effects. Sensitization tests in animals
could provide information on whether an allergic response to NDMA is likely
in humans. Additional studies also could determine if NDMA is a
transplacental carcinogen.
Neurotoxicity. Dogs that were orally treated with NDMA reportedly
experienced central nervous system depression, but it is likely that this
effect is a consequence of liver damage rather than direct neurotoxicity.
Additional information pertaining to neurotoxicity was not found.
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2. HEALTH EFFECTS
Neurotoxicity tests in animals exposed to NDMA could provide additional
information on possible neurotoxic effects.
Epidemiological and Human Dosimetry Studies. The only information
available concerning effects of NDMA in humans comes from cases of acute
poisoning and subsequent death. In these cases, hemorrhagic and necrotic
alterations and cirrhosis of the liver were observed. On the other hand,
effects in animals have been well documented (Section 2.2). Attempts have
been made to measure occupational exposure to NDMA, in particular in the
rubber industry. Unfortunately these attempts have failed because NDMA is
metabolized almost completely to CO2 and water. Excretion rates for NDMA
measured in experimental animals are in the order of 0.02% of the ingested
dose (Spiegelhalder 1984). Although unchanged NDMA is unlikely to be
detected in the urine, it may be possible to measure urinary excretion of
nonspecific DNA adducts (e.g., 7-methylguanine). As stated by Spiegelhalder
(1984), limited information is available on airborne exposures of individual
workers for the following reasons: 1) usually workers are exposed to a
variety of chemicals and there is cross-contamination between jobs, 2)
transfers from job to job involve different exposures, 3) increases in
cancer incidences most likely result from exposures that occurred in the
past, when no exposure data were available, and 4) no comprehensive study
has been conducted so far. Epidemiology studies of individuals who live in
areas where NDMA has been detected are necessary to obtain information on
whether NDMA induces effects in humans similar to those seen in animals.
Biomarkers of Disease. Since acute NDMA poisoning in humans caused
severe liver disease, sensitive clinical biochemistry liver function tests
might detect early hepatic damage from toxic exposure to NDMA. Recently,
Wild et al. (1987), using a radioimmunoassay, were able to detect elevated
levels of the promutagenic lesion O^-methyldeoxyguanosine in DNA of
esophageal cells from individuals with high incidence of esophageal and
stomach cancer. These individuals were found to consume foods with a
relatively high content of nitrosamines.
Disease Registries. The only known health effects of NDMA on humans are
those obtained from acute poisoning cases, in which postmortem examination
revealed severe liver damage. If disease states attributed to exposure to
NDMA could be identified by epidemiological studies, the number of
individuals affected, the exposure levels involved, and the factors
associated with identifying the disease in a given population, such as, the
vicinity to hazardous waste sites or industrial plants, could be determined.
Bioavailability from Environmental Media. No studies were located
regarding the bioavailability of NDMA from environmental media. Since NDMA
has been detected in ambient air, water and soil (ppb levels), it is
important to determine if NDMA can be absorbed by humans from environmental
samples. It must be noted that NDMA has been found in trace amounts in some
foods and beverages and that endogenous formation of NDMA has been found to
occur from the nitrosation of amines in the gastrointestinal tract. An
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2. HEALTH EFFECTS
understanding of the bioavailability of NDMA from environmental media may be
obtained by studying the biological fluids of individuals exposed in the
workplace or through the ingestion of NDMA-containing foods and beverages.
The limited information available regarding absorption parameters of NDMA
in experimental animals indicates that NDMA is rapidly absorbed from the
gastrointestinal tract; therefore, one can assume that if water or soil
contaminated with NDMA are ingested, NDMA will be readily absorbed.
Food Chain Bioaccumulation. No studies were available concerning food
chai,n bioaccumulation of NDMA from environmental sources. NDMA has been
detected in samples of cooked fish and meat. However, occurrence of NDMA in
these samples is not the result of bioaccumulation but is the result of
formation during preservation and/or cooking (Scanlan 1983). Estimation
techniques have been used to determine that NDMA would not bioaccumulate in
lipids of fish (see Section 5.3.1). Based on this limited amount of
information, it is speculated that human exposure to NDMA through diet is
not the result of food chain bioaccumulation. Monitoring for the
accumulation of NDMA in organisms from several trophic levels could be used
to support this conclusion.
Absorption, Distribution, Metabolism, Excretion. Examination of
Section 2.6 clearly indicates that oral administration of NDMA has been the
preferred route for studying its absorption, distribution, metabolism and
excretion. This is not surprising since oral administration is easier to
monitor when compared to other routes. The oral route seems to be the most
pertinent to study since humans are most likely to be exposed to
nitrosamines orally. Toxicokinetic data with regard to dermal and inhalation
exposure of NDMA are clearly lacking. Furthermore, dermal and inhalation
exposures may lead to different metabolic pathways and patterns of
distribution and excretion, which could account for differences in the
degree of toxicity exhibited by different routes of exposure. The metabolism
of NDMA in isolated microsomal preparations seems to be well understood, but
studies with cultured human cells could provide additional useful
information. However, exploration of the denitrosation mechanism as an
alternative to a-hydroxylation requires more attention. Determination of the
urinary excretion of NDMA in control human volunteers and in Individuals
known to consume foods with high contents of nitrosamines could provide
information concerning absorption and excretion of the xenobiotic.
Comparative Toxicokinetics. No studies were located regarding
comparative toxicokinetics of NDMA in vivo. In vivo studies are available
indicating differences in hepatic O^-methylguanine repair activity among
rodent species (O'Connor et al. 1982). A report by Prasanna et al. (1985)
indicates that the in vitro metabolism of NDMA by liver microsomes, from
hamsters, rats and chickens is qualitatively similar, but with different
rates. Montesano et al. (1982) showed that liver slices from humans have a
metabolic capacity to activate NDMA similar to that found in rats and
slightly lower than that found in liver slices from hamsters. Differences
among species in the toxic responses to a chemical can be attributed to
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2. HEALTH EFFECTS
differences in the toxicokinetic parameters. This seems to be particularly
true for N-nitrosamines in general (Lijinsky 1987). The fact that a number
of factors (animal species, route of exposure, dosing schedule) appear to
determine the organ-specificity and the severity of the effect of NDMA
indicates that caution must be exercised when assuming possible effects in
humans. Although little information is available regarding the
toxicokinetics of NDMA in humans, analysis of NDMA in the urine of
individuals accidentally exposed to the chemical or of individuals consuming
foods with a relatively high content of NDMA could provide quantitative
information on absorption and excretion.
2.9.3 On-going Studies
Two studies regarding the immunotoxicity of NDMA are known to be on-
going (Federal Research In Progress, 1988). One is investigating the
immunosuppressive activity of subchronic and chronic administration of NDMA,
specifically the in vitro antibody response of NDMA treated spleen cell
suspensions to a number of mutagens. This research is being performed by
Holsapple at Virginia Commonwealth University. A second study, performed by
Schook at the University of Illinois, is attempting to identify molecular
mechanisms for the immunosuppressive effects of NDMA.
In research being conducted by Anderson at the Division of Cancer
Etiology, National Cancer Institute, NDMA is being examined for its ability
to cause neurogenic tumors in mice by transplacental exposure.
In studies sponsored by NIEHS, Faustman at the Univerity of Washington
is evaluating NDMA and other related N-nitroso compounds for their in vitro
developmental toxicity (Faustman 1989).
A number of ongoing studies are investigating the metabolism of NDMA
(Federal Research in Progress, 1988). These include N-nitroso compound
detoxification by Jensen at Temple University, Philadelphia, PA, formation
and metabolism of nitrosamines in pigs by Magee at Temple University,
metabolism and genotoxicity of nitrosamines in rats by Rogan at the
University of Nebraska, Omaha, NE, and enzymology of nitrosamine metabolism
in rats, mice and rabbits in a NCI-sponsored study by Yang at the University
of Medicine and Dentistry, Newark, NJ. Other studies sponsored by NCI are
being conducted to find means of shifting the balance of the metabolic
pathway towards increasing inactivation and characterizing the possible role
of a-nitrosamino radicals in the metabolism of NDMA (written communication,
Keefer 1989).
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3. CHEMICAL AND PHYSICAL INFORMATION
3.1 CHEMICAL IDENTITY
Data pertaining to the chemical identity of NDMA are listed in Table
3-1.
3.2 PHYSICAL AND CHEMICAL PROPERTIES
The physical and chemical properties of NDMA are presented in Table
3-2.
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3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-1. Chemical Identity of N-Nitrosodimethylamine
Value
Reference
Chemical name
Synonyms
Trade name(s)
Chemical Formula
Chemical Structure
Methanamine, N-methyl-N-nitroso CAS 1988
N-nitrosodimethylamine; CAS 1988
dimethyInitrosamine;
DMNA; DMN; NDMA
ND
C2 H6 N2 0 SANSS 1988
(CH3)2N-N-0 SANSS 1988
Identification Numbers:
CAS Registry 62-75-9
NIOSH RTECS IQ0525000
EPA Hazardous Waste P082
OHM-TADS 7217418
DOT/UN/NA/IMCO ND
HSBD 1667
NCI ND
CAS 1988
RTECS 1988
RTECS 1988
OHM-TADS 1988
HSDB 1988
ND - No Data
CAS - Chemical Abstract Service
NIOSH - National Institute for Occupational Safety and Health
RTECS - Registry of Toxic Effects of Chemical Substances
EPA - Environmental Protection Agency
OHM-TADS - Oil and Hazardous Materials - Technical Assistance Data Base
DOT/UN/NA/IMCO - Department of Transportation/United Nations/North
America/International Maritime Consultive Organization
HSDB - Hazardous Substances Data Bank
NCI - National Cancer Institute
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3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-2. Physical and Chemical Properties of
N-Nitrosodimethylamine
Property Value Reference
Molecular weight
Color
Physical State
Melting point
Boiling point
Specific gravity, 20/4°C
Odor
Odor threshold
Solubility
Water
Organic solvents
Partition coefficient
Log octanol/water
Log Koc
Vapor pressure
Henry's Law constant
at 37"C
at 208C
74.08
yellow
liquid
-25°C (estimated)
-50°C (estimated)
154°C
1.0059
No distinct odor
Not available
Miscible
Soluble in alcohol, ether,
other organic solvents
-0.57
1.07 (estimated using
Equation 4-8)
2.7 nun Hg (20°C)
1.99x10atm-mVmol
2.63x10"^ atm-mVmol
(estimated using vapor
pressure and water
solubility data)
Weast 1983
IARC 1978
IARC 1978
Lyman 1985
EPA 1986
Weast 1983
Weast 1983
Frank and Berry 1981
Mirvish et al. 1976
Weast 1983,
IARC 1978
Hansch and Leo 1985
Lyman 1982
Klein 1982
Mirvish et al. 1976
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3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-2 (continued)
Property Value Reference
Autoignition
temperature, 0 C ND
Flashpoint, open cup ND
Flammability limits
in air ND
Conversion factors
ppm (v/v) to mg/ra^
in air (20°C) ppm (v/v) x 3.08 - mg/m^
mg/rn^ to ppm (v/v)
in air (20°C) mg/m^ x 0.325 - ppm (v/v)
ND - no data
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4. PRODUCTION, IMPORT, USE, AND DISPOSAL
4.1 PRODUCTION
NDMA is not produced for commercial use in the United States (HSDB
1988). The public portion of the U.S. EPA TSCA Production File indicates
that during 1977, the Ames Laboratories in Milford, CT and Columbia Organics
in Columbia, SC both prepared small research quantities of this chemical.
Eastman-Kodak in Rochester, NY and Teledyne McCormick Selph, an importer,
supplied no NDMA during 1977, although both had the capability to
produce/import this compound and had done so in the past (EPA 1977). Small
research quantities of this chemical presently are available from Sigma
Chemical Co. and Aldrich Chemical Co. NDMA can be prepared by reaction of
nitrous acid with dimethylamine or by addition of acetic acid and sodium
nitrite to dimethylamine (HSDB 1988).
4.2 IMPORT
Data pertaining to the import of NDMA into the U.S. were not located in
the available literature.
4.3 USE
NDMA is prepared in laboratory-scale quantities solely for use as a
research chemical (HSDB 1988). NDMA was formerly used (prior to April 1,
1976) as an intermediate in the production of 1,1-dimethylhydrazine, a
storable liquid rocket fuel, which was believed to have contained up to 0.1%
NDMA as an impurity (IARC 1978). NDMA has also been used or has been
proposed for use as an antioxidant, additive for lubricants, and as a
softener for copolymers (Windholz 1983). NDMA has also been used as a
solvent and rubber accelerator (Hawley 1981).
4.4 DISPOSAL
Combustion in an incinerator equipped with an afterburner and NOx
scrubber is the recommended method for disposing NDMA. Liquid wastes
should be neutralized, If necessary, filtered to remove solids, and then put
into closed polyethylene containers for transport. All equipment should be
thoroughly rinsed with solvent, which should be added to the liquid waste
for incineration. Great care should be practiced to insure that there is no
contamination on the outside of the solvent container. If possible, solid
waste should also be incinerated. If this is not possible, the nitrosamine
should be extracted from the waste and the extract should be handled as a
liquid waste. Any rags, papers or other materials which are contaminated
during the disposal process should be incinerated. Contaminated solid
materials should be enclosed in sealed plastic bags that are labeled cancer-
suspect agent, with the name and amount of carcinogen. Bags should be
stored in well-ventilated areas until they are incinerated (HSDB 1988).
Nitrosamine residues generated in laboratory research or accidental spills
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4. PRODUCTION, IMPORT, USE, AND DISPOSAL
in research laboratories should be diluted to a concentration of less than
10 /ig/L and then reduced to innocuous amines, ammonia, or alcohols by
aluminum-nickel alloy powder and aqueous alkali. This method of disposal is
applicable to a variety of media (water, mineral oil, olive oil,
dimethylsulfoxide, solutions of agar gel), but is not recommended for use in
solutions of acetone or dichloromethane because reactions are slow and
incomplete. After the reduced reaction mixture is filtered, the liquid can
be disposed of by pouring it over a sufficient amount of absorbent material
to convert it to a solid waste for incineration. The filtercake is
discarded with non-burnable solid wastes (HSDB 1988). Other methods of
destruction of NDMA in laboratory wastes (e.g., using hydrobromic acid or
potassium permanganate/sulfuric acid) are described by IARC (1982).
4.5 ADEQUACY OF THE DATA BASE
Section 104 (i) (5) of CERCLA, directs the Administrator of ATSDR (in
consultation with the Administrator of EPA and agencies and programs of the
Public Health Service) to assess whether adequate information on the health
effects of NDMA is available. Where adequate information is not available,
ATSDR, in cooperation with the National Toxicology Program (NTP), is
required to assure the initiation of a program of research designed to
determine these health effects (and techniques for developing methods to
determine such health effects). The following discussion highlights the
availability, or absence, of exposure and toxicity information applicable to
human health assessment. A statement of the relevance of identified data
needs is also included. In a separate effort, ATSDR, in collaboration with
NTP and EPA, will prioritize data needs across chemicals that have been
profiled.
4,5.1 Data Needs
Production, Use, Release, and Disposal. Uses, methods of synthesis,
and methods of disposal for NDMA are described in the literature and there
does not appear to be a need for further information on these topics. Lack
of information pertaining to the import of this compound is not surprising
since this compound has no commercial applications. Data regarding the
amount of NDMA released to air, water, and soil would be useful in order to
establish potential sources of exposure and levels of exposure from
environmental media. In particular, information releases from hazardous
waste landfills and industries in which this compound is inadvertently
formed may help determine whether people living in the vicinity of these
sites are exposed to elevated levels of this compound. According to the
Emergency Planning and Community Right to Know Act of 1986 (EPCRTKA),
(§313), (Pub. L. 99-499, Title III, §313), industries are required to submit
release information to the EPA. The Toxic Release Inventory (TRI), which
contains release information for 1987, became available in May of 1989.
This database will be updated yearly and should provide a more reliable
estimate of industrial production and emission.
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5. POTENTIAL FOR HUNAN EXPOSURE
5.1 OVERVIEW
NDMA is not an industrially or commercially important chemical;
nevertheless, it can be released into the environment from a wide variety of
manmade sources. This is due to the inadvertent formation of NDMA in
industrial situations when alkylamines, mainly dimethylamine and
trimethylamine, come in contact and react with nitrogen oxides, nitrous
acid, or nitrite salts, or when trans-nitrosation via nitro or nitroso
compounds occurs. Thus, potential exists for release into the environment
from industries such as tanneries, pesticide manufacturing plants, rubber
and tire manufacturers, alkylamine manufacture/use sites, fish processing
industries, foundries and dye manufacturers. At this time, NDMA has been
found in at least 1 out of 1177 hazardous waste sites on the National
Priorities List (NPL) in the United States (VIEW Database 1989).
Nitrosation reaction may also result in the formation of NDMA in the
environment. In air, NDMA may form as a product of the nighttime reaction
of dimethylamine with NOx. In water and soil, NDMA forms by the reaction of
widely-occurring primary, secondary or tertiary amines in the presence of
nitrite.
In the ambient atmosphere, NDMA should be rapidly degraded upon
exposure to sunlight. The half-life for direct photolysis of NDMA vapor is
on the order of 5 to 30 minutes. In surface water exposed to sunlight, NDMA
would also be subject to photolysis. On soil surfaces, NDMA would be
subject to removal by photolysis and volatilization. The volatilization
half-life of NDMA from soil surfaces under field conditions has been found
to be 1 to 2 hours. In subsurface soil and in water beyond the penetration
of sunlight, NDMA would be susceptible to slow microbial decomposition under
both aerobic and anaerobic conditions. In aerobic subsurface soil, the
half-life of NDMA has been found to be about 50 to 55 days. Degradation has
been found to proceed slightly faster under aerobic conditions than under
anaerobic conditions.
NDMA has been detected in ambient air, water and soil; however,
monitoring data are rather scant. Low levels of NDMA (measurable in terms
of ppb) are commonly found in the air of car interiors, food, malt beverages
(beer, whiskey), toiletry and cosmetic products, rubber baby bottle nipples
and pacifiers, tobacco products and tobacco smoke, pesticides used in
agriculture, hospitals, and homes, and sewage sludge.
The general population is exposed to NDMA from a variety of different
sources. Primary sources of exposure include; chewing tobacco, tobacco
smoke, foods [beer, liquor, cured meats (particularly bacon), fish, cheeses,
and other food items], cosmetics and toiletry articles, interior air of
cars, various household commodities such as detergents and home-and-garden
pesticides, and formation in the upper gastrointestinal tract during
digestion of secondary amine-containing foods. Infants may also be exposed
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5. POTENTIAL FOR HUMAN EXPOSURE
to NDMA from the use of rubber baby bottle nipples and pacifiers which may
contain very low amounts of NDMA, from ingestion of contaminated infant
formula, and from breast milk from some nursing mothers. Very low levels of
NDMA have been found in breast milk. Occupational settings in which there
is potential for exposure to NDMA include, but are not limited to: leather
tanneries, rubber an,d tire industries, rocket fuel industries, dye
manufacturers, soap, detergent and surfactant industries, foundries (core-
making) , fish-processing industries (fish-meal production), pesticide
manufacturers, warehouse and sale rooms (especially for rubber products),
and research laboratories where NDMA is synthesized/studied.
5.2 RELEASES TO THE ENVIRONMENT
5.2.1 Air
NDMA may occasionally be emitted into the atmosphere from sites of
manufacture/use of dimethylamine and other sites at which NDMA is
inadvertently formed, i.e. tanneries, pesticide manufacturing plants, rubber
and tire industries, etc. NDMA may also form in nighttime air as the result
of the atmospheric reaction of dimethylamine with NOx (Cohen and Bachman
1978, Fine et al. 1976a, Fine et al. 1976b, Hanst et al. 1977).
5.2.2 Water
NDMA may be released in waste streams from facilities at which NDMA was
inadvertently formed during manufacturing processes. This would include
such facilities as amine manufacturing plants, tanneries, rubber and tire
industries, fish processing industries, foundries, rocket fuel industries,
dye manufacturers, soap, detergent, arid surfactant industries, and pesticide
manufacturers (Cohen and Bachman 1978). In addition to industrial sources,
NDMA may form in aqueous systems, sewage and soil as the result of either
biological, chemical or photochemical processes. Biological formation
occurs via the reaction of a secondary or tertiary amine with nitrite. The
nitrite can arise in the environment from the microbial transformation of
ammonia or nitrate or through manmade production. Chemical formation of
nitrosamines occurs optimally under acidic conditions and may occur from the
reaction of primary, secondary or tertiary amines with nitrite (Ayanaba and
Alexander 1974; Mills and Alexander 1976). Formation of NDMA by
photochemical transformation of dimethylamine in the presence of nitrite has
been found to occur more readily under alkaline conditions than under acidic
or neutral conditions (Ohta et al. 1982). Nitrosamine precursors are
widespread throughout the environment, occurring in plants, fish, algae,
urine, and feces and are formed in the environment as pesticide degradation
products (Ayanaba and Alexander 1974, Greene et al. 1981, Neurath et al.
1977, Windholz 1983). The Contract Laboratory Program statistical data base
reports that NDMA has been detected in groundwater samples at one out of
1177 hazardous waste site on the National Priorities List (NPL). This site
is Martin Marietta (Denver Aerospace) in Waterton, CO (VIEW Database 1989).
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5. POTENTIAL FOR HUMAN EXPOSURE
No data are available regarding contamination of drinking water, irrigation
water, sewers, or storm drains in the vicinity of NPL sites.
5.2.3 Soil
NDMA may be released into the environment as the result of land
application of sewage sludge containing this compound or as the result of
land application of certain pesticides contaminated with this compound.
NDMA may also form in soils under conditions which favor nitrosation of
nitrosamine precursors (Mills and Alexander 1976, Pancholy 1978). There is
no data pertaining to the detection of NDMA in soil samples collected at or
in the vicinity of NPL sites.
5.3 ENVIRONMENTAL FATE
5.3.1 Transport and Partitioning
Organic compounds in the atmosphere having vapor pressures greater than
10"^ mm Hg are expected to exist almost entirely in the vapor phase
(Eisenreich et al. 1981). The estimated vapor pressure of NDMA [2.7 mm Hg
at 20"C (see Table 3-2)} indicates that this compound should not partition
from the vapor phase to particulates in the atmosphere.
Using linear regression equations based on log Kow data [log Kow -
-0.57 (see Table 3-2)], a bioconcentration factor of 0.2 and a soil
adsorption coefficient (Koc) of 12 have been estimated for NDMA (Bysshe
1982, Hansch and Leo 1985, Lyman 1982). These values, as well as the
complete water solubility of NDMA, indicate that bioaccumulation in aquatic
organisms and adsorption to suspended solids and sediments in water would
not be important environmental fate processes. The low value of the Henry's
Law Constant for NDMA [2.63x10"^ atm-m^/mol at 20°C (see Table 3-2)]
suggests that volatilization would be a relatively insignificant fate
process in water (Thomas 1982).
NDMA is expected to be highly mobile in soil and it has the potential
to leach into groundwater supplies (Dean-Raymond and Alexander 1976, Greene
et al. 1981, Swann et al. 1983). If NDMA were released to soil surfaces, as
might be the case during application of contaminated pesticides, a
substantial proportion of the nitrosamine would volatilize. The
volatilization half-life from soil surfaces under field conditions is
estimated to be on the order of 1-2 hours (Oliver 1979). If NDMA were
incorporated into subsurface soil, far less of the nitrosamine would enter
the atmosphere by volatilization and the rate of volatilization would be
greatly reduced. Under these circumstances volatilization would be of minor
importance (Oliver 1979).
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5. POTENTIAL FOR HUMAN EXPOSURE
5.3.2 Transformation and Degradation
5.3.2.1 Air
Iti the atmosphere, NDMA vapor would rapidly degrade by direct
photolysis to form dimethylnitramine. Based on experimental data, the
photolytic half-life of NDMA vapor exposed to sunlight has been determined
to be about 5 to 30 minutes (Hanst et al. 1977, Tuazon et al. 1984).
Reaction of NDMA with photochemically-generated hydroxyl radicals or ozone
molecules in the atmosphere would be too slow to be environmentally
significant (Atkinson and Carter 1984, Tuazon et al. 1984).
5.3.2.2 Water
Limited available data suggest that NDMA would be subject to slow
photolysis in natural waters exposed to sunlight (Polo and Chow 1976;
Callahan et al. 1979). In unlit waters, it appears that NDMA would be
rather persistent, eventually degrading as the result of microbial
transformation (Kaplan and Kaplan 1985, Kobayashi and Tchan 1978, Tate and
Alexander 1975). There is evidence which suggests that formaldehyde and
methylamine may form as biodegradation products of NDMA (Kaplan and Kaplan
1985). Insufficient data are available to predict the rate at which NDMA
would degrade in water, NDMA is not expected to chemically react under the
conditions found in natural waters (Callahan et al. 1979, Oliver et al.
1979).
5.3.2.3 Soil
It appears that microbial degradation would be an important removal
process for NDMA in subsurface soil. Oliver et al. (1979) amended
Metapeake loam with 10 ppm NDMA at 23°C and observed a half-life of 50 days
(Oliver et al. 1979). Loss of NDMA was attributed to volatilization and
biodegradation. Tate and Alexander (1975) amended silt loam with 22.5 ppm
NDMA at 30°C and observed a lag of approximately 30 days before slow
disappearance from soil commenced; 50% loss occurred after about 55 days
incubation and 60% loss occurred after about 70 days incubation. As part of
the same study, 40% loss was observed in 2 days in soil amended with 50 ppm
NDMA and 44% loss was observed in 5 days in soil amended with 250 ppm NDMA.
These initial losses were followed by very little or no loss over the next 3
weeks. Initial, rapid loss of NDMA was attributed to volatilization and
slow, gradual loss of NDMA was attributed to biodegradation. Mallik and
Tesfai (1981) incubated NDMA at 4, 25 and 37°C and found that at all three
temperatures, about 20-30% of added NDMA disappeared in the first 20 days of
incubation, but little loss was noted thereafter; even after 30 days of
incubation, over 50% of the NDMA was retained. The rate of disappearance of
NDMA was found to be slightly higher in sandy loam soil than in either clay
or silt loam soil. The rate of loss was also found to be slightly higher in
aerobic soil at field capacity compared to super saturated (anaerobic) soil.
After a 30-day incubation period, 60% of added NDMA remained in soil at
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5. POTENTIAL FOR HUMAN EXPOSURE
field capacity and 70% of added NDMA remained in super saturated soil.
Available data on the degradation of NDMA in water and air indicate that
photolysis may be an important removal process on soil surfaces.
5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT
5.4.1 Air
When it was used as a rocket fuel intermediate, NDMA was identified in
ambient air on-site and in the vicinity of factories which were
manufacturing rocket fuel (Fine et al. 1977b; Gordon 1978). At a plant in
Baltimore, MD, which was manufacturing unsynunetrical dimethylhydrazine
rocket fuel, the average concentration on-site was 11.600 ng/m, and in
neighboring residential communities it was 1,070 ng/m3, with levels ranging
between 30 to 100 ng/m3 in the downtown area (Fine et al. 1977b). As a
result of these findings, the use of NDMA was discontinued at this plant
(Shapley 1976). During December 1975, NDMA was found in air samples
collected in Belle, WV near a factory which was manufacturing dimethylamine.
The highest level found (980 ng/nr) was collected during a temporary weather
inversion (Fine et al. 1976b). NDMA has also been measured in ambient air
in urban areas with no known point sources of nitrosamines: Baltimore, MD
several miles upwind of the rocket fuel plant (0.02-0.1 ^g/m3); the Cross
Bronx Expressway in New York City (0.8 ^ig/nr); and Philadelphia, PA (0.025
ppb) (Fine et al. 1976b, Shapley 1976).
Occurrence of volatile nitrosamines in air has been associated with
tire and rubber products, leather tanneries, and automotive upholstery, and,
as a result, measurable levels of the nitrosamines have been found in
certain confined areas, e.g. automobile interiors. Concentrations of NDMA
in interior air of automobiles have been found to vary widely due to
differences in age of the car, design and decor. Levels of NDMA in interior
air of new cars were found to range from <0.02 to 0.83 /ig/m3 (Dropkin 1985,
Rounbehler et al. 1980).
5.4.2 Water
Data from the EPA STORET Water Quality data base indicate that NDMA is
not a common contaminant of surface waters in the United States (EPA 1988b).
During the time when NDMA was being used as a chemical intermediate at a
rocket fuel manufacturing plant in Baltimore, MD, concentrations up to 940
ng/L were found in adjacent surface waters. Mud puddles adjacent to the
facility contained 0.20-9.0 mg/kg (moist basis) of NDMA (Fine et al. 1977b).
Information found in STORET also reveals that NDMA is infrequently found in
groundwater samples. STORET gross analysis data input from 1980 to 1988
indicate that NDMA was positively identified in 0.9% of 2308 groundwater
samples collected in the United States. The average concentration of
positive samples was 12.4 jig/L (EPA 1988b). NDMA also has been detected at
a concentration of 10 ng/L in groundwater samples at one of 1177 hazardous
waste sites on the National Priorities List (NPL). This site is Martin
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5. POTENTIAL FOR HUMAN EXPOSURE
Marietta (Denver Aerospace) in Waterton, Co (VIEW 1989, VIAR 1987). NDMA
was reportedly found in tap water from Philadelphia, PA at levels of 0.003-
0.006 fMg/L (Kimoto et al. 1981). The authors of this study concluded that
NDMA did not form in the resin used to accumulate the nitrosamines, but that
it may have formed from the reaction of low concentrations of nitrite, an
oxidizing agent (possibly chlorine) and secondary amines present in the
water sample. NDMA has been found in deionized laboratory water at levels
ranging from 0.03-0.34 /ig/L (Fiddler et al. 1977, Gough et al. 1977). Anion
exchanger resins were identified as the source of NDMA found in the water
samples. There have been reports of NDMA occurring infrequently in
wastewater samples collected from various locations situated throughout the
United States. When present, levels of NDMA are generally in the low /ig/L
range (maximum reported concentration 2.7 Mg/L) (Cohen and Bachman 1978,
Ellis et al. 1982, EPA 1988b, Fine et al. 1977b).
5.4.3 Soil
NDMA has been found in soil at 1-8 ng/\ag (dry basis) in Belle and
Charleston, WV, New Jersey and New York City (Fine et al. 1977c). It is
speculated that occurrence of NDMA in soil may have arisen from (a)
absorption of NDMA in air, (b) absorption of dimethylamine from air and its
subsequent N-nitrosation, or (c) from pesticide application.
5.4.4 Other Media
N-Nitrosamines are formed in foods by the reaction of secondary and
tertiary amines with a nitrosating agent, usually nitrous anhydride, which
forms from nitrite in acidic, aqueous solution. NDMA is the most common
volatile amine found in food. Food constituents and the physical make-up of
the food can affect the extent of nitrosamine formation. Ascorbic acid and
sulfur dioxide have been used to inhibit the formation of nitrosamines.
NDMA has been found in some processed foods as a result of direct-fire
drying; it forms from the nitrosation of amines in drying food by oxides of
nitrogen in drying air (Scanlan 1983). Trace levels (usually less than 1
ppb) of NDMA have been found in a variety of foods; however, not all samples
of a particular type of food contain detectable levels of NDMA. Table 5-1
lists the levels of NDMA which have been found in food. NDMA may also occur
in human breast milk. In a study of 51 samples of breast milk collected
from 13 nursing women, NDMA concentrations greater than 0.2 ppb were found
in 23.5% of the samples, and the maximum concentration detected was 1.1 ppb
(Lakritz and Pensabene 1984). During this study, it was determined that
eating a meal containing bacon did not result in increased NDMA levels in
milk, although eating a meal containing bacon and a vegetable high in
nitrate occasionally resulted in higher levels of NDMA in breast milk.
NDMA has been found to occur in a variety of toiletry and cosmetic
products, including shampoos, hair conditioners, color toners, shower gels,
bath cremes and oils, children's shampoos, children's bath and health care
products, and face tonics, cleansers, and masks. In a study of 145
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71
5. POTENTIAL FOR HUMAN EXPOSURE
TABLE 5-1. Detection of N-Nitrosodimethylamine in Fooda
Food Item Concentration (Mg/kg)
Vegetable oils and margarines 0.22-1.01
Apple cider distillates 1-10^
Dried cheeses 0.2-0.3
(parmesan, romano, and American)
Soy-containing foods 0.1-0.6
Non-fat dry milk 0.17-4.47
Milk 0.05-0.60
Infant formula \
Dried legumes 0.2-0.8
Malt vinegar 0.4
Cereal products 0.3-4.2
Cooked fish 0.1-4,2
Chinese seafood 0.1-131.5
Meat 0.1-7.4
Fried bacon 1-44
aSources: Canas et al. 1986, Fazio and Havery 1982, Fiddler et al. 1981,
Goff and Fine 1979, Huang et al. 1981, Lakritz and Pensabene 1981, Lawrence
and Weber 1984, Sen and Seaman 1981b, Sen et al. 1984, Sen et al. 1985a,
Song and Hu 1988, Weston 1984
b Mg/L
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72
5. POTENTIAL FOR HUMAN EXPOSURE
products, 50 samples (34.5%) contained NDMA, with a maximum concentration
of 24 MgAg occurring in a sample of shampoo (Spiegelhalder and Preussman
1984).
The U.S. Food and Drug Administration (FDA) established an action
level, effective January 1, 1984, of 60 ppb total N-nitrosamines in rubber
nipples as measured by a dichloromethane extraction procedure (Thompson
et al. 1986). This means that the Consumer Product Safety Commission can
take action against any company which introduces baby bottle or pacifier
nipples into interstate commerce containing greater than 60 ppb total
N-nitrosamines. Compliance testing of infant pacifiers entered into
commerce after January 1, 1984 and sold in the U.S. revealed that total
N-nitrosamine levels ranged from not detectable to 36.9 ppb, and that NDMA
levels ranged from not detectable to 3.55 ppb, with infrequent occurrence of
NDMA (Billedeau et al. 1986). This compares well with levels found in
pacifiers entered into commerce prior to January 1, 1984, when total
N-nitrosamine levels as high as 332 ppb and NDMA levels as high as 6.78 ppb
were detected using the same analytical procedure (Billedeau et al. 1986).
It should be noted that several companies have discontinued supplying rubber
nipples since January 1984, because they could not meet the compliance
leve1.
Most malt beverages, regardless of origin, contain NDMA. This includes
many domestic and foreign beers and most brands of whiskey (Havery et al.
1981, Hotchkiss et al. 1981, Scanlan et al. 1980, Sen and Seaman 1981C). It
is generally accepted that the nitrosamine is formed in malt during the
direct-drying phase of its processing (Fazio and Havery 1982). At one time,
it was estimated that 64% by weight, of the dietary intake of NDMA of the
West German male^ population could be attributed to the consumption of beer
(Hotchkiss et al. 1981, Spiegelhalder et al. 1979). As a result of these
findings, the U.S. Food and Drug Administration established an action level
of 5 ppb for NDMA in malt beverages sold in the United States (Hotchkiss et
al. 1981). Compliance testing of domestic (United States) and imported
beers by the FDA showed that domestic beers (180 samples) contained NDMA
levels ranging from not detectable to 9 ppb, with the average level being
less than 1 ppb (1% contained greater than 5 ppb), and that imported beers
(80 samples) contained levels ranging from not detectable to 13 ppb, with an
average level of 1 ppb (5% contained greater than 5 ppb) (Havery et al.
1981). These results compared favorably with levels found during a market
survey carried out prior to establishment of the action level, when 81% of
domestic beers contained greater than or equal to 1 ppb and 17% contained
greater than 5 ppb (Hotchkiss et al. 1981). Compliance survey data indicate
that levels of NDMA in scotch whiskey (44 samples) ranged from not
detectable to 2 ppb, with an average of less than 1 ppb (Havery et al.
1981).
NDMA is commonly found in commercially-available tobacco products in
the United States. Results of one study showed that chewing tobaccos
purchased in the United States contained NDMA at levels ranging from <0.2 to
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73
5. POTENTIAL FOR HUMAN EXPOSURE
85.1 ppb (Brunnemann et al. 1985). NDMA also occurs in mainstream and
sidestream smoke from cigarettes and other tobacco products, with higher
levels occurring in sidestream smoke than in mainstream smoke (Brunnemann
et al. 1983, Chamberlain and Arrendale 1982, McCormick et al. 1973).
Sidestream smoke from commercially-available tobacco products purchased in
the United States were found to contain NDMA at the following levels: non-
filtered cigarette, 680 ng/cigarette; filtered cigarette, 736 ng/cigarette;
and small cigar, 1700 ng/cigarette. The ratio of NDMA in sidestream smoke
to NDMA in mainstream smoke in the non-filtered cigarette, filtered
cigarette and small cigar was found to be 52:1, 139:1, and 41:1,
respectively (Hoffman et al. 1987).
NDMA has been found to occur in various technical and commercial
pesticides used in agriculture, hospitals and homes as the result of (a)
formation during the manufacturing process, (b) formation during storage,
and (c) contamination of amines used in the manufacturing process (Bontoyan
et al. 1979). Herbicides in which NDMA has been found include the amine
salt formulations of 2,4-D, dicamba, MCPA, MCPP,and 2,3,6-trichlotobenzoic
acid. Levels ranging from 0.05 to 640 ppm have been detected in these
herbicides (Bontoyan et al. 1979, Cohen et al. 1978, Hindle et al. 1987,
Ross et al. 1977).
NDMA is a common constituent of municipal sewage sludge (Brewer et al.
1980, Munmia et al. 1984). NDMA was detected in dried sludges from 14 out of
15 cities geographically located throughout the U.S. at levels ranging from
0.6-45 ppb (Mumma et al. 1984). Occurrence of NDMA in sewage sludge appears
to be the result of biological and chemical transformation of alkylamlnes in
the presence of nitrite (Ayanaba and Alexander 1974, Mills and Alexander
1976, Pancholy 1978).
5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE
N-Nitrosamine precursors can be found in a large variety of man-made
and natural products. Such products include agricultural chemicals,
tobacco, detergents, rust inhibitors, rubber additives, solvents, drugs,
plastics, leather tanning, textiles, and cosmetics. Considering the
widespread occurrence of these products and the common occurrence of
nitrogen oxides in industry, there is a fairly high likelihood that
N-nitrosaraines are found in these products or in industrial setting in which
these products are used and/or produced (Fajen 1980). Occupational settings
in which there is potential for exposure to NDMA include, but are not
limited to: leather tanneries, rubber and tire industries, rocket fuel
industries, dye manufacturers, soap, detergent and surfactant industries,
foundries (core-making), fish-processing industries (fish-meal production),
pesticide manufacturers, and warehouse and sale rooms (especially for rubber
products) (Spiegelhalder 1984). When present in workroom air, NDMA levels
are typically less than 1 ppb (Fajen et al. 1982). Exposure may result from
inhalation or dermal contact. Results of a NIOSH survey carried out between
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74
5. POTENTIAL FOR HUMAN EXPOSURE
1981 and 1983 indicate that 747 workers are potentially exposed to NDMA in
occupational settings (NIOSH 1988).
Laboratory workers handling NDMA could potentially be exposed to the
nitrosamine as a result of diffusion through rubber gloves. Walker et al.
(1978) showed that rubber gloves worn in research laboratories do not
provide complete protection from dermal exposure to NDMA, because 11.8% of
the NDMA contained in a dichloromethane solution was found to diffuse
through latex surgical gloves into saline solution, over a period of 20
minutes. Dichloromethane is a common solvent for NDMA.
General population exposure to NDMA results from a number of different
sources, primarily chewing tobacco, tobacco smoke, foods (beer, cured meats,
fish, cheeses, and other food items), cosmetic products, interior air of
cars, and various household commodities. Exposure to NDMA may also result
from its in vivo formation during digestion in the upper gastrointestinal
tract of secondary amine-containing foods or drugs, especially those
containing dimethylamine (Groenen et al. 1980, Magee et al. 1976, Sakai et
al. 1984). Infants may be exposed to NDMA from baby bottle nipples and
pacifiers which may contain small amounts of NDMA, from ingestion of
contaminated infant formulas, and from breast milk from some nursing
mothers. Very low levels of NDMA have been found in breast milk. Based on
older estimates of dietary intake in Germany, the Netherlands, and England
and on recent data pertaining to occurrence of NDMA in various foods in the
U.S., it appears that the average adult dietary intake of NDMA in the U.S.
is less than 1 ng per day (Preussmann 1984). Insufficient data are
available to predict the average daily intake of NDMA from other sources of
exposure.
5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURE
It appears that those segments of the general population with
potentially high exposure to NDMA from exogenous sources would include
tobacco smokers and nonsmokers who come in contact with tobacco smoke for
extended periods of time, snuff dippers, people who are occupationally
exposed, and people who consume large quantities of food known to contain
NDMA, beer or whiskey.
5.7 ADEQUACY OF THE DATABASE
Section 104 (i) (5) of CERCLA, directs the Administrator of ATSDR (in
consultation with the Administrator of EPA and agencies and programs of the
Public Health Service) to assess whether adequate information on the health
effects of NDMA is available. Where adequate information is not available,
ATSDR, in cooperation with the National Toxicology Program (NTP), is
required to assure the initiation of a program of research designed to
determine these health effects (and techniques for developing methods to
determine such health effects). The following discussion highlights the
availability, or absence, of exposure and toxicity information applicable to
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75
5. POTENTIAL FOR HUMAN EXPOSURE
human health assessment. A statement of the relevance of identified data
needs is also included. In a separate effort, ATSDR, in collaboration with
NTP and EPA, will prioritize data needs across chemicals that have been
profiled.
5.7.1 Data Needs
Physical and Chemical Properties. Physical and chemical properties
are essential for estimating the partitioning of a chemical among
environmental media. Many physical and chemical properties are available
for NDMA; however, measured values for Koc and Henry's Law Constant at
ambient temperature are not available. Methods for estimating these
properties appear to provide relatively close estimates of Koc and Henry's
Law Constant. Nevertheless, measured values at environmentally significant
temperatures would assist in accurately predicting the fate of this compound
in the environment.
Environmental Fate. Sufficient data are available to develop a general
understanding of the environmental fate of NDMA. Kinetic data regarding
photolysis in water and on soil surfaces, biodegradation in water under
aerobic and anaerobic conditions, and biodegradation in soil under anaerobic
conditions are lacking. Natural water grab sample biodegradation studies
and soil metabolism studies carried out in the dark under aerobic and
anaerobic conditions would be useful in establishing the persistence of NDMA
in the environment. Photolysis studies carried out under simulated
environmental conditions in water and soil would be useful in establishing
the rate of photolytic degradation, the significance of this process as a
removal mechanism, and the products of this reaction in these media.
Exposure Levels in Environmental Media. Limited data suggest that NDMA
may be found in urban air, but recent comprehensive monitoring data
pertaining to the detection of NDMA in ambient air are needed to establish
this fact. Occurrence of NDMA in air has been associated with rubber
products, leather products, and cigarette smoke and measurable levels of
NDMA have been found in car interiors. This information, combined with the
fact that NDMA has been found in ambient air at various urban locations,
suggests that detectable levels of NDMA exist in the interior air of homes,
offices, etc. Studies pertaining to the monitoring of NDMA in indoor air
are needed to confirm this supposition.
Exposure Levels in Humans. Although numerous studies are available
concerning the detection of NDMA in various foods, a market basket study is
needed to provide a reliable estimate of the average daily dietary intake of
NDMA. Available monitoring data on NDMA need to be evaluated, and estimates
of the amount of exposure from each source need to be developed. These data
would be useful in establishing the relative importance of each source of
intake to overall human exposure and for predicting typical levels of
exposure to NDMA.
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5. POTENTIAL FOR HUMAN EXPOSURE
Exposure Registries. Since NDMA occurs most commonly in occupational
settings as a result of its inadvertent formation, it would be difficult to
develop a reliable estimate of occupational exposure to this compound.
Nevertheless, NIOSH has established a registry for occupational exposure to
NDMA. It would be difficult to develop a registry for environmental
exposure to NDMA since such exposure can occur from a wide variety of
sources and level of exposure can vary markedly depending upon an
individual's lifestyle. There is no registry available for environmental
exposure to this compound.
5.7.2 On-going Studies
There is no indication that there are any studies currently in progress
which are related to the level of NDMA in environmental media, environmental
fate of NDMA, or general population or occupational exposure to NDMA.
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77
6. ANALYTICAL METHODS
6.1 BIOLOGICAL MATERIALS
Methods used for the quantification of NDMA in biological samples are
given in Table 6-1. Two problems encountered in the analysis of NDMA are
poor recovery of the compound due to its high volatility and the artifactual
formation of this compound during sample storage and treatment (Fine 1982).
Since nitroso compounds are formed in acid solution, keeping the solution
alkaline during storage and treatment may reduce artifact formation (Kosaka
et al. 1984). Other authors have used ascorbic acid to inhibit in vitro
formation of nitrosamines and have used morpholine to measure the extent of
in vitro nitrosation during storage and handling (Dunn et al. 1986).
The method that has most selectivity for the quantification of this
compound is thermal energy analyzer (TEA). A few investigators have
oxidized this compound with pentafluoroperoxybenzoic acid to achieve higher
sensitivity with electron capture detector (ECD) than with TEA (Kimoto
et al. 1984). However, ECD detectors have less selectivity than TEA and
will require more sample clean up. The confirmation of NDMA in a sample is
usually done by mass spectrometry (MS). Samples containing small amounts of
NDMA cannot be detected by MS in the presence of large background impurities
(as in samples treated for TEA analysis). Photolysis at 366 nm affords an
alternative means for validating the presence of this compound identified by
TEA (Cooper et al. 1987). A method for the analysis of total N-nitroso
compounds in gastric juice is also available (Pignatelli et al, 1987).
6.2 ENVIRONMENTAL SAMPLES
Methods for quantifying NDMA in environmental samples are summarized in
Table 6-2, As with the biological samples, in situ artifact formation must
be avoided in order to get accurate results from the analysis of
environmental samples (Fisher et al. 1977; Fine et al. 1977a). The three
quantification methods that give satisfactory sensitivity for NDMA are
alkali flame ionization detector (in the nitrogen mode) (AFID), Hall
electrolytic conductivity detector (HECD) in the reductive mode and TEA.
The advantages and disadvantages of these detectors have been evaluated
(Rhoades et al. 1980; Usero et al. 1987). Of the three detectors, the TEA
detector has the highest sensitivity and selectivity. Because of its higher
selectivity, the TEA detector cannot be versatile enough for multipollutant
analysis. Mass spectrometric detector can be used not only for confirmation
of the presence of NDMA in a sample, but for quantification as well
(Eichelberger et al, 1983; Webb et al, 1979). When used in combination
with a high resolution GC column, this method has the ability to quantify a
large number of pollutants in a sample. The use of selected ion monitoring
(SIM) may increase the sensitivity by orders of magnitude. The SIM method
does not provide the full mass spectra necessary for the identification of
unexpected compounds, however (Bellar et al. 1979). A method for the
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TABLE 6-1. Analytical Methods for Determining N-Nitrosodimethylamine in Biological Samples
Sample Matrix
Sample Preparation
Analytical
Method
Detection
Accuracy
Limit
Reference
Whole blood
Blood, liver,
kidney, brain
Blood
Brain, liver,
kichey, pancreas
Urine
Distill alkaline solution, extract dis-
tillate in solvent and concentrate.
Sample with added sulfanic acid and anti-
foaming agent, subjected to simultaneous
distillation and extraction, extract con-
centrated.
Sample mixed with ascorbic acid and mor-
pholine, subjected to distillation in alka-
line solution, distillate extracted with
solvent and concentrated.
Alkaline sample dialyzed with solvent,
dialyzates separated and concentrated.
Vacuum distillation in mineral oil,
extracted with solvent and concentrated.
Sanple mixed with anmnium sulfamate,
homogenized and distilled under vacuum,
extracted with solvent, derivatized with
pertrifluoroacetic acid, cleaned by coluan
chromatography and concentrated.
Sample buffered at pH 10 extracted with
solvent, solvent concentrated.
GC-TEA
GC-TEA
GC-TEA
HRGC-MS
GC-TEA
GC-TEA and
GC-ECD
GC-HRttS
0.1 pg/L
95*
<1 ppb 93-97% at 2.3-4.2 ppb
8 pg or 0.05
jcg/kg (for 20 g
sanple)
3-4 pg
0.1 jig/L
NG
93X
60-70*
NG
54.7%
Lakritz et al. 1980
Pylypiw et al. 1985;
Pylypiw 1987
Dum et al. 1986
Kosaka et al. 1984
Gough et al. 1983
Cooper et al. 1987
CTi
>
o
>
r
s
tn
H
ac
o
o
in
•vj
oo
5 ng/L
99-103% at 10-80 ng/L Garland et al. 1986
NG = Not given; GC = gas chromatography; TEA - thermal energy analyses; HRGC = high resolution gas chromatography; NS = mass spectrometry;
ECD = electron capture detector; HRMS = high resolution mass spectrometry
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TABLE 6-2. Analytical Methods for Determining N-Nitrosodimethylamine in Environmental Samples
Sample Matrix Sample Preparation Analytical Detection Accuracy Reference
Method Limit
Ambient air Sample collected in impinger con-
taining KOH, extracted in solvent and
concentrated.
Sample sorbed on Tenax, thermally
desorbed.
Collected in Tenax, thermally desorbed
and trapped in a cryogenically cooled
trap and dissolved in solvent and con-
centrated.
Collected in ambient or cold ICON trap,
extracted in solvent and concentrated.
Hater, wastewater Sample extracted with solvent, colunn
chromatographic clean-up, concentration.
Extract with solvent at pH 7, concentrate
extract.
Uater
Water, wastewater
Soil
Minced fish and
surimi
Extract with solvent, concentrate extract.
Extracted with solvent, column chromato-
graphic clean-up if required, concentra-
tion of extract.
Extracted with water, water extracted
with solvent and concentrated.
sample eluted with solvent, cleaned
by colmn chromatography and concentrated
GC-MS
Cryofocusing
HRGC-MS
HRGC-MS
GC-TEA
GC-NPD or
GC-reductive
HECD or GC-TEA
(EPA Method 607)
Cryofocusing
HRGC-MS (EPA
Method 625.1)
GC-TEA
GC-AFID
GC-TEA
GC-reduction HECD
GC-TEA
10 pg
0.5 ppt (for
150 L air)
0.3 pg
1 ng/m
0.15 pg/L
1-10 /tg/L
2 ng/L
NG
NG
NG
Fisher et al. 1977
90-110% Sawicki et al. 1977
NG
43.6%
Webb et al. 1979
Fine et al. 1977a,b
32X at 0.8 ftg/L EPA 1982
42X at 100
>
s
H
b-l
o
p
£
H
JE
O
o
w
-~j
vo
GC-TEA 0.2 ppb 77-97% at 10 ppb Pensabene and Fiddler
1988
-------
TABLE 6-2 (continued)
Saaple Matrix Sample Preparation Analytical Detection Accuracy Reference
Method Limit
Neat, vegetable
Halt, beer, milk
powder, cured
¦eat
Vacuus disti 11 grtxnd saaple, extract
distillate with solvent, clean up by
colum chromatography, derivatize with
peroxytrif luoroacetic acid arid colum
chromatographic clean ip and concentrate.
Clean sample by dry column/elution or
Mineral oil distillation method, clean
qp further by colum chromatography,
oxidize with pentafluoroperoxybenzoie
acid, clean 14) by column chromatography
and concentrate.
GC-ECD
GC-TEA or GC-ECD
0.2 ppb (for
250 g sanple)
<1 ppb
<78%
NG
Telling 1972
Kimoto et al. 1984
o\
Malt beverages Clean saqple by celite colum chromato-
graphy, concentrate methylene chloride
eluate.
Beer Saaple treated with sulfamic acid, dis-
tillation under basic condition, extrac-
tion with solvent and concentration.
Fried bacon Clean saaple by acidic celite colum
GC-TEA
GC-TEA
GC-TEA
NG
0.1 ppb
NG
90%
78-112* at
0.08-4 ppb
Hotchkiss et al. 1961
Sen and Seaman 1981a
101% at 10 ppb Pensabene et al. 1962
GC = Gas chromatography; NS = mass spectrometry; HRGC = High resolution gas chromatography; TEA = thermal energy analyzer; NPD = nitrogen-
phosphorus detector; HECO = Hall electrolytic conductivity detector; AFID = alkali flame ionization detector; ECO = electron capture
detector; NG = not given
>
M
n
>
t-
3
W
H
JE
O
a
03
00
o
-------
81
6. ANALYTICAL METHODS
analysis of apparent total N-nitroso compounds in beer is also available
(Massey et al. 1987).
6.3 ADEQUACY OF THE DATABASE
Section 104 (i) (5) of CERCLA, directs the Administrator of ATSDR (in
consultation with the Administrator of EPA and agencies and programs of the
Public Health Service) to assess whether adequate information on the health
effects of NDMA is available. Where adequate information is not available,
ATSDR, in cooperation with the National Toxicology Program (NTP), is
required to assure the initiation of a program of research designed to
determine these health effects (and techniques for developing methods to
determine such health effects). The following discussion highlights the
availability, or absence, of exposure and toxicity information applicable to
human health assessment. A statement of the relevance of identified data
needs is also included. In a separate effort, ATSDR, in collaboration with
NTP and EPA, will prioritize data needs across chemicals that have been
profiled.
6.3.1 Data Needs
Methods for Determining Parent Compounds and Metabolites in Biological
Materials. NDMA is equally distributed in the cellular elements of the
blood and in the plasma and serum (Lakritz et al. 1980). Therefore, it is
advantageous to analyze whole blood for the quantification of NDMA.
Because NDMA is metabolized almost quantitatively in humans (Spiegelhalder
1984), determination of this compound in human urine needs an extremely
sensitive technique (Garland et al. 1986). The urinary excretion of NDMA
has been correlated with the concentration of N02 in air, suggesting that
ambient air may play a role in the exposure of people to nitrosoamines
(Garland et al. 1986). There is a paucity of data on the analytical methods
for the determination of N-nitrosodimethylamlne in human urine.
No metabolite of NDMA from human exposure to this compound has yet been
identified (see Subsection 2.6.3). A metabolite identified in laboratory
animal has been discussed in Subsection 2.6.3. The changes in metabolite
concentrations with time in human blood, urine, or other appropriate
biological medium may be useful in estimating its rate of metabolism in
humans. In some instances, a metabolite may be useful in correlating the
exposed doses to the human body burden. Such studies on the levels of
metabolites in human biological matrices are not available for this
compound.
Methods for Biomarkers of Exposure Recently, a radioimmunoassay was
used to detect elevated levels of the promutagenic lesion 06-
methyldeoxyguanosine in DNA cells from individuals with high incidence of
cancer who consumed foods with a high nitrosamine content (Wild et al,
1987). Although no correlation has been established between the DNA-adduct
-------
82
6. ANALYTICAL METHODS
and the level of NDMA in consumed foods, the DNA-adduct has the potential to
be used as a biomarker for exposure to NDMA.
Methods for Determining Parent Compounds and Degradation Products in
Environmental Media. The levels of this compound in environmental media
can be used to indicate exposure of humans to this compound through the
inhalation of air and ingestion of drinking water and foods containing
N-nitrosodimethylamine. If a correlation with human tissue or body fluid
levels were available, the intake levels from different environmental
sources could be used to estimate the body burden of the chemical in humans.
Such studies correlating the levels of this compound in any environmental
medium with the levels in any human tissue or body fluid are not available.
Although the products of biotic and abiotic processes of this compound
in the environment are known, no systematic study is available that measured
the concentrations of its reaction products in the environment. In
instances where the products of an environmental reaction are more toxic
than the parent compound, it is important that the level of the reaction
products in the environment be known. N-nitrosodimethylamine is not likely
to form more toxic products as a result of environmental reactions (see
Subsection 5.3.2). The analytical methods for the determination of the
levels of environmental reaction products of N-nitrosodimethylamine are
available.
6.3.2 On-going Studies
No ongoing studies are in progress for the improvement of the
analytical method for NDMA in biological samples. Studies are currently
conducted by J. Conboy and J. Hotchkiss at Cornell University, Ithaca, NY
and by D. Havery at FDA, Washington, DC, for the development of analytical
methods for this compound in environmental samples.
-------
83
7. REGULATIONS AND ADVISORIES
The International Register of Potentially Toxic Chemicals (IRPTC 1988)
lists regulations imposed by 13 countries for NDMA for occupational
exposure, packing, storing and transport, disposal, and warns of its
probable human carcinogenicity and its high level of toxicity by ingestion
or inhalation.
NDMA is regulated by effluent guidelines under the Clean Water Act for
the following industrial point sources: electroplating, steam electric
power generation, asbestos products manufacturing, timber products
processing, metal finishing, paving and roofing, paint formulating, ink
formulating, and carbon black manufacturing (EPA 1988a).
Additional national and state regulations and guidelines pertinent to
human exposure to NDMA are summarized in Table 7-1.
-------
84
7. REGULATIONS AND ADVISORIES
TABLE 7-1. Regulations and Guidelines Applicable to N-Nitrosodimethylamine
Agency
Description
Value
Reference
WHO
Regulations
EPA OERR
EPA
c.
Food
FDA
d. Other
EPA
EPA
ACGIH
Cancer Classification
INTERNATIONAL
Group 2Aa
NATIONAL
OSHA
Guidelines
a. Air
b. Water
EPA OURS
Reportable Quantity
(Proposed 1987)
Extremely Hazardous Substance
Emergency Planning and Release
Notification requirements:
Reportable Quantity
Threshold Planning Quantity
Cancer Designation
qj* (inhalation)
Ambient Water Quality Criteria for the
following lifetime increased cancer
risk levels:
(With exposure to water, fish
and shellfish)
(Uith exposure to fish and
shellfish only)
10
10
10"
10
10"
10"
-6
-5
Action Level for NDMA in barley malt
q.|* (oral)
Cancer Classification
Cancer Classification
10 lbs
1 lb
1,000 lbs
Cancer - suspect agent
51/mg/kg/day
14.0 ng/L
1.4 ng/L
0.14 ng/L
160,000 ng/L
16,000 ng/L
1,600 ng/L
10 ppb
51/mg/kg/day
Group B2a
Category A2b
IARC 1987a
EPA 1988a
EPA 1987
40 CFR 300 and 355
29 CFR 1910.1016
(7/1/88)
EPA 1988a
EPA 1980
45 FR 79318
(11/28/80)
Fed. Reg.1981
46 FR 39218
EPA 1988a
EPA 1988a
ACGIH 1989
-------
85
7. REGULATIONS AND ADVISORIES
TABLE 7-1 (continued)
Agency Description Value Reference
STATE
State
Acceptable Anfcient Air Concentrations
Kansas
North Carolina
Pennsylvania-Philadelphia
Virginia
Kentucky
0.0018 Kg/n£ (annual avg)
0.0000 Mg/nr (24 hr avg)
0.0004 ppb £1 yr avg)
3.0000 Mg/nr (24 hr avg)
BACT
State
Kansas
Minnesota
Acceptable Drinking Water Concentrations
0.0014 pg/L
0.014 jtg/L
NATICH 1987
NATICH 1987
NATICH 1987
NATICH 1987
State of Kentucky 1986
FSTRAC 1988
FSTRAC 1988
*Probable hunan carcinogen.
"Suspected human carcinogen. It is noted for NOMA that exposure by the cutaneous route can potentially
contribute to overall exposure.
cBest available control technology. Use of the best available technology to produce the maxinun reduction in
emissions at a specific emission site is required.
-------
87
8. REFERENCES
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9. GLOSSARY
Acute Exposure -- Exposure to a chemical for a duration of 14 days or less,
as specified in the Toxicological Profiles.
Adsorption Coefficient (KoC) -- The ratio of the amount of a chemical
adsorbed per unit weight of organic carbon in the soil or sediment to the
concentration of the chemical in solution at equilibrium.
Adsorption Ratio (Kd) -• The amount of a chemical adsorbed by a sediment or
soil (i.e., the solid phase) divided by the amount of chemical in the
solution phase, which is in equilibrium with the solid phase, at a fixed
solid/solution ratio. It is generally expressed in micrograms of chemical
sorbed per gram of soil or sediment.
Bioconcentration Factor (BGF) -- The quotient of the concentration of a
chemical in aquatic organisms at a specific time or during a discrete time
period of exposure divided by the concentration in the surrounding water at
the same time or during the same time period.
Cancer Effect Level (CEL) -- The lowest dose of chemical in a study or
group of studies which produces significant increases in incidence of
cancer (or tumors) between the exposed populaton and its appropriate
control.
Carcinogen -- A chemical capable of inducing cancer.
Ceiling Value (CL) - - A concentration of a substance that should not be
exceeded, even instantaneously.
Chronic Exposure -- Exposure to a chemical for 365 days or more, as
specified in the Toxicological Profiles.
Developmental Toxicity -- The occurrence of adverse effects on the
-developing organism that may result from exposure to a chemical prior to
conception (either parent), during prenatal development, or postnatally to
the time of sexual maturation. Adverse developmental effects may be detected
at any point in the life span of the organism.
Embryotoxicity and Fetotoxicity -• Any toxic effect on the conceptus as a
result of prenatal exposure to a chemical; the distinguishing feature
between the two terms is the stage of development during which the insult
occurred. The terms, as used here, include malformations and variations,
altered growth, and in utero death.
EPA Health Advisory --An estimate of acceptable drinking water levels for a
chemical substance based on health effects information. A health advisory is
not a legally enforceable federal standard, but serves as technical guidance
to assist federal, state, and local officials.
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9. GLOSSARY
Immediately Dangerous to Life or Health (IDIH) -- The maximum environmental
concentration of a contaminant from which one could escape within 30 min
without any escape-impairing symptoms or irreversible health effects.
Intermediate Exposure -- Exposure to a chemical for a duration of 15-364
days, as specified in the Toxicological Profiles.
Immunologic Toxicity - - The occurrence of adverse effects on the immune
system that may result from exposure to environmental agents such as
chemicals.
In vitro -- Isolated from the living organism and artificially maintained,
as in a test tube.
In vivo -- Occurring within the living organism.
Lethal Concentration(LO) (LC^g) -- The lowest concentration of a chemical in
air which has been reported to have caused death in humans or animals.
Lethal Concentration(50) (LC50) -- A calculated concentration of a chemical
in air to which exposure for a specific length of time is expected to cause
death in 50% of a defined experimental animal
population.
Lethal Dose(LO) (LDjjq) -- The lowest dose of a chemical introduced by a
route other than inhalation that is expected to have caused death in humans
or animals.
Lethal Dose(50) (UD50) -- 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.
LT50 (lethal time) - - A calculated period of time within which a specific
concentration of a chemical is expected to cause death in 50% of a defined
experimental animal population.
Malformations -- Permanent structural changes that may adversely affect
survival, development, or function.
Minimal Risk Level --An estimate of daily human exposure to a chemical
that is likely to be without an appreciable risk of deleterious effects
(noncancerous) over a specified duration of exposure.
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9. GLOSSARY
Mutagen -- A substance that causes mutations. A mutation is a change in the
genetic material in a body cell. Mutations can lead to birth defects,
miscarriages, or cancer.
Neurotoxicity - - The occurrence of adverse effects on the nervous system
following exposure to a chemical.
No-Observed-Adverse-Effect Level (NOAEL) -- That dose of chemical at which
there are no statistically or biologically significant increases in
frequency or severity of adverse effects seen between the exposed
population and its appropriate control. Effects may be produced at this
dose, but they are not considered to be adverse.
Octanol- Water Partition Coefficient (K^) -- The equilibrium ratio of the
concentrations of a chemical in n-octanol and water, in dilute solution.
Permissible Exposure Limit (PEL) --An allowable exposure level in
workplace air averaged over an 8-h shift.
qi* -- The upper-bound estimate of the low-dose slope of the dose-response
curve as determined by the multistage procedure. The q^* can be used to
calculate an estimate of carcinogenic potency, the incremental excess cancer
risk per unit of exposure (usually g/L for water, mg/kg/day for food, and
g/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.
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9. GLOSSARY
Short-Term Exposure Limit (STEL) - - The maximum concentration to which
workers can be exposed for up to 15 min continually. No more than four
excursions are allowed per day, and there must be at least 60 min between
exposure periods. The daily TLV-TWA may not be exceeded.
Target Organ Toxicity -- This term covers a broad range of adverse effects
on target organs or physiological systems (e.g., renal, cardiovascular)
extending from those arising through a single limited exposure to those
assumed over a lifetime of exposure to a chemical.
TD50 (toxic dose) -- A calculated dose of a chemical, introduced by a route
other than inhalation, which is expected to cause a specific toxic effect in
50% of a defined experimental animal population.
Teratogen -- A chemical that causes structural defects that affect the
development of an organism.
Threshold Limit Value (TLV) - - A concentration of a substance to which most
workers can be exposed without adverse effect. The TLV may be expressed as a
TWA, as a STEL, or as a CL.
Time-weighted Average (TWA) - - An allowable exposure concentration averaged
over a normal 8-h workday or 40-h workweek,
Uncertainty Factor (UF) - - A factor used in operationally deriving the RfD
from experimental data. UFs are intended to account for (1) the variation in
sensitivity among the members of the human population, (2) the uncertainty
in extrapolating animal data to the case of humans, (3) the uncertainty in
extrapolating from data obtained in a study that is of less than lifetime
exposure, and (4) the uncertainty in using LOAEL data rather than NOAEL
data. Usually each of these factors is set equal to 10.
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APPENDIX: PEER REVIEW
A peer review panel was assembled for N-nitrosodimethylamine. The
panel consisted of the following members: Dr. Russell Cattley, Department
of Microbiology, Pathology and Parasitology, College of Veterinary Medicine,
North Carolina State University; Dr. Elaine Faustman, Department of
Environmental Health, University of Washington; Dr. James Felton, Molecular
Biology Section, Lawrence Livermore National Laboratory, University of
California; Dr. Freddy Homburger, Bio-Research Consultants, Inc; and Dr.
Raymond Smith, Department of Pathology and Microbiology, University of
Nebraska Medical Center. These experts collectively have knowledge of N-
nitrosodimethylamine'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.
*U.S. GOVERNMENT PRINTING OFFICE:! 9 9 0 -7S2-3S1/
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