TOXICOLOGICAL PROFILE FOR
 

N-NITROSODI-n-PROPYLAMINE
 

Agency for Toxic Substances and Disease Registry (ATSDR)
 

U.S. Public Health Service
 

In collaboration with
 

U.S. Environmental Protection Agency (EPA)
 

December 1989
 
ii
 

DISCLAIMER
 

Mention of company name or product does not constitute endorsement by the
 

Agency for Toxic Substances and Disease Registry.
 










1
 

1. PUBLIC HEALTH STATEMENT
 

1.1 WHAT IS N-NITROSODI-n-PROPYLAMINE?
 

N-Nitrosodi-n-propylamine is a yellow liquid at room temperature that
 

does not disssolve in water and evaporates slowly. It is a man-made
 

chemical made in small amounts for use in research. There is no evidence
 

that N-nitrosodi-n-propylamine exists naturally in soil, air, food, or
 

water. Small amounts of N-nitrosodi-n-propylamine are produced as a side
 

reaction during some manufacturing processes, as a contaminant in some
 

commonly available weed killers (dinitroaniline-based), and during the
 

manufacture of some rubber products. When exposed to sunlight, N-nitrosodi-npropylamine usually does not last for more than a day. Without sunlight
 

(e.g, in water deeper than sunlight reaches or in subsurface soil)
 

N-nitrosodi-n-propylamine breaks down slowly. It takes between 14 and 80
 

days for one-half of any certain amount of N-nitrosodi-n-propylamine to
 

break down when it is released to the subsurface soil. More information can
 

be found in Chapters 3, 4, and 5.
 

1.2 HOW MIGHT I BE EXPOSED TO N-NITROSODI-n-PROPYLAMINE?
 

Persons may be exposed to N-nitrosodi-n-propylamine by eating foods
 

treated with nitrite preservatives (e.g., cheeses, cured meats) and drinking
 

certain alcoholic beverages. N-Nitrosodi-n-propylamine forms in the stomach
 

during digestion of nitrite-treated foods and foods that contain certain
 

amines, particularly di-n-propylamine. Amines occur in some medicines and
 

in a variety of foods. Levels of N-nitrosodi-n-propylamine found in food
 

and alcoholic beverages range between 0.03 parts per billion (ppb) in fried,
 

salt-preserved fish to 30 ppb in cheese. The general population may be
 

exposed to N-nitrosodi-n-propylamine in cigarette smoke. Workers making
 

molded rubber products have been exposed to levels of N-nitrosodi-n-propylamine
 

in workroom air that were measured in parts of compound per
 

trillion parts (ppt) of air. Workers applying contaminated weed killers may
 

also be exposed to extremely low (ppt) levels of N-nitrosodi-n-propylamine.
 

At this time, N-nitrosodi-n-propylamine has been found in at least 1 of
 

1177 hazardous waste sites on the National Priorities List (NPL) in the
 

United States. Workers and the general population at these sites could
 

possibly be exposed to this compound by skin contact, breathing, and eating
 

contaminated items. For more information, refer to Chapter 5.
 

1.3 HOW CAN N-NITROSODI-n-PROPYINE ENTER AND LEAVE MY BODY?
 

N-Nitrosodi-n-propylamine can enter the body when a person breathes
 

air that contains N-nitrosodi-n-propylamine, or eats food or drinks water
 

contaminated with N-nitrosodi-n-propylamine. N-nitrosodi-n-propylamine is
 

not likely to get into your body unless you eat certain foods, drink
 

alcoholic beverages, or are exposed to it at a waste disposal site by
 

breathing N-nitrosodi-n-propylamine vapors. It is likely that N-nitrosodi-npropylamine can enter the body by direct skin contact with wastes,
 
2
 

1. PUBLIC HEALTH STATEMENT
 

pesticides, or soil that contains it. Experiments with animals suggest that
 

if N-nitrosodi-n-propylamine enters the body, it will be broken down into
 

other compounds and will leave the body in the urine. More information on
 

how N-nitrosodi-n-propylamine can enter and leave your body is given in
 

Chapter 2.
 

1.4 HOW CAN N-NITROSODI-n-PROPYLAMINE AFFECT MY HEALTH?
 

The effects of short- or long-term exposures to N-nitrosodi-n-propylamine
 

on human health have not been studied. Little is known about
 

the health effects of short exposures to N-nitrosodi-n-propylamine in
 

experimental animals except that eating or drinking certain amounts of this
 

chemical can cause liver disease and death. Long-term exposure of
 

experimental animals to N-nitrosodi-n-propylamine in food or drinking water
 

causes cancer of the liver, esophagus, and nasal cavities. Although human
 

studies are not available, the animal evidence indicates that it is
 

reasonable to expect that exposure to N-nitrosodi-n-propylamine by eating
 

or drinking could cause liver disease and cancer in humans. It is not known
 

.whether other effects, such as birth defects, occur in animals or could
 

occur in humans exposed to N-nitrosodi-n-propylamine by eating or drinking.
 

It is also not known whether exposure to N-nitrosodi-n-propylamine by
 

breathing contaminated air or contact with the skin can affect the health of
 

animals or humans. Liver disease and cancer due to exposure to N-nitrosodi-npropylamine by breathing or skin contact are, however, a possibility and a
 

health concern. More information on the health effects of N-nitrosodi-npropylamine is given in Chapter 2.
 

1.5	 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO NNITROSODI-n-PROPYLAMINE?
 

The presence of N-nitrosodi-n-propylamine in blood and urine can be
 

measured by chemical analysis, but this analysis is not usually available
 

at your doctor's office and has not been used to test for human exposure or
 

to predict possible health effects. These considerations are discussed in
 

more detail in Chapter 2.
 

1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTS?
 

Tables l-1 through 1-4 show the relationship between exposure to
 

N-nitrosodi-n-propylamine and known health effects. As indicated in Tables
 

l-1 and 1-2, nothing is known about the health effects on humans or animals
 

of breathing N-nitrosodi-n-propylamine. Also, nothing is known-about the
 

health effects in humans of eating food or drinking water containing
 

N-nitrosodi-n-propylamine (Table l-3). A Minimal Risk Level (MRL) is also
 

included in Table l-3. This MRL was derived from animal data for short-term
 

exposure as described in Chapter 2 and in Table 2-1. The MRL provides a
 

basis for comparison with levels that people might encounter in drinking
 

water. If a person is exposed to N-nitrosodi-n-propylamine at an amount
 




7
 

1. PUBLIC HEALTH STATEMENT
 

below the MRL, it is not expected that harmful (noncancer) health effects
 

will occur. Because this level is based on information that is currently
 

available, some uncertainty is always associated with it. Also, because the
 

method for deriving MRLs does not use any information about cancer, an MRL
 

does not imply anything about the presence, absence, or level of risk of
 

cancer. The levels of N-nitrosodi-n-propylamine in food and drinking water
 

linked with known health effects in animals are given in Table l-4. It is
 

not known whether skin contact with N-nitrosodi-n-propylamine can affect the
 

health of humans or animals. More information on levels of exposure linked
 

with adverse health effects can be found in Chapter 2.
 

1.7	 RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT


 HUMAN HEALTH?
 

The EPA controls the release of N-nitrosodi-n-propylamine. It is
 

proposed that releases or spills of 10 pounds or more of N-nitrosodi-n-propylamine
 

must be reported to the National Response Center.
 

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
 

9
 

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
 

N-nitrosodi-n-propylamine. Its purpose is to present levels of significant
 

exposure for N-nitrosodi-n-propylamine 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 N-nitrosodi-n-propylamine and (2) a
 

depiction of significant exposure levels associated with various adverse
 

health effects.
 

2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF FXPOSURE
 

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.
 
10
 

2. HEALTH EFFECTS
 

For certain chemicals, levels of exposure associated with carcinogenic
 

effects may be indicated in the figures. These levels reflect the actual
 

doses associated with the tumor incidences reported in the studies cited.
 

Because cancer effects could occur at lower exposure levels, the figures
 

also show estimated excess risks, ranging from a risk of one in 10,000 to
 

one in 10,000,000 (10-4 to 10-7), as developed by EPA.
 

Estimates of exposure levels posing minimal risk to humans (MRLs) have
 

been made, where data were believed reliable, for the most sensitive
 

noncancer end point for each exposure duration. MRLs include adjustments to
 

reflect human variability and, where appropriate, the uncertainty of
 

extrapolating from laboratory animal data to humans. Although methods have
 

been established to derive these levels (Barnes et al. 1987; EPA 1980a),
 

uncertainties are associated with the techniques.
 

2.2.1 Inhalation Exposure
 

No studies were located regarding the following effects in humans or
 

animals following inhalation exposure to N-nitrosodi-n-propylamine:
 

2.2.1.1 Death 

2.2.1.2 Systemic Effects 

2.2.1.3 Neurological Effects 

2.2.1.4 Immunological Effects 

2.2.1.5 Developmental Effects 

2.2.1.6 Reproductive Effects 

2.2.1.7 Genotoxic Effects 

2.2.1.8 Cancer 

2.2.2 Oral Exposure 

2.2.2.1 Death 

No studies were located regarding lethality in humans following oral
 

exposure to N-nitrosodi-n-propylamine.
 

Druckrey et al. (1967) determined a single dose gavage LD50 of 480
 

mg/kg for N-nitrosodi-n-propylamine in rats. The value was determined using
 

an unspecified graphic technique but specific mortality data were not
 

reported. Deaths occurred after 3-7 days and appear to have been due
 

primarily to hepatotoxicity. Other acute oral lethality data were not
 

located in the reviewed literature. The 480 mg/kg LD50 is indicated in
 
11
 

2. HEALTH EFFECTS
 

Table 2-1 and Figure 2-l. No short-term studies of N-nitrosodi-n-propylamine
 

administered in drinking water were located; therefore, the dose level of
 

480 mg/kg, which was administered by gavage in water (Druckrey et al. 1967),
 

was converted to an equivalent concentration of 3400 ppm in water for
 

presentation in Table l-4.
 

Decreased longevity occurred in rats that were treated with
 

N-nitrosodi-n-propylamine at doses of 6.3 mg/kg/day (females) or 12.6
 

mg/kg/day (males) by gavage for 2 days/week for 30 weeks (Lijinsky and
 

Reuber 1983), or 5.1 mg/kg/day (males) via drinking water for 5 days/week
 

for 30 weeks (Lijinsky and Taylor 1978, 1979). Mortality in the Lijinsky and
 

Reuber (1983) study was 92-100% after 40-60 weeks compared to 5-10% after
 

100 weeks in controls; comparable data were reported by Lijinsky and Taylor
 

(1978, 1979) for the treated rats but a control group was not used. The
 

mortality in these studies was due to tumor development (see Section
 

2.2.2.8, Oral exposure, Cancer). The 5.1, 6.3 and 12.6 mg/kg/day doses are
 

serious LOAEL values for lethality in rats due to intermediate duration oral
 

exposure and are recorded in Table 2-l and plotted in Figure 2-l. No studies
 

were located regarding survival in animals following chronic oral exposure
 

to N-nitrosodi-n-propylamine.
 

2.2.2.2 Systemic Effects
 

No studies were located regarding systemic effects in humans following
 

oral exposure to N-nitrosodi-n-propylamine.
 

Hepatic Effects. Pathologic examinations of rats that received single
 

lethal doses of various nitrosamines, including N-nitrosodi-n-propylamine,
 

showed centrilobular necrosis and fatty degeneration of the liver (Druckrey
 

et al. 1967). Specific doses of N-nitrosodi-n-propylamine that produced
 

these effects were not reported, but the LD50 was determined to be 480
 

mg/kg; this dose is indicated in Table 2-l and Figure 2-l as a serious LOAEL
 

for hepatic effects in rats due to acute oral exposure. No short-term
 

studies of N-nitrosodi-n-propylamine administered in drinking water were
 

located; therefore, the dose level of 480 mg/kg, which was administered by
 

gavage in water (Druckrey et al. 1967), was converted to an equivalent
 

concentration of 3400 ppm in water for presentation in Table l-4.
 

Nishie et al. (1972) determined pentobarbital sleeping time (PST) in
 

mice that were treated by gavage with single doses or with four consecutive
 

daily doses of various nitrosamines, including N-nitrosodi-n-propylamine.
 

Doses of N-nitrosodi-n-propylamine were 160 mg/kg/day in the single dose
 

study and 40 mg/kg/day in the four-day study. N-nitrosodi-n-propylamine
 

treatment resulted in significantly prolonged PST in both studies. Liver
 

histology was evaluated in the four-day study, but results of the histologic
 

examinations were not reported specifically for any of the nitrosamines.
 

Hepatic histological alterations attributed to unspecified nitrosamines
 

included hepatocyte swelling and necrosis in the centrilobular areas; due to
 

the inadequately reported data, it cannot be determined whether N-nitrosodi­



15
 

2. HEALTH EFFECTS
 

n-propylamine was among the nitrosamines that produced these effects.
 

However, considering the aforementioned findings for nitrosamines in general
 

as well as evidence for hepatotoxicity of N-nitrosodi-n-propylamine and
 

other nitrosamines from other studies, the increase in PST provides an
 

indirect indication of adverse liver effects. Therefore, since N-nitrosodi-npropylamine markedly increased PST in the four-day study, 40 mg/kg/day can
 

be regarded as a LOAEL for less serious hepatic effects due to acute oral
 

exposure (Table 2-l and Figure 2-l). No short-term studies of N-nitrosodi-npropylamine administered in food were located; therefore, the dose level of
 

40 mg/kg/day, which was administered by gavage in olive oil (Nishie et al.
 

1972), was converted to an equivalent concentration of 308 ppm in food for
 

presentation in Table l-4.
 

Liver histology and activities of liver-associated serum enzymes (SGOT,
 

alkaline phosphatase, lactate dehydrogenase, gamma-glutamyl-transferase)
 

were unaltered in mice exposed to 9.5 mg/kg/day via drinking water for one
 

week (Tyndall et al. 1978). This dose represents a NOAEL for hepatic effects
 

due to acute duration exposure (Table 2-l and Figure 2-l). Because this
 

NOAEL is lower than the 40 mg/kg/day LOAEL for hepatic effects (Nishie et
 

al. 1972), it can be used as the basis for an acute MRL (Figure 2-l). Based
 

on this value, an acute oral MRL of 0.095 mg/kg/day was calculated, as
 

described in the footnote in Table 2-l. This MRL has been converted to an
 

equivalent concentration in drinking water (3.3 ppm) for presentation in
 

Table 1-3.
 

Other Effects. Plasma esterase profiles were examined in mice exposed
 

to various carcinogenic, weakly carcinogenic and noncarcinogenic chemicals
 

in the drinking water for one week (Tyndall et al. 1978). N-nitrosodi-npropylamine, administered at a dose 9.5 mg/kg/day, produced esterase
 

alterations that were similar to those produced by other N-nitrosodialkylamines.
 

The alterations were not accompanied by weight loss, altered liver-associated
 

serum enzymes or histologic effects. This study was conducted to determine whether
 

altered esterase patterns in plasma would provide a more sensitive indicator of
 

exposure to a carcinogenic chemical than standard clinical chemistry tests. It was
 

concluded that it is not known if the altered esterase profiles that were observed
 

for N-nitrosodi-n-propylamine and the other carcinogens are related to
 

carcinogenicity, toxicity or metabolism. Since the biological significance of the
 

altered esterase profiles is unknown, it cannot be determined if 9.5 mg/kg/day
 

represents a NOAEL or LOAEL for serum chemistry alterations due to acute
 

oral exposure.
 

No studies were located regarding the following effects in humans or
 

animals following oral exposure to N-nitrosodi-n-propylamine:
 

2.2.2.3 Immunological Effects
 

2.2.2.4 Neurological Effects
 
16
 

2. HEALTH EFFECTS 

2.2.2.5 Developmental Effects 

2.2.2.6 Reproductive Effects 

2.2.2.7 Genotoxic Effects 

Single doses of N-nitrosodi-n-propylamine, administered by gavage,
 

produced fragmentation of liver DNA in rats (Brambilla et al. 1981, 1987a).
 

Doses ranged from 0.31 to 25 mg/kg and the effect was dose-related.
 

2.2.2.8 Cancer
 

No studies were located regarding carcinogenic effects in humans
 

following oral exposure to N-nitrosodi-n-propylamine.
 

The carcinogenicity of N-nitrosodi-n-propylamine has been demonstrated
 

unequivocally in oral studies. High incidences of liver carcinomas, nasal
 

cavity carcinomas, esophageal carcinomas and papillomas, forestomach tumors
 

or tongue tumors occurred in rats that were exposed to N-nitrosodinpropylamine by gavage at doses of 6.3 or 12.6 mg/kg/day for 2 days/week for
 

30 weeks (Lijinsky and Reuber 1983), via drinking water at a dose of 2.6
 

mg/kg/day for 5 days/week for 30 weeks (Lijinsky and Reuber 1981), via
 

drinking water at a dose of 5.1 mg/kg/day for 5 days/week for 30 weeks
 

(Lijinsky and Reuber 1981; Lijinsky and Taylor 1978, 1979), and via diet
 

daily at reported doses of 4-30 mg/kg/day for life (survival duration not
 

specified) (Druckrey et al. 1967). Tumor incidences in the liver, nasal
 

cavity, esophagus and forestomach were generally in the range of 60-l00%,
 

and tongue tumor incidences ranged from 30-40%. The Lijinsky and Reuber
 

(1983) study was the only study that used control groups; no tumors
 

occurred in the control rats at any of the sites in which tumors developed
 

in the treated rats. The lack of controls in the other studies is not
 

considered to be a serious deficiency due to the high tumor incidences. As
 

indicated in Section 2.2.2.1 (Oral exposure, Death), tumor development in
 

all of the rat studies was life-shortening.
 

The lowest drinking water and gavage doses of N-nitrosodi-n-propylamine
 

that were carcinogenic to rats are 2.6 mg/kg/day (Lijinsky and
 

Reuber 1981) and 6.3 mg/kg/day (Lijinsky and Reuber 1983), respectively;
 

these are intermediate duration effect levels for carcinogenicity (cancer
 

effects levels, CELs) because exposure durations were 30 weeks (Table 2-l
 

and Figure 2-l). The lowest dose tested in the study of Druckrey et al.
 

(1967) (4 mg/kg/day) is also presented in Table 2-l and Figure 2-l in the
 

intermediate duration category as this study is used as the basis for a
 

carcinogenic potency factor for N-nitrosodi-n-propylamine (EPA 1988). The 4
 

mg/kg/day dose from the Druckrey et al. (1967) study is considered to be the
 

lowest CEL due to intermediate duration exposure because (1) time to tumor
 

data suggest that survival was generally less than one year, and (2)
 

survival was less than one year in the other cancer studies which used
 
17
 

2. HEALTH EFFECTS
 

similar or lower doses. Although a carcinogenic potency factor is based on
 

this study, it should be recognized that the study is limited by small
 

numbers of treated rats, no controls and unreported specific tumor
 

incidences. Using hepatocellular carcinoma response data from this study,
 

EPA (1988) derived and verified an oral slope factor (BH) of 7.0
 

(mg/kg/day)-1 for N-nitrosodi-n-propylamine. Using this slope factor the
 

10-4
 doses associated with upper bound lifetime cancer risk levels of to
 

10-7 are calculated to be 1.4 x 10-5 to 1.4 x 10-8 mg/kg/day, respectively.
 

The cancer risk levels are plotted in Figure 2-l in the chronic duration
 

category because they represent lifetime risks for humans.
 

In an oral carcinogenicity study conducted with mice, the animals
 

received an estimated N-nitrosodi-n-propylamine dose of 1 mg/kg by gavage,
 

twice a week for 50 weeks (Griciute et al. 1982). Incidences of forestomach
 

papillomas, forestomach carcinomas and pulmonary adenomas were significantly
 

higher than in mice that were similarly treated with 40% ethanol; a vehicle
 

(water) control was not used. The 1 mg/kg/day dose from the Griciute et al.
 

(1982) study represents an intermediate duration CEL in mice (Table 2-l and
 

Figure 2-l).
 

2.2.3 Dermal Exposure
 

No studies were located regarding the following effects in humans or
 

animals following dermal exposure to N-nitrosodi-n-propylamine:
 

2.2.3.1 Death 

2.2.3.2 Systemic Effects 

2.2.3.3 Neurological Effects 

2.2.3.4 Immunological Effects 

2.2.3.5 Developmental Effects 

2.2.3.6 Reproductive Effects 

2.2.3.7 Genotoxic Effects 

2.2.3.8 Cancer 

2.3 RELEVANCE TO PUBLIC HEALTH 

Death. Information regarding death of humans following exposure to
 

N-nitrosodi-n-propylamine by any route was not found. Case reports indicate
 

that intentional oral and accidental inhalation exposures to unknown levels
 

of N-nitrosodimethylamine, however, have resulted in deaths in humans
 

(Barnes and Magee 1954, Cooper and Kimbrough 1980, Freund 1937, Fussgaenger
 

and Ditschuneit 1980, Pedal et al. 1982); these deaths apparently were due
 
18
 

2. HEALTH EFFECTS
 

to hepatotoxicity. Limited data are available for acute lethality in
 

N-nitrosodi-n-propylamine-exposed animals. In the only acute study that used
 

a natural route of exposure, an oral LD50 value of 480 mg/kg was determined
 

for rats (Druckrey et al. 1967). Subcutaneous injection LD50 values have
 

been determined for N-nitrosodi-n-propylamine in various species; these are
 

consistent with the oral LD50 and include 487.2 mg/kg for rats (Reznik et
 

al. 1975), 689 mg/kg for mice (Dickhaus et al. 1977) and 600 mg/kg for
 

hamsters (Pour et al. 1973). Pathologic examinations revealed centrilobular
 

liver necrosis and hemorrhages in the lungs, stomach, kidneys and/or heart.
 

Oral administration of N-nitrosodi-n-propylamine at doses ranging from
 

5.1-12.6 mg/kg/day, on 2 or 5 days a week for 30 weeks, produced high
 

mortality in rats (Lijinsky and Reuber 1983; Lijinsky and Taylor 1978,
 

1979). Once-weekly subcutaneous injections of similar doses of N-nitrosodinpropylamine to rats (<24.4 mg/kg) (Reznik et al. 1975), mice (>34.5 mg/kg)
 

(Dickhaus et al. 1977) and hamsters (>3.75 mg/kg) (Pour et al. 1973, Althoff
 

et al. 1973a,b) also were life-shortening (average survival times of 27-54
 

weeks) . Weekly intraperitoneal injection of 40 mg/kg N-nitrosodi-n-propylamine
 

produced deaths in monkeys after an average period of 28 months
 

(Adamson and Sieber 1979, 1983). Mortality in the above studies is dose-


related and due to tumor development.
 

The available lethality data indicate that deaths resulting from acute
 

exposure to N-nitrosodi-n-propylamine are due primarily to hepatotoxicity,
 

that deaths resulting from repeated exposure to N-nitrosodi-n-propylamine
 

are due to tumors occurring primarily in the liver, and that causes of death
 

and lethal doses are similar in different species. The causes of death
 

produced by N-nitrosodi-n-propylamine also are consistent with those
 

produced by other dialkylnitrosamines (Magee et al. 1976).
 

Systemic Effects. Information regarding systemic effects in humans
 

following exposure to N-nitrosodi-n-propylamine was not found. Very limited
 

information is available for systemic effects of N-nitrosodi-n-propylamine
 

in animals because interest in this compound has focused overwhelmingly on
 

carcinogenicity.
 

As indicated in the previous subsection (see Death above), lethal
 

single oral or subcutaneous doses of N-nitrosodi-n-propylamine produced
 

hepatic necrosis and hemorrhagic lesions in the liver and other internal
 

tissues in rats and hamsters (Druckrey et al. 1967, Pour et al. 1973, Reznik
 

et al. 1975). Similar effects were reported by Nishie et al. (1972), who
 

observed that gavage doses of 40 mg/kg/day for 4 consecutive days produced
 

swelling of hepatocytes and possibly necrosis in the centrilobular area of
 

the liver in mice. Hepatotoxicity and hemorrhagic lesions in the liver and
 

other internal tissues are also the primary acute effects of other
 

dialkylnitrosamine compounds (Magee et al. 1976). Based on data for other
 

dialkylnitrosamines, it can be inferred that systemic effects of
 

intermediate or chronic duration exposure to N-nitrosodi-n-propylamine are
 

likely to include acute-type responses and preneoplastic alterations.
 
19
 

2. HEALTH EFFECTS
 

Although it is apparent that N-nitrosodi-n-propylamine produces
 

hepatotoxicity and hemorrhages in the lungs, stomach, kidney and heart at
 

acute lethal doses in animals, there is only limited information regarding
 

the threshold for these effects following acute exposure and documentation
 

of these effects following intermediate or chronic duration exposure is not
 

available. Although human data are not available, human fatalities due to
 

intentional oral and accidental inhalation exposures to unknown levels of
 

N-nitrosodimethylamine have been described in case reports in which
 

hemorrhagic, necrotic and cirrhotic alterations in the liver and diffuse
 

internal bleeding were observed (Barnes and Magee 1954; Cooper and Kimbrough
 

1980; Freund 1937; Fussgaenger and Ditschuneits 1980; Pedal et al. 1982).
 

The available information for N-nitrosodi-n-propylamine and related
 

nitrosamines therefore indicates that N-nitrosodi-n-propylamine is likely to
 

produce characteristic hepatic and/or hemorrhagic effects in humans exposed
 

orally or by inhalation. Systemic effects of N-nitrosodi-n-propylamine may
 

result from dermal exposure, since evidence indicates that dermal absorption
 

of N-nitrosodi-n-propylamine is likely (Section 2.6.1.3, Absorption, Dermal
 

exposure).
 

Developmental Effects. Limited information regarding developmental
 

effects of N-nitrosodi-n-propylamine in humans or in animals is available
 

from subcutaneous injection transplacental carcinogenesis studies with
 

hamsters (Althoff et al. 1977a; Althoff and Grandjean 1979). Injection of a
 

single dose of 100 mg N-nitrosodi-n-propylamine/kg on day 8, 10, 12, or 14
 

of gestation did not produce gross malformations in the offspring but the
 

scope of the examination was not specified. However, transplacental
 

carcinogenicity was observed in the offspring of dams treated with
 

N-nitrosodi-n-propylamine. There were no treatment-related effects on litter
 

size but postnatal mortality in the first four weeks was increased (Althoff
 

et al. 1977a). Transplacental transport of N-nitrosodi-n-propylamine by the
 

hamsters was demonstrated by detection of the chemical in the placenta,
 

fetus and amniotic fluid. No studies were located demonstrating that
 

N-nitrosodi-n-propylamine crosses the placenta in humans and it is not known
 

whether N-nitrosodi-n-propylamine can cause developmental effects in humans.
 

It is relevant to note, however, that limited evidence indicates that
 

N-nitrosodimethylamine is fetotoxic but not teratogenic. Also, it has been
 

estimated from studies with rodents that drugs with a molecular weight of
 

less than 1,000 can readily cross the placenta (Mirkin 1973); the molecular
 

weight of N-nitrosodi-n-propylamine is 130.2.
 

Genotoxic Effects. No studies were located regarding the genotoxicity
 

of N-nitrosodi-n-propylamine in humans by the inhalation, oral or dermal
 

routes. Fragmentation of DNA was observed, however, in human hepatocytes
 

cultured in the presence of N-nitrosodi-n-propylamine (Brambilla et al.
 

1987b).
 

Genotoxicity of N-nitrosodi-n-propylamine has been demonstrated
 

consistently in numerous in vitro studies. As indicated in Table 2-2,
 

21
 

2. HEALTH EFFECTS
 

N-nitrosodi-n-propylamine was mutagenic in bacteria (Salmonella
 

Typhimurium, Escherichia coli) and mammalian cells (mouse lymphoma L5178Y,
 

Chinese hamster V79), caused DNA effects (fragmentation, unscheduled
 

synthesis, repair) in rat hepatocytes, and chromosome aberrations in Chinese
 

hamster cells. The in vitro assays generally required addition of an
 

exogenous metabolic activation system for expression of effects; this is
 

consistent with the apparent indirect carcinogenicity of N-nitrosodinpropylamine. Single doses of N-nitrosodi-n-propylamine produced DNA
 

fragmentation in rats treated orally and sister chromatid exchange and DNA
 

synthesis suppression in mice treated by intraperitoneal injection (Table 2­

3). In addition, intraperitoneal injection (133 mg/kg) of N-nitrosodi-npropylamine
 

to rats results in propylation of DNA and RNA, an event regarded
 

as critical in the initiation of carcinogenesis by this and related
 

alkylating agents (Park et al. 1980).
 

The weight of evidence indicates that N-nitrosodi-n-propylamine is
 

genotoxic in mammalian cells. The effect observed in the study with human
 

hepatocytes (DNA fragmentation) (Brambilla et al. 1987b) is consistent with
 

the results of other assays, particularly the in vitro and in vivo rat
 

hepatocyte DNA fragmentation assays (Table 2-2 and 2-3). Given the type and
 

weight of genotoxicity evidence, one can predict that N-nitrosodi-npropylamine poses a genotoxic threat to humans.
 

Cancer. Information regarding the carcinogenicity of N-nitrosodinpropylamine in humans was not located. In animals, carcinogenicity of
 

N-nitrosodi-n-propylamine has been demonstrated in several species in all
 

studies that have been conducted. In rats observed for life, daily or
 

partial weekly (2 days/week or 5 days/week) oral exposure produced tumors
 

primarily in the liver, nasal cavity and esophagus (Druckrey et al. 1967;
 

Lijinsky and Reuber 1981, 1983; Lijinsky and Taylor 1978, 1979). In mice,
 

increased incidences of forestomach tumors occurred as a result of twice
 

weekly orally treatment for 50 weeks (Griciute et al. 1982). Weekly
 

subcutaneous injections of N-nitrosodi-n-propylamine to rats (Althoff et al.
 

1973b, Reznik et al. 1975), mice (Dickhaus et al. 1977) and hamsters
 

(Althoff et al. 1973a, 1977b; Pour et al. 1973, 1974) for life produced
 

high incidences of tumors primarily in the nasal cavity and other parts of
 

the respiratory system, but also in the liver and esophagus. Subcutaneous
 

injection of single 100 mg/kg doses of N-nitrosodi-n-propylamine into
 

hamsters during gestation induced tumors; primarily in the respiratory and
 

digestive tracts, in the dams and offspring (Althoff et al. 1977a; Althoff
 

and Grandjean 1979). Weekly intraperitoneal injections of 40 mg N-nitrosodinpropylamine produced death due to hepatocellular carcinomas in monkeys
 

after an average duration of 28 months (Adamson and Sieber 1979, 1983).
 

Overall, there is conclusive evidence that N-nitrosodi-n-propylamine is
 

carcinogenic in animals. The carcinogenicity of N-nitrosodi-n-propylamine
 

may be related to alkylation of DNA. It is important to recognize that
 

cancer was observed in the oral and injection studies after durations as
 

short as 20-30 weeks, and that once weekly oral exposures and single
 

23
 

2. HEALTH EFFECTS
 

exposure by injection were sufficient to induce cancer. Based on the
 

evidence of carcinogenicity in animals, it is reasonable to anticipate that
 

N-nitrosodi-n-propylamine will be carcinogenic in humans.
 

2.4 	 LEVELS IN HUMAN TISSUES AND FLUIDS ASSOCIATED WITH HEALTH EFFECTS
 

There is no known association between levels of N-nitrosodi-npropylamine
 

or its metabolites in human tissues and fluids and health
 

effects of N-nitrosodi-n-propylamine. N-nitrosodi-n-propylamine was detected
 

in the liver of 1 of 4 deceased subjects (Cooper et al. 1987). As indicated
 

in Section 2.6.2 (Distribution), the cause of death is not attributable to
 

N-nitrosodi-n-propylamine.
 

2.5 	 LEVELS IN THE ENVIRONMENT ASSOCIATED WITH LEVELS IN HUMAN TISSUES AND/OR
 

HEALTH EFFECTS
 

There is no known association between levels of N-nitrosodi-npropylamine
 

in the environment and levels of N-nitrosodi-n-propylamine or
 

its metabolites in human tissues and fluids or health effects of
 

N-nitrosodi-n-propylamine.
 

2.6 	TOXICOKINETICS
 

2.6.1 Absorption
 

2.6.1.1 Inhalation Exposure
 

No studies were located regarding absorption in humans or animals
 

following inhalation exposure to N-nitrosodi-n-propylamine.
 

However, structurally similar compounds, such as, N-nitrosodimethylamine and
 

N-nitrosodiethanolamine, are readily absorbed (70-90% of the dose) following
 

inhalation exposure in experimental animals (Klein and Schmezer 1984;
 

Preussmann et al. 1981). Absorption was inferred by monitoring urinary
 

excretion of the unchanged compounds.
 

2.6.1.2 Oral Exposure
 

No studies were located regarding absorption in humans following oral
 

exposure to N-nitrosodi-n-propylamine.
 

Specific information regarding absorption in animals following oral
 

exposure to N-nitrosodi-n-propylamine was not located. Gastrointestinal
 

absorption of N-nitrosodi-n-propylamine by rodents is indicated by the
 

occurrence of metabolites in the urine following oral treatment (Section
 

2.3.1.3) and systemic effects in oral carcinogenicity and toxicity studies
 

(Section 2.2). Other nitrosamines are rapidly absorbed from the
 

gastrointestinal tract after oral exposure. Diaz Gomez et al. (1977) found
 

that less than 2% of radiolabelled dimethylnitrosamine could be recovered
 
24
 

2. HEALTH EFFECTS
 

from the stomach and intestine of rats 15 minutes after administration. Also
 

in rats, Lijinsky et al. (1981) and Preussmann et al. (1978) estimated
 

absorption rates of 25% and 70% of the dose for N-nitrosodiethanolamine,
 

respectively (estimates are from urinary excretion).
 

2.6.1.3 Dermal Exposure
 

No studies were located regarding absorption in humans following dermal
 

exposure to N-nitrosodi-n-propylamine. However, absorption of Nnitroso-di-n-propylamine through human skin in vivo (Edwards et al. 1979) and
 

in vitro (Bronaugh et al. 1979, 1981) has been demonstrated.
 

Diffusion of N-nitroso-di-n-propylamine through rat skin in vitro has
 

been demonstrated (Wishnok et al. 1982). Information regarding dermal
 

absorption of N-nitroso-di-n-propylamine by animals in vivo was not located
 

in the reviewed literature. Dermal absorption of N-nitrosodiethanolamine has
 

been determined in pigs (Marzulli et al. 1981), monkeys (Marzulli et al.
 

1981), and rats (Airoldi et al. 1984; Lijinsky et al. 1981). The degree of
 

absorption varied greatly (4-78%) depending on the site of the application
 

and the vehicle used. Based on the data for N-nitrosodi-n-propylamine and
 

N-nitrosodiethanolamine, it is likely that N-nitrosodi-n-propylamine will be
 

absorbed following dermal exposure.
 

2.6.2 Distribution
 

Route-specific distribution data for N-nitrosodi-n-propylamine in
 

humans were not located in the reviewed literature. Quantitative analyses of
 

six volatile nitrosamines in postmortem organs (brain, liver, kidneys,
 

pancreas) from four human subjects were conducted (Cooper et al. 1987).
 

N-nitrosodi-n-propylamine was detected only in the liver of one of the
 

subjects (female, age 84 years) at a concentration of 19.30 ng/50 g of
 

tissue. The ages of the other subjects (two males, one female) ranged from
 

47-80 years. Unusual sources of nitrosamine exposure or causes of death were
 

not indicated.
 

Transplacental transport of N-nitrosodi-n-propylamine was shown in
 

pregnant hamsters (Althoff et al. 1977a, Althoff and Grandjean 1979). After
 

a single 100 mg/kg subcutaneous injection, N-nitrosodi-n-propylamine was
 

detected in the maternal blood, placenta, fetus, and amniotic fluid. The
 

concentration of the chemical in maternal blood reached a maximum at 45 and
 

90 minutes after the injection, whereas a single peak at 90 minutes was
 

observed in the fetus. Analysis for metabolites was not conducted, but 1.6%
 

of the unchanged compound was found in the placenta and 1.3% in the fetus at
 

day 14 of gestation. Detection of 06

-methylguanine in human placental DNA by
 

immunoassay indicates that nitrosamines, as a group, can reach the placenta
 

in humans (Foiles et al. 1988).
 

Limited data are available regarding the distribution of related
 

nitrosamines. Daugherty and Klapp (1976) reported that after oral
 

administration of 14C-N-nitrosodimethylamine to mice radioactivity could be
 
25
 

2. HEALTH EFFECTS
 

detected in the homogenates of heart, forestomach, esophagus, liver and
 

lungs. Radioactivity was detected in all organs and tissues of rats after
 

oral doses of 14C-N-nitrosodiethanolamine (Lethco et al. 1982). After
 

intravenous injection of 14C-N-nitrosodi-n-butylamine to rats the highest
 

concentrations of radiolabel occurred in the nasal mucosa, liver and
 

preputial gland (Brittebo and Tjalve 1982).
 

2.6.3 Metabolism
 

No studies were located regarding metabolism in humans following
 

exposure to N-nitrosodi-n-propylamine. .
 

In vitro and in vivo studies with rodents have been conducted that
 

provide evidence that N-nitrosodi-n-propylamine can be metabolized via
 

oxidation at the alpha, beta and gamma carbon positions (Figure 2-2). Alpha
 

carbon oxidation (hydroxylation) is regarded as the primary pathway,
 

resulting in formation of propionaldehyde and 1-propanol and 2-propanol as
 

metabolites (Farrelly et al. 1984; Park and Archer 1978; Park et al. 1977).
 

1-Propanol and 2-propanol are formed via propyldiazohydroxide and a propyl
 

cation (carbonium ion). It is generally believed that the carbonium ions can
 

also react with nucleic acids to form propylated adducts, but Park et al.
 

(1980) have suggested that propylation takes place via a bimolecular
 

reaction. However, reaction of DNA with propylnitrosourea (a direct acting
 

equivalent of N-nitrosodi-n-propylamine) results in formation of n-propyl
 

and isopropyl DNA adducts, suggesting carbonium ions are involved.
 

Alkylation of nucleic acids and proteins by metabolites of nitrosamines has
 

been suggested as the mechanism responsible for the toxic and carcinogenic
 

properties of these substances.
 

Beta-carbon hydroxylation yields N-nitroso-2-hydroxy-propylpropylamine
 

which is excreted as the glucuronide or further oxidized to a small extent
 

to N-nitroso-2-oxopropylpropylamine (Bauman et al. 1985; Leung and Archer
 

1981; Park and Archer 1978; Suzuki and Okada 1981). Methylated hepatic
 

nucleic acids have been recovered from rats and hamsters treated with
 

N-nitrosodi-n-propylamine (Althoff et al. 1977b; Kruger 1971, 1973; Kruger
 

and Bertram 1973; Leung and Archer 1984). Putative methylating
 

intermediates, formed from N-nitroso-2-oxo-n-propylamine, are
 

N-nitrosomethylpropylamine and diazomethane.
 

Gamma-carbon hydroxylation yields N-nitroso-3-hydroxy-propylpropylamine
 

and its oxidation product, N-propyl-N-(2-carboxyethyl)nitrosamine (Baumann
 

et al. 1985; Blattmann and Preussman 1973, Suzuki and Okada 1981). Urinary
 

N-propyl-N-(2-carboxyethyl)nitrosamine amounted to approximately 5% of a 300
 

mg/kg oral dose of N-nitrosodi-n-propylamine in rats (Suzuki and Okada
 

1981).
 

Documented and postulated metabolites of N-nitrosodi-n-propylamine have
 

been shown to be carcinogenic in hamsters and rats (IARC 1978). These
 

include N-nitroso-bis-(2-hydroxy-n-propyl)amine, N-nitroso-2-oxo-n­

27
 

2. HEALTH EFFECTS
 

propylpropylamine, N-nitroso-bis(2-oxo-n-propyl)amine and N-nitroso-bis(2­

acetoxy-n-propyl)amine. Main tumor sites of many of these metabolites
 

include those associated with N-nitrosodi-n-propylamine treatment (Section
 

2.2.2.8, Oral exposure, Cancer).
 

2.6.4 Excretion
 

2.6.4.1 Inhalation Exposure
 

No studies were located regarding excretion in humans or animals
 

following inhalation exposure to N-nitrosodi-n-propylamine.
 

2.6.4.2 Oral Exposure
 

No studies were located regarding excretion in humans following oral
 

exposure to N-nitrosodi-n-propylamine.
 

Rats excreted metabolites but not unchanged N-nitrosodi-n-propylamine
 

in the urine following oral dosing with N-nitrosodi-n-propylamine (Blattmann
 

and Preussmann 1973, Suzuki and Okada 1981). The principal metabolite in the
 

Suzuki and Okada (1981) study, N-propyl-N-(2-carboxyethyl)nitrosamine,
 

amounted to approximately 5% of the administered dose. Additional
 

information regarding the extent or rate of excretion in either of the
 

studies was not reported.
 

2.6.4.3 Dermal Exposure
 

No studies were located regarding excretion in humans following dermal
 

exposure to N-nitrosodi-n-propylamine.
 

Excretion of unchanged N-nitrosodiethanolamine in the urine of rats has
 

been reported in several studies after cutaneous application of
 

N-nitrosodiethylamine (Airoldi et al. 1984; Lijinsky et al. 1981; Preussmann
 

et al. 1981).
 

2.7 INTERACTIONS WITH OTHER CHEMICALS
 

Ethanol was found to enhance the carcinogenicity of N-nitrosodinpropylamine. Mice that were treated with estimated 1 mg/kg doses of
 

N-nitrosodi-n-propylamine dissolved in 40% ethanol by gavage, twice a week
 

for 50 weeks, developed higher incidences of tumors than mice that were
 

similarly treated with the same dose of compound given in water (Griciute et
 

al. 1982). The most pronounced tumor enhancement was in the forestomach (51%
 

carcinomas vs. 10% in N-nitrosodi-n-propylamine/water group), but increases
 

in pulmonary adenomas and lymphomas also occurred.
 
28
 

2. HEALTH EFFECTS
 

2.8 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE
 

No populations with unusual susceptibility to health effects of
 

N-nitrosodi-n-propylamine have been identified. However, heavy consumers of
 

alcoholic beverages might be considered to be a susceptible population based
 

on a single report in which ethanol was shown to potentiate the
 

carcinogenicity of N-nitrosodi-n-propylamine in mice (Griciute et al. 1982).
 

2.9 ADEQUACY OF THE DATABASE
 

Section 104 (i) (5) of CERCLA, directs the Administrator of ATSDR (in
 

consultation with the Administrator of EPA and agencies and programs of the
 

Public Health Service) to assess whether adequate information on the health
 

effects of N-nitrosodi-n-propylamine 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.
 

2.9.1 Existing Information on Health Effects of N-Nitrosodi-n-propylamine
 

Information regarding health effects of N-nitrosodi-n-propylamine in
 

humans is not available. Health effects of N-nitrosodi-n-propylamine in
 

animals have been investigated only in oral exposure studies. As indicated
 

in Figure 2-3, animal oral data are available for lethality, acute systemic
 

effects, genotoxicity and cancer. These data indicate that the acute
 

toxicity of N-nitrosodi-n-propylamine is attributable to hepatic effects and
 

that intermediate duration exposure is life-shortening due to cancer.
 

2.9.2 Data Needs
 

Single Dose Exposure. Information on lethality (LD50) and severe
 

systemic effects in rats are available from one single dose oral study.
 

Similar information is available from single dose subcutaneous injection
 

studies with rats, mice and hamsters. Another oral study reported a nonlethal
 

effect (increased pentobarbital sleeping time) but none of the other
 

studies reported non-lethal doses or attempted to identify dose-response
 

data for other subtle systemic effects. Additional single dose oral studies
 

would provide better information on thresholds for lethality and systemic
 

toxicity as well as interspecies differences. Inhalation and dermal studies
 

with N-nitrosodi-n-propylamine have not been conducted; single dose studies
 

involving exposure by these routes would provide information on lethality,
 

systemic effects and skin and eye irritation.
 

30
 

2. HEALTH EFFECTS
 

Repeated Dose Exposure. Oral studies provide limited information on
 

the threshold for hepatotoxicity in mice. Several intermediate duration oral
 

studies with rats, one limited oral study with mice and injection studies
 

with rats, mice, hamsters and monkeys provide survival data but
 

noinformation on effects other than cancer. Additional short-term repeated
 

dose oral studies (e.g., 14-28 day studies) in various species could provide
 

additional information on systemic effects, particularly dose-response
 

characterization of hepatic/hemorrhagic effects. Repeated dose inhalation
 

studies are lacking and could provide useful information regarding lethality
 

and systemic effects.
 

Chronic Exposure and Carcinogenicity. Chronic oral toxicity data for
 

N-nitrosodi-n-propylamine are not available because treated animals have
 

died of cancer within one year of treatment. Animals treated with doses
 

lower than those used in the intermediate duration studies may survive
 

chronic exposure and provide information on nonneoplastic effects. With the
 

exception of a single study with mice, species other than rat have not been
 

tested for carcinogenicity by the oral route.
 

Genotoxicity. The genotoxicity of N-nitrosodi-n-propylamine is
 

documented but only one in vivo study used an environmentally relevant route
 

of exposure (oral), and only two studies (in vitro) evaluated human cells.
 

Additional studies, particularly types providing information on the
 

potential for heritable mutations in humans, would add to the data base on
 

genotoxicity.
 

Reproductive Toxicity. Information on the reproductive toxicity of
 

N-nitrosodi-n-propylamine is not available. 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
 

N-nitrosodi-n-propylamine in animals, which may be related to possible
 

reproductive effects in humans.
 

Developmental Toxicity. Some data on developmental toxicity are
 

available from single-dose subcutaneous injection studies with hamsters.
 

Developmental effects of N-nitrosodi-n-propylamine have not been
 

investigated in animals exposed by natural routes. Developmental studies in
 

animals by natural routes of exposure would provide information on possible
 

developmentally toxic effects, including transplacental carcinogenicity,
 

that might be relevant to humans. These studies should include postnatal
 

evaluations for neonatal mortality, as well as for tumor incidence in adult
 

animals.
 

Immunotoxicity. Histological examination of organs and tissues of the
 

immunological system from animals exposed in subchronic and chronic studies
 

would provide relevant information as immunotoxicity data for N-nitrosodi-npropylamine are not available. Specific immunotoxicity tests or a battery of
 

immunotoxicity tests would provide a better assessment of possible
 
31
 

2. HEALTH EFFECTS
 

immunotoxic effects. Sensitization tests in animals might provide
 

information on whether there is likely to be an allergic response to
 

N-nitrosodi-n-propylamine. Although the low molecular weight of
 

N-nitrosodi-n-propylamine would probably preclude activity as an antigen by
 

itself, it is possible that a higher molecular weight moiety resulting from
 

alkylation of proteins by N-nitrosodi-n-propylamine could produce an
 

allergic response.
 

Neurotoxicity. Information on the neurotoxicity of N-nitrosodi-n-propylamine
 

is not available. A battery of tests for neurotoxicity would
 

provide further information of neurotoxicity in animals, which then might be
 

related to possible neurotoxic effects in humans.
 

Epidemiological and Human Dosimetry Studies. Health effects of
 

N-nitrosodi-n-propylamine have not been described in humans. Effects in
 

treated animals, however, include hepatotoxicity and cancer. As discussed in
 

Chapter 5, the potential for environmental exposure to N-nitrosodi-n-propylamine
 

is very low, and segments of the general population with
 

potentially high or specific exposure to N-nitrosodi-n-propylamine have not
 

been identified. N-nitrosodi-n-propylamine has been detected in rubber
 

manufacturing facilities but concentrations are low and exposure is
 

complicated by the presence of other nitrosamines and additional chemicals.
 

If N-nitrosodi-n-propylamine or its metabolites in urine can be
 

correlated with exposure in humans, it may be possible to monitor humans for
 

exposure. If toxic effects of N-nitrosodi-n-propylamine are identified in
 

humans, it may then be possible to correlate urinary levels of N-nitrosodinpropylamine or one its metabolites with systemic effects.
 

Biomarkers of Disease. No disease states in humans produced by
 

exposure to N-nitrosodi-n-propylamine are known. If epidemiological studies
 

are conducted that correlate exposure with diseases, it may be possible to
 

identify subtle changes, such as altered blood chemistry indices, associated
 

with a particular disease state.
 

Disease Registries. Diseases in humans produced by exposure to
 

N-nitrosodi-n-propylamine are not known. If epidemiological studies
 

identify particular diseases produced by N-nitrosodi-n-propylamine, it may
 

be possible to determine the number of people affected and the factors
 

associated with identifying the disease in certain populations, such as,
 

those with exposure to high levels near hazardous waste sites.
 

Bioavailability from Environmental Media. No studies were located
 

regarding the bioavailability of N-nitrosodi-n-propylamine from
 

environmental media. The lack of data concerning levels in human tissues
 

and fluids does not necessarily indicate a lack of bioavailability since the
 

monitoring literature reports that N-nitrosodi-n-propylamine is present in
 

some foods, water, beverages and workroom air. It is, therefore, important
 

to determine if N-nitrosodi-n-propylamine can be absorbed by humans from
 
32
 

2. HEALTH EFFECTS
 

environmental samples. An understanding of the bioavailability of
 

N-nitrosodi-n-propylamine from environmental media may be obtained by
 

studying the biological fluids of individuals exposed to N-nitrosodi-n-propylamine
 

in the workplace or through the ingestion of N-nitrosodi-n-propylamine- containing
 

foods and beverages such as cheeses, cured meats, and
 

whiskey. Limited information is available regarding absorption parameters of
 

N-nitrosodi-n-propylamine in experimental animals. However, one could
 

assume, based on data obtained with other nitrosamines, that N-nitrosodi-npropylamine would be readily absorbed from the gastrointestinal tract if
 

ingested from contaminated soil.
 

Food Chain Bioaccumulation. No studies were available concerning food
 

chain bioaccumulation of N-nitrosodi-n-propylamine from environmental media.
 

The monitoring literature indicates that N-nitrosodi-n-propylamine has been
 

detected in samples of cooked fish and meat; however, occurrence of
 

N-nitrosodi-n-propylamine in these samples was not the result of
 

bioaccumulation, but was the result of formation resulting from preservation
 

and/or cooking. Various studies have also shown that N-nitrosamines, such
 

as N-nitrosodi-n-propylamine, form in the gastrointestinal tract during
 

digestion of foods containing secondary amines. Estimation techniques have
 

been used to determine that N-nitrosodi-n-propylamine would not
 

bioaccumulate in lipids of fish (see Section 5.3.1, Transport and
 

Partitioning). Based on this limited amount of information it is speculated
 

that human exposure to N-nitrosodi-n-propylamine through diet is not the
 

result of food chain bioaccumulation. Monitoring for the accumulation of
 

N-nitrosodi-n-propylamine in organisms from several trophic levels could be
 

used to support this conclusion.
 

Absorption, Distribution, Metabolism, Excretion. The general
 

metabolic pathways of N-nitrosodi-n-propylamine in animals have been
 

identified, but the relative contribution of the pathways in vivo,
 

particularly following exposure by natural routes, is inadequately
 

characterized. The identity of the alkylating agent(s) associated with
 

carcinogenesis is unclear. Information is available regarding absorption and
 

distribution of N-nitrosodi-n-propylamine. Evidence from other nitrosamines
 

indicates that a number of factors (e.g., species, route of exposure, dosing
 

schedule) appear to determine the organ specificity and the severity of the
 

effects induced by these compounds. Therefore, to fully characterize the
 

pharmacokinetics of N-nitrosodi-n-propylamine, studies of absorption,
 

distribution, metabolism, and excretion in animals following exposure by all
 

three routes are needed.
 

Comparative Toxicokinetics. The toxic and carcinogenic effects of
 

N-nitrosodi-n-propylamine are attributable to activity of metabolites but
 

no data are available to determine if there are quantitative differences in
 

metabolism among species. Information from other nitrosamines suggests that
 

there are species-characteristic tumors induced by nitrosamines. This seems
 

to be the reflection of differences in metabolic activities (and also repair
 

mechanisms) existing among animal species; therefore, caution must be
 
33
 

2. HEALTH EFFECTS
 

exercised when extrapolating possible effects in humans. Although toxicity
 

and carcinogenicity of N-nitrosodi-n-propylamine has been demonstrated in
 

rodents and monkeys, the animal species that serves as the best model for
 

extrapolating results to humans may be difficult to identify.
 

2.9.3 On-going Studies
 

No on-going studies of N-nitrosodi-n-propylamine were identified.
 

35
 

3. CHEMICAL AND PHYSICAL INFORMATION
 

3.1 CHEMICAL IDENTITY
 

Data pertaining to the chemical identity of N-nitrosodi-n-propylamine
 

are listed in Table 3-1.
 

3.2 PHYSICAL AND CHEMICAL PROPERTIES
 

The physical and chemical properties of N-nitrosodi-n-propylamine are
 

presented in Table 3-2.
 



39
 

4. PRODUCTION, IMPORT, USE, AND DISPOSAL
 

4.1 PRODUCTION
 

N-Nitrosodi-n-propylamine is not produced for commercial use in the
 

United States (HSDB 1988). The public portion of the EPA TSCA Production
 

File indicates that The Ames Laboratories in Milford, CT prepared <1000
 

pounds during 1977, and that Eastman-Kodak in Rochester, NY prepared none
 

during 1977, although it had the capability to do so and had prepared small
 

research quantities in the past (EPA 1977). N-nitrosodi-n-propylamine may
 

be produced as an impurity in the pesticides trifluralin, isopropalin, and
 

oryzalin (Cohen et al. 1978, Wotherspoon and Hindle 1988). N-Nitrosodinpropylamine can be prepared by the reaction of nitrous acid with di-npropylamine
 

(HSDB 1988).
 

4.2 IMPORT
 

No U.S. import data were found for N-nitrosodi-n-propylamine.
 

4.3 USE
 

N-Nitrosodi-n-propylamine is prepared in laboratory-scale quantities
 

solely for use as a research chemical (HSDB 1988).
 

4.4 DISPOSAL
 

Landfill disposal procedures should be confirmed by responsible
 

environmental engineers and regulatory officials (OHM-TADS 1988).
 

N-nitrosodi-n-propylamine may be destroyed by high temperature incineration
 

in an incinerator equipped with an NOx scrubber (OHM-TADS 1988). Chemical
 

treatment methods may also be used to destroy N-nitrosodi-n-propylamine.
 

These methods involve (a) denitrosation by reaction with 3% hydrobromic acid
 

in glacial acetic acid, (b) oxidation by reaction with potassium
 

permanganate-sulfuric acid, or (c) extraction of the nitrosamine from the
 

waste using dichloromethane and subsequent reaction with triethyloxonium
 

tetrafluoroborate (TOEF) (Castegnaro et al. 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 N-nitrosodi-n-propylamine 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
 
40
 

4. PRODUCTION, IMPORT, USE, AND DISPOSAL
 

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 are described in the literature and there does not
 

appear to be a need for further information in these topics. Lack of
 

information pertaining to the import of this compound is to be expected
 

since this compound has no commercial significance and it is doubtful that
 

research quantities would be imported rather than prepared by laboratories
 

in the United States. Data regarding the amount of N-nitrosodi-npropylamine
 

released to air, water, and soil are needed in order to
 

establish potential sources of exposure and levels of exposure from
 

environmental media. In particular, releases from hazardous waste landfills
 

and industries in which this compound is inadvertently formed should be
 

established in order to 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.
 

Information on the production and environmental sources of di-npropylamine,
 

tri-n-propylamine and the N-oxide of tri-n-propylamine is
 

needed due to the possible presence of N-nitrosodi-n-propylamine as a
 

contaminant, and the possibility of inadvertent formation of N-nitrosodinpropylamine from reaction to these compounds with ubiquitous nitrate. There
 

is also a need to investigate whether N-nitrosodi-n-propylamine occurs in
 

waste sites where these precursor compounds are disposed due to occurrences
 

as an impurity or in situ formation.
 
41
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

5.1 OVERVIEW
 

N-nitrosodi-n-propylamine is not an industrially or commercially
 

important chemical. It is produced in small, laboratory-scale quantities
 

for research purposes. It is also produced inadvertently during certain
 

manufacturing processes, occurring as an impurity in some dinitroaniline
 

pesticides and during manufacture of some extruded rubber products. Nitrosodin-propylamine could also be present in certain secondary amines
 

(di-n-propylamine, tri-n-propylamine and the N-oxide of tri-n-propylamine)
 

as an impurity or due to inadvertent nitrosation of these amines in
 

industrial processes other than those mentioned above. Low levels of Nitrosodi-npropylamine may be released to the environment from contaminated
 

products, from industrial sites of inadvertent production or from disposal
 

of wastes containing this chemical. N-nitrosodi-n-propylamine could also be
 

released to the environment from waste disposal sites where the precursor
 

secondary amines have been discharged, but the potential for human exposure
 

from nitrosation of precursors at waste sites has not been evaluated.
 

N-Nitrosodi-n-propylamine is not expected to be a persistent
 

environmental contaminant. If released to the ambient atmosphere, it
 

should be degraded by direct photolysis and/or reaction with sunlight-


produced hydroxyl radicals (overall half-life typically on the order of
 

several hours). In water with significant exposure to sunlight,
 

N-nitrosodi-n-propylamine would be subject to rapid photolysis (half-life
 

about 2-3 hours). On soil surfaces, N-nitrosodi-n-propylamine would be
 

subject to rapid removal by photolysis and volatilization. The
 

volatilization half-life of N-nitrosodi-n-propylamine from soil surfaces
 

after spray application of a dinitroaniline herbicide was found to be
 

between 2 to 6 hours. In subsurface soil and in water beyond the
 

penetration of sunlight, N-nitrosodi-n-propylamine would be susceptible to
 

biodegradation under both aerobic and anaerobic conditions. In subsurface
 

soil, the half-life of N-nitrosodi-n-propylamine has been found to range
 

from 14 to 40 days under aerobic conditions and 47 to 80 days under
 

anaerobic conditions. At this time, N-nitrosodi-n-propylamine has been
 

found in at least 1 of 1177 hazardous waste sites on the National Priorities
 

List (NPL) in the United States (VIEW Database 1989).
 

Limited data are available concerning exposure of the general
 

population to N-nitrosodi-n-propylamine. It appears that exposure possibly
 

results from formation in the upper gastrointestinal tract during digestion
 

of certain foods or drugs that contain secondary amines, ingestion of some
 

foods containing N-nitrosodi-n-propylamine (e.g., certain cheeses, cured
 

meats and fishes and alcoholic beverages), and inhalation of cigarette
 

smoke.
 
42
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

5.2 RELEASES TO THE ENVIRONMENT
 

5.2.1 Air
 

Occurrence of part per million levels of N-nitrosodi-n-propylamine in
 

various dinitroaniline herbicides may result in release of small amounts of
 

the nitrosamine into the atmosphere during and after application
 

(Cohen et al. 1978, Crosby 1979, Oliver 1981). Occurrence of N-nitrosodi-npropylamine in air in the production area of a rubber products plant where
 

common nitrosating agents (e.g., oxides of nitrogen) were used in
 

conjunction with rubber formulations containing secondary amine-based
 

compounds, suggests that plants using this type of production process are a
 

potential source of N-nitrosodi-n-propylamine emissions (NIOSH 1982).
 

5.2.2 Water
 

N-Nitrosamines may be formed inadvertently in situations in which
 

amines come in contact with nitrogen oxides, nitrous acid, nitrite salts,
 

nitro compounds or nitroso compounds (Fajen et al. 1980). This suggests
 

that under appropriate industrial conditions where di-n-propylamine is
 

present, N-nitrosodi-n-propylamine could be formed inadvertently and
 

released to the environment via effluent discharges. Limited monitoring
 

data which support this supposition indicate that N-nitrosodi-n-propylamine
 

has been released in wastewater from some textile plants and manufacturers
 

and/or users of amines. Small amounts of N-nitrosodi-n-propylamine may also
 

be released to surface waters either directly or indirectly (e.g., in
 

runoff) as a result of using dinitroaniline herbicides containing the
 

nitrosamine as an impurity.
 

5.2.3 Soil
 

Small amounts of N-nitrosodi-n-propylamine may be released to soil
 

during the application of some dinitroaniline herbicides. For example, a
 

typical 1 kg per hectare application of trifluralin containing 1 part per
 

million (ppm) N-nitrosodi-n-propylamine would result in application of 0.01
 

ng nitrosamine per square centimeter (Oliver 1979). Federal regulations
 

require trifluralin formulations to contain <l ppm N-nitrosodi-n-propylamine
 

(EPA 1979). Data pertaining specifically to the formation of N-nitrosodi-npropylamine in soil were not found in the literature; however, formation of
 

N-nitrosodimethylamine (NDMA) in soil containing dimethylamine and nitrate
 

or nitrite suggests that a similar mechanism may exist for N-nitrosodi-npropylamine (Mills and Alexander 1976, Oliver 1981, Pancholy 1976).
 

5.3 ENVIRONMENTAL FATE
 

5.3.1 Transport and Partitioning
 

Organics having a vapor pressure of >10-4 mm Hg should exist almost
 

entirely in the vapor phase in the atmosphere (Eisenreich et al. 1981). The
 
43
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

estimated vapor pressure of N-nitrosodi-n-propylamine [0.086 mm Hg at 25°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 = 1.36
 

(see Table 3-2)], a bioconcentration factor of 6 and an adsorption
 

coefficient (Koc) of 129 have been estimated for N-nitrosodi-n-propylamine
 

(Bysshe 1982; Hansch and Leo 1985; Lyman 1982). These values indicate that
 

bioaccumulation in aquatic organisms and adsorption to suspended solids and
 

sediments in water would not be important fate processes. The low Henry's
 

Law constant for N-nitrosodi-n-propylamine [1.47x10-6 atm-m3/mol (see Table
 

3-2)] suggests that volatilization would be a relatively insignificant fate
 

process in water.
 

If a herbicide containing N-nitrosodi-n-propylamine were applied to
 

warm, moist soil surfaces, most of the nitrosamine would be expected to
 

volatilize. The volatilization half-life from soil surfaces under field
 

conditions is estimated to be on the order of 2 to 6 hours (Berard and
 

Rainey 1979, Oliver 1979). If a herbicide containing N-nitrosodi-npropylamine were incorporated into soil (below the soil surface),
 

volatilization would be of minor importance (Oliver 1979). When
 

incorporated into soil, N-nitrosodi-n-propylamine is expected to be highly
 

mobile and it has the potential to leach into shallow groundwater supplies
 

(Saunders et al. 1979, Swann et al. 1983).
 

5.3.2 Transformation and Degradation
 

5.3.2.1 Air
 

In the atmosphere, N-nitrosodi-n-propylamine vapor would be rapidly
 

degraded by direct photolysis and/or reaction with photochemically-generated
 

hydroxyl radicals. Crosby et al. (1980) determined a pseudo-first order
 

half-life of 5 to 7 hours for photolysis of N-nitrosodi-n-propylamine vapor
 

in air exposed to sunlight. Although experimental conditions did not
 

closely simulate environmental conditions (the concentration of N-nitrosodi-npropylamine was relatively high), results of this study did indicate that
 

N-nitrosodi-n-propylamine is susceptible to rapid photolysis. The half-life
 

for the reaction of N-nitrosodi-n-propylamine vapor with photochemically-


generated hydroxyl radicals has been estimated to be about 16 hours in
 

typical ambient air. This value is based on a reaction rate constant of
 

2.42x10-11

 cm3/molecules-see at 25°C which was estimated using the method of
 

Atkinson (1987).
 

5.3.2.2 Water
 

N-nitrosodi-n-propylamine is not expected to undergo abiotic
 

degradation under the conditions found in natural waters (Callahan et al.
 

1979, Oliver et al. 1979, Saunders and Mosier 1980). The dominant removal
 

process for N-nitrosodi-n-propylamine in surface water is probably
 
44
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

photolysis. A study of low levels (0.65 ppm) of N-nitrosodi-n-propylamine
 

in lake water resulted in a photolytic half-life of about 2.5 hours. The
 

major photoproduct was found to be n-propylamine, but the formation of
 

di-n-propylamine was also observed (Saunders and Mosier 1980). Beyond the
 

reach of sunlight it appears that N-nitrosodi-n-propylamine would be subject
 

to slow microbial degradation in aerobic waters (Tabak et al. 1981, Tate and
 

Alexander 1975). Insufficient data are available to predict the rate at
 

which this would occur.
 

5.3.2.3 Soil
 

It appears that microbial degradation would be the dominant removal
 

process for the nitrosamine in subsurface soil under aerobic conditions.
 

Half-lives ranging from 14 to 40 days have been observed in aerobic
 

subsurface soil and from 47 to 80 days in anaerobic subsurface soil (Oliver
 

et al. 1979, Saunders et al. 1979, Tate and Alexander 1975). Initial losses
 

were due primarily to volatilization; however, biodegradation was the
 

dominant fate process. Available data on the degradation of the nitrosamine
 

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
 

There is no indication in the available literature that N-nitrosodi-npropylamine has been detected in ambient air in the United States. Air
 

samples collected above agricultural fields before, during, and after
 

application of the pesticide trifluralin contained no detectable levels of
 

N-nitrosodi-n-propylamine (detection limit 50 ng/m3) (Day et al. 1982, West
 

and Day 1979).
 

5.4.2 Water
 

No data were available regarding the monitoring and detection of
 

N-nitrosodi-n-propylamine in ambient surface water, groundwater, or drinking
 

water in the United States except at EPA National Priorities List (NPL)
 

hazardous waste sites. There were only a couple of monitoring studies
 

available pertaining to the occurrence N-nitrosodi-n-propylamine in treated
 

wastewater. In a survey of 32 U.S. textile plants, N-nitrosodi-n-propylamine
 

was detected at concentrations of 2-20 μg/L in 2 out of 32
 

samples of secondary effluent, while no detectable levels were found in
 

samples of raw wastewater from these same plants (Rawlings and Samfield
 

1979). This suggests that N-nitrosodi-n-propylamine was formed during the
 

treatment process. N-nitrosodi-n-propylamine has also been detected at a
 

maximum concentration of 1.2 μg/L in the final effluent from a German
 

chemical manufacturing plant involved in the manufacture and/or use of
 

amines (Hartmetz and Slemrova 1980). A survey of stormwater runoff samples
 

collected from 15 cities geographically located across the U.S. revealed
 
45
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

that N-nitrosodi-n-propylamine is not a typical contaminant of stormwater
 

runoff (Cole et al. 1984). Water samples collected from agricultural fields
 

immediately following application of the pesticide trifluralin contained no
 

detectable levels of N-nitrosodi-n-propylamine (detection limit 0.01-0.02
 

μg/L) (Ross et al. 1978, West and Day 1979).
 

5.4.3 Soil
 

Soil samples collected from agricultural fields immediately following
 

application of the pesticide trifluralin contained no detectable levels of
 

N-nitrosodi-n-propylamine (detection limit 0.2-l ng/g) (Ross et al. 1978,
 

West and Day 1979). It has been detected in at least 1 of 1177 NPL
 

hazardous waste sites (VIEW 1989).
 

5.4.4 Other Media
 

A number of studies have focused on the monitoring of volatile
 

N-nitrosamines in various foodstuffs, including cheese, cured meats, cooked
 

fish, and alcoholic beverages; however, N-nitrosodi-n-propylamine has rarely
 

been detected (Alliston et al. 1972, Gavinelli et al. 1988, Goff and Fine
 

1979, Gross and Newberne 1977, Huang et al. 1981, Sen et al. 1987). The
 

nitrosamines appear to have formed in these foods as the result of the
 

reaction of secondary amines with the preservative sodium nitrite (Gray and
 

Dugan 1974). N-nitrosodi-n-propylamine has been monitored in food at the
 

following levels: salt-preserved fish (steamed), 0.050 μg/kg; salt-preserved
 

fish (fried), 0.030 μg/kg; salt-preserved fish (raw), not detected; cheese,
 

5-30 μg /kg; apple brandy, up to 3.6 μg/kg; cognac, rum and whiskey, up to
 

0.2 μg /kg (Cerutti et al. 1975, Gross and Newberne 1977, Huang et al. 1981,
 

IARC 1978). A study of cigarette smoke condensate from European cigarettes
 

showed that N-nitrosodi-n-propylamine was found at a level equivalent to 1
 

ng per cigarette in smoke condensate from 1 out of 11 types of cigarettes,
 

while condensate from 10 out of 11 cigarettes had levels below the detection
 

level of 0.5 ng per cigarette (McCormick et al. 1973). Although a number of
 

volatile N-nitrosamines have been identified in children's pacifiers and
 

baby-bottle nipples, N-nitrosodi-n-propylamine was not among them (Billedeau
 

et al. 1986, Gavinelli et al. 1988, Westin et al. 1987). Crops and plants
 

harvested from fields treated with the pesticides trifluralin, benefin, or
 

oryzalin contained no detectable levels of N-nitrosodi-n-propylamine
 

(detection limit 0.2 ng/g) (Ross et al. 1978, West and Day 1979).
 

In the mid-to-late 1970s, N-nitrosodi-n-propylamine was detected in the
 

herbicide trifluralin at levels as high as 154 mg/L, oryzalin at <l mg/L and
 

isopropalin at 39-87 mg/L (Cohen et al. 1978, Ross et al. 1977). Subsequent
 

to these findings, the production process for trifluralin was modified;
 

current levels of the nitrosamine in technical trifluralin are <l mg/L (EPA
 

1979, Maybury and Grant 1983, Wotherspoon and Hindle 1988).
 
46
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE
 

The potential for inhalation of N-nitrosodi-n-propylamine during
 

application and soil incorporation of trifluralin containing N-nitrosodi-npropylamine is extremely low; N-nitrosodi-n-propylamine levels in breathing
 

zone air of field workers should be on the order of several parts per
 

trillion or less (Day et al. 1982). During 1982, NIOSH carried out a
 

monitoring study at a plant where workers were involved in the production of
 

extruded rubber parts for automobile part interiors. Samples of personal
 

breathing-zone air were found to contain N-nitrosodi-n-propylamine at
 

concentrations ranging from 1.3 to 3.3 μg/m3

 (241-611 ppt), with a mean
 

concentration of 2.3 μg/m3

 (430 ppt). Airborne nitrosamine levels at this
 

plant were consistent with those found by NIOSH in other rubber industries
 

where the same type of extruding process was used. Volatile nitrosamines,
 

such as N-nitrosodi-n-propylamine, are emitted from heated rubber after
 

formation by the reaction of common nitrosating agents (e.g., oxides of
 

nitrogen) with secondary amine-based compounds frequently used in rubber
 

formulations (NIOSH 1982). N-nitrosodi-n-propylamine has been detected in
 

soil samples from at least one NPL site, and workers at NPL sites or other
 

hazardous waste sites could potentially be exposed to this compound by
 

inhalation and dermal contact. It is not certain whether direct skin
 

contact with N-nitrosodi-n-propylamine would allow the chemical to enter the
 

body.
 

Based on limited data it appears that the general population may be
 

exposed to part per trillion levels of N-nitrosodi-n-propylamine in some
 

sodium nitrite-treated foods and certain alcoholic beverages. The general
 

population may be exposed to N-nitrosodi-n-propylamine as a result of its in
 

vivo formation during digestion in the upper gastrointestinal tract of
 

nitrite-containing and secondary amine-containing foods or drugs, especially
 

those containing di-n-propylamine (Groenen PJ et al. 1980, Magee et al.
 

1976; Sakai et al. 1984). One study pertaining to exposure to N-nitrosodi-npropylamine through inhalation of cigarette smoke suggests that there is a
 

possibility that low levels of this compound (on the order of 1 ng per
 

cigarette) may occur in cigarette smoke. There is no evidence of general
 

population exposure to N-nitrosodi-n-propylamine through ingestion of
 

contaminated drinking water or through dermal contact.
 

5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURE
 

Data are not available for determining those segments of the general
 

population with potentially high exposure.
 
47
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

5.7 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 N-nitrosodi-n-propylamine is available. Where adequate
 

information is not available, ATSDR, in cooperation with the National
 

Toxicology Program (NTP), is required to assure the initiation of a program
 

of research designed to determine these health effects (and techniques for
 

developing methods to determine such health effects). The following
 

discussion highlights the availability, or absence, of exposure and toxicity
 

information applicable to human health assessment. A statement of the
 

relevance of identified data needs is also included. In a separate effort,
 

ATSDR, in collaboration with NTP and EPA, will prioritize data needs across
 

chemicals that have been profiled.
 

5.7.1 Data Needs
 

Physical and Chemical Properties. Physical and chemical properties are
 

essential for estimating the partitioning of a chemical in the environment.
 

Many physical and chemical properties are available for N-nitrosodi-npropylamine, but most do not have extensive experimental descriptions
 

accompanying the data so that an evaluation of the accuracy of the data is
 

difficult to make. Specifically, measured water solubility, vapor pressure,
 

Koc) and Henry's Law constant would be helpful in removing any doubt
 

concerning the accuracy of the data as well as provide information
 

concerning the uncertainty of these types of data. These data form the
 

basis for much of the input requirements for environmental models that
 

predict the behavior of a chemical under specific conditions including
 

hazardous waste landfills.
 

Environmental Fate. Data are available to establish, in general, the
 

environmental fate of N-nitrosodi-n-propylamine. It has been predicted that
 

in surface waters, beyond the reach of sunlight, N-nitrosodi-n-propylamine
 

would be subject to slow microbial degradation; however, data are needed to
 

determine its degradation rate in unlit surface water under aerobic or
 

anaerobic conditions. Natural water grab sample biodegradation studies and
 

soil metabolism studies carried out in the dark under both aerobic and
 

anaerobic conditions would be useful in establishing the persistence of
 

N-nitrosodi-n-propylamine in the environment. The dominant removal
 

mechanisms for N-nitrosodi-n-propylamine in air are expected to be
 

photolysis and reaction with photochemically generated hydroxyl radicals;
 

however, no data are available concerning the reaction pathway and the
 

products of these types of reactions. These types of data would be useful
 

in establishing what happens to this compound when it is released to the
 

environment.
 

Exposure Levels in Environmental Media. Data are needed to relate the
 

levels of N-nitrosodi-n-propylamine found at hazardous waste landfills to
 
48
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

levels of exposure resulting from its occurrence at these sites. Studies in
 

which air monitoring (ambient and personal air) in the vicinity of
 

contaminated sites and water sampling (groundwater and drinking water) at
 

locations where contamination from the site is most likely to occur would be
 

useful in establishing the extent of human exposure from contaminated sites.
 

N-Nitrosodi-n-propylamine has been detected on a few occasions in some
 

sodium nitrite-treated foods and alcoholic beverages and ingestion appears
 

to be a potential route of exposure; although, recent comprehensive data
 

regarding the occurrence of N-nitrosodi-n-propylamine in foods were not
 

available. A comprehensive survey of those food items in which N-nitrosodin-propylamine may occur, including cheese, cured meats and fish, and
 

alcoholic beverages, would be useful in understanding the potential for
 

human exposure to N-nitrosodi-n-propylamine. Only one study was available
 

regarding the occurrence of N-nitrosodi-n-propylamine in cigarette smoke.
 

Results of this study do not provide strong conclusive evidence for
 

occurrence of measurable levels of N-nitrosodi-n-propylamine in cigarette
 

smoke and further studies need to be carried out before any conclusions can
 

be made.
 

Exposure Levels in Humans. Limited data were available regarding human
 

exposure to N-nitrosodi-n-propylamine. It appears that the general
 

population may be exposed to N-nitrosodi-n-propylamine through various
 

foodstuffs, some alcoholic beverages, and possibly cigarette smoke; however,
 

data are needed to predict with certainty the frequency and level of
 

exposure. A few broad-based monitoring studies of air, water, and typical
 

diets would be useful in deriving estimates of typical exposure levels in
 

humans.
 

Exposure Registries. An exposure registry currently is not available.
 

The development of a registry for exposures would provide a useful reference
 

tool in assessing exposure levels and frequency. In addition, a registry
 

would allow an assessment of the variations in exposure concentrations from,
 

for example, geography, season, regulatory actions, presence of hazardous
 

waste landfills, or manufacturing facilities. These assessment would, in
 

turn, provide a better understanding of the needs for some type of research
 

or data acquisition based on current exposure concentrations. Occupational
 

exposure to this compound is mainly through its inadvertent formation, so an
 

occupational exposure registry would be difficult to obtain.
 

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 N-nitrosodi-n-propylamine in environmental
 

media, environmental fate of N-nitrosodi-n-propylamine, or general
 

population or occupational exposure to N-nitrosodi-n-propylamine.
 
49
 

6. ANALYTICAL METHODS
 

6.1 BIOLOGICAL MATERIALS
 

Methods used for the analysis of N-nitrosodi-n-propylamine in
 

biological samples are shown in Table 6-l. The use of vacuum distillation
 

at low temperature (60-70°C) and trapping the distillate in dry ice/acetone
 

bath is the preferred method for the isolation of the compound from
 

biological matrices. Because of its selectivity and sensitivity, methods
 

using Thermal Energy Analyzer (TEA) detectors are selected for
 

quantification of this compound. In cases where analysis of multiple
 

pollutants are necessary, mass spectrometric detectors, in spite of their
 

lower sensitivity for nitrosodi-n-propylamine, may be favored over the TEA
 

detector.
 

6.2 ENVIRONMENTAL SAMPLES
 

Methods used for the analysis of N-nitrosodi-n-propylamine in
 

environmental samples are given in Table 6-2. Two pretreatment methods are
 

most suitable for the analysis of this compound in environmental samples.
 

When the matrix is not too complex, as in the case of drinking water,
 

surface water, groundwater and wastewater, solvent extraction is the
 

preferred method. With more complex matrices as soil and foodstuffs, vacuum
 

distillation and cold trapping is more suitable. The three methods
 

commonly used for the quantification of this compound in environmental
 

samples are mass spectrometry, nitrogen-phosphorus detectors (NPD) and TEA
 

in chemilumin escence mode. Each of these detectors has its own advantages
 

and disadvantages. When a high sensitivity is required, a method using a
 

TEA detector may be the method of choice. For multipollutant analysis in a
 

single sample, mass spectrometry may be more suitable. Nitrogen-phosphorus
 

detectors, on the other hand, may be more cost-effective and will provide
 

reasonable specificity and sensitivity for nitroso compounds. A Hall
 

detector in the pyrolytic mode may be preferable over NPD detectors because
 

it may require less sample clean-up (Rhoades et al. 1980).
 

6.3 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 N-nitrosodi-n-propylamine 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
 




54
 

6. ANALYTICAL METHODS
 

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 Compound and Metabolites in Biological
 

Materials. Analytical methods of suitable sensitivity and specificity are
 

available for the quantification of N-nitrosodi-n-propylamine in biological
 

samples. The study of the levels of the parent compound in human blood,
 

urine or other biological matrices can be useful in deriving a correlation
 

between the level of this compound found in the environment and those found
 

in human tissue and body fluid. Such correlation studies are not available
 

for N-nitrosodi-n-propylamine. 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, although metabolic
 

products of this compound from animal and in vitro studies have been
 

identified (see Subsection 2.6.3) and analytical methods for their
 

quantification are available.
 

Methods for Biomarkers of Exposure. No known biomarker for exposure to
 

N-nitrosodi-n-propylamine has been identified (see Subsection 2.9.2). 7­

Methyldeoxyguanosine and 06-methyldeoxyguanosine adducts are formed as a
 

result of exposure to methylated nitrosoamines. Immunological assays are
 

available for the determination of these adducts (Degan et al. 1988, Foiles
 

et al. 1988). If propyl-substituted deoxyguanosine adducts are formed from
 

N-nitrosodi-n-propylamine by similar reaction, it could be used as a
 

biomarker for N-nitrosodi-n-propylamine exposure. If such a biomarker were
 

available and a correlation were found between the level of the biomarker
 

and exposure, it could be used as a measure of exposure.
 

Methods for Determining Parent Compounds and Degradation Products in
 

Environmental Media. Analytical methods of suitable sensitivity and
 

specificity are available for the quantification of this compound in
 

environmental samples. The levels of this compound in different
 

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-nitrosodi-n-propylamine. 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. Although the products of biotic and abiotic processes
 

of this compound in the environment are adequately known, no systemic study
 

is available that measured the concentrations of its degradation products in
 

the environment. In instances where the product(s) of an environmental
 

reaction is more toxic than the parent compound, it is important that the
 

level of the degradation products in the environment be known. However, the
 
55
 

6. ANALYTICAL METHODS
 

degradation products of this compound in environmental media are less toxic
 

compounds, namely n-propylamine, di-n-propylamine etc. (see Subsection
 

5.3.2). The analytical methods for the determination of the levels of these
 

and other environmental degradation products of N-nitrosodi-n-propylamine
 

are available.
 

6.3.2 On-going Studies
 

No significant on-going studies are in progress for the development of
 

analytical methodologies for this compound in environmental or biological
 

samples.
 

57
 

7. REGULATIONS AND ADVISORIES
 

International, National and State regulations and guidelines pertinent
 

to human exposure to N-nitrosodi-n-propylamine are summarized in Table 7-l.
 

______________________ 

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Napalkov NP. 1969. Sequences of exposure to chemical carcinogen during
 

pregnancy. Bull Int Union Cancer 713-4.
 
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NIOSH (National Institute for Occupational Safety and Health). 1982.
 

Health Hazard Evaluation. Report No. HETA 82-156-1231. Seller-Globe
 

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*Nishie K, Norred WP, Wasserman A, et al. 1972. Phototoxicity and
 

differential hepatotoxicity as biological indicators of nitrosamine
 

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*OHM-TADS (Oil and Hazardous Materials-Technical Assistance Data System).
 

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Olah GA, Donovan DJ, Keefer LK. 1975. Carcinogen chemistry. I.
 

Reactions of protonated dialkylnitrosamines leading to alkylating and
 

aminoalkylating agents of potential metabolic significance. J Nat1 Cancer
 

Inst 54:465-472.
 

*Oliver JE. 1979. Volatilization of some herbicide-related nitrosamines
 

from soils. J Environ Qua1 8:596-601.
 

*Oliver JE. 1981. Pesticide-derived nitrosamines. Occurrence and
 

environmental fate. Agric Symposium series 174:349-362.
 

*Oliver JE, Kearney PC, Kontson A. 1979. Degradation of herbiciderelated
 

nitrosamines in aerobic soils. J Agric Food Chem 27:887-891.
 

*Pancholy SK. 1976. Gas chromatographic analysis of carcinogenic
 

nitrosamines in soil. Soil Biol Biochem 8:75-76.
 

*Park KK, Archer MC. 1978. Microsomal metabolism of N-nitrosodi-npropylamine:
 

formation of products resulting from alpha- and betaoxidation.
 

Chem Biol Interact 22:83-90.
 

*Park KK, Archer MC, Wishnok JS. 1980. Alkylation of nucleic acids by
 

N-nitrosodi-n-propylamine: Evidence that carbonium ions are not
 

significantly involved. Chem Biol Interact 29:139-144.
 

*Park KK, Wishnok JS, Archer MC. 1977. Mechanism of alkylation by
 

N-nitroso compounds: Detection of rearranged alcohol in the microsomal
 

metabolism of N-nitrosodi-n-propylamine and base-catalyzed decomposition of
 

N-n-propyl-n-nitrosourea. Chem-Biol Interact 18:349-354.
 

*Parodi S, Taningher M, Santi L: 1982. Alkaline elution in vivo:
 

Fluorometric analysis in rats. Quantitative predictivity of
 

carcinogenicity, .as compared with other short-term tests. In: Indicators
 

of genotoxic exposure. Banbury Report 13:137-155.
 

*Parodi S, Zunino A, Ottaggio L, et al. 1983. Quantitative correlation
 

between carcinogenicity and sister chromatid exchange induction in vivo for
 

a group of 11 N- nitroso derivatives. J Toxicol Environ Health 11:337-346.
 
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*Pedal I, Besserer K, Goertitler K, et al. 1982. Fatal nitrosamine
 

poisoning. Arch. Toxicol. 50:101-112.
 

*Phillipson CE, Ioannides C. 1985. Metabolic activation of nitrosamines to
 

mutagens by various animal species including man. Biochem Pharmacol
 

34:441-442.
 

*Pour P, Cardesa A, Althoff J, et al. 1974. Tumorigenesis in the nasal
 

olfactory region of Syrian golden hamsters as a result of
 

dipropylnitrosamine and related compounds. Cancer Res 34:16-26.
 

*Pour P, Krueger FW, Cardesa A, et al. 1973, Carcinogenic effect of
 

dipropylnitrosamine in Syrian golden hamsters. J Nat Cancer Inst 51:1019­

1027.
 

*Preussmann R, Wuertele G, Eisenbrand G, et al. 1978. Urinary excretion of
 

N-nitrosodiethanolamine administered orally to rats. Cancer Lett 4:207­

209.
 

*Preussmann R, Spiegelhalder B, Eisenbrand G, et al. 1981. Urinary
 

excretion of N-nitrosodiethanolamine in rats following its epicutaneous and
 

intratracheal administration and its formation in vivo following skin
 

application of diethanolamine. Cancer Lett 13:227-232.
 

*Probst GS, McMahon RE, Hill LE, et al. 1981. Chemically-induced
 

unscheduled DNA synthesis in primary rat hepatocyte cultures: A comparison
 

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*Rao TK, Allen BE, Winton W, et al. 1981. Nitrosamine-induced mutagenesis
 

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aliphatic nitrosamines. Mutat Res 89:209-215.
 

*Rao TK, Epler JL, Lijinsky W. 1982. Structure activity studies with
 

N-nitrosamines using Salmonella Typhimurium and Escherichia coli. IARC Sci
 

Pub1 41:543-551.
 

*Rao TK, Young JA, Lijinsky W, et al. 1979. Mutagenicity of aliphatic
 

nitrosamines in Salmonella Typhimurium. Mutat Res 66:1-7.
 

*Rawlings GD, Samfield M. 1979. Toxicity of Secondary Effluents from
 

Textile Plants. In: Proc Symp Process Meas Environ Assess 1978. Off Res
 

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*Reznik G, Mohr U, Krueger FW. 1975. Carcinogenic effects of
 

dipropylnitrosamine, beta-hydroxypropylpropylnitrosamine, and
 

methylpropylnitrosamine on Sprague-Dawley rats. J Nat1 Cancer Inst 54:937­

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of wastewaters for N-nitrosamines using various detectors. IARC Sci Pub1
 

31:377-387.
 

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di alkyl nitrosamines in jejunal and ileal segments of rats. NaunynSchmiedeberg's Arch Pharmacol 325:R4.
 

*Ross RD, Morrison J, Roundbehler DP, et al. 1977. N-Nitroso compound
 

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*Ross R, Morrison J, Fine DH. 1978, Assessment of dipropylnitrosamine
 

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*Wotherspoon, D, Hindle R. 1988. Determination of N-nitrosodipropylamine
 

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*Yahagi T, Nagao M, Seino Y, et al. 1977. Mutagenicities of N-nitrosamines
 

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*Yamazaki H, Mori Y, Toyoshi K, et al. 1985. Genotoxicity of carcinogenic
 

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75
 

9. GLOSSARY
 

Acute Exposure -- Exposure to a chemical for a duration of 14 days or less,
 

as specified in the Toxicological Profiles.
 

Adsorption Coefficient (Koc) -- The ratio of the amount of a chemical
 

adsorbed per unit weight of organic carbon in the soil or sediment to the
 

concentration of the chemical in solution at equilibrium.
 

Adsorption Ratio (Kd) -- The amount of a chemical adsorbed by a sediment or
 

soil (i.e., the solid phase) divided by the amount of chemical in the
 

solution phase, which is in equilibrium with the solid phase, at a fixed
 

solid/solution ratio. It is generally expressed in micrograms of chemical
 

sorbed per gram of soil or sediment.
 

Bioconcentration Factor (BCF) -- The quotient of the concentration of a
 

chemical in aquatic organisms at a specific time or during a discrete time
 

period of exposure divided by the concentration in the surrounding water at
 

the same time or during the same time period.
 

Cancer Effect Level (CEL) -- The lowest dose of chemical in a study or
 

group of studies which produces significant increases in incidence of
 

cancer (or tumors) between the exposed 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.
 
76
 

9. GLOSSARY
 

Immediately Dangerous to Life or Health (IDLH) -- The maximum environmental
 

concentration of a contaminant from which one could escape within 30 min
 

without any escape-impairing symptoms or irreversible health effects.
 

Intermediate Exposure -- Exposure to a chemical for a duration of 15-364
 

days, as specified in the Toxicological Profiles,
 

Immunologic Toxicity -- The occurrence of adverse effects on the immune
 

system that may result from exposure to environmental agents such as
 

chemicals.
 

In vitro -- Isolated from the living organism and artificially maintained,
 

as in a test tube.
 

In vivo -- Occurring within the living organism.
 

Lethal Concentration(L0) (LCLo) -- 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(L0) (LDLO) -- The lowest dose of a chemical introduced by a
 

route other than inhalation that is expected to have caused death in humans
 

or animals.
 

Lethal Dose(50) (LD50) -- The dose of a chemical which has been calculated
 

to cause death in 50% of a defined experimental animal population.
 

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.
 
77
 

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 (Kow) -- The equilibrium ratio of the
 

concentrations of a chemical in n-octanol and water, in dilute solution.
 

Permissible Exposure Limit (PEL) -- An allowable exposure level in
 

workplace air averaged over an 8-h shift.
 

q1* - - The upper-bound estimate of the low-dose slope of the dose-response
 

curve as determined by the multistage procedure. The ql* 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.
 
78
 

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.
 
 

79
 

APPENDIX: PEER REVIEW
 

A peer review panel was assembled for N-nitrosodi-n-propylamine. The
 

panel consisted of the following members: Dr. Edmond LaVoie, College of
 

Pharmacy, Rutgers University; Dr. Raymond Smith, Instructor, Department of
 

Pathology and Microbiology, University of Nebraska Medical Center; Dr.
 

Frank Lu, Private Consultant, Miami, FL; and Dr. Vincent Garry, Laboratory
 

of Medicine and Pathology, University of Minnesota. These experts
 

collectively have knowledge of N-nitrosodi-n-propylamine'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 1991-535-152