United States
Environmental Protection
Agency
FINAL DRAFT
ECA0-CIN-P180
July, 1986
srEPA Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS
PROFILE FOR NITROSAMINES.
Prepared for
OFFICE OF SOLID WASTE AND
EMERGENCY RESPONSE
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati, OH 45268
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DISCLAIMER
This report Is an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
The first draft of this document was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112. This document was subsequently
reviewed and revised by ECAO-ClnclnnaU and the Carcinogen Assessment Group,
the Exposure Assessment Group and the Reproductive Effects Assessment Group
of the Office of Health and Environmental Assessment. This document was
prepared for the Office of Solid Waste (OSW) to support listings under the
Resource Conservation and Recovery Act {Section 3001). The Reportable
Quantity (RQ) chapter of this document was prepared under the Comprehensive
Environmental Response Compensation and Liability Act [Section 101(2)]. The
literature searched for this document and the dates searched are Included 1n
"Appendix: Literature Searched." Literature search material Is current up
to November, 1985. Final draft document dates (front cover) reflect the
date the document Is sent to the program office (OSW).
111
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EXECUTIVE SUMMARY
Nltrosamlnes consist of a nltroso group (O^N-) and an amine group (-N-),
which are attached to an alkyl or aryl group. N- and p-n1trosod1phenylam1ne
appear to be the only two nltrosamlnes that are produced and used In signif-
icant amounts. According to the 1977 TSCA Inventory (U.S. EPA, 1977), pro-
duction for each chemical ranged from <1000-1,000,000 pounds. Nltrosamlnes
are used primarily 1n the rubber Industry {Hawley, 1981; IARC, 1982; Taylor
and Son, 1982; Wlndholz et al., 1983).
The primary fate mechanism for nltrosamlnes In water Is probably photo-
degradation. N-N1trosod1methylam1ne, N-n1trosod1ethylam1ne and N-n1trosod1-
n-butylam1ne photodegraded rapidly In an aquatic environment (Polo and Chow,
1976; Zhang et al., 1983; Saunders and Mosler, 1980; Burns and AlHston,
1971). Results of aqueous blodegradatlon studies on the nltrosamlnes In
batch and continuous culture, using Inocula from soil, lake, water, sewage
and pure cultures are inconsistent. Volatilization from water will probably
not be significant except possibly for N-n1trosod1phenylamlne (Henry's Law
constant ^ 6.4x10"« atm*m3/mol). A BCF of 100 has been measured for
N-nltrosodlmethylamlne In sludge (Patterson and Kodukala, 1981) and 217 for
N-n1trosod1phenylam1ne In blueglll sunflsh (Barrows et al., 1980a).
In the atmosphere, N-n1trosod1methylam1ne, N-n1trosod1ethylamlne and
N-n1trosod1-n-propylam1ne are rapidly removed with half-lives or residence
times of <1 day (Cupltt, 1980; Hanst et al., 1977; Tuazone et al., 1984;
Grosjean et al., 1978; Crosby et al., 1980).
N-N1trosod1methylam1ne may form 1n soil (Greene et al., 1981; Mills and
Alexander, 1976; Pancholy, 1978), and may also leach readily through soil
(Dean-Raymond and Alexander, 1976; Greene et al., 1981). Since no Informa-
tion was located regarding soil mobility of the other nltrosamlnes, Kqc
1 v
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values were estimated, and ranged from 3 for N-n1trosod1ethanolam1ne (highly
mobile) to 1905 for p-n1trosodlphenylam1ne (Immobile). N-NHrosodlmethyl-
amlne, N-n1trosod1ethy1am1ne and N-n1trosod1-n-propylam1ne were found to
volatilize rapidly from soil (Oliver, 1979). Oliver et al. (1979) found
that under laboratory conditions N-n1trosod1methylam1ne, N-n1trosod1ethyl-
amlne and N-n1trosod1-n-propylam1ne had half-Hves of ~3 weeks In aerobic
soils. The primary removal processes in this study were volatilization and
blodegradatlon.
Nltrosamlnes have been found In wastewaters, wastewater effluents, salt-
water, drinking water and deionlzed laboratory water. N-N1trosod1methyl-
amine, N-n1trosod1ethylam1ne, N-n1trosod1-n-propylamlne and N-n1trosod1-n-
butylamlne have been found In foods. N1trosam1nes have been detected In the
air at tire manufacturing plants, chemical companies, surfactant producers,
foundries, fish processors and tanneries. N1trosam1nes have also been
detected In the Interior of new cars (Fine et al., 1980; Rounbehler et al.,
1980b), 1n cigarette smoke (Brunnemann et al., 1983; McCormlck et al.,
1973), 1n dlesel crankcase emissions (Goff et al., 1980) and In exhaust from
catalyst equipped cars (Smith, 1980).
From the available data, It appears that most dermal exposure to nltros-
amlnes occurs from cosmetics, toiletries and cutting fluids; the most common
nltrosamlne found In these products appears to be N-n1trosod1ethanolam1ne.
Gastrointestinal absorption of N-n1trosod1methylam1ne and N-n1trosod1-
ethanolamlne by rats 1s rapid and extensive (Diaz Gomez et al., 1977; Head-
ing et al., 1974; Ishlwata et al., 1977; Kun1sak1 et al., 1978; Preussmann
et al., 1978; LlJInsky et al., 1981a). Specific Information regarding the
other N-n1trosam1nes 1s not available, but gastrointestinal absorption of
Nitrosomethyl ethyl amine, N-n1trosod1 ethyl amine, N-n1trosod1-n-propyl amine,
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N-n1trosod1-n-butylam1ne, N-nltrosomethylvlnylamlne and N-nUrosodlphenyl-
amlne by rodents and other species 1s Indicated by the occurrence of
systemic effects In oral carcinogenicity studies with these compounds.
N-N1trosod1ethanolam1ne 1s also moderately to extensively absorbed by rats
following Intratracheal Instillation (Preussmann et al., 1981) and by rats
(Lljlnsky et al., 1981a; Preussmann et al., 1981; Lethco et al., 1982;
Alroldl et al., 1984a) and monkeys (Harzulll et al., 1981) following dermal
application. Limited evidence Indicates that N-n1trosod1ethanolam1ne can be
absorbed by human skin (Edwards et al., 1979; Bronaugh et al., 1979, 1981).
N-N1trosod1methylam1ne, N-n1trosod1-n-butylam1ne and N-nltrosodlethanol-
amine are rapidly and uniformly distributed to all tissues of rats or mice
following Intravenous Injection or oral administration (Johansson and
Tjalve, 1978; Magee, 1956; Kun1sak1 et al., 1978; Wlshnok et al., 1978;
Brlttebo and Tjalve, 1982; Lethco et al., 1982). After oral administration
of N-n1trosod1ethanolam1ne, the highest concentrations occurred 1n the liver
and kidneys, with tissue levels 1n rats peaking at 8 hours (Lethco et al.,
1982). Transplacental distribution of unmetabollzed N-nltrosodlmethylamlne,
N-nHrosodlethylamlne, N-nltrosodl-n-propylamlne and N-nltrosodl-n-butyl-
amlne has been demonstrated In hamsters and mice following Injection
(Althoff et al., 1976, 1977; Johansson-Brlttebo and Tjalve, 1979; Brlttebo
et al., 1981). Transplacental distribution of N-n1trosod1methylam1ne,
N-n1trosod1ethylam1ne and N-n1trosod1-n-butylam1ne and their metabolites 1n
hamsters, mice or rats 1s also Indicated by transplacental carcinogenicity
of these nltrosamlnes following Injection or oral administration (IARC,
1978; Althoff and Grandjean, 1979; Reznlk-Schuller and Tomaszewskl, 1980).
N-N1trosod1methylam1ne, N-nltrosomethylethylamlne and N-n1trosod1ethyl-
amlne appear to be metabolized by a common pathway In which the a-carbon
1s hydroxylated (Montesano and Bartsch, 1976; Schut and Castonguay, 1984).
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With the longer chain N-n1trosod1alkylam1nes, B-ox1dat1on or «-l-oxidation
may occur In addition to a-C-hydroxylat1on. Oxidative monodealkylatlon by
microsomal enzymes subsequently occurs, and the aldehyde that Is generated
Is further oxidized to yield CO^. Generally, the monoalkylnltrosamlne
decomposes to generate alkylating Intermediates. N-N1trosod1ethanolam1ne 1s
primarily eliminated as unmetabollzed compound In the urine. Limited
evidence Indicates that N-n1trosod1phenylam1ne may be denltrosated to nitric
oxide and dlphenylamlne, with subsequent conversion of the nitric oxide Into
nitrite and nitrate, or reduction to the corresponding hydrazine derivative
(Appel et al., 1984; Tatsuml et al.t 1983).
N-N1trosod1methylam1ne, N-n1trosod1ethylam1ne and N-nltrosodlethanol-
amlne appear to be rapidly eliminated (essentially within 24 hours) through
the urine as unchanged compound or metabolites and through the lungs as
C02 following Injection, oral or Intratracheal administration (Magee,
1956; Magee et al., 1973; Preussmann et al., 1978, 1981; L1J1nsky et al.,
1981a; Lethco et al., 1982).
Numerous chronic and subchronlc oral studies primarily conducted with
rodents have unequivocally demonstrated the carcinogenicity of N-n1trosod1-
methylamlne, N-n1trosod1ethylam1ne, N-n1trosod1-n-propylam1ne and N-nltroso-
d1-n-butylam1ne (1ARC, 1978; Druckrey et al., 1967; Aral et al., 1979;
L1JInsky and Reuber, 1981, 1983, 1984a; Hjlnsky et al., 1981b; L1j1nsky and
Taylor, 1978, 1979; Peto et al., 1984). Numerous additional studies have
demonstrated that these d1-n-alkyln1trosam1nes are carcinogenic following
more limited oral exposures as well as by Injection {subcutaneous, Intra-
peritoneal or Intravenous) 1n all species that have been tested. Generally,
high Incidences of malignant and benign tumors occur primarily 1n the liver,
bladder, esophagus, forestomach or nasal cavity depending upon chemical,
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species and routes. The carcinogenicity of N-n1trosomethylethylamlne,
N-nHrosomethylv1nylam1ne and N-n1trosod1ethanolamlne have been less exten-
sively Investigated In chronic and subchronlc oral studies with rats and
mice, but Information Indicating noncarclnogenlcUy has not been reported
(Druckrey et al., 1967; HJlnsky and Reuber, 1980, 1981, 1984b; lljlnsky et
a 1., 1980, 1982, 1983; LlJInsky and Kovatch, 1985; Preussmann et al., 1982).
These nltrosamlnes primarily Induced tumors 1n the liver and nasal cavities.
Chronic dietary administration of N-n1trosod1phenylam1ne Induced bladder
carcinomas 1n rats but not mice (NCI, 1979), but carcinogenicity was not
demonstrated In less adequate drinking water or gavage studies (Druckrey et
al., 1967; Argus and Hoch-L1getl, 1961; BRL, 1968) or by weekly Intraperi-
toneal Injections (Boyland et al., 1968). The carcinogenicity of p-n1troso-
dlphenyTamlne does not appear to have been assessed.
Mutagenicity, clastogenlclty and DNA-damaglng ability of N-n1trosod1-
methylamlne, N-n1trosod1ethylam1ne, N-n1trosod1-n-propylam1ne and N-nltroso-
d1 -n-butylam1ne have been demonstrated In numerous bacterial and mammalian
cell assays in vitro and In several Jh} vivo mammalian systems. The other
d1-n-alkyln1trosamlnes have been evaluated In several studies and appear to
have similar effects; N-nltrosomethylethylamlne was mutagenic in S. typhi -
murium (Kerklaan et al., 1983; PhllUpson and Ioannldes, 1985) and Chinese
hamster V79 cells (Jones and Huberman, 1980), N-n1trosomethylv1nylam1ne
Induces sex-1Inked recessive lethal mutations In D. melanoqaster (Pasternak,
1964) and N-n1trosod1ethanolam1ne was mutagenic 1n S. typhlmurlum (Hesbert
et al., 1979; McMahon et al., 1979) and E. coli (HcMahon et al., 1979).
N-Nltrosod1phenylam1ne Is nonactlve In numerous bacterial, mammalian cell
and Intact animal assays, but uncorroborated evidence of reversion and
mitotic aneuploldy In yeast (de Serres and Hoffmann, 1981), DNA damage In
v111
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yeast (de Serres and Hoffmann, 1981) and rat hepatocytes in vitro (Althaus
et al., 1982; S1na et al., 1983) have been reported. N-Nltrosodlphenylamlne
also transformed Syrian hamster embryo cells (Plenta and Kawalek, 1981) BHK
cells, (Daniel and Oehnel, 1981) and rat embryo cells Infected with Rauscher
murine leukemia virus (Dunkel et al., 1981). In the only study of p-n1tro-
sodlphenylamlne located, administration to 0. melanoqaster did not produce
sex-linked recessive lethal mutations.
N-N1trosod1methylam1ne produced fetotoxlc effects (stillborns and neo-
natal deaths) when administered orally to mice throughout gestation (Ander-
son et al., 1978) or to rats on single days during gestation (Alexandrov,
1967; N1sh1e, 1983). Single oral doses of N-nltrosodlethylamlne or N-nltro-
sodl-n-butylamlne during gestation also were fetotoxlc 1n rats (Alexandrov,
1973). Teratogenicity was not observed In any of the above studies.
Similar effects (fetotoxlclty without teratogenicity) reportedly resulted
from single Intraperitoneal or Intravenous Injections of N-n1trosod1methyl-
amlne In rats, single Intraperitoneal Injection of N-n1trosod1ethylam1ne or
N-n1trosod1-n-butylamlne 1n rats, or Intraplacental Injection of N-n1troso-
dlmethylamlne or N-n1trosod1ethylam1ne 1n rats (Alexandrov, 1973, 1974).
Single Intraperitoneal doses of N-n1trosod1methylam1ne caused reversible
mild necrotic alterations In the testes of rats (Hard and Butler, 1970).
Limited Information 1s available regarding chronic or subchronlc toxic
effects of the nltrosamlnes because Interest 1n these compounds Is over-
whelmingly related to their carcinogenicity. Toxic effects Included cysts
and hypertrophled parenchymal cells In the livers of rats treated with
N-nltrosodlmethylamlne In the drinking water for up to 120 weeks (Terraclnl
et al., 1967), Infarcts, thromboses and abscesses In the livers of mice
treated with N-n1trosod1methylam1ne 1n the drinking water for 306 days
1 x
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(life) (Clapp et al., 1968), and microabscesses, cyst-like structures and
hypertrophled parenchymal cells 1n the livers of mice treated with N-n1tro-
sodlethylamlne 1n the drinking water for 22 weeks (Clapp and Craig, 1967).
Administration of N-n1trosod1phenylam1ne 1n the diet for life Induced
corneal opacity In rats of both sexes and submucosal Inflammation and
epithelial hyperplasia 1n the bladders of female mice (NCI, 1979).
Case reports of humans that Ingested N-n1trosod1methylam1ne Indicate
that exposure produced acute effects (Hver damage and diffuse Internal
bleeding) similar to those observed 1n animals (Freund, 1937; Barnes and
Hagee, 1954; Fussgaenger and Dltschunert, 1980; Cooper and Klmbrough, 1980;
Pedal et al., 1982). The primary effects were hemorrhagic/necrotic altera-
tions In the liver that subsequently developed Into cirrhosis. Carcinogen-
icity of the subject nltrosamlnes In humans has not been reported.
In general, acute toxicity of different nltrosamlnes to aquatic organ-
Isms tends to Increase as number of carbon atoms Increase (Bresch and Spiel-
hoff, 1974); however, N-n1trosod1methylam1ne and N-n1trosod1ethylam1ne, the
two nltrosamlnes for which there 1s the most Information, appear to be
roughly equivalent 1n acute toxicity. Of the nltrosamlnes for which there
are data available, the most acutely toxic 1s N-n1trosod1phenylam1ne, which
has a 96-hour LC,.p of 5.85 mg/l for bluegllls (Buccafusco et al., 1981;
U.S. EPA, 1978).
Nltrosamlnes (N-n1trosod1methylam1ne, N-n1trosod1ethylam1ne and N-n1tro-
sodl-n-butylam1ne) have been found to cause cancer 1n fish and amphibians.
As Is the case with mammals, metabolic activation of nltrosamlnes by micro-
somal enzymes 1s apparently necessary for carcinogenicity. Factors that
stimulated enzyme activity (Inducers, high temperature) generally enhanced
nltrosamlne carcinogenicity (Kyono, 1978; Kyono and Egaml, 1977; Shelton et
al., 1984).
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Noncarclnogenlc effects of long-term sublethal exposures were also
reported. The most sensitive fish species was the guppy, which experienced
hlstopathologlcal effects In liver tissue after three 24-hour exposures to
0.125 mg/8, N-n1trosod1ethylam1ne (Parland and Baumann, 1985). The most
sensitive Invertebrate species tested was the mussel, M. edulls. which
experienced adverse histological effects when exposed to 0.25-1.0 mg/8.
N-n1trosod1methylam1ne or N-n1trosod1ethylam1ne for 4-9 weeks (Aubert et
al.( 1982; Petit et al., 1984). Because they are rapidly degraded, nltros-
amlnes do not bloaccumulate or bloconcentrate to high tissue concentrations
In aquatic organisms {Jouany et al., 1985).
Human carcinogenic potency factors (Bu) were determined for N-n1troso-
dimethylamlne, N-nttrosomethylethylam1ne, N-n1trosodlethylamlne, N-nltroso-
d1-n-propylamine and N-n1trosod1-n-butylam1ne using dose-response relation-
ships (Druckrey et al., 1967; Druckrey, 1967; Peto et al., 1984) derived
from chronic drinking water studies with rats and the one-hit model. Human
carcinogenic potency factors (q-j*) for N-n1trosod1ethanolam1ne and
N-nltrosod1phenylamlne were determined from chronic drinking water studies
with rats (L1J1nsky and Kovatch, 1985; NCI, 1979) using the multistage
linear model. A potency factor could not be calculated for N-n1trosomethyl-
vlnylamlne because for quantitative purposes, the available animal data
(Druckrey et al., 1967; Druckrey, 1967) are Insufficient to develop a
potency (risk) estimate. Carcinogenicity data for p-n1trosod1phenylamlne
were not located In the available literature as cited In the Appendix. The
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human carcinogenic potency factors and water concentrations associated with
10"5, 10~* and 10~7 risk levels calculated for the above N-nltros-
amlnes are listed below:
Risk
Levels (mq/l)
Chemical
Bh or q-|*
(mg/kg/dayT1
10"5
10"*
10"'
N-n1trosod1methylamine
51
6.86x10"®
6.86xl0~7
6.86X10"8
N-nltrosomethylethylamlne
21.75
1.61xl0"s
1.61x10"6
1.61x10"'
N-n1trosod1ethylam1ne
150
2.33x10"®
2.33x10"'
2.33x10""
N-nltrosodl-n-propylamine
7.02
4.99xl0~s
4.99x10"®
4.99x10"'
N-n1trosod1-n-butylamine
1.19
2.94x10 ~
2.94xl0"5
2.94x10®
N-nitrosomethyl vinyl amine
ND
ND
ND
ND
N-n1trosod1ethanolam1ne
2.81
1.25x10"^
1.25x10"s
1.25x10"®
N-nUrosodlphenylamlne
4.92xl0~3
7.11x10"*
7.11x10"®
7.11x10*
p-N1trosod1phenyl amine
ND
ND
ND
ND
ND = Not derived
RQ rankings based on chronic toxicity were calculated for N-n1trosod1-
methylamlne, N-n1trosod1ethylam1ne and N-n1trosod1phenylam1ne. An RQ of 10
for N-nltrosodlmethylamlne Is based on evidence of fetotoxiclty 1n rats
(Anderson et al., 1978). Histological alterations In the livers of mice
(Clapp and Craig, 1967) were used as the basis for an RQ of 100 for N-n1tro-
sodlethylamlne. Corneal opacity 1n rats (NCI, 1979) 1s the basis for an RQ
of 1000 for N-n1trosod1phenylamtne.
The data used to calculate the human carcinogenic potency factors were
also used to calculate potency factors (F = 1/E0^q) for the same N-n1tros-
amlnes. The potency factors were used with the degree of evidence of
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carcinogenicity based on EPA criteria to rank the chemicals according to
hazard. The CERCLA rankings for the N-n1trosam1nes are summarized as
follows:
N1trosam1ne
F-Factor
(mq/kq/dav)"1
Potency
Group
EPA
Group
CERCLA
Hazard
Ranking
N-N1trosod1methylam1ne
510
1
B2
HIGH
N-N1trosomethylethylam1ne
217.5
1
B2
HIGH
N-N1trosod1ethylam1ne
1485
1
B2
HIGH
N-N1trosod1-n-propylamine
70.2
2
B2
MEDIUM
N-N1trosod1-n-butylam1ne
11.9
2
B2
MEDIUM
N-N1trosomethylv1nylam1ne*
not calculated
B2
HIGH
N-N1trosod1ethanolamine
10.6
2
B2
MEDIUM
N-N1trosod1phenyl amine
0.12
4
B2
LOW
p-N1trosod1phenylam1ne
not calculated
*The animal studies with N-nltrosomethylv1nylam1ne, while flawed, provide
evidence suggestive of a carcinogenic potential for N-nltrosomethylvlnyl-
amlne In rats. This evidence, together with a recognition of the structure
and related carcinogenic activity of similar compounds, Is sufficient to
classify N-n1trosomethylv1nylam1ne as a U.S. EPA Group B2 and a CERCLA high
hazard compound.
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TABLE OF CONTENTS
Page
1. INTRODUCTION 1-1
1.1. STRUCTURE AND CAS NUMBER 1-1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1-1
1.3. PRODUCTION DATA 1-1
1.4. USE DATA 1-1
1.5. SUMMARY 1-1
2. ENVIRONMENTAL FATE AND TRANSPORT PROCESSES 2-1
2.1. HATER 2-1
2.1.1. Volatilization 2-1
2.1.2. Bloconcentratlon 2-1
2.1.3. Photolysis 2-3
2.1.4. Blodegradatlon 2-3
2.2. AIR 2-6
2.3. SOIL 2-6
2.3.1. Formation 2-6
2.3.2. Leaching 2-6
2.3.3. Volatilization 2-8
2.3.4. Blodegradatlon 2-8
2.4. SUMMARY 2-10
3. EXPOSURE 3_1
3.1. HATER 3_1
3.2. FOOD 3-4
3.3. INHALATION 3-7
3.4. DERMAL 3-10
3.5. SUMMARY 3-10
4. PHARMAC0KINE1CS 4-1
4.1. ABSORPTION 4-1
4.2. DISTRIBUTION 4-3
4.3. METABOLISM 4-7
4.4. EXCRETION 4-9
4.5. SUMMARY 4-10
xtv
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TABLE OF CONTENTS (cont.)
Page
5. EFFECTS 5-1
5.1. CARCINOGENICITY 5-1
5.1.1. N-N1trosod1methylam1ne 5-2
5.1.2. N-N1trosomethylethylam1ne 5-14
5.1.3. N-N1trosod1ethylam1ne 5-17
5.1.4. N-NUrosod1-n-propylam1ne 5-31
5.1.5. N-N1trosod1-n-butylam1ne 5-35
5.1.6. N-N1trosomethylv1nylam1ne 5-42
5.1.7. N-NUrosodlethanolamlne 5-43
5.1.8. N-NUrosod1phenylam1ne 5-55
5.1.9. p-NUrosodlphenylamlne 5-61
5.2. MUTAGENICITY 5-61
5.3. TERATOGENICITY 5-67
5.4. OTHER REPRODUCTIVE EFFECTS 5-70
5.5. CHRONIC AND SUBCHRONIC T0X1CIIY 5-71
5.6. OTHER RELEVANT INFORMATION 5-73
5.7. SUMMARY 5-75
6. AQUATIC TOXICITY 6-1
6.1. ACUTE 6-1
6.2. CHRONIC 6-1
6.3. PLANTS 6-7
6.4. RESIDUES 6-7
6.5. OTHER RELEVANT INFORMATION 6-8
6.6. SUMMARY 6-10
7. EXISUNG GUIDELINES AND STANDARDS 7-1
7.1. HUMAN 7-1
7.2. AQUATIC 7-1
8. RISK ASSESSMENT 8-1
8.1. N-NilROSODIMETHYLAMINE 8-2
8.2. N-NITROSOMETHYLETHYL AMINE 8-6
8.3. N-NITROSOMETHYLETHYL AMINE 8-8
8.4. N-NITROSOD1 -N-PROPYLAMINE 8-12
8.5. N-NITROSODI-N-BUTYLAMINE 8-14
8.6. N-NITROSOMETHYL VINYL AMINE 8-20
8.7. N-NITROSODIETHANOLAMINE 8-21
8.8. N-NITROSODIPHENYLAMINE 8-26
8.9. p-NHROSODI PHENYL AMINE 8-28
8.10. SUMMARY 8-28
xv
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TABLE OF CONTENTS (cont.)
Pace
9. REPORTABLE QUANTITIES 9-1
9.1. REPORTABLE QUANTITY (RQ) RANKING BASED ON CHRONIC
TOXICITY 9-1
9.2. WEIGHT OF EVIDENCE AND POTENCY FACTOR (F=l/EO-|0)
FOR CARCINOGENICITY 9-7
9.2.1. N-N1trosod1methylam1ne 9-11
9.2.2. N-NUrosomethylethylam1ne 9-15
9.2.3. N-NUrosod1ethylam1ne 9-17
9.2.4. N-N1trosod1-n-propylam1ne 9-20
9.2.5. N-NHrosodl-n-butylamlne 9-23
9.2.6. N-N1trosomethylv1nylam1ne 9-26
9.2.7. N-N1trosod1ethanolam1ne 9-28
9.2.8. N-NUrosod1phenylam1ne 9-32
9.2.9. p-N1trosod1phenylam1ne 9-34
9.3. SUMMARY 9-34
10. REFERENCES 10-1
APPENDIX: LITERATURE SEARCHED A-l
xv1
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LIST OF TABLES
No. Title Page
1-1 Common Names, CAS Registry Numbers, Molecular Weights,
Empirical Formulas and Structures of Selected N1trosam1nes. . 1-2
1-2 Synomyms for Nltrosamines 1-4
1-3 Selected Physical and Chemical Properties 1-5
1 -4 1977 Production Data for Selected Nltrosamines 1-6
1-5 Use Data for Selected Nltrosamines 1-8
2-1 Henry's Law Constants for Nltrosamines 2-2
2-2 Atmospheric Half-Lives of Nltrosamines 2-7
2-3 Estimated Koc Values 2-9
3-1 Nltrosamines In Water 3-2
3-2 Nltrosamines 1n Foods and Beverages 3-5
3-3 Occupational Exposure to Nltrosamines 3-8
3 4 Nltrosamines In Ambient Air 3-11
3-5 Nltrosamines In Cigarette Smoke 3-12
3-6 Nltrosamines Content of Products that may Contact
the Dermis 3-13
5-1 Dietary Administration of N-N1trosod1methylam1ne In
Arachls 011 to Porton Strain Rats 5-5
5-2 Chronic Administration of N-N1trosod1methylam1ne to
Wlstar Rats In Diet for 96 Weeks 5-6
5-3 Administration of N-Nltrosodlmethylam1ne In Drinking
Water to Hale RF/Un Strain Mice 5-11
5 4 N1ne-Dose Lifetime Carcinogenicity Study of N-N1troso-
dlethylamlne Administered 1n Drinking Water to BD-II
Rats of Unspecified Sex 5-18
5-5 Dose-Response Study of N-N1trosod1ethylam1ne Administered
1n Drinking Water to Female F344 Rats 5-21
5-6 Administration of N-N1trosod1-n-butylam1ne to C57BL/6
H1ce In Drinking Water 5-38
xv 11
-------
LIST OF TABLES (cont.)
No. Title Page
5-7 Administration of N-N1trosod1-n-butylam1ne to Hale ICR
Mice 1n Diet 5-41
5-8 Lifetime Administration of N-N1trosod1ethanolam1ne to
Hale Sprague-Dawley Rats In Drinking Water 5-45
5-9 Lifetime Administration of N-N1trosod1ethanolam1ne to
Hale and Female F344 Rats 1n Drinking Water 5-48
5-10 Lifetime Administration of N-N1trosod1ethanolam1ne to Male
and Female F344 Rats In Drinking Water (Low-Dose Study) . . . 5-52
5-11 Bloassay of N-N1trosod1phenylam1ne (98% Pure) Administered
1n Diet 5-57
5-12 Positive Short-Term Assays of D1alky1n1trosam1nes 5-62
5-13 Acute Oral LO50 Values of Selected N-N1trosam1nes 5-74
6-1 Acute Toxicity of Nltrosamlnes to Aquatic Organisms 6-2
6-2 Results of Long-Term Studies with H1trosam1nes and
Aquatic Organisms 6-3
6-3 N-N1trosod1methylam1ne Levels In Three Species Exposed to
Different Concentrations of Thlram and Nitrite for 24 Hours . 6-9
8-1 Chron1c/Subchron1c Oral Carcinogenicity Studies of
N-N1trosod1methy1am1ne 8-3
8-2 Chronlc/Subchronlc Oral Carcinogenicity Studies of
N-N1trosod1ethylam1ne 8-9
8-3 Subchronlc and Chronic Oral Carcinogenicity Studies of
N-N1trosod1-n-butylam1ne 8-16
8-4 Subchronlc and Chronic Oral Carcinogenicity Studies of
N-N1trosod1ethanolam1ne 8-22
8-5 Cancer Data Sheet for Derivation of q-j* 8-24
8-6 Cancer Data Sheet for Derivation of q-j* 8-25
8-7 Potency Factors and Water Concentrations Associated with
Increased Lifetime Risks of Exposure to Nltrosoamlnes .... 8-29
xv111
-------
LIST OF TABLES (cont.)
No. Title Page
9-1 Composite Scores for Toxicity of N-N1trosod1methylam1ne,
N-N1trosod1ethylam1ne and N-N1trosod1phenylam1ne 9-5
9-2 N-N1trosod1methylam1ne: Minimum Effective Oose (MED) and
Reportable Quantity (RQ) 9-8
9-3 N-N1trosod1ethylam1ne: Minimum Effective Dose (MED) and
Reportable Quantity (RQ) 9-9
9 4 N-N1trosod1phenylam1ne: Minimum Effective Dose (MED) and
Reportable Quantity (RQ) 9-10
9-5 Derivation of Potency Factor (F); Agent: N-NUroso-
dlethanolamlne 9-30
9-6 Derivation of Potency Factor (F); Agent: N-Nltroso-
dlethanolamlne 9-31
9-7 Derivation of Potency Factor (F); Agent: N-N1troso-
dlphenylamlne 9-35
9-8 Ranking of Nltrosamlnes According to Degree of
Carcinogenic Hazard 9-36
xlx
-------
LIST OF ABBREVIATIONS
BCF B1oconcentrat1on factor
BHK Baby hamster kidney
CAS Chemical Abstract Service
CS Composite score
DMSO Dimethyl sulfoxide
DNA Deoxyribonucleic acid
Koc Soil sorption coefficient standardized
Kow Octanol/water partition coefficient
LC50 Concentration lethal to 50% of recipients
LO50 Oose lethal to 50% of recipients
MED Minimum effective dose
NOEC No-observed-effee t-concentrat1on
PCB PolychlorInated blphenyl
ppb Parts per billion
ppm Parts per million
ppt Parts per thousand
RQ Reportable quantity
RV(j Dose-rating value
RVe Effect-rating value
TWA Hme-welghted average
xx
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1. INTRODUCTION
1.1. STRUCTURES AND CAS NUMBERS
Table 1-1 lists the common names, CAS Registry numbers, molecular
weights, empirical formulas and structures of the nltrosamlnes discussed In
this document. Synonyms for these nltrosamlnes are listed 1n Table 1-2.
1.2. PHYSICAL ANO CHEMICAL PROPERTIES
Nltrosamlnes consist of a nitroso group (0=N-) and an amine group
(-N-), which are attached to an alkyl or aryl group. Some of the physical
and chemical properties of the nltrosamlnes discussed 1n this document are
listed 1n Table 1-3.
1.3. PRODUCTION DATA
The most recent production data available are presented in Table 1-4.
N-n1trosodlphenylamine and p-nltrosodlphenylamlne appear lo be produced 1n
the greatest quantities. No production data were located for N-nltroso-
methylethylamlne, N-n1trosod1-n-butylam1ne and N-n1trosomethylv1nylam1ne.
1.4. USE DATA
Table 1-5 lists some uses for nltrosamlnes; Information on uses was
available for only 4 of the 9 nltrosamlnes (I.e., N-n1trosod1methylam1ne,
N-n1trosod1ethylam1ne, N- and p-n1trosod1phenylam1ne), which are probably
produced 1n the greatest quantities and are used In the production of rubber.
1.5. SUMMARY
Nltrosamlnes consist of a nitroso group (0=N-) and an amine group
(-N-), which are attached to an alkyl or aryl group. N- and p-nltrosodl-
phenylamlne appear to be the only two nltrosamlnes that are produced and
used In significant amounts. According to the 1977 1SCA Inventory (U.S.
EPA, 1977), production for each chemical ranged from <1000-1,000,000 pounds.
Their primary use Is In the rubber Industry (Hawley, 1981; IARC, 198?;
Taylor and Son, 1982; Wlndholz et al., 1983).
0745p 1-1 05/29/86
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TABLE 1 -1
Common Names, CAS Registry Numbers, Molecular Weights, Empirical Formulas
and Structures of Selected Nltrosamlnes
Common Name CAS Registry Molecular Empirical Structure
Number Height Formula
N-N1trosod1methylam1ne
62-75-9
74.1
C2H6N20
ch3
/
0-N-N
\
ch3
N-N1trosomethylethylamlne
10595-95-6
88.1
C3H0N2O
ch3
/
0-N-N
\
CH2-CH3
CH2-CH3
/
N-N1trosod1ethylamlne
55-18-5
102.1
C4H10N20
0=N-N
\
CH2-CH3
CH2-CH2-CH3
/
0=N-N
\
CH2-CH2-CH3
N-NUrosodl -n-propylam1ne
621-64-7
130.2
c6h14n2°
-------
TABLE 1-1 (cont.)
Common Name
CAS Registry
Number
Molecular
Weight
Empirical
Formula
Structure
CH2-CH2-CH2-CH3
/
N-N1trosod1-n-butylam1ne 924-16-3 158.2 CqHiqN^O 0=N-N
\
CH2-CH2-CH2-CH3
N-Nltrosomethylvlnylamlne 4549-40-0 86.1 C3H5N2O 0=N-H
\
ch3
/
v
CH=CH2
CH2-CH2OH
N-Nltrosodlethanolamine 1116-54-7 134.1 C4H10N2O3 0=N-N
/
\
CH2-CH2OH
N-Nltrosodlphenylamlne
86-30-6 198.2 C^Hiq^O
O-N-N
p-Nltrosodlphenylamine
156-10-5 198.2 C12H10N2O
V.v/ w
-------
TABLE 1-2
Synomyms for Nltrosamlnes
Chemical Name
(CAS Number)
Synonyms
N-N1trosod1methylam1ne
(62-75-9)
N-Nltrosomethylethyl amine
(10595-95-6)
N-Nltrosodlethylamlne
(55-18-5)
N-n1trosod1-n-propyl amine
(621 -64-7)
N-NUrosodi -n-butylamine
(924-16-3)
N-N1trosomethylv1nylam1ne
(4549-40-0)
N-NHrosodl ethanol amine
(1116-54-7)
N-N1trosod1phenylamine
(86-30-6)
p-N1trosod1phenylamine
(156-10-5)
methanamlne, N-methyl-N-n1troso; dlmethyl-
nHrosamlne; DHNA; NDHA; DMN
ethanamlne, N-methyl-N-nltroso-; ethylamlne,
N-methyl-N-nltroso-; ethylmethylnUrosamlne;
N,N-methylethyln1trosamlne; NEMA; NHEA
ethanamlne, N-ethyl-N-n1troso; dlethylnltros-
amlne; N,N-d1ethyln1trosam1ne; NDEA; DEN
1-propanamlne, N-n1troso-N-propyl; dlpropyl-
amlne, N-nltroso; dl-N-propylnltrosamlne;
d1propyln1trosam1ne; N,N-d1-n-propylnltros-
amlne; DPNA; NDPA; OPN
1-butanamlne, N-butyl-N-nltroso; dlbutyl
amine, N-nltroso; d1-N-butyln1trosam1ne;
N,N-d1-n-butyln1trosamlne; DBNA; NODA; DBN
ethenamlne, N-methyl-N-nltroso; vlnylamlne,
N-methyl-N-nltroso; ethenylamlne, N-methyl-
N-nltroso; methylvlnylnltrosamlne; NHVA
ethanol, 2,2*-(nltrosolmlno)bls-; ethanol,
2,2'-n1tros1m1nod1-; b1s(B-hydroxyethyl)-
nltrosamlne; d1ethanoln1trosam1ne; N-nltroso-
b1s(2-hydroxyethyl)amine; nltrosolmlno,
dlethanol; NDELA
benzenamlne, N-nltroso-N-phenyl; dlphenyl-
nltrosamlne; N-n1troso-N-phenylanilIne;
Vultrol* (B.F. Goodrich Co.); NDPhA
benzenamlne, 4-nltroso-N-phenyl; dlphenyl-
amlne, 4-nltroso-; p-nltroso-N-phenylanlllne
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TABLE 1-3
Selected Physical and Chemical Properties
Chemical Name
Melting
Point
r C)
Boiling
Point
CO
Specific
Gravity
Vapor Pressure
(in Hg)
Uater
Solubility
Nonaqueous
Solubility
Log Kow a
Physical State at
Room Temperature
N-Nltrosodlmethylamlne
NR
N-Nltrosomethylethylamlne NR
N-Nltrosod1ethylam1ne
NR
N-Nltrosodl-n-propylamlne NR
N-Nltrosodl-n-butylamlne NR
N-Nltrosomethylvlnylamlne NR
N-Nltrosodlethanolamlne NR
151-153b
163 at 747
mn Hgd
175-177^
81 at
5 mm Hgd
116 at
14 mm Hgd
47-48 at
30 im Hg<*
1 25 at
0.01 mm Hgb
N-N1trosod1pheny1am1ne 66.Se 153 at
774 mm Kgf
p-Nltrosodlphenylamlne 144-145b NR
1.004Bb
(d|»)
0.9448
(dj8)d
0.9422b
(df)
0.9160
{d|0,d
0.9009
(d|«)d
NR
NR
1.006
(d20)9
NR
?.7 at 20*CC
1.1 at 20*Cc
0.86 at 20*CC
0.086 at 20*CC
0.03 at 20"CC
6.8 at 20*CC
5x10"4 at 20*CC
0.1 at 25*Ch
NR
very alcohol. etherb
soluble^
30%d organic solvents''
-10X*1 alcohol, etherb
l%d organic solvents'1
0.12Xd organic solvents,
vegetable oils'*
3X organic solvents*1
mlsclble*1 polar organic
solvents"
40 ppm alcohol, benzene,
at 25*Cb ether, sulfuric ac1d9
slightly alcohol, ether,
soluble" chloroform, benzene1*
-0.570
(measured)
-0.239
(calculated)
0.4B0
(measured)
1.360
(measured)
1.920
(measured)
•0.003
(calculated)
-1.583
(calculated)
3.130
(measured)
3.503
(calculated)
yellow 11qu1db
yellow liquid*1
slightly yellow
1 Iqu ldb
yellow liquid*1
yellow oil*1
yellow liquid*1
yellow, viscous
liquid*
greenish crystals?
orange-brown solid*
green plates with
bluish luster or
steel-blue prisms
or platesb
aHedChem, 1964
bW1ndholz et al.. 1983
cK1etn, 1982
dIARC, 1978
eIARC, 1982
fAldr1ch, 1984
SHawley, 1981
hflabey et al., 1981
NR = Not reported
-------
TABLE 1-*
1977 Production Data for Selected Nltrosamlnes*
Chemical
Producer and Location
Production
Volume
(pounds)
N-Nltrosodlmethylamlne
Kodak Park Division
Rochester, NY
none
Columbia Organic Chemicals Co.
Columbia, SC
<1000
Teledyne HcCormlck Selph
HolHster, CA
none
The Ames Laboratories, Inc.
Mllford, CT
<1000
N-N1trosod1ethylamine
Kodak Park Division
Rochester, NY
<1000
The Ames Laboratories, Inc.
HUford, CT
<1000
N-N1trosod1-n-propylam1ne
Kodak Park Division
Rochester, NY
none
The Ames Laboratories, Inc.
Mllford, CT
<1000
N-N1trosod1ethanolam1ne
Columbia Organic Chemicals Co.
Columbia, SC
<1000
N-NHrosodlphenylamlne
B.F. Goodrich Chemical Dlv.
Akron, OH
NR
Unlroyal, Inc.
Naugatuck, CT
NR
Unlroyal, Inc.
Gelsmar, LA
NR
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TABLE 1-4 (cont.)
Chemical
Producer and Location
Production
Volume
(pounds)
N-N1trosod1phenylam1ne
Sartomer Company 01 v.
West Chester, PA
NR
Goodyear T1re and Rubber Co.
Akron, OH
100,000-
1,000,000
p-N1trosod1phenylam1ne
Unlroyal, Inc.
Gelsmar, LA
100,000-
1,000,000
~Source: U.S. EPA, 1977
NR ^ Not reported
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TABLE 1-5
Use Data for Selected Nltrosamlnes
Chemical
Use
Reference
N-N1trosod1methylamlne
antioxidant, additive for
lubricants, softeners for
copolymers rocket fuels,
solvent, rubber accelerator
Ulndholz
et al., 1983;
Hawley, 1981
N-Nltrosod1ethylamine
gasoline and lubricant addi-
tive stabilizer, antioxidant
Wlndholz
et al., 1983
N-N1trosod1phenylamine
rubber accelerator, staining
retarder for natural and
synthetic rubbers vulcaniza-
tion retarder (0.5-1.OX) In a
variety of rubbers, manufac-
ture of p-n1trosod1phenylam1ne
Hawley, 1981;
Taylor and
Son, 1982;
IARC, 198?
p-N1trosod1phenylamine
accelerator In vulcanizing
rubber
Ulndholz
et al., 1983
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2. ENVIRONMENTAL FATE AND TRANSPORT PROCESSES
2.1. UATER
2.1.1. Volatilization. Henry's Law constants were calculated for six of
the nine nltrosamlnes discussed In this document (Table 2-1). Henry's Law
constants were not calculated for N-n1trosod1methylamlne and N-n1trosod1-
ethanolamlne because of ambiguous solubility data for N-n1trosod1methy1am1ne
[very soluble (Wndholz et al., 1983)] and because N-n1trosod1ethanolam1ne
Is mlsdble with water (IARC, 1978); however, because of their high water
solubility and low vapor pressures, volatilization from water Is not
expected to be significant. Since no vapor pressure data were found for
p-n1trosod1phenylam1ne, a Henry's Law constant was not calculated. N-N1tro-
sodlphenylamlne Is the most volatile (Henry's Law constant = 6.4x10"*
atm«m3/mol) of the six compounds for which values were calculated.
Although volatilization from water may be a significant removal process for
N-n1trosod1phenylam1ne (Lyman et al., 1982), volatilization will probably
not be a significant removal process for the other nltrosamlnes.
2.1.2. Bloconcentratlon. A BCF of 100 was reported for N-n1trosod1-n-
propylamlne on sludge (Patterson and Kodukala, 1981). Barrows et al.
(1980a) reported a BCF of 217 for N-n1trosod1phenylam1ne In blueglll sunflsh
exposed to an average water concentration of 9.21 yg N-n1trosod1phenyl-
amlne/8. for 14 days. No Information was located on bloconcentratlon for
the other nltrosamlnes. N-N1trosod1-n-butylam1ne and p-n1trosod1phenyl-
amine, however, have Kqw values greater than that of N-n1trosod1-n-propyl-
amlne; therefore, these compounds may have BCFs equal to or greater than
N-n1trosod1-n-propylam1ne. Bloconcentratlon of the other nltrosamlnes 1s
not expected to be significant because of their high water solubilities and
low K values,
ow
0746p
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TABLE 2-1
Henry's Law Constants for Nltrosamlnes*
Chemical
Henry's Law Constant
(atm«mVmol)
N-N1trosod1methylam1ne
NC
N-NUrosomethylethylamlne
4.1xl0~7
N-N1trosodlethylam1ne
1.1x10"*
N-Nltrosod1-n -propylamine
1.4x10"*
N-N1trosod1-n-butylam1ne
5.1x10"*
N-N1trosomethylvlnylam1ne
2.6xl0"5
N-N1trosod1ethanolam1ne
NC
N-N1trosod1phenylamine
6.4x10"*
p-N1trosod1phenylamine
NC
*Vapor pressures and solubilities used for calculations are from Table 1-3.
NC = Hot calculated because of ambiguous solubility data (I.e., "very
soluble")
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2.1.3. Photolysis. Polo and Chow (1976) found that N-nltrosodlmethyl-
amlne (Initial concentration of 74 mg/a) photodegraded In distilled water
with a half-life of 79 hours. N-N1trosod1-n-propylam1ne (1-10 ppm) was
found to rapidly degrade 1n lake water exposed to sunlight with the greatest
amount of photolysis occurring at the lake surface (Saunders and Mosler,
1980). In one experiment, -90% of the N-n1trosod1-n-propylam1ne (Initial
concentration of 0.65 ppm) degraded after 8 hours exposure to sunlight.
N-N1trosod1-n-butylam1ne photodegrades 1n aqueous solution more rapidly at
low pH (Burns and AlHston, 1971). When exposed to sunlight for 7 hours at
33-35°C, photolysis of N-n1trosod1ethylam1ne was 88.7% complete (Zhang et
al.. 1983).
2.1.4. B1odegradat1on. Tate and Alexander (1976) Inoculated enrichment
cultures with soil and sewage but found no organisms capable of metabolizing
N-nHrosodlmethylamlne, N-n1trosod1ethylam1ne or N-n1trosod1-n-propylamlne.
The lack of degradation of N-n1trosod1emthylam1ne does not appear to be due
to Its toxicity but may be due to the Inability of the microorganisms to
cleave the nitrogen-nitrogen bond. In an earlier study, Tate and Alexander
(1975) found that the concentrations of N-n1trosodlmethylam1ne, N-n1troso-
dlethylamlne and N-n1trosod1-n-propylam1ne In lake water did not change
after 108 days incubation at 30°C 1n the dark.
Yordy and Alexander (1980) found that microorganisms In samples from two
lakes slowly metabolized N-n1trosod1ethanolam1ne but did not mineralize 1t.
N-N1trosodlethanolam1ne was most rapidly degraded In a lake water sample
taken In August (N-n1trosod1ethanolam1ne at an Initial concentration of 1.0
fig/mil was completely converted to soluble products 1n 9 days); however,
no metabolism of N-n1trosod1ethano1am1ne was observed after 32 days Incuba-
tion at 2?°C 1n a lake sample taken 1n January.
0746p
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Tabak ei al. (1981) used settled domestic wastewater as the Inoculum for
static blodegradatlon tests on N-n1trosod1-n-propylam1ne and N-nltrosodl-
phenylamlne, and found that 50% of the Initial N-n1trosod1-n-propy1am1ne (5
mg/l) was degraded after three subcultures that totaled 28 days of Incuba-
tion. Under the same experimental conditions, 100% of N-n1trosod1phenyl-
amine (Initial concentration of 5 mg/l) blodegraded.
Fochtman and Elsenberg (1979) found that from 47-72% of N-n1trosod1-
methylamlne was blodegraded In static blodegradatlon tests using seed from
an activated sludge plant. Incubation was for 7 days. N-N1trosod1methyl-
amlne was readily degraded In a continuous biological reactor Inoculated
with seed from an activated sludge plant. For example, N-n1trosod1methy1-
amlne at an Initial concentration of 1.93 mg/l was reduced to <0.01 mg/l
in the effluent from the reactor (based on a 24-hour composite sample). The
feed for both the static and continuous cultures contained a nutrient
solution based on yeast extract.
Kaplan and Kaplan (1985) used an Inoculum of activated sludge, anaerobic
sludge digest and garden soil to study the blodegradatlon of N-nltrosodl-
methylamlne In lake water. They found that the rate of mineralization
Increased with decreasing initial concentrations of N-nltrosodtmethylamlne.
After 114 days Incubation at room temperature with basal salts added, 16.4%
of N-n1trosod1methy1am1ne at an initial concentration of 15 »g/ml (15
mg/l) was mineralized. On the other hand, 78.6% of N-nltrosodlmethylamlne
was mineralized when the Initial concentration was 1.62x10"* jig/ml
(0.162 »g/l). No lag phase was evident In lake water with basal salts.
Patterson and Kodukala (1981) studied the removal percentages of
N-n1trosod1methy1am1ne, N-nltrosodl-n-propylamlne and N-nltrosodlphenyl-
amlne. An activated sludge treatment plant removed >95% of the -2000
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N-nltrosodlmethylamlne/t In the Influent. N-Nltrosodl-n-propylamlne
Influent concentration of 0.5 and 6.7 yg/8, were reduced by 86 and 99%,
respectively, 1n municipal activated sludge treatment plants; however, 0%
removal was reported at two Industrial activated sludge treatment plants
with an average N-nltrosodl-n-propylamlne influent concentration of 11
ng/t. At an average influent concentration of 5.3 jig/t, an average
of >84X N-n1trosod1phenylam1ne was removed at two Industrial activated
sludge treatment plants. At an Industrial aerated lagoon, 67% of an Initial
concentration of 3 >»g N-nUrosodlphenylamlne/l was removed.
In addition to mixed culture studies, several researchers have tested
pure cultures of microorganisms for their ability to metabolize and, hence,
degrade nltrosamlnes. Rhodopseudomonas capsulata. a photosynthetlc bacte-
rium, metabolized 100 mg N-nltrosod1methylam1ne/l. under anaerobic condi-
tions (Kobayashl and Ichan, 1978). Rhlzopus oryzae. Streptococcus cremorIs
and Saccharomyces rouxl1 were able to degrade N-n1trosodlmethylam1ne,
N-nltrosodlethylamlne and N-nltrosodl-n-propylamlne (Harada and Yamada,
1979). Nalllk and lesfal (1981) found that Pseudomonas fluorescens and a
Streptomyces sp. were better able to degrade N-nHrosod1methylam1ne 1n a
salt solution that was supplemented with glucose and ammonium sulfate.
late and Alexander (1976), however, found that when Incubated for 72
hours Pseudomonas stutzer1. P. fragl. Bacillus mvcoldes. B. cereus. B.
subtllls. Clostridium acetobutvllcum. C. pasteurlanum. Arthrobacter plco-
llnophllus. A. suboxydans. and four unclassified strains of Arthrobacter
were not able to metabolize N-nltrosodlmethylamlne at concentrations of 25
or 150 ppm nltroso-N.
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2.2. AIR
Data regarding the atmospheric fate of the nltrosamlnes are presented In
Table 2-2. Data available for N-n1trosod1methylam1ne, N-n1trosod1ethylam1ne
and N-n1trosod1-n-propylam1ne Indicate that these compounds are rapidly
degraded 1n the atmosphere. Although no data were located on the atmos-
pheric fate of the other six nltrosamlnes, they also may be rapidly degraded
and, hence, would not persist In the atmosphere.
2.3. SOIL
2.3.1. Formation. Mills and Alexander (1976) found that N-n1trosod1-
methylamlne was formed In both sterile and nonsterlle soil that was supple-
mented with 250 ppm dlmethylamlne and 100 ppm n1tr1te-N. After 48 hours In
soil of pH 5.2, 2.A and 2.5 ppm n1troso-N (12.7 and 13.2 ppm N-n1trosod1-
methylamlne) had formed In sterile and nonsterlle soils, respectively.
Pancholy (1978) found that N-n1trosod1methylam1ne formed 1n both sterile and
nonsterlle soils to which nitrite and dlmethylamlne were added. In
addition, Pancholy (1978) analyzed soil samples from fertilized and polluted
areas but did not detect any nltrosamlne; however, when 10 ppm dlmethylamlne
was added to these soil samples, 0.10-0.50 ppm of nltrosamlnes were formed.
Greene et al. (1981) continuously percolated sewage that was treated
with 250 vg d1methylam1ne/mi and 50 n1tr1te-N/mi through soil.
They found that the highest level of N-n1trosod1methylam1ne 1n the effluent
from this soil column was 219 ng/mi (219 yg/l) on day 3 of the experi-
ment. By day 5, however, the N-n1trosod1methylam1ne level had fallen to
0.72 ng/ml (0.72 iig/t).
2.3.2. Leaching. N-N1trosod1methy1am1ne was found to leach through four
different soils as readily as chloride 1on (Dean-Raymond and Alexander,
1976). Greene et al. (1981) also found that N-n1trosod1methylam1ne readily
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TABLE 2-2
Atmospheric Half-lives of Nltrosamlnes
Chemical
Estimated
Half-Life
Removal Process
Reference
N-N1trosod1methylam1ne
~5 minutes
3 days
>2 years
photolys Is
reaction with
OH radicals
reaction with O3
Tuazon
et al., 1984
-30 minutes
degradation by
full sunlight
Hanst
et al., 1977
<0.3 days*
probably
photolysis
Cupltt, 1980
N-N1trosodiethylam1ne
<0.4 days*
probably
photolysis
Cupltt, 1980
-1-2 hours
sunlight Irra-
diation In
Teflon outdoor
smog chamber
Grosjean
et al., 1978
N-N1trosod1-n-propylamlne
5-7 hours
sunlIght
wavelength
Irradiation
Crosby
et al., 1980
~Estimated atmospheric residence time
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leached through soils. Pertinent data regarding son mobility of the other
eight nltrosamlnes could not be located In the available literature as cited
In the Appendix; therefore, Kqc values were estimated using the equation
log K = 0.544 log K * 1.377 (Lyman et al., 198?) and K values
oc ow ow
from HedChem (1984) (Table 2-3).
2.3.3. Volatilization. Oliver (1979) found that N-n1trosod1methylam1ne,
N-n1trosod1ethylam1ne and N-n1trosod1-n-propylam1ne volatilized rapidly from
soil. From 30-80% was lost during the first few hours after surface appli-
cation to a soil at ambient temperature. Volatilization was slower when the
chemical was Incorporated 7.5 cm Into the soil.
Berard and Ralney (1979) found that N-n1trosod1-n-propylam1ne also
rapidly volatilized from soil surfaces of a field test plot. Two hours
after application of 571 ng N-nitrosodi-n-propylamine/m* soil, 52.6% of
the applied compound was recovered, Indicating that 47.4% had dissipated.
Oliver et al. (1979) found that N-n1trosod1methylam1ne, N-n1trosod1-
ethylamlne and N-n1trosod1-n-propylam1ne have half-lives of ~3 weeks In the
soils used in their laboratory studies. During the first few days of the
experiments, significant losses of the nltrosamlnes resulted from volatili-
zation.
Pertinent data regarding volatilization of the other nltrosamlnes from
soil could not be located 1n the available literature as cited in the
Appendix.
2.3.4. B1odegradat1on. Oliver et al. (1979) found that N-n1trosod1-
methylamlne, N-nltrosodlethylamlne and N-nitrosod1-n-propylam1ne had half-
lives of -3 weeks in aerobic soils under laboratory conditions. The primary
removal processes were volatilization and microbial degradation. Hallik and
Tesfal (1981) found that 17% of added N-n1trosod1methylam1ne was lost from a
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TABLE 2-3
Estimated Koc Values
Chemical
Log Kowa
i/ b
*oc
Soil Mob111tyc
N-N1trosod1methylam1ne
-0.570
(measured)
12
highly mobile
N-Nltrosomethylethylamine
-0.239
(calculated)
18
highly mobile
N-N1trosod1ethylam1ne
0.480
(measured)
43
moderately mobile
N-NUrosodl -n -propyl amine
1.360
(measured)
128
mobile
N-Nltrosodl-n-butylamlne
1.920
(measured)
263
mobile
N-N1trosomethylv1nylani1ne
-0.003
(calculated)
24
highly mobile
N-N1trosod1ethanolam1ne
-1.583
(calculated)
3
highly mobile
N-n11r os od1pheny1amine
3.130
(measured)
1202
Immobile
p-NUrosodlphenylamlne
3.503
(calculated)
1905
Immobile
aHedChem, 1984
bLyman et al., 1982
Compounds having a Koc value of -1000 are tightly bound to organic
matter In son and are considered Immoblle; those below are moderately to
highly mobile (Kenaga, 1980).
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sandy loam soil after 10 days Incubation, but that no further loss was noted
during the next 30-day Incubation period. The N-n1trosod1methylam1ne
concentration was 25 jig n1troso-N/g of soil (132 jig N-nltrosodlmethyl-
am1ne/g soil or 132 ppm), and Incubation was In the dark at 30°C. When
wheat straw was added to the soil, Increasing organic matter content from
2.16-17.5%, >60% of the added N-n1trosod1methylam1ne was lost by day 15 of
the Incubation period. Under similar conditions, 68% of the N-n1trosod1-
phenylamlne (354 pg N-n1trosod1phenylam1ne/g soil) degraded In 30 days; In
the amended soil (organic matter content, 17.5%), N-n1trosod1phenylam1ne
disappeared completely by day 10 of Incubation.
2.4. SUMMARY
The primary fate mechanism for nltrosamlnes In water Is probably photo-
degradation. N-N1trosod1methylam1ne, N-n1trosod1ethylam1ne and N-n1trosod1-
n-butylam1ne photodegraded rapidly (Polo and Chow, 1976; Zhang et al., 1983;
Saunders and Hosier, 1980; Burns and Alllston, 1971). Results of aqueous
blodegradatlon studies on the nltrosamlnes In batch and continuous culture,
using Inocula from soil, lake, water, sewage and pure cultures are Inconsis-
tent. Volatilization from water will probably not be significant except
possibly for N-n1trosod1phenylam1ne (Henry's Law constant =¦ 6.4xl0~4
atm*m3/mol). A BCF of 100 has been measured for N-n1trosodlmethylam1ne
1n sludge (Patterson and Kodukala, 1981) and 217 for N-nltrosodlphenylamlne
1n blueglll sunflsh (Barrows et al., 1980a).
In the atmosphere, N-nltrosodlmethylamlne, N-n1trosod1ethy1am1ne and
N-n1trosod1-n-propylam1ne are rapidly removed; half-Hves or residence times
were <1 day (Cupltt, 1980; Hanst et al., 1977; Tuazone et al., 1984;
Grosjean et al., 1978; Crosby et al., 1980).
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N-Nltrosodlmethylamlne may form in soil (Greene et al., 1981; Hills and
Alexander, 1976; Pancholy, 1978), and may also leach readily through soil
(Dean-Raymond and Alexander, 1976; Greene et al., 1981). Since no Informa-
tion was located regarding soil mobility of the other nltrosamlnes, KQC
values were estimated, and ranged from 3 for N-n1trosod1ethanolam1ne (highly
mobile) to 1905 for p-n1trosod1phenylam1ne (Immobile). N-N1trosod1methyl-
amine, N-n1trosod1ethylam1ne and N-n1trosod1-n-propylamlne were found to
volatilize rapidly from soil (Oliver, 1979). Oliver et al. (1979) found
that N-n1trosod1methylam1ne, N-nltrosodlethylamlne and N-n1trosod1-n-propyl-
amlne had half-Hves of -3 weeks In aerobic soils under laboratory condi-
tions. The primary removal processes 1n this study were volatilization and
blodegradatlon.
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3. EXPOSURE
3.1. UATER
Nltrosamlnes have been found 1n wastewaters, wastewater effluents, salt-
water, drinking water and delonlzed laboratory water. Table 3-1 presents
Information regarding nltrosamlnes In water and data on nltrosamlnes In
sludge and aqueous extracts of rubber. These data are Included because
nltrosamlnes may leach out and enter surface or groundwaters. For example,
nltrosamlnes In sludge may be released to the soil 1f the sludge Is applied
to agricultural land.
N-N1trosod1methylam1ne was found 1n Philadelphia tap water at concentra-
tions of 0.003-0.006 yg/a (Klmoto et al., 1981). If a person drinks
2 8. of water/day, a dally Intake of 0.006-0.012 pg N-n1trosod1methyl-
amlne would result.
Nltrosamlnes may be released Into waters because of Industrial activi-
ties or form naturally 1n waters. Yordy and Alexander (1981) demonstrated
N-n1trosod1ethanolam1ne formation In lake water from dlethanolamlne [used In
liquid detergents for emulsion paints, cutting oils, shampoos, cleaners and
polishes and as Intermediates for resins and plastlclzers (Hawley, 1981)].
In their study, N-n1trosod1ethanolam1ne formed without the addition of
nitrite or pH adjustment of the lake water; however, they pointed out that
even 1f N-nltrosodlethanolamlne formed, 1t would be In the pg/mi or lower
concentration range. In addition, data regarding the detection of N-nltro-
sodlethanolamlne In lake water could not be located 1n the available litera-
ture as cited 1n the Appendix.
N-N1trosod1ethylam1ne formed at concentrations from 0.13-7.02 pg/j.
1n river water samples from the reaction of nitrite with two commonly-used
tracer dyes, Rhodamlne B and Rhodamlne WT (Abldl, 1982). In this study.
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TABLE 3-1
Nltrosamlnes In Water
Chemical
ConcentratIon
Sample Description
Reference
N-NHrosodlmethylamlne
HO
effluent from Addison, 1L, wastewater treatment
plant
Ellis et at.. 19B2
2 ng/mt
anaerobic lagoon. Belle, WV
Fine el al.. 1977a
?700 ng/l
sewer sample, Baltimore, MO
o.?-o.3 wq/».
wastewater
Rhoades et al., 1980
0.374 yg/g
municipal sewage sludge sample
Brewer et al., I960
53 ppb
dried sludge from Syracuse, NY, treatment plant
Mumma et al., 19B4
9040 nq/t
chemical plant effluent released to a river
Hartmetz and Slemrova, 19B0
0.003-0.006 t>g/t
Philadelphia tap water
Klmoto et al., 1981
0.03-0.34 ppb
water exposed to delonlzlng resins
fiddler et al.. 1977
0.06 t>g/l
delonlzed, distilled laboratory water
Gough et al., 1977
35-940 ng/t
saltwater front Curtis Bay and Stonehouse Cove,
Baltimore, HD
f Ine et al., 1977a
2.1 ppba
aqueous rubber extract**
Ireland et al., 19B0
0.2 ng/mt
Influent to wastewater treatment plant. Belle, UV
fIne et al., 1977a
0.5 ng/mt
lagoon seepage, Belle. WV
0.?2 ng/mt
Newark Bay. Elizabeth. NJ
N-NItrosodlethylamlne
132 ng/t
chemical plant effluent released to a river
Hartmetz and Slemrova, 1980
3.8 ppb
dried sludge from Syracuse, NY, treatment plant
Nuima et al., 1984
5.52 jig/g
municipal sewage sludge sample
Brewer et al., 1980
86 ppba
aqueous rubber extract11
Ireland et al., 1980
0.33, 0.63 ppb
delonlzed water
Fiddler et al., 1977
<0.0001-0.0007 ug/i
Philadelphia tap water
Klmoto et al., 1981
-------
TA8LE 3-1 (cont.)
Chemical
Concentration
Sample Description
Reference
N-N Itrosod\-n-propylamine
O.S vg/t
wastewater
Rhoades et al., 1980
?-20 mg/m1
secondary effluent from textile plants
Rawllngs and Samfleld, 1979
N-NUrosodl -n-butylamlne
16 ppba
aqueous rubber extract1*
Ireland et al., I960
N-MUrosodl phenyl amine
11 jig/t
wastewater after primary treatment
Young. 1978
<10 vg/t
final effluent from the Los Angeles Joint Water
Pollution Control Plant
Young, 1978
Volatile nltrosamlnes
<0.005 |ig/l
tap water
Gough et al.. 1977
Volatile N-nltrosamlnes
<2 ng/i
Baltimore drinking water
Fine et al., 1977a
aParts/we1ght N-nltrosamlne per billion parts by weight of polymer extracted
bRoom temperature, 5-day extraction from compounded, cured polychloroprene polymer
NQ • Not quantified
-------
nitrite (sum of the naturally occurring and added nitrite) was In a molar
excess of 10-1000 times that of the tracer dye.
Klmoto et al. (1981) found N-n1trosod1methylam1ne In tap water at con-
centrations of 0.003-0.006 pg/4 (see Table 3-1). The authors concluded
that N-n1trosod1methylam1ne did not form In the resin used to accumulate
nltrosamlnes but may have formed from the reaction of low concentrations of
nitrite, an oxidizing agent (possibly chlorine) and secondary amines present
In the tap water.
Oliver (1981) concluded that extensive nltrosamlne formation In natural
waters Is not likely because of low nitrite concentrations, low levels of
nltrosatable amines and expected third-order kinetics.
3.2. FOOD
N-N1trosod1methylamine, N-nItrosodlethylamine, N-nltrosodl-n-propylamine
and N-n1trosod1-n-butylam1ne have been found In a number of foods
(Table 3-2).
In addition to N-n1trosod1methylam1ne exposure from Infant formula.
Infants may also be exposed to N-n1trosod1-n-butylam1ne In the rubber
nipples of pacifiers (Thompson et al., 1984). Thompson et al. (1984) did 15
artificial saliva extractions of Intact pacifier nipples and found that a
total of 824 ppb N-n1trosod1-n-butylam1ne had been extracted.
Sen et al. (1985), using simulated gastric conditions, Investigated the
possibility of nltrosamlne formation In the stomach after eating fish. They
hypothesized that amines In fish might react with salivary nitrite In the
stomach and produce nltrosamlnes; however, experimentation revealed that
significant amounts of volatile nltrosamlnes did not form. The most
dramatic Increase In nltrosamlne concentration occurred with a salted
mackerel. Before Incubation under simulated gastric conditions, the f1sh
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TABLE 3-2
Nl trosamlnes In Foods and Beverages
Chemical
Coneentratton*
Food or Beverage
Reference
N-N1trosodlmethylamlne
0.2
suklyakl broth
Shlbamoto et al.. 1981
ND-7.7
beer
Andrzejewskl et al., 1981
3.559 (average)
nonfat dry milk
Sen et al.. 1984
2.7 (average)
fried bacon
Hotchklss et al.. 1980a
-2 wg/g
chewing tobacco from India
Bhlde et al., 1981
200-1400 ng/kg
fried salted yellow croaker
Huang et al., 1981
0.10 (average)
0.09 (average)
0.10 (average)
0.32 (average)
0.58 (average)
1.69 (average)
pasteurized whole milk
pasteurized low-fat milk
pasteurized skim milk
evaporated milk
sweetened condensed milk
nonfat dry milk
Lakrltz and Pensabene, 1981
2.7 (average)
68 (maximum)
draft, bottled and canned beer
Splegelltalder et al., 1979
~ .5
1.8
nonfat dry milk
dried buttermilk
Llbbey et al.. 1980
2.6
cooked bacon
Rounbehler et al., 1980a
0.49
0.26
0.51
0.64
0.93
0.52
corn oil
soybean oil
olive oil
sunflower oil
other edible oils
margarines
Fiddler et al.. 1981
0.2 (average)
0.6 (average
0.6 (average)
4.2
frozen cod and sole fillet
miscellaneous smoked fish
miscellaneous salted/dried fish
salted/dried hake (fish)
Sen et al., 1985
0.3
margarine
Sen and Seaman, 1981
22-110
comnerclally malted barley
Hotchklss et at., 1960b
-------
TABLE 3-? (cont.)
Chemical
Concentration*
Food or Beverage
Reference
N-N1trosodlmethylamlne
(cont.)
trace
trace
trace
trace
cheddar cheese
Cheshire cheese
streaky bacon
uncooked, fresh cod
Alllston et al.. 1972
1.1
1.2
4.2
0.8
2.6
0.3
0.2
0.8
0.4
whole wheat biscuits
whole wheat biscuits
wheaten cornflour
flour
maize meal
rye biscuits
dried peas
dried beans
malt vinegar
Weston, 1984
0.26
crab from Rarltan River, NJ
Fine et al.. 1977a
7.7 (average)
4.0 (average)
5 (average)
0.7 (average)
2.8 (average)
pllser lager beer
low-calorie lager
ale
dark lager
malt lager
Scanlan et al., 1980
0.3
1.0
ISO
skim milk powder
Infant formula
barley malt
Lawrence and Meber, 1984
N-N1trosod1ethylam1ne
1.5
1.5
1.5
Cheshire cheese
fried back bacon
uncooked pig's liver
Alllston et al.. 1972
3
beer
Splegelhalder et al.. 1979
10 ng/kg
100 ng/kg
fried salted yellow cracker
steamed salted yellow cracker
Huang et al., 1981
N-N1trosod1-n-propy1amlne
50 ng/kg
30 ng/kg
steamed salted yellow croaker
fried salted yellow croaker
Huang et al., 1981
N-N1trosod)-n-butylam1ne
50 ng/kg
fried salted yellow croaker
Huang et al., 1981
trace
pork luncheon meat
Alllston et al., 1972
'Concentrations are In ppb unless otherwise specified.
ND = Not detected
-------
contained 0.2 ppb N-n1trosod1methylam1ne; after Incubation, 1t contained 1.3
ppb N-n1trosod1methylam1ne (6.5-fold Increase).
Plant uptake of nltrosamlnes from the soil has also been studied.
N-N1trosod1methylam1ne was shown to be assimilated by the roots and trans-
located to the tops of lettuce and spinach plants (Dean-Raymond and
Alexander, 1976).
N-N1trosod1-n-propylam1ne was found as a contaminant 1n the herbicide
Treflan* (trlfluralln) at a concentration of -150 ppm (Berard and Ralney,
1979). To determine 1f the N-n1trosod1-n-propylam1ne 1n Treflan* would be
taken up by field plants, Berard and Ralney (1979) grew soybeans In field
soil treated with N-n1trosod1-n-propylam1ne at a level corresponding to a
N-n1trosod1-n-propylam1ne-contam1nat1on level 1n Treflan* of 2275 ppm
(15-570 times the expected level from Treflan®). Ihey concluded that the
soybeans harvested from the plants grown In the treated soil were free of
N-n1trosod1-n-propylam1ne residues.
3.3. INHALATION
Exposure to nltrosamlnes through Inhalation may occur 1n occupational
settings or from ambient air. Table 3-3 presents data regarding occupa-
tional exposure to nltrosamlnes. Nltrosamlnes have been found 1n the air at
tire manufacturing plants, chemical companies, surfactant producers,
foundries, fish processers and tanneries. N-N1trosod1ethanolam1ne was found
In the air at manufacturers and users of cutting fluids at concentrations up
to 0.08 yg/m3 (Fajen et al., 1982); a large number of workers may be
exposed to low levels of this compound since cutting fluids are used 1n
metalworklng (for example, welding, tool and die making, plpeflttlng).
Agricultural workers using the herbicide Treflan* (trlfluralln) were found
to be exposed to 0.016 yg N-n1trosodl-n-propylamlne/m3 (Oay et al.,
1982).
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TABLE 3-3
Occupational Exposure to Nltrosamlnos
Chemical
Concentration
Industry or Location
Reference
N-N1trosod1methylam1ne
<47 pg/m1
leather tannery
Rounbehler et al.. 1979
0.1 ng/m»
0.1 pg/m*
dye Industry
foundry
fajen et al., 1982
NR
Sheller-Globe Corp., Keokuk, IA
Lee. 1982
29-21? ppt
Rubbermaid, Inc., Mooster, OH
Albrecht, 1981
0.5 pg/m*
0.14 pg/m*
tire chemical factory
Industrial rubber products factory
Fajen et al., 1979
160 ng/m*
91 ng/m»
140 ng/mJ
amines plant area In Belle, WV
Du Pont plant, Belle, WV
amines pumping area at a plant In Belle, WV
Fine et al.. 1977a
4.4 pg/m»
0.16-0.49 pg/m®
hot process area at a tire manufacturing plant
TWA breathing zone concentration at a tire
manufacturing plant
HcGlothlIn et al.. 1981
1.02 pg/m»
Firestone Tire and Rubber Co., Akron, OH
HcGlothlIn, 1980
11,600 ng/m* (average)
chemical factory In Baltimore, HQ
Fine et al., 1977b
0.01-0.06 pg/m*
0.03 pg/m1 (average)
<0.03-0.01 pg/m»
<0.03 pg/m* (average)
<0.05-47 pg/m'
3.4 pg/m* (average)
0.02-5.5 pg/m'
0.6 pg/m* (average)
0.03-0.8 pg/m'
0.2 pg/m* (average)
fish processing
dye industries
leather Industries
rubber Industries
surfactant
Rounbehler and Fajen, 1983
N-N1trosodlethylamlne
<0.03-0.06 pg/m*
0.04 pg/m* (average)
0.13-1.4 pg/m»
0.77 pg/m' (average)
0.02-1.4 pg/m1
0.26 pg/m' (average)
dye Industries
rubber Industries
foundry
Rounbehler and Fajen, 1983
1.4 pg/mJ
rubber Industries
Fajen et al., 1982
-------
TABLE 3-3 (cont.)
Chemical
Concentration
Industry or Location
Reference
N-Nltrosodlethylamlne
NR
Sheller-61obe Corp., Keokuk, IA
Lee. 198?
100-153 mg/kg
concentration In pesticide active. Ingredient,
dlnltramlne
Zwetg et al., 1980
0.48 ug/m»
Firestone Tire and Rubber Co., Akron, OH
HcGlothlIn, 1980
N-Nltrosod1-n-propylam1ne
0.016 jig/m*
0.015 mQ/"1
breathing zone of field worker applying
Treflan* herbicide
same as above
Day et al., 1982
NR
Sheller-Globe Corp., Keokuk, IA
Lee, 198?
N-NHrosodlethanolanlne
<0.01-0.08 vg/m»
0.01 yg/n' (average)
cutting fluids
Rounbehler and Fajen, 1983
0.08 pg/n*
manufacturers and uses of cutting fluids
FaJen et al., 1982
-120 ng/8 hours
Chrysler Forge and Axle Plant, Detroit, HI
Fan and Fajen. 1978
N-Nltrosod1phenylamtne
0.01-1230 yg/n»
37.5 tig/n* (average)
rubber Industries
Rounbehler and Fajen. 1983
158 nq/n1
Unlroyal, Inc., Hlshawaka, IN (rubber)
Hollett et al.. 1982
47 vg/rn*
tire chemical factory
Fajen et al.. 1979
NR = Not reported
-------
Data on ambient air exposure are given In Table 3-4. The Interior air
of new automobiles contained an average of 0.3 yg N-n1trosod1methyl-
am1ne/ma and 0.11 yg N-n1trosod1ethylam1ne/m3 (Fine et al., 1980).
Nltrosamlnes are also found 1n cigarette smoke (Table 3-5). Brunnemann
et al. (1983) found a maximum n1trosod1methylam1ne concentration of 1880 ng
1n the smoke from one cigarette.
Goff et al. (1980) found that heavy duty dlesel engines emitted from
4.4-136 vg N-n1trosod1methylam1ne/hour. The maximum N-n1trosod1methyl-
amlne concentration In the dlesel crankcase emissions was 17.2 yg/m3.
N-N1trosod1methylam1ne has also been detected 1n the exhaust from catalytic
converter equipped cars (Smith, 1980).
Anderson (1983) reported that -15,000 people In the United States are
exposed to 1 ng N-nUrosodlmethylamlne/m3, while -400,000 are exposed to
0.1 ng N-n1trosod1methylam1ne/ma.
3.4. DERMAL
From the available data, 1t appears that most dermal exposure to nltros-
amlnes will be from cosmetics, toiletries and cutting fluids (Table 3-6).
The most common nltrosamlne found 1n these products appears to be N-nltroso-
dlethanolamlne.
3.5. SUMMARY
N1trosam1nes have been found In wastewaters, wastewater effluents, salt-
water, drinking water and delonlzed laboratory water. N-N1trosod1methyl-
amlne, N-n1trosod1ethylam1ne, N-n1trosod1-n-propylam1ne and N-n1trosod1-n-
butylamlne have been found In foods. Nltrosamlnes have been detected In the
air at tire manufacturing plants, chemical companies, surfactant producers,
foundries, f 1 sh processors and tanneries. Nltrosamlnes have also been
detected In the Interior of new cars (Fine et al., 1980; Rounbehler et al.,
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TABLE 3 4
Nltrosamlnes In Ambient Air
Chemical
Concentration
Industry or Location
Reference
N-N1trosod1methylamlne
32,000 ng/m*
56 ng/«»
S80 ng/m'
East Brooklyn area of Baltimore, MD. November 1975
Union Carbide, So. Charleston, WV, December 1975
Du Pont, Belle, WV, December 1975
Pelizzari, 1V/7
1070 ng/m1 (average)
30-100 ng/m*
residential community near a chemical plant,
Baltimore, MD. August to November 1975
downtown Baltimore, MD, 1975
Fine et al., 1977b
0.07-0.83 vg/<»*
0.29 pg/m' (average)
front passenger area of new automobiles
Rounbehler et al., 1980b
0.03 i»g/m' (average)
Interior of new automobiles
Fine et al.. 1980
0.02-0.05 ng/l
smoke-filled rooms
Stehllk et al.. 19B2
15.6 ng/m1
New York City area
Fine et al., 1977a
0.01-0.2 ng/m»
Paris, May to December 1977
Chuong et al., 1978
0.03-0.15 ng/m*
Hldazubo City, Japan, September 1978 to March 1979
Athara and SMnozakl, 1980
N-NUrosodl ethyl amine
-100 ppt
(Isenhower Tunnel, CO
Pelllzzarl, 1977
0.11 ng/m* (average)
Interior of new automobiles
Fine et al., 1980
0.04-0.39 ug/m»
0.11 ng/m' (average)
front passenger area of new 1979 automobiles
Rounbehler et al., 1980b
N-M1trosodl-n-butylamlne
0.01 pg/ma (average)
Interior of new automobiles
Fine et al.. 1980
-------
TABLE 3-5
N1trosam1nes 1n Cigarette Smoke
N1trosam1ne
Concentration
(ng/clgarette)
Reference
N-N1trosodlmethylamlne
N-N1trosodimethylamlne
N-N1trosomethylethyl amine
N-NHrosodl ethyl amine
N-NHrosodl-n-propylam1ne
N-N1trosodl-n-butylam1ne
5-180
460-1880
<0.3-40
<0.4-28
<0.5-1
<1.0-3
McCormlck et al., 1973
Brunnemann et al., 1983
McCormlck et al., 1973
McCormlck et al., 1973
McCormlck et al., 1973
McCormlck et al., 1973
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TABLE 3-6
Nltrosamlnes Content of Products that may Contact the Dermis
Chemical
Concentration
Industry or
Location
Reference
N-N1trosod1methyl-
amlne
24 yg/kg
(maximum)3
cosmetics and
toiletries
Splegelhalder
and Preussmann,
1984
N-HUrosodlethanol -
amine
1400 yg/kg
(maximum)"
cosmetics and
toiletries
Splegelhalder
and Preussmann,
1984
<10-49,000 ng/g
cosmetic
Fan et al.,
1977a
<10 to >140 ng/g
<10-260 ng/g
lotion
shampoo
5.53 mg/g
(maximum)
cutting fluid
Williams
et al., 1978
0.02-2.99%
synthetic
cutting fluids
Fan et al.,
1977b
300-400 ppm
grinding
fluids0
Rappe and
Zlngmark, 1978
a50/145 samples analyzed contained N-nltrosodlmethylamlne.
^24/145 samples analyzed contained N-n1trosod1ethanolam1ne.
cN-N1trosod1ethanolam1ne In grinding fluids containing trlethanolamlne,
NaNO? and coloring matter.
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1980b), In cigarette smoke (Brunnemann et al., 1983; HcCormlck et al.,
1973), In dlesel crankcase emissions (Goff et al., 1980) and In exhaust Prom
catalytic converter equipped cars (Smith, 1980).
From the available data, 1t appears that most dermal exposure to
nltrosamlnes will be from cosmetics, toiletries and cutting fluids; the most
common nltrosamlne found in these products appears to be N-n1trosod1ethanol-
amlne.
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4. PHARMACOKINETICS
4.1. ABSORPTION
Gastrointestinal uptake of N-n1trosod1methylam1ne by rats Is rapid (D1az
Gomez et al.f 1977; Heading et a!.. 1974; Kunisakl et al., 1978). Of the
radioactivity from a 2 mg/kg oral dose of l4C-d1methyln1trosam1ne, <2% was
recovered from the contents of the stomach or Intestine of four female
Wlstar rats 15 minutes after Intubation (D1az Gomez et al., 1977). The
methylatlon of liver DNA resulting from similar administration of N-nltroso-
dlmethylamlne In the range of 1 yg/kg to 10 mg/kg (four rats/dose) was
directly proportional to dose, suggesting that extent of gastrointestinal
absorption Is Independent of dose. Experiments with Ugated Wlstar rat
stomachs and small Intestines showed that uptake of l4C-N-n1trosod1methyl-
amlne was much more rapid from the small Intestine (50% absorbed In <5
minutes) than the stomach (>50% unabsorbed after 30 minutes (Heading et al.,
1974). An abstract of a Japanese study reported that the disappearance
curve of N-n1trosod1methylam1ne was monoexponentlal within 20 minutes after
Injection Into Ugated guinea pig stomach and small Intestine (Ishlwata et
al., 1977).
Urinary excretion data Indicate that N-n1trosod1ethanolam1ne may be
extensively absorbed by the gastrointestinal tract of male B0 rats. As
detailed 1n Section 4.4., Intubation of 100, 500 or 1000 mg N-nltrosodl-
ethanolamlne/kg In saline resulted In 70-79% excretion of unchanged compound
In the urine within the first 24 hours (Preussmann et al., 1978). In
another study, N-n1trosodlethanolam1ne was detected In the blood of three
male F344 rats 5 minutes after gavage treatment with 50 mg aqueous solution
(Lijinsky et al., 1981a); -30% of the dose was collected as unchanged com-
pound 1n the urine during the first 24 hours (Section 4.4.).
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Limited additional quantitative data were located regarding the gastro-
intestinal absorption of the nltrosamlnes discussed In this document. One
hour after oral administration of 30 mg/kg to goats, levels of N-nltroso-
dlmethylamlne, N-n1trosod1ethylam1ne and N-n1trosodl-n-propylam1ne In the
blood were 10, 11.9 and 1.6 mg/kg, respectively (Juszklewlcz and Kowalskl,
1974).
The gastrointestinal absorption of N-n1trosod1methylam1ne, N-n1troso-
methylethylamlne, N-n1trosod1ethylam1ne, N-n1trosod1-n-propylam1ne, N-n1tro-
sodl-n-butylamlne, N-n1trosomethylv1nylam1ne, N-n1trosod1ethanolam1ne and
H-n1trosodlphenylamlne by rodents Is Indicated by the occurrence of systemic
neoplasia 1n these animals in oral carcinogenicity studies (Section 5.1.).
Intratracheal instillation of 24-38 mg of aqueous N-nltrosodlethanol -
amine resulted In 75-95% urinary excretion (average 89%) of unchanged
compound 1n 10 male SO rats (Preussmann et al., 1981).
N-n1trosod1ethanolam1ne 1s also absorbed dermally. Edwards et al.
(1979) reported that -2% of N-n1trosod1ethanolam1ne that was applied In a
contaminated cosmetic to the chest and back of a volunteer was recovered In
the urine. N-nltrosodlethanolamlne absorption through excised human skin
has also been demonstrated (Bronaugh et al., 1979, 1981). From urinary
excretion data, HarzulU et al. (1981) estimated that 34 and 11.5% of
unspecified doses of uniformly labeled l4C-N-n1trosod1ethanolam1ne were
absorbed by uncovered monkey abdomen skin and pig back skin, respectively,
during 24-hour dermal exposure periods. Similar exposure to N-n1trosod1-
ethanolamlne 1n skin lotion resulted 1n 23.4 and 4.OX mean dermal absorption
by monkeys and pigs, respectively.
Studies using rats have shown that cutaneous application of N-nltrosod1-
ethanolamlne results in peak blood levels within 1-3 hours (LlJInsky et al.,
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1981a; A1rold1 et al., 1984a). The maximum amount of N-nHrosodlethanol-
amlne In the blood of male F344 rats 1 hour after the application of 50 mg
of undiluted compound was calculated to be 78% of the applied dose (Lljlnsky
et al., 1981a). A1rold1 et al. (1984a) used blood level/time data following
cutaneous application of 5 mg N-n1trosod1ethanolam1ne/kg {1:1 water:acetone
vehicle) to male CD-COBS rats to calculate bioavailability to be 27%.
Elimination studies summarized 1n Section 4.4. Indicate that 24-hour urinary
excretion of unchanged N-n1trosod1ethanolam1ne by rats range from -3-80% of
the topical dose (Alroldl et al., 1984a; Lethco et al., 1982; Lljlnsky et
al., 1981a; Preussmann et al., 1981).
4.2. DISTRIBUTION
Whole-body (hemlsectlon) low temperature autoradiography was used to
study the distribution of 14C-N-nUrosodlmethylam1ne In groups of one
C57/B1 mice following Intravenous Injection of 1.7 mg/kg (Johansson and
Tjalve, 1978). Results obtained from the use of metabolic Inhibitors
Indicated a uniform distribution of unmetabollzed N-n1trosod1methylam1ne.
Radioactivity was concentrated In the liver and cortex of the kidney 1-30
minutes following Injection, reportedly reflecting degradatlon/alkylatlon
reactions. Subsequently (1-24 hours, 5 days), radioactivity was concen-
trated 1n tissues with rapid cell turnover (e.g., blood-forming organs,
lymphoid system, gastrointestinal mucosa) and high rates of protein synthe-
sis {e.g., exocrine, pancreas, salivary glands); evidence Indicated that
this was attributable to Incorporation of radioactivity from 14C-formal-
dehyde metabolite Into the one-carbon pool.
Intravenous administration of 50 mg N-n1trosodlmethylam1ne/kg to Porton
strain rats resulted 1n uniform distribution (similar concentrations) In the
liver, kidney, spleen, brain, heart and lungs, Intestinal tract and carcass
when determined 0.5, 1, 2 or 4 hours after Injection (Hagee, 1956); one rat
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at each sacrifice time was analyzed. In another experiment with two rats,
1t was determined that N-n1trosodlmethylam1ne concentration In the blood was
similar to concentrations 1n the above tissues 4 hours after Injection.
It was noted 1n the abstract of a Japanese study that oral administra-
tion of an unspecified dose of N-n1trosod1methylam1ne to rats resulted In
maximum concentrations of N-n1trosod1methylam1ne In the blood, liver and
kidney In 1 hour (Kun1sak1 et al., 1978); subsequently, concentrations
rapidly decreased and N-n1trosod1methylam1ne was not detectable after 4
hours.
Whole body autoradiography of Sprague-Dawley rats 1 minute after Intra-
venous Injection of l4C-N-n1trosod1-n-butylam1ne showed that the highest
concentration of radioactivity occurred In the nasal mucosa, liver and
preputial gland (Brlttebo and TJalve, 1982). Radioactivity was also concen-
trated In the urine, kidneys, tracheobronchial mucosa and esophagus mucosa
after 5 minutes. Rats killed 30 minutes and 4 hours postlnjectlon showed,
In addition to the above tissues, high radioactivity in the Intestinal
contents. The highest concentration of radioactivity 24 hours after
Injection was In the mucosa of the esophagus and tongue and In the preputial
glands; radioactivity had decreased considerably In the nasal/tracheo-
bronchlal mucosa. Distribution of N-n1trosod1-n-butylamlne was considered
to be uniform because other experiments indicated that labeling In the above
tissues was consistent with local metabolism and because radioactivity was
evenly distributed In tissues other than those Indicated above.
Wlshnok et al. (1978) monitored concentrations of N-n1trosod1methyl-
amine, N-nltrosod1ethylam1ne and N-n1trosod1-n-butylamlne In the blood of
male Sprague-Oawley rats following Intraperitoneal Injection of 3 mg/kg (In
saline), 25 mg/kg (In saline) and 100 mg/kg (undiluted), respectively. The
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disappearance of each of these from the blood showed first-order kinetics,
and the corresponding half-lives (calculated from reported rate constants)
were 38.5, 40.6 and 69.3 minutes. Hepatic clearance of N-nitrosodlethyl-
amlne and N-n1trosod1-n-butylam1ne also followed first-order kinetics
(half-Hves of 49.5 and 69.3 minutes, respectively), but the time dependence
of N-nltrosodlmethylamlne concentration In liver tissue was anomalous.
Apparent volumes of distribution were also calculated for these nltrosamlnes
(Wlshnok et al., 1978). Distribution volumes of 1.1 and 1.2 for N-nltroso-
dlmethylamlne and N-n1trosod1-n-butylam1ne, respectively, suggest near even
distribution throughout the body, although a high CQ liver value for
N-nltrosodl-n-butylam1ne Indicates possible concentration In the liver. It
was noted that N-nltrosodA-n-butylamlne has a hexane/phosphate buffer parti-
tion coefficient (117) that favors solubility In nonaqueous media, whereas
N-nltrosodlmethylamlne and N-n1trosod1ethylam1ne have partition coefficients
(0.03 and 0.53, respectively) that favor solubility In aqueous media.
Radioactivity from single oral doses of aqueous uniformly-labeled
l4C-N-n1trosod1ethanolam1ne (0.5 or 50 mg/kg) was distributed to all
organs and tissues (21) In Osborne-Hendel rats (Lethco et al., 1982).
Groups of one or two rats were sacrificed 4, 8, 24, 48, 96 and 168 hours
after administration. In addition to the stomach and Intestines, the
highest concentrations were found 1n the liver, kidneys, bladder and urine.
Tissue levels peaked after 8 hours, but some activity (highest In the liver)
remained after 1 week. The dose had little effect on the distribution
pattern. Topical application of 0.5 and 50 rag l4C-N-n1trosod1ethanol-
amlne/kg 1n acetone resulted In similar patterns of distribution, but the
compound was slowly but continuously absorbed over 1 week.
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Blood concentration-time plots following the Intravenous administration
of N-n1trosod1ethanolam1ne (5 mg/kg 1n saline) in male CD-COBS rats showed a
triphasic profile with apparent half-Hves (calculated from rate constants)
of 9.6 minutes, 1.2 and 5.8 hours (Alroldl et al., 1984a). The different
rate constants suggest a fast Initial distribution of N-n1trosod1ethanol-
amlne and slower elimination from the body, consistent with a 3-compartment
pharmacokinetic model. Hepatic N-n1trosod1ethanolam1ne levels paralleled
blood levels following treatment. Indicating that this organ does not
significantly accumulate N-n1trosod1ethanolam1ne to a significant extent.
The organospedflc carcinogenic effects of the nltrosamlnes (Section
5.1.), such as the respiratory tract (mainly the trachea) 1n hamsters,
appear to be related to tissue specific metabolism rather than preferential
distribution or accumulation.
Transplacental distribution of several of the aliphatic nltrosamlnes has
been demonstrated In hamsters. Althoff et al. (1977) reported that
N-n1trosod1methylam1ne, N-n1trosod1ethy1am1ne, N-n1trosodl-n-propylamlne and
N-n1trosod1-n-butylam1ne reached fetal tissue In measurable amounts follow-
ing subcutaneous administration of an unspecified dose to Syrian hamsters.
N-Nltrosodlmethylamlne, N-n1trosod1ethylam1ne and N-n1trosodl-n-propylam1ne
reportedly were present for <2 hours In maternal blood, placenta, fetus and
amniotic fluid, but N-n1trosodl-n-butylam1ne was still measurable (not
elaborated) after 6 hours. After Intraperitoneal Injection of 50 mg/kg,
N-n1trosod1-n-butylamlne reportedly also crossed the placenta of Syrian
hamsters and reached fetal tissues unaltered (Althoff et al., 1976).
Unmetabollzed N-n1trosod1methylam1ne and N-n1trosod1ethylam1ne cross the
placenta of NMRI mice following Intravenous administration and are evenly
distributed In most fetal tissues, although metabolites may be localized for
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short periods In specific tissues such as the respiratory tract and liver
(Johansson-Brlttebo and Tjalve, 1979; Brlttebo et al., 1981). Transpla-
cental carcinogenicity of N-nltrosodlmethylamlne, N-n1trosod1ethylam1ne and
N-n1trosod1-n-butylam1ne has been demonstrated 1n hamsters, mice or rats
following Injection or oral administration (IARC, 1978; Alexandrov, 1968;
Oruckrey, 1973a,b; Althoff and Grandjean, 1979; Reznlk-Schuller and
Tomaszewskl, 1980); these studies Indicate transplacental distribution of
the unaltered nltrosamlnes and/or metabolites.
4.3. NETABOLISH
Studies of the metabolism of the nltrosamlnes have been related primar-
ily to elucidation of the mechanisms of carcinogenic action, particularly
tissue-specific activation and alkylatlon. An overview of metabolism,
primarily based on the review of Schut and Castonguay (1984), is presented
because Independent review of the considerable number of available studies
Is beyond the scope of this report. The pathways outlined are Indicated or
Inferred from vivo and .In vitro studies with various species.
The metabolism of N-n1trosod1methylam1ne, N-n1trosod1ethylam1ne and
N-nltrosomethylethylamlne appears to follow a common pathway In which the
a-carbon Is hydroxylated (Schut and Castonguay, 1984). The resulting
a-hydroxy N-n1trosam1ne has a very short lifetime under physiological
conditions and rearranges to an aldehyde and primary nltrosamlne. The
primary N-n1trosam1ne can tautomerlze to a dlazohydroxlde that. In the
cytosol, 1s In equilibrium with unstable alkyldlazonlum 1on. The alkyldla-
zonlum 1on can react directly with cellular nucleophlles or lose nitrogen to
yield a carbonlum 1on. In vitro studies suggest that N-n1trosod1methylam1ne
Is metabolized by the human liver and lung by the same metabolic pathway as
other mammalian species (IARC, 1978; Schut and Castonguay, 1984).
0748p
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Limited evidence Indicates that N-nltrosodl-n-propylamlne can be
hydroxylated on the a-carbon, resulting In formation of proplonaldehyde,
1-propanol and 2-propanol (Schut and Castonguay, 1984). The propanols
apparently form by tautomerlzatlon of n-propyln1trosamlne and subsequent
formation of n-propylcarbon1um Ion. Secondary pathways Include B-carbon
hydroxylatlon and w-carbon oxidation.
Metabolism of N-nltrosodl-n-butylamlne proceeds by hydroxylatlon at the
w-, a- and fl-carbons of one butyl chain (Schut and Castonguay, 1984;
Suzuki and Okada, 1980, 1985), but the major pathways are the u- and
a-ox1dat1ons, which yield N-butyl-N-(3-carboxypropylJnltrosamlne and
N-butyl-N-(3-hydroxybutyl)n1trosam1ne, respectively. The hydroxynltros-
amlnes are either excreted Into the urine unchanged or as glucuronic acid
conjugates, or are further oxidized. Oxidation of the unconjugated
w-carbon hydroxylatlon product to N-butyl-N-(3-carboxypropyl)nltrosam1ne
Is considered to be Involved In the Induction of bladder tumors 1n rats,
apparently by subsequent B-oxldatlon by the bladder mucosa. N-nltrosodl-n-
butylamlne Is extensively metabolized by rats (no unchanged compound Is
found In the urine) and N-butyl-N-(3-carboxylpropyl)nltrosam1ne 1s the
principal (~10%) urinary metabolite (Suzuki and Okada, 1980).
Limited data are available regarding the metabolism of N-nltrosodl-
ethanolamlne, but jm vitro evidence shows that N-(2-hydroxyethyl)-N-(formyl-
methyl)n1trosam1ne and N-(2-hydroxyethy1)-N-(carboxymethyl)nltrosamlne are
formed as a result of B-oxIdatlon (Alroldl et al., 1984b). As detailed In
Section 4.4., large percentages of oral, Intratracheal and cutaneous doses
of N-n1trosodlethanolam1ne are excreted unchanged In the urine by rats
(Preussmann et al., 1978, 1981; Lljlnsky et al., 1981a; Lethco et al., 1982;
Alroldl et al., 1984a); these findings might explain the relatively low
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carcinogenic potential of this compound. Approximately 2% of orally-
administered and OX of subcutaneously-admlnlstered N-n1trosod1ethanolam1ne
was eliminated as CO^ by rats and hamsters, respectively (Schut and
Castonguay, 1984).
N-N1trosod1phenylam1ne was denltrosated to nitric oxide and dlphenyl-
amlne In the rat, with subsequent conversion of the nitric oxide Into
nitrite and nitrate (Appel et al., 1984). Reductive metabolism of N-n1tro-
sodlphenylamlne to the corresponding hydrazine derivative was demonstrated
In guinea pigs (Tatsuml et al., 1983).
4.4. EXCRETION
Limited Information 1s available regarding excretion of the N-nltros-
amlnes discussed 1n this document, 1n part because many are rapidly metabo-
lized. Hagee (1956) administered 50 mg N-nUrosodlmethylamlne/kg orally to
two rats, and recovered 1.7% of the dose as unchanged compound In the urine
within 23 hours; -0.6% of the dose appeared In the urine within 4.5 hours,
and negligible quantities were recovered In the urine after 24 hours and In
the feces after 23 or 24 hours. Unspecified Injection of 14C-labeled
N-n1trosod1methylam1ne and N-n1trosod1ethylam1ne to rats at doses slightly
below the median lethal level produced -60 and 45% of the radioactivity,
respectively. In exhaled C0? within 12 hours (Hagee et al., 1973); the
corresponding urinary excretions were 4 and 14%, respectively.
Preussmann et al. (1978) administered N-n1trosod1ethanolam1ne to male
BD-V1 rats by gavage at doses of 100, 500 and 1000 mg/kg In saline and found
that 72% (range 60-83%, nine rats), 79% (range 56-95%, eight rats) and 70%
(range 56-82%, 10 rats), of the administered doses, respectively, were
excreted unchanged 1n the urine. Hore than 95% of the excreted amounts were
recovered within 24 hours of administration with very little (unspecified)
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recovered between 24 and 48 hoars. About 30% of a 50 mg/kg dose of aqueous
N-n1trosod1ethanolamlne was collected 1n the urine of four F344 rats during
the first 24 hours (Ujlnsky et al., 1981a). Approximately 69 and 87% of
the radioactivity of oral doses of 0.5 and 50 mg J4C-N-n1trosod1ethanol-
amlne was recovered In the urine of Osborne-Mendel rats In 24 hours (Lethco
et al., 1982); recovery was similar after 48 hours and essentially complete
after 96 hours (-104 and 93%, respectively).
Intratracheal Instillation of 24-38 mg of aqueous N-n1trosod1ethanol-
amlne to 10 male SO rats resulted In 75-95% (average 89%) urinary excretion
of unchanged compound within 24 hours (Preussmann et al., 1981).
Cutaneous application of 90-184 mg aqueous N-n1trosod1ethanolam1ne to
male SD rats resulted 1n considerable excretion of unchanged compound 1n the
urine within 24 hours (Preussmann et al., 1981). Ujlnsky et al. (1981a)
applied 50 mg of undiluted N-n1trosod1ethanolam1ne to the skin of male F344
rats and found that 20-33% appeared as unchanged compound 1n the urine 1n 24
hours. Urinary excretion of unchanged H-n1trosod1ethanolam1ne and Us
metabolite, N-(2-hydroxyethyl)-N-carboxymethyln1trosam1ne, by male C0-C0BS
rats was 25+6% and 2.5^0.4% of a topically applied dose (5 mg/kg In 1:1
water:acetone vehicle), respectively, after 24 hours (A1rold1 et al., 1984a).
4.5. SUMMARY
Gastrointestinal absorption of N-n1trosod1methylam1ne and N-n1trosod1-
ethanolamlne by rats 1s rapid and extensive (D1az Gomez et al., 1977; Head-
ing et al., 1974; Ishlwata et al., 1977; Kunlsakl et al., 1978; Preussmann
et al., 1978; L1j1nsky et al., 1981a). Specific Information regarding the
other N-n1trosamlnes 1s not available, but gastrointestinal absorption of
N-nltrosomethylethylamlne, N-n1trosod1ethylam1ne, N-n1trosod1-n-propylamlne.
0748p
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N-n1trosod1-n-butylam1ne, N-nttrosomethylvtnylamlne and N-n1trosod1phenyl-
amlne by rodents and other species 1s Indicated by the occurrence of
systemic effects In oral carcinogenicity studies with these compounds.
N-N1trosod1ethanolam1ne Is also moderately to extensively absorbed by rats
following Intratracheal Instillation (Preussmann et al., 1981) and by rats
(Lljlnsky et al., 1981a; Preussmann et al., 1981; Lethco et al., 1982;
A1rold1 et al., 1984a) and monkeys (MarzulU et al., 1981) following dermal
application. Limited evidence Indicates that N-n1trosod1ethanolam1ne can be
absorbed by human skin (Edwards et al., 1979; Bronaugh et al., 1979, 1981).
N-N1trosod1methylam1ne, N-n1trosod1-n-butylam1ne and N-n1trosod1ethanol-
amlne are rapidly and uniformly distributed to all tissues of rats or mice
following Intravenous Injection or oral administration (Johansson and
Tjalve, 1978; Magee, 1956; Kunlsakl et al.. 1978; Wlshnok et al., 1978;
Brlttebo and Tjalve, 1982; Lethco et al., 1982). The highest concentrations
occurred In the liver and kidneys, and tissue levels In rats peaked 8 hours
after oral administration of N-n1trosod1ethanolam1ne (Lethco et al., 1982).
Transplacental distribution of unmetabollzed N-n1trosod1methylam1ne,
N-n1trosod1ethylam1ne, N-n1trosod1-n-propylamlne and N-n1trosod1-n-butyl-
amlne has been demonstrated In hamsters and mice following Injection
(Althoff et al., 1976, 1977; Johansson-Brlttebo and Tjalve, 1979; Brlttebo
et al., 1981). Transplacental distribution of N-n1trosodlmethylam1ne,
N-n1trosod1ethylam1ne and N-n1trosod1-n-butylamlne and/or their metabolites
1n hamsters, mice or rats 1s Indicated by transplacental carcinogenicity of
these nltrosamlnes following Injection or oral administration (IARC, 1978;
Althoff and Grandjean, 1979; Reznlk-Schuller and Tomaszewskl, 1980).
N-N1trosod1methylam1ne, N-n1trosomelhylethylam1ne and N-nltrosodlethyl-
amlne appear to be metabolized by a common pathway 1n which the a-carbon
Is hydroxylated (Hontesano and Bartsch, 1976; Schut and Castonguay, 1984).
0748p
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With the longer chain N-n1trosod1alky1amlnes, 6-ox1dat1on or -oxidation
may occur In addition to a-C-hydroxylat1on. Oxidative monodealkylatlon by
microsomal enzymes subsequently occurs, and the aldehyde that Is generated
1s further oxidized to yield CO^. Generally, the monoalkylnltrosamlne
decomposes to generate alkylating Intermediates. N-N1trosod1ethanolam1ne 1s
primarily eliminated as unmetabol1zed compound 1n the urine. Limited
evidence Indicates that N-n1trosod1phenylam1ne may be denltrosated to nitric
oxide and dlphenylamlne, with subsequent conversion of the nitric oxide Into
nitrite and nitrate, or reductlvely metabolized to the corresponding
hydrazine derivative (Appel et al., 1984; Tatsuml et al., 1983).
N-N1trosod1methylam1ne, N-n1trosod1ethylam1ne and N-n1trosod1ethanol-
amlne appear to be rapidly eliminated (essentially within 24 hours) by the
urine as unchanged compound or metabolites and by the lungs as CO^ follow-
ing Injection, oral or Intratracheal administration {Magee, 1956; Magee et
al., 1973; Preussmann et al., 1978, 1981; Lljlnsky et al., 1981a; Lethco et
al., 1982).
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5. EFFECTS
5.1. CARCINOGENICITY
The carcinogenic activity of n-nUrosam1nes, 1n general, 1s well estab-
lished. Carcinogenicity has been demonstrated for many of the members of
the class In numerous species exposed by natural (primarily oral) and paren-
teral routes for short as well as long durations. Tumors have been Induced
1n a variety of tissues with many of the compounds exhibiting target organ
specificity that may be modified by the route of administration. The
response to particular compounds also varies among species; neonatal and
young animals are particularly sensitive. Reviews of the carcinogenicity of
N-nltrosamlnes (and other N-n1troso compounds) have been prepared by Magee
et al. (1976) and U.S. EPA (1980a), and many of the specific compounds were
reviewed by 1ARC (1982).
The carcinogenicity of N-n1trosod1methylam1ne, N-n1trosod1ethylam1ne,
N-n1trosod1-n-propylamlne and N-n1trosod1-n-butylam1ne has been established
unequivocally 1n numerous studies. Host of these studies, however, tend to
address structure-activity relationships or mechanisms of action or used the
compounds (particularly N-n1trosod1ethylam1ne) as tumor Inducers, and used
exposure duration or routes that are Inappropriate for quantitative risk
assessment. Also, relatively few of the studies provided dose-response
data. Therefore, because of the overwhelming number of carcinogenicity
studies with N-n1trosod1methylam1ne, N-nUrosod1ethylam1ne, N-n1trosod1-n-
propylamlne and N-n1trosod1-n-butylam1ne, only those of greatest relevance
to quantitative risk assessment will be summarized. The carcinogenicity of
the other d1-n-alkyln1trosam1nes that are of concern In this report
(N-nHrosomethylethylamlne, N-n1trosomethylv1nylam1ne and N-n1trosod1-
ethanolamlne) and N-n1trosod1phenylam1ne 1s less extensively documented and
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all relevant Information will be summarized. Data regarding the carcino-
genicity of p-n1trosod1phenylam1ne could not be located in the available
literature as cited 1n the Appendix.
5.1.1. N-N1trosod1methylam1ne. Magce and Barnes (1962) administered
N-n1trosod1methylam1ne dissolved In arachls oil 1n the diet of Porton strain
female rats (6/group) at concentrations of 5, 10 and 20 ppm for 104, 102 and
102 weeks, respectively. The Incidences of hepatocellular carcinomas 1n
rats surviving >30 weeks were 0/6 (5 ppm), 2/6 (10 ppm) and 5/5 (20 ppm).
Kidney tumors did not occur and a control group was not used.
Druckrey et al. (1967) administered 4 mg N-n1trosodlmethylam1ne/kg/day
In the drinking water to 20 BD rats of unspecified sex 5 days/week. The
duration of treatment was not specifically reported but appears to be for
life. Hepatocellular carcinomas developed in 11/20 of the rats after an
average Induction time of 270 days (average total dose to Induce tumors 1n
50% of the animals, 0.4 g/kg). Control data were not reported. This
experiment was part of a carcinogenicity survey of 65 N-n1troso compounds.
An extensive study has been conducted In which groups of 48, 6-week-old
Colworth rats of each sex were exposed to 0.033, 0.066, 0.132, 0.264, 0.528,
1.056, 1.584, 2.112, 2.640, 3.168, 4.224, 5.280, 6.336, 8.448 or 16.896 ppm
N-nltrosod1methylamlne 1n the drinking water (Peto et al., 1984). Six rats
from each group were sacrificed after 6 and 12 months of treatment, and the
remainder were allowed to live until natural death. The approximate dally
water consumption was reported to be 41 and 72 mi/kg In adult males and
females, respectively. Untreated control groups consisting of 192 rats of
each sex were maintained similarly with 24 rats from each group sacrificed
after 6 and 12 months. The extent of pathological examinations was not
specifically Indicated but, with the exception of liver tumors, all tumors
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were classified as benign or malignant. A general statement regarding
survival Indicated that most animals given the eight lowest doses survived
well Into old age (median, 31 and 28 months of treatment In the males and
females, respectively), while most of those In the eight highest treatment
groups died earlier from tumors. Tumors occurred primarily In the liver,
and mortality from the combination of all causes other than tumors of the
liver was not significantly related to treatment. Pooled data from both
sexes Indicated possible positive trends for tumors In the lung, skin,
seminal vesicles and lymphatlc/hematopoletlc system. Additional specific
Information regarding the design or results of this study (Including tumor
Incidences for Individual treatment groups) was not reported, however,
because the purpose of the report was extensive Welbull analysis of the
liver tumor dose-response data. Analysis of the liver tumor (all types)
dose-response data showed the following relationships of cumulative
Incidence (CI) to dose (d) In mg/kg/day and time (t) In years:
CI = 37.43(d»-0.1 )*t7 (males)
CI = 51,45(d + 0.1)H7 (females)
As Indicated, the rate of onset of liver tumors 1s proportional to approxi-
mately the seventh power of the duration of exposure at a given dose level.
Peto et al. (1984) noted that a detailed report of this study was drafted by
the United Kingdom government departments that sponsored this study but a
publication date was not Indicated.
Terraclnl et al. (1967) summarized the results of various experiments In
which groups of 5-62 Porton strain rats of both sexes (4-6 weeks old) were
exposed to N-nltrosodlmethylamlne In the diet (arachls oil vehicle) at
concentrations of 0, 2, 5, 10, 20 or 50 ppm for up to 120 weeks. Upon
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necropsy, histological examinations of the liver, kidneys and macroscopic-
ally abnormal tissues were conducted on all rats. Treatment-related tumors
occurred only 1n the liver; Incidences are tabulated In Table 5-1. It
should be recognized that these data were gathered from an unspecified
number of experiments conducted over a period of years rather than from a
single multldose study
Groups of 24 s1x-week-old Wlstar rats of each sex were given diets
containing 0.1, 1.0 or 10.0 ppm N-n1trosod1methylam1ne for 96 weeks (Aral et
al., 1979). Control groups consisted of 18 untreated rats of each sex.
Surviving rats were sacrificed In the 96th experimental week and subjected
to complete necropsies that Included limited histological examinations
(liver, kidneys, spleen). N-n1trosod1methylam1ne had no clear effect on
survival as Indicated by the effective number of rats at the end of treat-
ment, body weight gain or food consumption. As detailed In Table 5-2, low
Incidences of tumors occurred 1n the livers of the rats In the 1.0 and 10.0
ppm groups. Renal tumors or renal hyperplasia were not found In any of the
rats In this study. Interstitial cell tumors of the testis also occurred at
higher Incidences In treated rats than the controls.
N-N1trosod1methylam1ne of unreported purity was administered to 20,
7- to 8-week-old F344 rats In drinking water at doses that provided 0.66 mg
compound/day (LlJInsky and Reuber, 1981). Unspecified numbers of rats of
both sexes were Included 1n the treatment group and treatment was 5 days/
week for 30 weeks. Controls were not Included In this study. Complete
necropsies that Included histological examination of all lesions and unspec-
ified major organs were conducted at the time of natural death or sacrifice
when moribund; there were no survivors at 20 weeks postexposure.
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TABLE 5-1
Dietary Administration of N-N1trosod1methylam1ne In
Arachls Oil to Porton Strain Rats3
Sex
Dose
(ppm)
Duration of
Treatment
(weeks)b
Duration
of Study
(weeks)"
Target
Organ
Tumor
Typec
Tumor
Incldenc*
F
50
104
104
liver
hepatoma
10/12
F
20
104
104
11ver
hepatoma
15/23
F
10
104
104
1 Iver
hepatoma
2/5
F
5
104
104
1 Ivor
hepatoma
4/62
M
5
104
104
11ver
hepatoma
1/6
F
5
62
104
1 Iver
hepatoma
3/15
F
2
104
104
1 iver
hepatoma
0/18
H
2
104
104
liver
hepatoma
1/19
F
0
104
104
liver
hepatoma
0/29
M
0
104
104
liver
hepatoma
0/12
QUALITY OF EVIDENCE
Strengths of Study: Multiple doses and a long duration; exposure In diet.
Weaknesses of Study: Data were from an unspecified number of separate
experiments conducted over a period of years rather
than a single multldose study. Statistical analysis
of data was not conducted.
Comments: Purity not reported; vehicle (arachls oil) controls
were used.
aSource: Terraclnl et al., 1967
bSurv1vors at 104 weeks were usually killed, but a "few" animals (number
and treatment group not specified) were treated for 120 weeks.
c33 of the 36 hepatomas were hepatocellular carcinomas.
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TABLE 5-2
Chronic Administration of N-N1trosod1methylam1ne
to Wlstar Rats In Diet for 96 Weeksa»b
Sex Dose Target Tumor lype Tumor
(ppm) Organ Incidence
0
liver
hepatocellular carcinoma
0/7
liver
hemangioendothelioma
0/7
liver
fibrosarcoma
0/7
1 Iver
nodular hyperplasia
0/7
testis
Interstitial cell
2/7
0.1
liver
hepatocellular carcinoma
0/9
1 Iver
hemangloendothel1oma
0/9
1 Wer
fibrosarcoma
0/9
11ver
nodular hyperplasia
0/9
testis
Interstitial cell
4/9
1.0
1 Iver
hepatocellular carcinoma
1/15
11ver
hemangloendothelloma
0/15
1 Iver
fibrosarcoma
1/15
11ver
nodular hyperplasia
1/15
testis
Interstitial cell
9/15
10.0
1 Iver
hepatocellular carcinoma
1/17
liver
hemangloendothelloma
3/17
liver
fibrosarcoma
5/17
1 Iver
nodular hyperplasia
6/17
testis
Interstitial cell
9/17
0
1 Iver
hepatocellular carcinoma
0/12
1 Iver
hemangloendothelloma
0/12
liver
fibrosarcoma
0/12
1 Iver
nodular hyperplasia
0/12
0.1
1 Iver
hepatocellular carcinoma
0/17
1 Iver
hemangloendothelloma
0/17
11ver
fibrosarcoma
0/17
1 Iver
nodular hyperplasia
0/17
1.0
liver
hepatocellular carcinoma
3/17
1 Iver
hemangloendothelloma
1/17
1 Wer
fibrosarcoma
0/17
1 Iver
nodular hyperplasia
6/17
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TABLE 5-2 (cont.)
Sex Dose
Target Tumor Type
Tumor
(ppm)
Organ
Incidence
F 10.0
liver hepatocellular carcinoma
2/9
liver hemangioendothelioma
3/9
liver fibrosarcoma
0/9
liver nodular hyperplasia
4/9
QUALITY OF EVIDENCE
Strengths of Study:
Long duration and multiple dose levels.
Weaknesses of Study:
Small numbers of animals and histological
examinations
limited In scope.
Comments:
Purity not reported.
aSource: Aral et al., 1979
^Duration of treatment (96 weeks) = duration of study
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Eighteen of the 20 rats died with tumors that occurred primarily 1n the
liver (hemanglosarcomas In 17/20) and lung (metastases of liver hemanglo-
sarcomas In 17/20); related nonneoplastic findings Included hemoperItoneum
1n 12/20 rats.
The results of a subchronlc drinking water study with rats exposed to
lower doses of N-n1trosod1methylam1ne have been reported (L1j1nsky and
Reuber, 1984a). N-N1trosod1methylam1ne of unspecified purity was adminis-
tered at concentrations of 5.5 and 13 mg/i, to groups of 20 female 7- to
8-week-old F344 rats, 5 days/week for 30 weeks. Cages of four rats were
given 80 ml of the water solutions on each treatment day; since "almost"
all of the solutions were consumed with "little" spillage, -0.11 and 0.26
mg/day were provided to each rat In the low- and high-dose groups, respec-
tively. Following the treatment period, the rats were observed until death
or 110 weeks (16/20 and 1/20 low-dose rats were alive at weeks 80 and 110,
respectively, and 15/20 and 0/20 high-dose rats were alive at weeks 70 and
100, respectively) when all gross lesions, major organs and tissues, Includ-
ing nasal cavities, were histologically examined. Groups of 20 rats of each
sex served as controls. Treatment-related tumors occurred only In the
liver; Incidences In the control, low- and high-dose groups for carcinomas
were 0/20, 9/20 and 10/20, respectively. The Incidence of hemanglosarcomas
and neoplastic nodules were 0/20, 0/20 and 7/20, and 2/20, 5/20 and 2/20 1n
the control, low- and high-dose groups, respectively. The total number of
animals with carcinomas, hemanglosarcomas or neoplastic nodules were 2/20
(controls), 14/20 (low dose) and 17/20 (high dose).
Crampton (1980) reported preliminary results of a 15 dose drinking water
study conducted with groups of 60 Ulstar rats/sex. Mean dally dosages of
N-n1trosod1methylam1ne ranged from 2-1080 »ig/kg for males and 3-1470
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yg/kg for females. The lowest concentrations at which significantly
(p<0.05) Increased Incidences of unspecified liver tumors occurred were 132
ppb In males and 264 ppb 1n females; survival periods below these levels
were >900 and >800 days, respectively. Hyperplastic nodules were observed
at all treatment levels. Additional relevant Information regarding the
design or results of this study {e.g., treatment levels, tumor Incidences)
were not reported. Experiments 1n which N-n1trosod1methylam1ne was adminis-
tered to groups of 10 or 12 mice and hamsters at 15 dose levels postweanlng
and after 20 weeks of age were also conducted, but additional Information
was not provided.
Twenty 8-week-old male ICR mice were exposed to 50 ppm N-n1trosod1-
methylamlne In the diet (peanut oil vehicle) for 10 months (Takayama and
Oota, 1965). The average Intake of N-n1trosodlmethylam1ne/mouse was report-
ed to be 9.04 mg/kg/day. "Thorough" necropsies and histological examina-
tions of unspecified organs showed that treatment-related tumors occurred 1n
the livers (hemangloendothellal sarcomas In 4/17) and lungs (adenomas 1n
8/17, carcinomas In 5/17). Untreated mice of this strain (ICR) were not
Included In this study.
Clapp et al. (1968) administered N-n1trosod1methylam1ne 1n the drinking
water at a concentration of 5 mg/a to a group of 126 eight- to 10-week-old
male RF/Un mice for life. Water consumption data Indicated that the dally
Intake was 0.94 mg/kg. Groups of four mice were sacrificed and necropsled
after 3, 4, 5, 6, 7, 8, 9 and 12 months of treatment, and the remaining mice
were necropsled when moribund or at the time of natural death. Lungs,
livers, kidneys, spleens and unspecified tissues from -70% of the mice were
histologically examined. A group of 162 similarly handled untreated males
served as controls. Lung adenomas and liver tumors occurred In 93/94 and
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90/94 of the histologically examined mice, respectively {63/162 and 7/162 In
the controls, respectively). Most (84/90) of the Hver tumors were
hemanglosarcomas) although hemangioendotheliomas occurred In 5/90 mice.
Survival time was 40% shorter 1n the treated mice than 1n the controls (mean
was 306 and 553 days, respectively); death was apparently due to rupture of
the liver tumors. N-N1trosodlmethylamlne treatment was not leukemogenlc.
Groups of 17-94 male RF/Un strain mice, 8-10 weeks old, were treated
with N-n1trosod1methylam1ne of unspecified purity 1n the drinking water at
concentrations that provided dally doses of 1.8, 0.40, 0.43 and 0.91 mg/kg
bw for 49 days, 224 days, life (average 406 days) and life (average 266
days), respectively (Clapp and Toya, 1970). Mean survival time was reported
to be 15, 19, 17 and 12 months, respectively. A group of 262 untreated male
mice that survived for an average of 20.5 months served as controls. Mice
were necropsled at the time of natural death or sacrificed when moribund,
but unspecified tissues for histological examination were taken from -70% of
the mice. As detailed 1n Table 5-3, treatment-related tumors occurred In
the liver (hemanglosarcomas) primarily In the lifetime studies and In the
lungs (adenomas). Leukemia Incidences were similar In the treated and
control groups. It should be noted that there was a high spontaneous
Incidence of lung adenomas In the control group.
A subsequent study evaluated tumorlgenesls In a strain of mice (Balb/c)
with lower spontaneous Incidences of tumors (Clapp et al., 1971). A group
of 18 males were given N-n1trosod1methylam1ne In the drinking water at a
concentration that provided 1.7 mg/kg bw/day for -177 days (cumulative dose,
300 mg/kg). The mice were observed until natural death or when moribund
(experiment terminated after 210 days; mean observation, 182 days).
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TABIE 5-3
Administration of N-Nltrosodlmethylamlne In Drinking Hater to Hale RF/Un Strain Mice3
Duration of Duration
Dose Treatment of Studyb Target Tumor Type Tumor
(mg/kg/day) (days) (months) Organ Incidence
0
0
20.5
liver
1 Iver
lung
hemanglosarcoma
hepatocellular carcinoma
adenoma
1/20
7/174
97/250
1.8
49
15
1 iver
11ver
lung
hemanglosarcoma
hepatocellular carcinoma
adenoma
9/68
0/68
82/03
0.40
224 .
19
1 Iver
1 Iver
lung
hemanglosarcoma
hepatocellular carcinoma
adenoma
0/17
2/10
13/17
0.43
life
(mean 406 days)
17
1 iver
1 iver
lung
hemanglosarcoma
hepatocellular carcinoma
adenoma
24/47
1/47
40/47
0.91
life
(mean 266 days)
1?
1 Iver
1 Iver
lung
hemanglosarcoma
hepatocellular carcinoma
adenoma
09/93
0/93
91/92
-------
TABLE 5-3 (cont.)
QUALITY OF EVIDENCE
Strengths of Study: Two of the treatments were for lifetime duration; exposure In drinking water.
Weaknesses of Study: Ambiguous description of experimental design {discrepancy between lifetime treatment
and study durations); short treatment duration at low dose; high spontaneous
Incidence of lung adenomas; limited histological examinations.
Comments: Purity not reported; cumulative doses were 0, 87, 89, 170 and 243 mg/kg.
aSource: Clapp and loya, 1970
bmean survival time
-------
In 10/15 histologically examined mice, tumors were detected In the lung
(adenomas In 7/15) and liver (hemanglosarcomas 1n 3/15). Tumors were not
Induced 1n the stomach or esophagus, but the extent of the histological
examinations was not otherwise Indicated. Tumors did not occur 1n 30
untreated male control mice that were observed for up to 631 days.
Druckrey et al. (1967) reported that twice weekly Inhalation of N-nltro-
sodlmethylamlne at a concentration corresponding to 2 mg/kg for 30 minutes
Induced malignant nasal tumors (aesthes1oneuroep1thel1omas and squamous cell
carcinomas 1n the ethmoturblnals) In 8/12 BD rats. The duration of treat-
ment was not specified, but the average tumor Induction time was 400 days
and the average total dose to Induce tumors In 50% of the rats was 0.14
g/kg. Similar treatment with 4 mg/kg produced ethmoturblnal tumors In 4/b
rats (average tumor Induction time, 400 days; average total dose to Induce
tumors in 50% of the animals, 0.25 g/kg).
An abstract of a Russian study reported that Increased Incidences and
varieties of neoplasms developed 1n Wlstar rats and Balb/C mice that contin-
uously Inhaled N-n1trosod1methylamlne at a concentration of 0.005 mg/m3
for 17 months (Holseev and Benemansk11, 1975). Additional Information
(I.e., Incidences or types of tumors) was not reported.
Benemanskll and Levlna (1985) reported that 10 applications of 0, 0.5,
2.5 or 5.0 mg/kg N-n1trosod1methylam1ne to the skin of rats within 10 days
produced renal, hepatic or mammary gland tumor Incidences of 3.3, 6.6, 20.0
or 93.3%, respectively. Incidences of specific tumors or group sizes were
not reported, but 1t was noted that the Increased Incidences of total tumors
at the two highest doses were statistically significant and that local
tumors were not Induced.
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Adamson and Sleber (1983) reported the Interim results of a carcinogen-
icity study with macaque monkeys. Four rhesus and two cynomologus monkeys
of unspecified sex were given bimonthly Intraperitoneal injections of 10 mg
N-n1trosod1methylam1ne/kg. Four of the monkeys (species not Indicated) were
necropsled, and hlstopathologlcal examinations were performed after an
unspecified treatment period; none had developed tumors, but severe hepato-
toxlclty (e.g., toxic hepatitis, cirrhosis and hyperplastic nodules) was
observed.
Numerous additional studies, many of which are summarized by IARC
(1978), also have demonstrated the carcinogenicity of N-n1trosod1methyl-
amlne. In addition to shorter duration (subchronlc and single dose) oral
studies, these Include single or weekly subcutaneous and Intraperitoneal
Injection studies, N-n1trosod1methylam1ne appears to be carcinogenic in all
species tested (e.g., rats, mice, hamsters, guinea pigs, rabbits), and Is
carcinogenic when administered prenatally and to newborn and suckling
animals. N-N1trosod1methylam1ne produces tumors primarily In the liver,
kidneys and respiratory tract (IARC, 1978).
5.1.2. N-N1trosomethylethylam1ne. Druckrey et al. (1967) administered
N-n1trosomethylethylam1ne to 4 and 11 BD rats In drinking water at doses of
1 and 2 mg/kg/day, respectively, 7 days/week for life. Hepatocellular
carcinomas developed In 9/15 rats. The average Induction times and average
total doses to Induce tumors 1n 50% of the animals were 500 days and 0.42
g/kg, respectively (1 mg/kg/day), and 360 days and 0.75 g/kg, respectively
(2 mg/kg/day). Esophageal tumors were not observed and controls were not
Included In the study. Additional relevant Information regarding the design
or results of this experiment, which was part of a survey of the carcinogen-
icity of 65 N-nltroso compounds, was not reported.
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N-N1trosomethylethylam1ne of unreported purity was administered to 20,
7- to 8-week-old F344 rats 1n drinking water that provided 3.0 mg compound/
day (LlJInsky and Reuber, 1981). Unspecified numbers of rats of both sexes
were Included In the treatment group and treatment was for 5 days/week for
30 weeks. Controls were not Included 1n this study. Complete necropsies
that Included histological examination of all lesions and unspecified major
organs were conducted at the time of natural death or sacrifice when mori-
bund; there were no survivors at 15 weeks postexposure. Nineteen of the 20
rats died with tumors that occurred primarily In the Hver (hepatocellular
carcinoma 1n 19/20, hemanglosarcoma 1n 17/20, cholanglocardnoma In 3/20).
Lung metastases or liver hemanglosarcomas, esophageal papillomas and
esophageal carcinomas occurred In 5/20, 4/20 and 3/20 rats, respectively.
Related nonneoplastic findings Included hemoperltoneum (4/20) and acute
Inflammation of the lung (3/20).
N-N1trosomethylethylam1ne containing unspecified traces of Impurities
was administered In the drinking water to groups of 20 elght-week-old male
F344 rats at concentrations of 6 and 30 mg/i, 5 days/week for 30 weeks
(LlJInsky and Reuber, 1980). Weekly doses reportedly corresponded to 600
yg and 3 mg/rat. At the end of the treatment, the rats were observed
until moribund or natural death, and all were subjected to complete hlsto-
pathologlcal examinations. An untreated control group was not used In this
study. Survival 1n the low-dose group was 100 and 75% at 30 and 70 weeks
postexposure, respectively; In the high-dose group 1t was 70 and OX at 30
and 90 weeks postexposure, respectively. The total number of rats with
tumors 1n the low- and high-dose groups was 3/20 and 12/20, respectively.
0749p
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All of the tumors In the low-dose rats were In the liver (hepatocellular
carcinomas). The tumors in the high-dose group occurred 1n the liver
(hepatocellular carcinoma 1n 9/20), nasal cavity (unspecified type In 4/20)
and esophagus (papilloma In 1/20).
In a similar single dose study with no controls, N-n1trosomethylethyl -
amine of unspecified purity was administered to twenty 7- to 8-week-old male
F344 rats 1n the drinking water, 5 days/week for 30 weeks (L1JInsky et al.,
1982). Cages containing four rats were provided with 80 mil of 30 mg/8,
solution on the treatment days, Indicating that the dally dosages were -0.12
mg/rat/day. Thorough necropsies that Included hlstopathologlcal examina-
tions of all lesions and unspecified major tissues and organs were conducted
at the time of natural death or morlbundUy. Survival at postexposure weeks
30 and 60 was 70 and 0%, respectively. Tumors were observed in 14/20 rats
and occurred primarily 1n the liver (hepatocellular carcinoma In 9/20) and
nasal cavity (uncharacterized tumors In 4/20).
In another study by the same group of Investigators, N-nHrosomethyl-
ethylamlne was administered In the drinking water at a concentration of 6
mg/t, to a group of twenty 7- to 8-week-old female F344 rats (L1 j Insky et
al., 1983). Treatment was 5 days/week for 30 weeks, but water consumption
data were not reported. A group of 20 female F344 rats served as untreated
controls. Sections of all gross lesions and unspecified major organs were
collected from all rats at the time of natural death for histological exami-
nation, Survival data showed that 75 and 100% mortality occurred at 60 and
90 weeks postexposure, respectively. The number of rats with tumors was
reported to be 19, but leukemia was the only response (18/20) that may have
been treatment-related (12/20 in controls). Incidences of tumors in the
liver, nasal cavity or esophagus did not exceed 1/20 in the treated or
0749p
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control groups. The lack of tumors 1n the liver and nasal cavity 1n this
study may be attributable to the low dosage since the experimental design 1s
similar to previous studies In all aspects other than dose.
Mlchejda et al. (1984) reported that a group of 20 F344 rats of unspeci-
fied sex that were administered N-n1trosomethylethylam1ne In the drinking
water at a dose of 8 mg/kg for 15 weeks died from liver tumors 45 weeks
(median time) after the start of treatment. Incidence data or additional
Information regarding the design or results of this study were not reported.
5.1.3. N-N1trosod1ethylam1ne. Druckrey et al. (1963) reported the
results of a dose-response study 1n which N-n1trosod1ethylam1ne was adminis-
tered In the drinking water to groups of 25-80 BD-1I rats. Dosages ranged
from 0.075-14.2 mg/kg/day and treatment was 7 days/week for life. As
detailed in Table 5-4, all dosages >0.15 mg/kg/day produced tumors 1n 100%
of the surviving animals, primarily In the liver. Results of this study are
complicated by the occurrence of Intercurrent Infections In many of the rats
(particularly at the low dose) and the lack of control data.
Another dose-response study was conducted 1n which groups of 20 female
F344 rats (one group consisted of 12 rats) were administered N-n1trosod1-
ethylamlne In the drinking water at concentrations that ranged from 0.45-113
mg/ft, 5 days/week for 17-104 weeks (Lljlnsky et al., 1981b). The treat-
ment concentrations and durations are detailed In Table 5-5. Rats were
allowed to die naturally or were killed when moribund or at week 130 of the
experiment, and all gross lesions and major organs from each animal were
histologically examined. As summarized In Table 5-5, treatment-related
tumors occurred primarily In the liver (hepatocellular carcinoma, particu-
larly at the higher dosages) and esophagus (basal cell carcinoma). Tumors
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TABLE 5-4
Nlne-Oose Lifetime Carcinogenicity Study of N-N1trosod1ethylam1ne Administered In
Drinking Water to B0-I1 Rats of Unspecified Sexa»b
Oose
(mg/kg/day)
°50c
(mg/kg)
*50d
(days)
Target Organ
Tumor Type
Tumor
Inc1dencee
0.075
64
840
1 Iver
esophagus
liver and esophagus
carcinoma
hepatoma
carcinoma
papilloma
carcinoma
1/4
4/4
0/4
3/4
1/4 (60)f
0.15
91
609
1 Iver
esophagus
liver and esophagus
carcinoma
hepatoma
carcinoma
papilloma
carcinoma
18/30
4/30
9/30
13/30
27/30 (45)
0.3
137
457
11ver
esophagus
liver and esophagus
carcinoma
hepatoma
carcinoma
papilloma
carcinoma
62/67
1/67
23/67
7/67
67/67 (80)
0.6
213
355
liver
esophagus
liver and esophagus
carcinoma
hepatoma
carcinoma
pa p11loma
carcinoma
49/49
2/49
5/49
4/49
49/49 (60)
-------
TABLE 5-4 (cont.)
Oose D5qc t5q*^ Target Organ Tumor Type Tumor
(mg/kg/day) (mg/kg) (days) Inc1dencee
1.2
285
238
liver
esophagus
Hver and esophagus
carcinoma
hepatoma
carcinoma
papilloma
carcinoma
36/36
0/36
0/36
0/36
36/36 (40)
2.4
460
192
11ver
esophagus
liver and esophagus
carcinoma
hepatoma
carcinoma
papilloma
carcinoma
34/34
0/34
0/34
0/34
34/34 (35)
4.8
660
137
1 Iver
esophagus
liver and esophagus
carcinoma
hepatoma
carcinoma
papilloma
carcinoma
25/25
0/25
0/25
0/25
25/25 (25)
9.6
963
101
11 ver
esophagus
liver and esophagus
carcinoma
hepatoma
carcinoma
papilloma
carcinoma
25/25
0/25
0/25
0/25
25/25 (25)
14.2
1000
68
1 Iver
esophagus
liver and esophagus
carcinoma
hepatoma
carcinoma
papilloma
carcinoma
5/25
0/25
0/25
0/25
5/25 (25)
-------
TABLE 5-4 (cont.)
QUALITY OF EVIDENCE
Strengths of Study: Multiple dose levels, relevant route and lifetime duration.
Weaknesses of Study: No control data; Intercurrent infections; dose range too high.
Comments: Purity not reported
aSource: Oruckrey et al., 1963
^Duration of treatment and study was life.
cAverage total dose to induce tumors in 50% of the animals.
^Average induction time for tumors in 50% of the animals (palpable liver tumors).
eNumber of rats with carcinomas/number of survivors at appearance of first tumor. Many rats were lost to
Intercurrent Infections; number at start in each group given in parentheses.
^40 of the original 60 rats succumbed to a pneumonia infection during the first 600 days; there were only
three survivors by the time (850 days) hepatic carcinoma was Identified.
-------
TABLE 5-5
Dose-Response Study of N-N1trosod1ethylam1ne Administered In Drinking Hater to Female F344 Ratsa
Dose^
Duration of
Duration
Treatment
of Studyc
Target Organ
Tumor Type
Tumor Incidence
(mg/4)
(weeks)
(weeks)
0
130
130
1 Iver
hepatocellular carcinoma
0/20
esophagus
basal cell carcinoma
0/20
forestomach
basal cell papilloma
0/20
tongue
basal cell carcinoma
0/20
pituitary
carc1noma
4/20
hematoploetlc
monocytic leukemia
6/20
113
17
20
11ver
hepatocellular carcinoma
17/20
(192 mg/rat
esophagus
basal cell carcinoma
14/20
total dose)
forestomach
basal cell papilloma
2/20
tongue
basal cell carcinoma
0/20
pituitary
carcinoma
1/20
hematopoietic
monocytic leukemia
1/20
45
22
30
1 Iver
hepatocellular carcinoma
9/20
(99 mg/rat
esophagus
basal cell carcinoma
15/20
total dose)
forestomach
basal cell papilloma
2/20
tongue
basal cell carcinoma
0/20
pituitary
carcinoma
0/20
hematopoietic
monocytic leukemia
0/20
18
30
40
11ver
hepatocellular carcinoma
1/18
(54 mg/rat
esophagus
basal cell carcinoma
10/18
total dose)
forestomach
basal cell papilloma
0/18
tongue
basal cell carcinoma
0/18
pituitary
carcinoma
0/18
hematopoietic
monocytic leukemia
0/18
-------
TABLE 5-5 (cont.
Doseb
(mg/i)
(21 mg/rat
total dose
2.8
(8.4 mg/rat
total dose)
1.1
(3.3 mg/rat
total dose)
1.1
(6.6 mg/rat
total dose)
Duration of
Treatment
(weeks)
Duration
of Study0
(weeks)
30
70
30
130
30
130
60
130
Target Organ
11ver
esophagus
forestomach
tongue
pituitary
hematopolet1c
11ver
esophagus
forestomach
tongue
pituitary
hematopoietic
liver
esophagus
forestomach
tongue
pituitary
hematopoietic
11ver
esophagus
forestomach
tongue
pituitary
hematopoietic
Tumor Type
Tumor Incidence
hepatocellular carcinoma
1/20
basal cell carcinoma
13/20
basal cell papilloma
1/20
basal cell carcinoma
6/20
carcinoma
0/20
monocytic leukemia
1/20
hepatocellular carcinoma
5/20
basal cell carcinoma
18/20
basal cell papilloma
3/20
basal cell carcinoma
6/20
carcinoma
2/20
monocytic leukemia
13/20
hepatocellular carcinoma
5/20
basal cell carcinoma
3/20
basal cell papilloma
4/20
basal cell carcinoma
1/20
carcinoma
8/20
monocytic leukemia
9/20
hepatocellular carcinoma
3/20
basal cell carcinoma
17/20
basal cell papilloma
2/20
basal cell carcinoma
4/20
carcinoma
5/20
monocytic leukemia
4/20
-------
TABLE 5-5 (cont.)
Dose^
(mg/t)
Duration of
Treatment
(weeks)
Duration
of Study0
(weeks)
Target Organ
Tumor Type
Tumor Incidence
0.45
30
130
liver
hepatocellular carcinoma
1/20
(1.35 mg/rat
esophagus
basal cell carcinoma
0/20
total dose)
forestomach
basal cell papilloma
1/20
tongue
basal cell carcinoma
0/20
pituitary
carc1 noma
10/20
hematopoietic
monocytic carcinoma
13/20
0.45
60
130
11 ver
hepatocellular carcinoma
6/20
(2.7 mg/rat
esophagus
basal cell carcinoma
2/20
total dose)
forestomach
basal cell papilloma
2/20
tongue
basal cell carcinoma
1/20
pituitary
carcinoma
7/20
hematopolet1c
monocytic leukemia
11/20
0.45
104
130
liver
hepatocellular carcinoma
4/20
{4.7 mg/rat
esophagus
basal cell carcinoma
8/20
total dose)
forestomach
basal cell papilloma
5/20
tongue
basal cell carcinoma
2/20
pituitary
carcInoma
8/20
hematopoietic
monocytic leukemia
11/20
-------
TABLE 5-5 (cont.)
QUALITY OF EVIDENCE
Multiple dose levels and comprehensive histopathologlcal examinations.
Long treatment durations and low doses were used only In several groups; group sizes
relatively small.
Purity not specified; statistical analyses were conducted only for tumors in rats
treated for 0, 30, 60 and 104 weeks at 0.45 mg/i or 0, 0.45, 1.1 and 2.8 mg/t
for 30 weeks; significant dose-related trends for Incidences of esophagus carcinoma,
liver carcinoma, forestomach papilloma (common dose analysis), forestomach carcinoma
(common duration analysis) and tongue carcinoma (common duration analysis).
aSource: L1J1 nsky et al.f 1981b
&80 mi of solution was placed In cages containing four rats for 5 days/week (400 ml/cage/week).
"Almost all" of the solutions were consumed.
Strengths of Study:
Weaknesses of Study:
Comments:
cL1fet1me observation
-------
of the forestomach (basal cell papilloma), tongue (basal cell carcinoma) and
pituitary (carcinoma) as well as monocytic leukemia occurred more frequently
1n several of the lower dose, longer duration treatment groups.
An extensive study was conducted 1n which groups of 48 s1x-week-old
Colworth rats of each sex were exposed to 0.033, 0.066, 0.132, 0.264, 0.528,
1.056, 1.584, 2.112, 2.640, 3.168, 4.224, 5.280, 6.336, 8.448 or 16.896 ppm
N-nltrosodlethylamlne 1n the drinking water (Peto et al., 1984). Six rats
from each group were sacrificed after 6 and 12 months of treatment, and the
remainder were allowed to live until natural death. The approximate dally
water consumption was reported to be 41 and 72 ml/kg In adult males and
females, respectively. Untreated control groups consisting of 192 rats of
each sex were maintained similarly, with 24 rats from each group sacrificed
after 6 and 12 months. The extent of pathological examinations was not
specifically indicated but, with the exception of liver tumors, all tumors
were classified as benign or malignant. A general statement regarding
survival Indicated that most animals given the eight lowest doses survived
well Into old age (median 31 and 28 months of treatment 1n the males and
females, respectively), while most of those 1n the eight highest treatment
groups died earlier from tumors. Tumors occurred primarily In the liver and
esophagus, and mortality from the combination of all causes other than
tumors at these sites was not significantly related to treatment. Pooled
data from both sexes Indicated possible positive trends for tumors 1n the
nasopharynx, lower jaw, stomach, kidney, ovaries and seminal vesicles.
Additional specific Information regarding the design or results of this
study (Including tumor Incidences for the Individual treatment groups) was
not reported, however, as the purpose of this report was extensive Welbull
analysis of the liver and esophageal tumor dose-response data. Analysis of
0749p
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these data showed the following relationships of cumulative Incidence (CI)
to dose (d) In mg/kg/day and time (t) In years:
Hver (males) CI = 18.70 (d f 0.04)*tT
liver (females) CI = 32.09(d * 0.04)«t7
esophagus (males) CI = 21.17 d3t7
esophagus (females) CI = 11.16 dat7
As Indicated, the rate of onset of liver or esophageal tumors Is propor-
tional to approximately the seventh power of the duration of exposure at a
given dose level. Peto et al. (1984) noted that a more detailed report of
this study was drafted by the United Kingdom government departments that
sponsored this study but a publication date was not Indicated.
Related experiments Involved administration of N-nl trosodlethyl amine at
the same concentrations In drinking water to groups of six 3- or 20-week-old
Colworth rats of each sex for 2.5 years, to groups of ten 12-week-old female
C57-Bo mice for 25 months, and to groups of ten 20-week-old female Syrian
hamsters for 22 months (Peto et al., 1984).
Twice weekly gavage administration of 10 mg/kg aqueous N-nltrosod1ethyl-
amlne to a group of 40 male 100-day-old Sprague-Oawley rats for life pro-
duced high Incidences of 11ver tumors (32/40) and esophageal tumors (13/40)
(Habs et al., 1980). Greater than 90% of the liver tumors were reported to
be malignant (unspecified hepatocellular and angiomatous types), but the
esophageal tumors were predominately (>80%) multifocal papillomas. Histo-
logical examinations were limited to the Hver and tissues that appeared
macroscoplcally abnormal. An unexposed control group was not Included in
the study and the median survival time was 201 days (range 56-232 days).
N-N1trosod1ethylam1ne was given to groups of 30-125 male RF mice (8-10
weeks old) In the drinking water at dally doses of 2-11.5 mg/kg for varying
0749p
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durations (cumulative doses of 57-943 mg/kg, corresponding to -9-222 days)
(Clapp et al., 1970). A control group consisted of 162 untreated mice.
Tumors occurred In the lungs (adenomas), 11 vers (hepatomas) and forestomach
(squamous cell carcinomas) In all the treated groups at Incidences that
markedly exceeded those In the control group. Incidences of lung, liver and
forestomach tumors In mice that were treated with 3.5 mg/kg/day for 223 days
(cumulative dose, 780 mg/kg; mean survival 9.7 months) and 6 mg/kg/day for
157 days (cumulative dose, 943 mg/kg; mean survival 9.0 months) were 70/115,
74/103 and 115/124, and 24/42, 37/42 and 42/42, respectively; the corre-
sponding Incidences 1n the control group (mean survival 20.5 months) were
63/155, 6/139 and 0/unspec1fled number. The treatment schedules and tumor
Incidences In the other treatment groups are not detailed because the
treatment durations are much shorter (9-106 days), but the Incidences of
liver tumors Increased linearly with cumulative dose (maximum Incidences of
-90% at cumulative doses of >32 mg/kg).
Clapp et al. (1971) administered N-n1trosod1ethylam1ne to groups of 18,
73 and 82 twelve-week-old male Balb/c mice In drinking water at dally doses
of 0, 3.6 and 6.7 mg/kg/day, respectively. Treatment durations were not
specified but are estimated from cumulative doses of 515 mg/kg (low dose)
and 1010 mg/kg (high dose) to be -143 and 150 days, respectively. Histo-
logical examinations were performed on -80% of the mice at the time of
natural death or morlbundlty (experiment terminated after 631, 201 and 161
days 1n the control, low- and high-dose groups, respectively). Tumors
occurred 1n 0/30, 14/15 and 49/60 of the control, low- and high-dose mice,
respectively, primarily In the liver (hemanglosarcomas In 0/30, 4/15 and
14/60; no hepatocellular tumors), forestomach (primarily squamous cell
carcinomas and "some" papillomas 1n 0/30, 13/15, 35/60) and esophagus
(squamous cell carcinomas In 0/30 controls and 6/15 low-dose groups;
0749p 5-27 05/29/86
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esophagus not consistently examined 1n the high-dose group). A leukemogenlc
effect reportedly was not Indicated.
Administration of N-n1trosod1ethylam1ne 1n the drinking water, 5 days/
week for 16-51 weeks Induced hepatic carcinomas In 14/15 male hybrid guinea
pigs (Argus and Hoch-L1get1, 1963). Dally doses were not specifically
reported but appeared to be In the range of 1-2 mg, and unspecified varia-
tions or Intervals without treatment that were due to toxicity or appetite
were Indicated; total doses reportedly ranged from 200-360 mg/an1mal. Lung
adenomas developed In 7/9 guinea pigs that were treated for 44-51 weeks.
Control animals were not used In this study.
Hepatic carcinomas developed 1n 13/13 New Zealand white rabbits
("mostly" female) that received 0.042 g N-nltrosodlethylamlne/l of drink-
ing water, 6 days/week for periods ranging from 52-8? weeks (Rapp et al.,
1965). Measurements made early In the study reportedly showed that each
rabbit consumed -200 ml of N-n1trosod1ethylam1ne solution dally, Indicat-
ing that the dally dosages were 8.4 mg/rabb1t. The animals were sacrificed
and examined histologically when weekly examinations showed palpable tumors,
but additional treatment-related tumors other than metastases were not
observed. Three untreated control rabbits that were examined at 20 months
appeared normal.
Primary hepatic neoplasms of various types developed In 14/14 male
mongrel dogs after 52-70 weeks of N-n1trosod1ethylam1ne treatment In the
drinking water and 52-175 weeks of observation (Hlrao et al., 1974). The
water contained 50, 100 or 500 ppm N-n1trosod1ethylam1ne, but the varying
treatment durations preclude tabulation of tumor Incidences by treatment
concentration; total Intake of N-n1trosod1ethylam1ne ranged from 3120-6960
mg. Tissues other than the liver and metastatic lesions were not histo-
logically examined and controls were not used.
0749p 5-28 05/29/86
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Hepatic cell carcinomas were Induced 1n .3/5 1-day-old Cynamolgus
monkeys, 2/6 1-day-old rhesus monkeys and one of four adult Capuchin monkeys
that were treated orally with N-n1trosod1ethylam1ne for 14-23 months (Kelly
et al., 1966). Treatments varied but Initially ranged from 2-5 mg/kg bw (5
doses/week every third week or 7 doses/week) and were Incrementally In-
creased to 25-50 mg/kg bw (5 doses/week); total doses/monkey were 6.1-14.7 g
for the Cynamolgus monkeys (14.4-22.0 months of treatment), 13.6 and 17.8 g
for the rhesus monkeys (24.0 and 23.0 months of treatment, respectively) and
25.7 g for the Capuchin monkey (23.0 months of treatment).
Hepatocarc1nogen1c effects of orally administered N-n1trosod1ethylam1ne
1n monkeys have also been reported by Adamson and Sleber (1983). Adminis-
tration of 40 mg/kg, 5 days/week produced hepatocellular carcinomas in 29/41
monkeys; 14 were Cynamolgus monkeys that were treated for 90 weeks (18.0 g
average total dose, 26-month average latent period), 12 were rhesus monkeys
that were treated for 127 weeks (25.4 g average total dose, 49-month average
latent period) and 3 were African green monkeys that were treated for 275.5
weeks (55.1 g average total dose, 105-month average latent period). Addi-
tional specific Information regarding these trials were not reported, but 1t
was noted that administration of test compound was usually Initiated within
24 hours of birth. Results from what appear to be the same trials were also
reported by Adamson and Sleber (1979). Intraperitoneal Injection of 40
mg/kg N-n1trosod1ethylam1ne bimonthly for -2 years (Adamson and Sleber,
1979, 1983) or 20 mg/kg N-nHrosodlethylamlne monthly for 3-5 years (Reubner
et al., 1976) also produced high Incidences (>80%) of hepatocellular
carcinomas In the same strains of monkeys.
Fifteen weekly Intratracheal Instillations of 1 mg N-n1trosod1ethylam1ne
(suspended In 0.1 ml phosphate buffer solution) produced lung or trachea
0749p
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tumors In 12/12 female Syrian hamsters after 107-237 days of observation
(Yamamoto et al., 1985). The tumors consisted of 3 squamous cell carcinomas
(lungs), 3 adenomas (lungs) and 11 squamous papillomas (trachea). Respira-
tory system tumors did not occur In 15 control hamsters similarly treated
with the vehicle only. Neoplasms did not occur 1n the main visceral organs
In the treated or control hamsters. In another study, weekly Intratracheal
Instillations of 0.05 ml of a 1.14 aqueous solution of N-n1trosod1ethyl-
amlne for 1-6 months Induced tumors (predominately squamous-cell papillomas)
1n the trachea and bronchi of male (14/14 and 10/14, respectively) and
female (11/11 and 4/11, respectively) Syrian hamsters (Herrold and Dunham,
1963). Undifferentiated carcinomas of the nasal cavity (ethmoid region)
occurred In 1/13 males and 3/9 females, but liver tumors were not observed.
Significant abnormalities were not Identified in five hamsters of each sex
that received Intratracheal Injections of distilled water.
Spray Inhalation of 1-2 mg N-n1trosod1ethylam1ne twice weekly for 5
months produced tumors of the trachea or lungs 1n 18/33 Syrian golden
hamsters (Dontenwlll et al., 1962). Spray Inhalation of a dilute (1:250)
aqueous solution of N-n1trosod1ethylam1ne for 4 months produced liver
carcinomas In 8/17 rats, but no lung tumors (Dontenwlll and Mohr, 1962).
Additional Information regarding these German Inhalation studies was not
reported.
Skin application studies summarized by 1ARC (1978) reported that
N-n1trosod1ethylam1ne produced nasal cavity tumors In mice and hamsters but
not local tumors. Twice-weekly applications of N-n1trosod1ethylam1ne (two
drops of 0.2% solution In acetone) to the skin of mice for 10 months Induced
squamous cell carcinomas In the nasal cavity In 17/24 mice (Hoffmann and
Graff 1, 1964). Skin painting with aqueous N-nltrosodlethylamlne produced
0749p
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epithelial papillomas of the nasal cavity In 6/8 Syrian hamsters but no skin
tumors (Herrold, 1964a,b). Additional Information regarding the above
studies was not reported In the IARC (1970) review.
Numerous additional studies have demonstrated that N-n1trosod1ethylam1ne
Is carcinogenic by shorter duration (subchronlc and single dose) oral
exposure, by subcutaneous, Intraperitoneal or Intradermal Injection, by
rectal Instillation and by prenatal exposure. N-N1trosod1ethylam1ne appears
to be carcinogenic 1n all animals tested (e.g., rats, mice, guinea pigs,
hamsters) Including newborns. The primary target organs for N-nltrosodl-
ethylamlne tumorlgenesls are the liver, respiratory tract, upper digestive
tract and the kidneys (IARC, 1978).
5.1.4. N-N1trosod1-n-propylam1ne. Druckrey et al. (1967) administered
N-n1trosod1-n-propylam1ne to BD rats of unspecified sex in the drinking
water at doses of 4, 8, 15 or 30 mg/kg/day for life. The total number of
rats tested was 48, but the size of each treatment group was not specified;
It 1s Inferred from the results that 16, 16, 15 and 1 rats were treated In
the low- to high-dose groups, respectively. Of the 48 treated rats, 45
developed liver carcinomas; the average Induction times and average total
dose to Induce tumors 1n 50% of the rats were 300 days and 1.15 g/kg, 202
days and 1.52 g/kg, 155 days and 1.86 g/kg and 300 days and 3.2 g/kg,
respectively, In the 4, 8, 15 and 30 mg/kg/day groups, respectively. Papll-
lomas/carclnomas of the esophagus and carcinomas of the tongue occurred 1n
eight and six rats, respectively, that were treated with 8 or 15 mg/kg/day.
Control data were not reported.
HJInsky and Taylor (1978, 1979) administered N-n1trosod1-n-propylam1ne
of "high" purity to fifteen 8- to 9-week-old male Sprague-Oawley rats In
drinking water that provided 1.8 mg compound/day, 5 days/week for 30 weeks
0749p
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(total dose 270 rag). Complete necropsies that Included histological exami-
nation of all tumors and other gross lesions were conducted at the time of
natural death or sacrifice when moribund; there were no survivors at week
60. Fourteen of the 15 rats died with tumors that primarily occurred In the
liver (carcinomas In 9/15), esophagus (papillomas 1n 6/15, carcinomas In
8/15), and nasal turbinates (adenocarcinomas In 8/15). A control group was
not Included 1n this study.
In a similar study, N-nltrosodl-n-propylam1ne of unreported purity was
administered to 20, 7- to 8-week-old F344 rats In drinking water that pro-
vided 0.9 mg compound/day (L1j1nsky and Reuber, 1981). Unspecified numbers
of rats of both sexes were Included 1n the treatment group and treatment was
5 days/week for 30 weeks. Controls were not used In this study. Upon
necropsy at the time of natural death or sacrifice when moribund, histologi-
cal examinations of all lesions and unspecified major organs were performed;
there were no survivors at 10 weeks postexposure. Tumors occurred primarily
In the esophagus (carcinomas in 20/20) and forestomach (unspecified tumors
In 12/20).
LlJInsky and Reuber (1983) administered N-n1trosod1-n-propylam1ne (>98%
purity) 1n corn oil by gavage to 7- to 8-week-old F344 rats, twice weekly
for 30 weeks. Groups of 20 males and 12 females were treated with dosages
of 4.4 and 2.2 mg, respectively, and groups of 20 untreated rats of each sex
served as controls. The rats were allowed to die naturally and were
subjected to hlstopathologlcal examination of all gross lesions and unspeci-
fied major organs and tissues. There were no surviving males at week 40 or
females at week 70. In all the treated rats, tumors occurred primarily 1n
the liver (carcinoma 1n 18/20 males and 8/100 females), nasal cavity
0749p
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(carcinomas In 14/20 males and 8/11 females) and esophagus (unspecified
tumors In 12/20 males, 4/11 females; carcinoma In 7/20 males and 2/20
females). Tumors did not occur at these sites 1n the controls.
The results of a lifetime subcutaneous study with 12-week-old Sprague-
Dawley rats were reported by Reznlk et al. (1975). Groups of 10 males and
10 females received weekly N-n1trosod1-n-propylam1ne Injections of 24.36,
48.72 or 97.44 mg/kg (representing 1/20, 1/10 and 1/5 the LD^q. respec-
tively) for life or until sacrifice when moribund. Groups of vehicle-
treated (0.9% NaCl) and untreated rats of equal numbers were used as
controls. Average survival 1n the treated rats ranged from 24.8-35.0 weeks
In the males and 27.8-38.2 weeks 1n the females vs. 77.2-79.8 weeks and
85.1-86.0 weeks 1n the vehicle and negative control groups, respectively.
Necropsies that Included microscopic examinations of unspecified organs and
decalcified skulls were conducted. Incidence of rats with tumors were high
1n all of the treated groups, ranging from 6/10 In the m1d-dose males to 7/8
In the low-dose females. The tumors occurred primarily In the nasal cavity
(40-70% Incidence In the apical parts, 0-60% In the endoturblnals), liver
(0-60%), lungs (0-40%) and esophagus (0-50%), but also 1n the kidneys and
brain. Malignant tumors occurred primarily In the liver (hepatocellular
carcinomas), lungs (adenocarcinomas and squamous cell carcinomas) and nasal
cavity endoturblnals (not characterized), and only benign types developed In
the esophagus (squamous cell papillomas) and brain (not specified). The
occurrence of tumors, particularly malignant types, was not related to dose
at several of the sites. With the exception of benign nasal cavity tumors
In one male and one female vehicle-control rats, tumors did not develop In
any of the control groups.
0749p
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In a similar study, groups consisting of 20 male and 20 female 6- to
8-week-old Syrian golden hamsters were treated subcutaneously with 1.2%
N-n1trosod1-n-propylam1ne 1n olive oil at dosages of 0 {vehicle control),
3.75, 7.5, 15, 30 or 60 mg/kg once weekly for life (Pour et al., 1973;
Althoff et al., 1973). Average survival ranged from 29 weeks at the low
dose to 54 weeks at the high dose. Neoplasms were first observed after 16
weeks and Incidences were Increased in all treatment groups. Tumors
primarily occurred in the nasal and paranasal cavities, laryngobronchlal
tract and lungs, with Incidences ranging from 69-92%, 66-98% and 13-68%,
respectively. The nasal/paranasal tumors were primarily benign epidermoid
and mucoepldermold types with adenocarcinoma at the high dose; the laryngo-
bronchlal tumors were primarily polypous or papillomatous In the upper
trachea, and lung tumors were primarily carcinomas at the higher doses.
Weekly subcutaneous injections of 60 mg N-nltrosodl-n-propylamlne/kg In
olive o11 for life (28-30 weeks) produced Increased Incidences of nasal
olfactory region carcinomas In Syrian hamsters of both sexes (16/19 males,
12/18 females) (Pour et al., 1974). Increased Incidences of these tumors
did not occur In groups of 15-20 hamsters of either sex exposed to lower
dosages of the compound (3.75, 7.5, 15 or 30 mg/kg) or In solvent controls
(50 of each sex). Sites other than the nasal cavity were not examined 1n
this study.
Althoff and Grandjean (1979) administered single subcutaneous Injections
of 100 mg N-n1trosod1-n-propylam1ne 1n 0.9% NaCl to groups of five Syrian
hamsters on days 8, 10, 12 and 14 of gestation. Overall tumor Incidences In
the f 1 males (44/82) and F] females (33/91) were somewhat higher than 1n
vehicle-treated controls (18/113 and 19/100, respectively). Tabulation
by organ system showed unequivocal Increases only In the digestive tract
0749p
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(25.6 vs. 7.0% 1n males, 14.3 vs. 3.5% 1n females) and endocrine system
(25.6 vs. 12.0% In males, 20.9 vs. 10.9% 1n females). Respiratory system
tumors occurred 1n 4.9% of the males (0% 1n controls), 2.2% of the
females (0% In controls) and 60% of the dams (4.8% 1n controls). Tumors
were not tabulated by type or gestation treatment day.
Weekly Intraperitoneal Injections of 40 mg N-n1trosod1-n-propylamlne/kg
produced hepatocellular carcinomas 1n 6/6 macaque monkeys (4 rhesus and 2
Cynomolgus of unspecified sex) after an average total dose of 7.0 g and an
average latent period of 28 months (Adamson and Sleber, 1979, 1983). The
Incidence of unspecified tumors In unspecified controls that are presumed to
be historical was 7/90 (7.8%). The only additional Information reported was
a general statement applicable to all chemicals 1n this survey Indicating
that maximally tolerated doses were used.
Numerous studies have shown that documented and postulated metabolites
of N-n1trosod1-n-propylamlne are also potent carcinogens 1n hamsters and
rats (1ARC, 1978). These Include N-n1troso-2-hydroxy-n-propyl-n-propyl-
amlne, N-n1troso-b1s(2-hydroxy-n-propyl)am1ne, N-n1troso-2-oxo-n-propyl-n-
propylamlne, N-n1troso-b1s(2-oxo-n-propyl)am1ne, N-n1troso-b1s(2-acetoxy-n-
propyl)am1ne and N-n1troso-2,2'-d1methyld1-n-propylam1ne. Main tumor sites
are consistent with those associated with N-n1trosod1-n-propylamlne treat-
ment and Include the liver, nasal cavities, other areas of the respiratory
tract, kidneys and pancreas. Many of the hamster studies of N-n1trosod1-n-
propylamlne metabolites Involved weekly subcutaneous Injections for life 1n
order to develop a model for pancreatic carcinogenesis studies.
5.1.5. N-N1trosod1-n~butylam1ne. Druckrey et al. (1967) administered
N-n1trosod1-n-butylamlne to BD rats of unspecified sex In diets that
provided doses of 75, 37, 20 or 10 mg/kg bw/day. Although not specifically
0749p
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stated for this compound, treatment appeared to be for life. Controls were
not used 1n this study. In the high-dose group, liver carcinomas occurred
In 4/4 rats. The Incidences of liver carcinomas were lower In the 37, 20
and 10 mg/kg/day groups (13/16, 4/10 and 2/10, respectively), but malignant
tumors also occurred 1n the esophagus (5/16, 8/10 and 2/10, respectively)
and bladder (5/16, 7/10 and 2/10, respectively). The average total dose to
Induce tumors In 50% of the animals and the average time to Induce tumors In
50% of the animals were, respectively, 10 g/kg and 150 days (75 mg/kg/day),
8.3 g/kg and 262 days (37 mg/kg/day), 6.4 g/kg and 450 days (20 mg/kg/day)
and 3.9 g/kg and 540 days (10 mg/kg/day). Additional solvent Information
regarding this study, which was part of a survey of the carcinogenicity of
65 N-nltroso compounds, was not reported.
Lljlnsky and Reuber (1983) administered N-n1trosod1-n-butylam1ne (>98%
purity) In corn oil by gavage to a group of twenty 7- to 8-week-old male
F344 rats at a dose of 5.4 mg, twice weekly for 30 weeks. Groups of 20
untreated rats of both sexes were used as controls. The rats were allowed
to die naturally and subjected to hlstopathologlcal examination of all gross
lesions and unspecified major organs and tissues. Survival at postexposure
weeks 50, 90 and 100 was 18/20, 14/20 and 8/20. Tumors developed In 19/20
treated rats, primarily 1n the liver (12/20 with carcinomas), forestomach
(10/20 with carcinoma), lung (carcinoma In 9/20, adenoma in 4/20) and
bladder (carcinoma In 7/20). Tumor Incidences In the male and female
controls did not exceed 1/20 at any site.
Administration of 20 ml of drinking water containing 2.87 mM N-n1tro-
sod1-n-butylam1ne (-44.3 mg) dally for 20 weeks produced liver cancer and
hyperplasia In 5/9 and 9/9 ACI/N male rats, respectively, after 0-2 weeks of
observation (Okada et al., 1976). Hyperplasia and papillomas of the bladder
0749p
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occurred 1n 5/9 and 1/9 of the rats, respectively, but cancer of the bladder
or esophagus was not detected. Control data were not reported. In another
subchronlc drinking water study of limited scope, administration of 0.02%
N-n1trosod1-n-butylam1ne for 26 weeks produced hyperplastic nodules and
carcinomas In the Hvers of 5/29 and 1/29 male F344 rats, respectively
(Perelra et al., 1983). These lesions did not occur 1n 11 untreated
controls that were observed for 26 weeks, and tissues other than the liver
were not examined.
Subchronlc drinking water studies summarized by IARC (1978) also
Indicate that the urinary bladder Is a primary target organ for N-n1trosod1-
n-butylam1ne tumorlgenesls rats. Kunze and Schauer (1971) reportedly found
16 papillomas and 2 carcinomas In the bladders of 30 female Wlstar rats
treated with 20 mg/kg/day for an unspecified duration. Administration of
0.05% N-n1trosod1-n-butylam1ne solution in the drinking water for 28 weeks
produced transitional cell carcinomas of the bladder In 12/12 adult Wlstar
rats of unspecified sex (Ito, 1973).
N-N1trosod1-n-butylam1ne was administered continuously in the drinking
water to groups containing 50 male and 50 female C57BL/6 mice (10-12 weeks
old) at concentrations of 60 and 240 mg/l (Bertram and Craig, 1970).
Mater consumption measurements Indicated that the dally doses of the com-
pound were 7.6 and 8.2 mg/kg/day (low-dose males and females, respectively)
and 29.1 and 30.9 mg/kg/day (high-dose males and females, respectively).
Treatment continued for life (moribund or death) except for -50% of the
high-dose males and females that were given untreated water after 197 days
because of gross hematuria In the majority of the high-dose males. As
detailed 1n Table 5-6, tumors occurred 1n all of the treated mice, predomi-
nantly squamous cell carcinomas and papillomas In the esophagus and bladder.
0749p
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TABLE 5-6 (cont.)
QUALITY OF EVIDENCE
Strengths of Study: Two dose levels; natural route of administration.
Weaknesses of Study: No control groups; duration Indirectly reported (I.e., total dose).
Comments: Purity not reported
aSource: Bertram and Craig, 1970
^Duration of study was for life.
cDoses calculated by authors from consumption of water containing 60 and 240 mg/Jt, N-n1trosod1-n-butylam1ne.
^Treatment was discontinued after 197 days In 20/45 of the high-dose males and 21/45 of the high-dose
females because of gross hematuria In the majority of the high-dose males.
-------
Tumors of the forestomach occurred In five of the low-dose mice (sex not
specified) and a total of 13 tumors of the soft palate and tongue occurred
in all groups. Neoplastic or nonneoplastic alterations were not observed In
the liver or kidneys. Although "complete" necropsies with histological
examinations were conducted 1n the study, unexposed control groups were not
Included. The hematuria observed during treatment did not occur consis-
tently and was thought to precede the bladder tumors.
Diets containing 50 ppm N-n1trosod1-n-butylam1ne dissolved In warm
peanut oil was administered to 39 male ICR mice for 12 months (Takayama and
lmalzuml, 1969). A control group of 30 mice received a basal diet for 15
months. Survival at the end of the 12- and 15-month periods was 33/39 and
28/30, respectively. As detailed 1n Table 5-7, treatment-related tumors
occurred primarily In the forestomach (squamous cell carcinoma 1n 27/33) and
liver (adenoma in 10/33 and trabecular hepatoma In 5/33). Additional
Information regarding the design or results of this study (I.e., extent of
pathological examinations) were not provided 1n this brief study.
In a study that did not use controls, groups of 100 male Syrian hamsters
and 100 male Chinese hamsters were treated once weekly for life with 300
mg/kg N-n1trosod1-n-butylam1ne 1n olive oil by gavage (Althoff et al.,
1971). The animals were 3 months old at the start of the experiment and all
organs (unspecified) were examined histologically. All 100 of the Syrian
golden hamsters were examined with 46% surviving 45-50 weeks of treatment,
but only 66 of the Chinese hamsters were examined with 53% survival at 25
weeks and 5% survival at 35 weeks. The Syrian hamsters developed bladder
papillomas (32/100) and carcinomas (13/100), papillomas and carcinomas of
the trachea (41/100) and lungs (14/100) and forestomach papillomas (28/100)
but no forestomach carcinomas. The Chinese hamsters developed bladder
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1AHI E 6 -6
Administration of N-Nitrosodl-n-butylamine to C57BL/6 Mice in Drinking Watera»b
Sex Dosec Duration of Target Organ Tumor Type Tumor
(mg/kg/day) Treatment Incidence
H
7.6
(1986 mg/kg
mean total dose)
life
esophagus
bladder
esophagus
bladder
and
squamous carcinomas
and papillomas
squamous carcinomas
and papillomas
squamous carcinomas
and papillomas
45/47
17/47
46/47
H
29.1
(6310 mg/kg
mean total dose)
197 days or
11 fed
esophagus
bladder
esophagus
bladder
and
squamous carcinomas
and papillomas
squamous carcinomas
and papillomas
squamous carcinomas
and papillomas
40/45
36/45
45/45
F
8 2
(2096 mg/kg
mean total dose)
life
esophagus
bladder
esophagus
bladder
and
squamous carcinomas
and papillomas
squamous carcinomas
and papillomas
squamous carcinomas
and papillomas
40/42
2/42
40/42
F
30.9
(7115 mg/kg
mean total dose)
197 days or
11 fed
esophagus
bladder
esophagus
bladder
and
squamous carcinomas
and papillomas
squamous carcinomas
and papillomas
squamous carcinomas
and papillomas
45/45
8/45
45/45
-------
TABLE 5-7
Administration of N-N1trosod1-n-butylam1ne to Hale ICR Mice In Diet*
Dose
Duration of
Duration
Target
Tumor
(ppm)
Treatment
of Study
Organ
Tumor Type
Incidence
(months)
(months)
fore-
squamous cell
stomach
carcinoma
0/28
squamous papilloma
0/28
carcinoma or
papilloma
0/28
1 iver
adenoma
0/28
trabecular hepatoma
0/28
adenoma or
trabecular hepatoma
0/28
lung
adenoma
2/28
fore-
squamous cell
stomach
carcinoma
27/33
squamous papilloma
6/33
carcinoma or
papilloma
33/33
liver
adenoma
10/33
trabecular hepatoma
5/33
adenoma or
trabecular hepatoma
15/33
lung
adenoma
8/33
QUALITY OF EVIDENCE
Strengths of Study: The compound was administered In diet and tumors
occurred at multiple sites.
Weaknesses of Study: Single dose was used and extent of pathological exami-
nations not Indicated.
Comments: Purity not reported; very brief report
~Source: Takayama and Imolzuml, 1969
0749p
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papillomas (12/66) and carcinomas (9/66) and forestomach papillomas (39/66)
and carcinomas (21/66) but no tumors of the trachea or lungs.
As summarized by IARC (1978) and Bertram and Craig (1970), Ivankovlc and
Bucheler (1968) administered 40 mg N-n1trosod1-n-butylam1ne kg/day to guinea
pigs In drinking water, 5 times/week for life (estimated total dose 24
g/kg). Hepatocellular carcinomas occurred In 15/15 animals that lived >550
days, and cholanglomas were seen 1n a "few" animals. Papillomas and
squamous cell carcinomas of the urinary bladder occurred In 3/15 and 4/15 of
the animals, respectively. Control data were not reported.
Numerous additional studies have demonstrated that N-n1trosod1-n-butyl-
amlne 1s carcinogenic following oral (short-term), subcutaneous, Intraperi-
toneal and Intravenous administration. N-N1trosod1-n-butylamlne appears to
be carcinogenic In all species that have been tested (e.g., rats, mice,
hamsters, guinea pigs, rabbits) and is carcinogenic when administered In
single doses, prenatally and to newborn animals. Benign and malignant
tumors are produced in the bladder, esophagus, liver, respiratory tract,
stomach and Intestine; leukemia Is also produced. N-N1trosod1-n-butylamlne
Is particularly effective as a bladder carcinogen (IARC, 1978).
5.1.6. N-N1trosomethylv1nylam1ne. N-N1trosomethylv1nylam1ne was adminis-
tered In the drinking water at doses of 0.3 and 0.6 mg/kg bw/day to groups
of 14 and 5 BD rats of unspecified sex, respectively (Druckrey et al.,
1967). The duration of treatment was not specifically stated but appears to
be life. Of the 19 rats, 17 had squamous cell carcinomas of the esophagus,
5 had carcinomas of the pharynx and 4 had carcinomas of the tongue. In
addition, 2 rats developed papillomas of the esophagus and 8 showed bile-
duct proliferation and cysts In the liver. Incidences of these tumors at
each dose, however, were not reported. The average total dose that caused
0749p
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-------
tumors In 50% of the animals and the average time for tumor Induction 1n 50%
of the animals were 0.11 g/kg and 390 days (0.3 mg/kg/day) and 0.16 g/kg and
270 days (0.6 mg/kg/day), respectively.
Ten of 18 BD rats of unreported sex that were exposed to 25 or 50 ppm
N-n1trosomethylv1nylam1ne in air for 30 minutes (-1 or 2 mg/kg, respec-
tively) twice weekly for an unspecified chronic period died early (not
elaborated) from severe respiratory tract Inflammation (Druckrey et al.,
1967). Of the remaining eight rats, five developed nasal cavity tumors
(three squamous cell carcinomas, two cholesteatomas). Aesthes1oneuroep1the-
Homa of the ethmoturblnals, carcinoma of the pharynx and papillomas of the
esophagus occurred In one, one and two of the rats, respectively. The tumor
Incidences were not tabulated by dose, but the average total dose that
caused tumors In 50% of the animals and the average time for tumor Induction
In 50% of the animals were 0.05 g/kg and 300 days (1 mg/kg) and 0.09 g/kg
and 270 days (2 mg/kg), respectively. Two rats that survived a single vapor
exposure to 18 mg/kg (duration not specified) died 277 and 374 days later
with carcinomas of the nasal cavities (Druckrey et al., 1967). No addi-
tional Information was reported. Although the animal studies with N-n1tro-
somethylvlnylamlne are flawed In the reporting of data, the general study
detail and design provide a notable amount of evidence for the carcinogenic
potential of N-nltrosomethylvlnylamlne In rats when exposed by drinking
water or Inhalation.
5.1.7. N-NHrosod1ethanolam1ne. The carcinogenicity of N-n1trosod1-
ethanolamlne has been assessed 1n several long-term multiple dose oral
studies with rats. Interest In this compound Is related to Its occurrence
In cosmetics and cutting oils and the likelihood that 1t Is probably the
nltrosamlne to which human exposure Is the greatest.
0749p
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Druckrey et al. (1967) administered N-n1trosod1ethanolam1ne dally 1n the
drinking water to groups of 4 and 16 BD rats at average concentrations of
600 and 1000 mg/kg, respectively, for life. A control group was not used.
All 20 rats developed hepatocellular carcinomas and 4 (dose not specified)
also had kidney adenomas. The average doses to Induce tumors In 50% of the
animals were 150 g/kg (600 mg/kg/day) and 300 g/kg (1000 mg/kg/day), and the
averages time to Induce tumors In 50% of the animals was 290 days.
Preussmann et al. (1982) administered N-n1trosod1ethanolam1ne (purity
>99%) 1n the drinking water to groups of 36-88 male Sprague-Dawley rats at
doses of 0, 1.5, 6, 25, 100 and 400 mg/kg/day, 5 days/week for life. The
rats were -100 days old at the start, and livers, nasal cavities and organs
with gross abnormalities from all rats were examined histologically at the
time of natural death or when moribund. Survival was dose-dependent,
ranging from a median of 778 days In the controls to 351 days at the highest
dose. As detailed In Table 5-8, high Incidences of liver tumors (60-92%,
primarily adenocarcinomas) occurred at >6 mg/kg/day; the Incidence In the
low-dose group was -10% (7/72) and no liver tumors occurred In the controls.
Increased Incidences (17%) of nasal cavity tumors (squamous cell carcinomas
and neuroepitheliomas) occurred 1n two of the higher dose groups. A trend
test (Peto et al., 1980) Indicated that the occurrences of the tumors 1n the
liver and nasal cavity were significant (p<0.00005 and p<0.02, respec-
tively). Ihe difference between the Incidences of liver tumors In the
low-dose and control groups was also reported to be significant (p<0.05),
but specific comparisons of other treatment groups and the controls were not
conducted. Tumors at sites other than the liver and nasal cavity were not
considered to be treatment-related.
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TABLE 5-8
Lifetime Administration of N-Nltrosodiethanolamlne to Hale Sprague-Dawley Rats In Drinking Hater3
Duration of
Dose** Treatment and Study Target Organ Tumor Type Tumor Incidence
(mg/kg/day) (days)c (p value)
0
778
liver
nasal cavity
all sites
hepatocellular carcinoma*1
squamous cell carcinoma
and neuroepithelioma
malignant and benign
0/88
0/88
43/88f
(p<0.00005)e
(p<0.02)d
1.5
(median total
dose 0.86 g/kg)
801
liver
nasal cavity
all sites
hepatocellular carcinoma*1
squamous cell carcinoma
and neuroepithelioma
malignant and benign
7/72
2/72
32/72f
(p<0.05)
6.0
(median total
dose 3.47 g/kg)
809
liver
nasal cavity
all sites
hepatocellular carcinoma11
squamous cell carcinoma
and neuroepithelioma
malignant and benign
43/72
0/72
68/72f
25.0
(median total
dose 11.14 g/kg)
624
liver
nasal cavity
all sites
hepatocellular carcinoma*1
squamous cell carcinoma
and neuroepithelioma
malignant and benign
33/36
6/36
45/36f
100.0
(median total
dose 33.21 g/kg)
465
1 Iver
nasal cavity
all sites
hepatocellular carcinoma*1
squamous cell carcinoma
and neuroepithelioma
malignant and benign
32/36
6/36
44/36f
-------
TABLE 5-8 (cont.)
Duration of
Doseb Treatment and Study
(mg/kg/day) {days)c
Target Organ
Tumor Type
Tumor Incidence
(p value)
400.0
351
11 ver
hepatocellular carcinoma0
31/36
(median total
nasal cavity
squamous cell carcinoma
1/36
dose 100.3 g/kg)
and neuroepithelioma
38/36f
all sites
malignant and benign
QUALITY OF
EVIDENCE
Strengths of Study:
Lifetime exposure
in drinking water, five dose levels.
Weaknesses of Study:
Histological examinations of sites
other than liver and nasal
cavity not conducted
unless there were
gross lesions; only one sex was tested.
Comments:
Purity >99%.
aSource: Preussmann et al., 1982
^Treatment was 5 days/week
cHedlan survival time (lifetime treatment and observation)
dlf a rat showed more than one tumor of different organ site, each was counted separately. If a rat
showed more than one tumor of different histology In the same organ, it was counted only once.
etrend test of observed vs. expected Incidence In the treated groups in comparison with the control
group.
fL1ver tumors were predominately (93-100%) hepatocellular carcinomas except In 1.5 mg/kg/day group (71%
hepatocellular carcinomas and 29% adenomas and neoplastic nodules).
-------
F344 rats of both' sexes were administered N-n1trosod1ethanolam1ne (>99%
purity) In the drinking water, 5 days/week at concentrations of 0 mg/a (40
rats/sex), 400 mg/a for 50 weeks (16 rats/sex), 400 mg/a for 75 weeks
(16 rats/sex), 1000 mg/a for 50 weeks (20 rats/sex) and 2500 mg/a for 45
weeks (20 rats/sex) (Hjlnsky and Reuber, 1984a). Water consumption was
controlled to 20 ml/rat/day. The treated rats were allowed to die
naturally, but the controls were sacrificed at week 95 (12 males, about the
time the last treated rats died) or week 130 (28 males; all females).
Mortality was dose-related, with 50% mortality ranging from 89 and 92 weeks
1n the low-dose (50 weeks) females and males, respectively, to 47 and 58
weeks 1n the high-dose females and males, respectively. All lesions and
major organs and tissues from all rats were histologically examined. As
detailed in Table 5-9, high Incidences of tumors occurred 1n the liver
(primarily hepatocellular carcinomas with "some" cholanglocarcinomas) and
nasal cavity (primarily adenocarcinomas with some squamous cell carcinomas
and olfactory carcinomas) occurred In the treated rats; the Incidences of
hepatocellular carcinomas ranged from 87.5-100%. Low Incidences (10-25%) of
unspecified kidney tumors occurred at the higher doses.
A more recent drinking water study assessed the carcinogenicity of lower
doses of N-n1trosod1ethanolam1ne In 7- to 8-week-old F344 rats of both sexes
(Lljlnsky and Kovatch, 1985). Treatments were 5 days/week at concentrations
of 0 mg/a (20 rats/sex), 28 mg/a for 100 weeks (39 rats/sex), 64 mg/a
for 50 weeks (20 rats/sex), 64 mg/a for 100 weeks (20 rats/sex) and 160
mg/a for 50 weeks (27 rats/sex). All lesions and major organs from all
rats were examined histologically at the time of natural death or morlbund-
1 ty or after 130 weeks. Survival was similar between the treated and
control groups until 100 weeks (55-81%), but subsequently survival In the
treated males was shortened. Hepatocellular carcinomas and neoplastic
0749p
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TABLE 5-9
Lifetime Administration of N-NHrosodlethanolamlne to Male and Female F344 Rats In Drinking Hater3
Duration of Duration
Sex Dose Treatment of Study Target Organ Tumor Type Tumor
(mg/i)b (weeks)0 (weeks)11 Incidence
M
0
0
95
1iver
nasal
cavlty
hepatocellular carcinoma
cholanglocarclnoma
adenocarcinoma
squamous cell carcinoma
olfactory carcinoma
0/12
0/12
0/12
0/12
0/12
M
0
0
130
1 Iver
nasal
cavity
hepatocellular carcinoma
cholanglocarclnoma
adenocarcinoma
squamous cell carcinoma
olfactory carcinoma
0/28
0/28
0/28
0/28
0/28
M
400
(2 g/rat,
total dose)
50
100
1 Iver
nasal
cavity
hepatocellular carcinoma
cholanglocarclnoma
adenocarcinoma
squamous cell carcinoma
olfactory carcinoma
14/16
4/16
5/16
0/16
0/16
M
400
(3 g/rat,
total dose)
75
100
11 ver
nasal
cavity
hepatocellular carcinoma
cholanglocarclnoma
adenocarcinoma
squamous cell carcinoma
olfactory carcinoma
14/16
2/16
9/16
0/16
1/16
H
1000
(5 g/rat,
total dose)
50
90
1 Iver
nasal
cavity
hepatocellular carcinoma
cholanglocarclnoma
adenocarcinoma
squamous cell carcinoma
olfactory carcinoma
18/20
6/20
8/20
0/20
5/20
-------
TABLE 5-9 (cont.)
Sex
Dose
-------
TABLE 5-9 (cont.)
Sex
Dose
(mg/«.)b
Duration of
Treatment
(weeks)c
Durat ion
of Study
(weeks)"
Target Organ
Tumor Type
Tumor
Incidence
F
2500
(11 g/rat,
total dose)
45
50
11 ver
nasal cavity
hepatocellular carcinoma
cholanglocarclnoma
adenocarcInoma
squamous cell carcinoma
olfactory carcinoma
20/20
5/20
1/20
1/20
1/20
QUALITY OF EVIDENCE
Strengths of Study: Lifetime exposure In drinking water with good survival; three doses/four treatments;
both sexes.
Weaknesses of Study: Total tumors at specific sites not tabulated; statistical analysis of data not
conducted.
Comments: Purity was >99% with no Identifiable volatile nltrosamlnes >0.03 ppm; age of rats
not specified.
aSource: Lljlnsky and Reuber, 1984b
^Treatment was 5 days/week.
cL1fet1me exposure (100* mortality) for treated rats; survival data reported at 10-week intervals.
^Treated rats were allowed to die naturally; control rats were sacrificed at week 95 (12 males), or week
130 (28 males and all females).
-------
nodules In the Hver were the principal neoplasms that could be attributed
to treatment (Table 5-10). The Incidences of hepatocellular neoplasms In
the males and females at the high dose (160 mg/9.) were 70 and 100%,
respectively; at the low dose (28 mg/l), there was a significantly
Increased Incidence (25%) of liver neoplasms (total) only In the females.
The lower Incidences of liver tumors 1n the male rats at all dose levels was
attributed to higher body weights. Low Incidences (5-11%) of kidney tubular
cell adenoma/carcinoma that were not statistically significant occurred 1n
most of the treatment groups.
In an earlier study, LlJInsky et al. (1980) supplied N-n1trosod1ethano1-
amlne In the drinking water to groups of 10 F344 rats of each sex at concen-
trations of 0, 3900, 7800, 15,600 and 31,250 ppm. Treatment consisted of
giving the solutions ad 11b1tum 7 days/week for the first 12 weeks and 20
ml/rat/day (average volume), 5 days/week for the next 2? weeks. A "few"
rats from the 15,600 and 31,250 ppm groups died before the end of treatment,
and all surviving animals were sacrificed at the end of treatment.
Histological examinations of gross lesions and most "normal" tissues were
conducted on all animals. All of the treated rats developed hepatocellular
carcinomas and 50-100% of the rats at the three highest doses also had
cholanglocellular carcinomas. Metastases occurred 1n many of the males
(90-100%) and females (30-80%) at the two highest dose levels. Liver tumors
did not occur In any of the controls.
Lljlnsky et al. (1980) also conducted a similar study with B6C3F1 mice.
Groups of 10 animals of each sex were given 5 ml of N-n1trosod1ethanol-
amine drinking water solutions ranging 1n concentration from 3900-62,500
ppm/day, 5 days/week for 32 weeks. CholanglofIbrosls, cirrhosis and hyper-
plastic nodules reportedly were found In the livers of many of the mice that
received the higher dosages, but tumors were not observed. The results
0749p
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TABI E 5-10
Lifetime Administration of N-NUrosodlethanolamlne to Hale and Female
F344 Rats In Drinking Water (Low Dose Study)3
Sex
Dose
(mg/t)b
Duration of
Treatment
(weeks)c
Duration
of Study
(weeks)"
Target
Organ
Tumor Type
Tumor Incidence
(p value)
H
0
130
130
1 Iver
hepatocelluTar carcinoma
neoplastic nodule
cholanglocelTular
carc1 noma/adenoma
total
0/20
4/20
0/20
4/20
M
28
(280 mg/rat,
total dose)
100
130
11ver
hepatocellular carcinoma
neoplastic nodule
cholanglocellular
carcinoma/adenoma
total
0/39
6/39
0/39
6/39
(NS)
M
64
(320 mg/rat.
total dose)
50
120
1 Iver
hepatocelluTar carcinoma
neoplastic nodule
cholangloceTlular
carc1 noma/adenoma
total
1/20
2/20
0/20
0/20
-------
TABLE 5-10 (cont.)
Sex
Dose
(mg/i)b
Duration of
Treatment
(weeks )L"
Duration
of Study
(weeks)®
Target
Organ
Tumor Type
Tumor Incidence
(p value)
M
160
(800 mg/rat,
total dose)
50
130
1 Wer
hepatocellular carcinoma
neoplastic nodule
cholanglocellular
carc1noma/adenoma
total
7/27
17/27
2/27
19/27
(p=0.014)
(p<0.001)
F
0
130
130
liver
hepatocellular carcinoma
neoplastic nodule
cholanglocellular
carcinoma/adenoma
total
0/20
1/20
0/20
1/20
F
28
(280 mg/rat,
total dose)
100
130
11 ver
hepatocellular carcinoma
neoplastic nodule
cholanglocellular
carcinoma/adenoma
total
5/39
8/39
0/39
10/39
(NS)
(NS)
(NS)
(p=0.051)
F
64
(320 mg/rat,
total dose)
50
130
1 Iver
hepatocellular carcinoma
neoplastic nodule
cholanglocellular
carcinoma/adenoma
total
2/20
4/20
0/20
5/20
(NS)
(NS)
(NS)
(NS)
F
64
(640 mg/rat,
total dose)
100
130
11 ver
hepatocellular carcinoma
neoplastic nodule
cholangiocellular
carc inoma/adenoma
total
7/20
13/20
2/20
14/20
(p-0.004)
(p<0.001)
-------
1ABLE 5-10 (cont.)
Sex
Dose
(mg/*)b
Duration of
Treatment
(weeks)c
Duration
of Study
(weeks
Target
Organ
Tumor Type
Tumor Incidence
(p value)
F
160
(800 mg/rat,
total dose)
50
130
1 iver
hepatocellular carcinoma
neoplastic nodule
cholangiocellular
carcinoma/adenoma
total
19/27 (p<0.001)
19/27
1/27
27/27 (p<0.001)
QUALITY OF EVIDENCE
Strengths of Study: Lifetime exposure to low doses In drinking water, three doses/four treatments, both
sexes.
Comments
Purity >99/4 with no identifiable volatile nitrosamines >0.03 ppm.
aSource: Lijlnsky and Kovatch, 1985
''Average water consumption was 20 mi/rat/day.
treatment was 5 days/week.
dLlfetime exposure for most of the control and treated rats.
-------
would appear to Indicate that mice are less sensitive to N-nltrosodlethanol-
amlne than rats, but additional Information regarding this study was not
reported.
Hale and female Syrian golden hamsters that had their oral cavities
swabbed with 20 mg N-n1trosod1ethanolam1ne (0.9% NaCl solution) 3 times/week
for 45 weeks developed nasal cavity tumors (17/38) and tracheal tumors
(6/38) (Hoffmann et al., 1983). Tumors were not observed 1n the oral cavity
of treated hamsters or In vehicle-treated controls. Nasal cavity and
tracheal tumors occurred 1n 5/30 and 4/30 Syrian golden hamsters of both
sexes that were topically (shaved back) treated with 25 mg N-n1trosod1-
ethanolamlne 1n acetone 3 times/week for 36 weeks (Hoffmann et al., 1983).
Tumors did not develop at these sites In hamsters similarly exposed to lower
doses (2.5 or 8 mg/appl 1 cat 1 on) or In untreated controls. The hamsters 1n
the above experiments were observed until moribund or 20 months.
Weekly or biweekly subcutaneous Injections of N-n1trosod1ethanolam1ne
also produced malignant treatment-related tumors In the nasal cavity and
trachea of hamsters (Hllfrlch et al., 1978; Schmeltz et al., 1978; Pour and
Wallcave, 1981; Hoffmann et al., 1983).
5.1.8. N-N1trosod1phenylam1ne. A carcinogenesis bloassay of N-nltrosodl-
phenylamlne has been conducted In which 98X pure compound containing two
unspecified Impurities was administered In the diet at two dose levels to
groups of fifty 6-week-old F344 rats and fifty 6-week-old B6C3F1 mice of
each sex (NCI, 1979). The rats were fed diets that contained 1000 or 4000
ppm of the compound for 100 weeks. Male mice were fed diets that contained
10,000 or 20,000 ppm for 101 weeks. The female mice Initially received 5000
or 10,000 ppm for 38 weeks, but because of excessive mean weight gain
depression, treatment was discontinued for 3 weeks and then continued at
1000 and 4000 ppm, respectively, for 60 weeks; the 1WA doses were 2475 and
0749p
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-------
6139 ppm, respectively. Matched control groups consisted of 20 untreated
rats and mice of each sex. Comprehensive pathological examinations were
conducted on all moribund animals and survivors; animals that died during
the study were also examined unless precluded whole or 1n part by autolysis
or cannibal1zat1on.
Mean body weights of the treated male and female rats were lower than
those of the corresponding controls and were dose-related for the males
throughout the bloassay and for the females sometime between weeks 40 and 68
(body weights were not recorded during this period). Mortality was dose-
related In the female rats (p=0.024) but not 1n males; survival at the end
of the study In the control, low- and high-dose groups was 80, 88 and 86%,
respectively, in the males and 90, 88 and 70%, respectively, In the females.
As detailed 1n Table 5-11, statistically increased Incidences (p<0.001) of
transitional cell carcinomas of the urinary bladder occurred In both sexes.
Epithelial hyperplasia and squamous metaplasia of the bladder also occurred
1n treated rats of each sex (Section 5.5.). Additionally, flbromas of the
Integumentary system (subcutls and skin) occurred 1n the male rats at Inci-
dences that were dose-related (p=0.003), but not significantly higher than
those In the control group In direct comparison. These results reportedly
suggest an association of the flbromas with treatment since the Incidence of
Integumentary system flbromas 1n historical male controls at the same
laboratory was 6/285 (2%).
Dose-related decreases in body weight gain occurred in mice of both
sexes throughout the bloassay, but mortality was not significantly affected
by treatment. Survival at the end of the study 1n the control, low- and
high-dose groups was 90, 92 and 82%, respectively, In the males and 80, 84
and 62%, respectively, 1n the females. Similar Incidences and types of
tumors occurred In both the control and treated mice; however, submucosal
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-------
TAHLE 5-11
Bloassay of N-N1trosod1phenylam1ne (98% Pure) Administered In D1eta
Duration of
Duration
Species/
Sex
Dose
Treatment
of Study
Target
Tumor Type
Tumor
Incidence
Strain
(ppm)
(weeks)
(weeks)
Organ
(p value)
Rat/F344
H
0
100
100
bladder
transitional
cell
0/19
(p<0.001)b
carcinoma
1,000
100
100
bladder
transitional
cell
0/46
(NS)
carcinoma
4,000
100
100
bladder
transitional
cell
16/45
(p=0.001)c
carcinoma
F
0
100
100
bladder
transitional
cell
0/18
.o
r—
O
O
©
V
CL
carcinoma
1,000
100
100
bladder
transitional
cell
0/48
(NS)
carcInoma
4,000
100
100
bladder
transitional
cell
40/49
(p<0.001)c
carcinoma
Mouse/
M
0
101
101
bladder
transitional
cell
1/20
(p=0.003)b
86C3F1
carcinoma
10,000
101
101
bladder
transitional
cell
1/50
(NS)
carcinoma
20,000
101
101
bladder
transitional
cell
10/50
(NS)
carcinoma
-------
TABLE 5-11 (cont.)
QUALITY OF EVIDENCE
Strengths of Study: Adequate numbers of both sexes of rats and mice were treated at two dose levels for a
significant portion of their lifespan. Sufficient numbers of animals were at risk In
all groups for the development of late-appearIng tumors.
Weakness of Study: Excessive depression of weight gain in female mice required cessation of treatment
during weeks 38-41 and subsequent continuation at lower doses.
Overall Adequacy:
Comments:
Adequate
It was concluded that under the conditions of this bloassay, N-n1trosod1phenylamlne
was carcinogenic to F344 rats of both sexes, Inducing transitional cell carcinomas of
the bladder, but not to B6C3F1 mice of either sex.
aSource: NCI, 1979
bCochran-Armltage test for linear trend
c0ne-ta11ed Fisher Exact test
NS - Not significant
-------
Inflammation and epithelial hyperplasia of the bladder occurred 1n treated
mice of both sexes (Section 5.5.).
Oruckrey et al. (1967) administered N-n1trosod1phenylam1ne to a group of
20 BO rats of unspecified sex In drinking water that provided a dally dose
of 120 mg/kg and a total dose of 65 g/kg. No tumors appeared within 700
days. Additional Information regarding the design or results of this exper-
iment, which was part of a survey of the carcinogenicity of 65 N-n1troso
compounds, was not reported.
Argus and Hoch-Llgetl (1961) administered N-nltrosodlphenylamlne of
unspecified purity by gavage to 25 male Wlstar rats at a dose of 1.07 mg,
suspended 1n 1 ml of IX aqueous methylcellulose, 5 days/week for 45 weeks
(total dose 244 mg/rat). All rats survived to 53 weeks at which time the
experiment was terminated. A control group was not used In this study, but
tumors were not observed In any of the rats by gross examination or histo-
logical examination of the liver, spleen, kidneys, lung and other organs
with macroscopic alterations. A relatively low dose was used In this study.
BRl (1968) and Innes et al. (1969) evaluated the carcinogenicity of
orally administered N-n1trosod1phenylam1ne 1n two strains of mice, B6C3F1
(C57BL/6 females x C3HAnF males) and B6AKF1 (C57B1/6 females x AKR males).
Commercial grade compound (Impurities not specified) was administered to
groups of 18 mice of each sex according to the following schedule: dally
Intubation of 1000 mg/kg In DMSO vehicle from 7-28 days of age, followed by
administration of 3769 ppm In the diet until 81 (B63CF1 mice) and 83 (B6AKF1
mice) weeks of age. The dosages represented maximum tolerated levels as
determined 1n preliminary subchronlc studies; the dose was not adjusted to
the changing body weight during the 3 weeks of stomach tubing, but a single
adjustment was made at the time of conversion from stomach tube In Incorpo-
ration In the feed.
0749p
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-------
Control groups of 18 mice of each strain and sex received no treatment
(four groups) or 0.5% gelatin (one group). Twelve and 15 male and female
B6C3F1 mice and 18 male and 17 female B6AKF1 mice, respectively, survived to
the end of the treatment period. The survivors were subjected to gross
pathological examinations, and histological examinations were conducted on
only selected tissues (chest contents, liver, spleen, kidneys, adrenals,
stomach, Intestines and genitals); mice that were sacrificed when moribund
were subjected to gross examinations, but histological examinations were
performed only when deemed appropriate (criteria not specified). No statis-
tically significant (p<0.05) Increases In tumor Incidences were found In any
of the treated groups. The total numbers of mice with tumors were 7/15
(male B6C3F1), 1/15 (female B6C3F1), 3/18 (male B6AKF1) and 3/18 (female
B6AKF1) compared with 22/19, 8/87, 16/90 and 7/82 1n the pooled control
groups, respectively. Weak carcinogenic effects may not have been detected
because of the relatively small test group size and limited nature of the
hlstopathologlcal examinations.
Iversen (1980) treated the Intrascapular region of groups of 16 male and
24 female hairless hr/hr Oslo strain mice (age not specified) with single
weekly 0.1 ml applications of a IX solution of N-nltrosodlphenylamlne
(purity not specified) for ?0 weeks. Necropsies that apparently Included
histological examinations only of the lungs and palpable lesions were per-
formed on surviving animals after 80 weeks of observation. The only tumors
detected In 14 male and 21 female survivors were lung adenomas In 3 of the
males; local tumors were not observed. Control groups were not used In this
study, but 1t was noted that historical experience Indicated that lung
adenomas were observed 1n dermal studies only after carcinogen treatment.
0749p
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-------
Treatment-related neoplasms were not observed In a group of 24 male CB
rats (6-7 weeks of age) that received once weekly Intraperitoneal Injections
of 2.5 mg N-n1trosod1pehnylam1ne (purity unspecified) In polyethylene glycol
400 for 6 months (total dose 325 mg/rat) and observed for 18 months (Boyland
et al., 1968). A group of 24 rats Injected with the vehicle only served as
controls. Five of the treated and 10 of the control rats survived until
18-24 months. Histological examinations Included all tumors and tissues
showing macroscopic abnormalities.
Groups of 18 B6C3F1 and 18 B6AKF1 mice of each sex were administered a
single 1000 mg/kg subcutaneous Injection of N-n1trosod1phenylam1ne 1n DHS0
In the nape of the neck at -28 days of age and observed for -18 months (BRL,
1968). Control groups of 24 mice of each strain and sex were similarly
treated with DMS0 alone. Pathological examinations were conducted as In the
oral study described previously. A significantly Increased Incidence of
reticulum cell sarcomas occurred In the male B6C3F1 mice (4/16 vs. 0/24 In
the control group) but not In female B6C3F1 or B6AKF1 mice of either sex.
Statistically significant (p<0.05) Increased tumor Incidences did not occur
at other sites 1n any of the treated groups.
5.1.9. p-N1trosod1phenylam1ne. Pertinent data regarding the carcinogen-
icity of p-n1trosod1phenylam1ne could not be located 1n the available
literature as cited 1n the Appendix.
5.2. MUTAGENICITY
The mutagenlc/clastogenlc potential of most of the dlalkyl nltrosamlnes
(N-n1trosod1methylam1ne, N-n1trosod1ethylam1ne, N-n1trosod1-n-propylamine
and N-nltrosod1-n-buty1am1ne) has been unequivocally demonstrated In
numerous studies. Only representative studies are summarized In Table 5-12,
since 1t Is beyond the scope of this document to review all of the available
0749p
5-61
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-------
TABLE 5-12
Positive Short-Tern Assays of Dlalkylnttrosamlnes
N1trosamlne
Assay
References
N-N1trosodlmethylemlne
SalnraneTla tvohlmurlum reverse mutation3 (predominantly
strain TA100 but also TATS30 and TA1535)
IARC, 1978; Yahagt et al.. 1977; Probst et al..
1981; Khudoley et al., 1981; Ralnerl et al.. 1981;
Kerklaan et al.. 1983; Arakl el al.. 1984; Oe Flora
et al.. 1984; Horl et al., 1985; Phllllpson and
Ioannldes, 1985; Moore et al., 1985
Escherichia coll reverse mutation and growth Inhibition3
(predominantly strains UP?, WP?uvrA- or derivatives)
IARC, 1978; HcCarrolT et al., 1981; Probst et al.,
1981; Arakl et al., 1984; Oeflora et al., 1984
Chinese hamster V79a (8-azaguanlne-. ouabain- or B-thlo-
guanlne-reslstant mutants)
Kurokl et al., 1977; Bartsch et al., 1980; Jones
and Huberman, 1980
mouse lymphoma L5178Y TK«V-d
Cllve et al., 1979; Amacher and Palllet, 198?, 1983
unscheduled ONA synthesis In vltroa (rat heoatocvtes.
rat respiratory epithelial cells, human fibroblasts.
Hela cells)
IARC. 1978; Hartln et al.. 1978; Probst et al.,
1981; Mitchell et al.. 1983; Doollttle et al.. 1984
In vitro transformation (hamster embryo cells, rat liver
epithelial cells)
IARC. 1978; Plenta. 1980; Dunkel et al.. 1981
sex-linked recessive lethal (Drosophlla melanoqaster)
Lee et al.. 1983
ONA fragmentation (alkaline elutlon/rat liver jn vivo)
Brambllla et al.. 1981; Bradley et al.. 198?
chromosome aberrations (Chinese hamster cells in vitro*,
rat lymphocytes .In vivo)
IARC 1978; Kaneko et al.. 1978; Ratsuoka et al..
1979
sister-chromatid exchange (human lymphocytes In vitro3.
Chinese hamster bone marrow jn vivo, mouse bone marrow
and fetal mouse liver Ui vivo)
Inoue et al., 1983; Neal and Probst, 1983; Sharma
et al., 1983
N-NHrosomethylethylamlneb
S. typhi murium reverse mutation3 (strains TA100 and
TAT 535)
Kerklaan et al.. 1983; Phllllpson and Ioannldes,
1985
Chinese hamster V793 (ouabain- and B-thtoguanlne-
reslstant mutants)
Jones and Huberman. 1980
-------
TABLE 5-12 (cont.)
N1trosam1ne
Assay
References
N-Nltrosodlethylamlne
S, typhlmurlum reverse mutation4 (predominantly strain
TA100 but also TA153Q and TA1535)
1ARC, 1978; Yahagl et al., 1977; NcNahon et al.,
1979; Khudoley et al., 1981; Probst et al,, 1981;
Ralnerl et al., 1981; Kerklaar et al., 1983; Arakl
et al., 198*; Norl et al., 1985; Noore et al., 1985
E. coll reverse mutation, forward mutation or growth
Inhibition3 (predominantly strains WP2, WP2uvrA_,
W3110 pol AVp3478 pol A" or derivatives)
I ARC, 1978; NcNahon et al.. 1979; McCarroll et al.,
1981; Probst et al., 1981; Rao et al., 1981; Namber
et al., 1983
Chinese hamster V79a (8-aiaguan1ne-, ouabain- or
B-thloguanlne-reslstant mutants)
Kurokl et al., 1977; Bartsch et al., 1980; Jones
and Huberman, 1980
mouse lymphoma 15178* TK »/-a
C11ve et al., 1979; Amacher and Palllet, 1982
unscheduled ONA synthesis In vitro3 (rat hepatocytes.
human fibroblasts, Hela cells)
Hart In et al., 1978; Probst et al., 1981; Mitchell
et al., 1983
In vitro transformation (Hamster embryo cells)
Plenta, 1980; Ounkel et al., 1981
DMA fragmentation (alkaline elutlon/rat liver In vivo)
Brambtlla et al., 1981; Bradley et al., 1982
chromosome aberrations (Chinese hamster cells 1n vitro3)
Kaneko et al., 1978; Natsuoka et al., 1979
sister-chromatid exchanqe (human lymphocytes In vitro3)
Inoue et al., 1983
mlcronucleus test (fetal mice by transplacental
exposure)1
Cole et al., 1982
N-Nltrosodl-n-propyl amine
S. tvohlmurlum reverse mutation3 (predominantly strains
TA100 or TA1535)
1ARC, 1978; Yahagl et al., 1977; NcNahon et al.,
1979; Probst et al., 1981; Andrews and L1JInsky,
1980; Arakl et al., 1984; Guttenplan and Hu, 1984;
Noore et al., 1985; Ph111Ipson and loannldes, 1985
E. colt reverse mutation and forward mutation3 [strains
HP2, WP2uvrA". K12(343/113)]
NcNahon et al., 1979; Probst et al.. 1981; Rao
et al.. 1981
Chinese hamster V79a (8-aiaguan1ne-, ouabain- or
8-Ut1oguan1ne-res1stant mutants)
Kurokl et al., 1977; Bartsch et al., 1980; Jones
and Huberman, 1980
-------
TABLE 5-1? (cont.)
Nltrosamlne
Assay
References
N-M1trosodl-n-propylam1ne
mouse lymphoma (LS178YTK »/-a
Cllve et al., 1979
unscheduled ONA synthesis In v1troa (rat heoatocvtes
and Hela cells)
Hart In et al.. 1970; Probst et al., 1981
DNA fragmentation (alkaline elutlon/rat liver In vivo
Brambtlla et al., 1981; Bradley et al., 198?
chromosome aberrations (Chinese hamster cells In vltroa)
Kaneko et al., 1978; Natsuoka et al.. 1979;
Ishldate et al., 1981
N-NUrosodt-n-butylam1ne
S. tvoM murium reverse mutation3 (predominantly strains
TA100 and TA1535)
IARC, 1978; Yahagl et al., 1977; Andrews and
Lljlnsky, 1980; Arakl et al.. 1984; Noore et al.,
1985
E. coll* (strains WPPuvrA/pKHlOl)
Arakl et al., 1984
Chinese hamster V79a (8-azaguanlne-, ouabain- or
B-thloguanlne-reslstant mutants)
Kurokl et al.. 1977; Bartsch et al., 1980; Jones
and Huberman, 1980
unscheduled ONA synthesis In vitro3 (Hela cell!
Martin et al., 1978
ONA fraamentatIon (alkaline elutlon/rat liver In vivo)
Brambllla et al., 1981; 8radley et al., 198?
chromosome aberrations (Chinese hamster cells 1n vitro3)
Kaneko et al., 1978; Hatsuoka et al., 1979
N-Nltrosomethylvlnylamlne
sex-linked recessive lethal (0. melanoqaster)
Pasternak. 1964
N-N1 trosodlethanolani1nee
S. tvohlmurtum reverse mutation* (strains G-4b. TA100d.
1A1535C)
Hesbert et al., 1979; HcHahon et al., 1979
E. col 1 reverse mutatlona (strains WP2 and WP2uvrA")
McHahon et al., 1979
aNetabol1c activation preparation used
bNot mutagenic In E. col I Kl2(343/113) forward and reverse mutation assays (Rao et al., 1901)
cM1cronucle1 not Induced In standard mouse assay (Wild, 1978; Trros et al., 1970; Jenssen and Ramel, 1980)
^Mutagenic without metabolic activation preparation (Hesbert et al., 1979)
eChromosomal aberrations or mlcronuclel in bone marrow not Induced In mice Jji v1 vo (Gilbert et al., 1981)
-------
evidence. An attempt has been made, however, to gather all of the available
Information for the less extensively studied dialkyl compounds (e.g.,
N-nltrosomethylethylamlne and N-n1trosod1ethanolam1ne).
As Indicated 1n Table 5-12, N-n1trosod1methylam1ne, N-n1trosod1ethyl-
amlne, N-n1trosod1-n-propylam1ne and N-n1trosod1-n-butylam1ne are mutagenic
1n bacteria (S. typhlmurlum. £. coll) and mammalian cells exposed in vitro
(Chinese hamster V79, mouse lymphoma L5178Y0), caused unscheduled DNA
synthesis in vitro. DNA fragmentation in vivo and produced chromosomal
aberrations in vitro. Additionally, N-n1trosod1methylam1ne and N-n1trosod1-
ethylamlne Induced sister chromatid exchanges, mlcronuclel and in vitro
transformation (see Table 5-12). Of the less extensively studied dlalkyl-
nltrosamlnes, N-n1trosomethylethylam1ne 1s mutagenic In S. typhlmurlum
(Kerklaan et al., 1983; Phllllpson and loannldes, 1985) and Chinese hamster
V79 cells (Jones and Huberman, 1980), and N-n1trosomethylv1nylam1ne produced
sex-l1nked recessive lethal mutations In D. melanoqaster (Pasternak, 1964).
N-N1trosod1ethanolam1ne was mutagenic In S. typhlmurlum (Hesbert et al.,
1979; McHahon et al., 1979) and E. coli (HcHahon et al., 1979), but did not
Induce chromosomal aberrations or mlcronuclel 1n mice in vivo (Gilbert et
al., 1981). Mutagenicity of the dlalklynltrosamlnes 1n the Ames Salmonella
assays was expressed primarily 1n strains TA100 and TA1535, Indicating that
these compounds are base-pair mutagens. Mutagenic expression In essentially
all of the in vitro bacterial and mammalian cell assays required a metabolic
activation system, which 1s consistent with the apparent carcinogenic action
(I.e., Indirect) of these chemicals.
N-N1trosod1phenylam1ne has been tested 1n numerous short-term carcinogen
screening assays with negative results. These Include reverse/forward
mutation and DNA repair assays In bacteria (IARC, 1982; Nagao and Takahashl,
0749p
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1981; Brooks and Dean, 1981; Trueman, 1981; Rowland and Severn, 1981;
Gatehouse, 1981; Hubbard et al., 1981; Ichlnotsubo et al., 1981; Kada, 1981;
Venltt and Crofton-Sle1gh, 1981; Skopec et al., 1981; Tweats, 1981; Rosen-
kranz et al., 1981; Matsushlma et al., 1981; Green, 1981; Thomson, 1981;
Garner et al., 1981; Somanl et al., 1981; Arakl et al., 1984; Rannug et al.,
1984), gene mutation and recomblnogenlclty assays In yeast {I ARC» 1982; de
Serres and Hoffmann, 1981; Rosenkranz et al., 1981; Lelfer et al., 1981;
Hamber et al., 1983; Arakl et al., 1984), and mutation assays with mouse
lymphoma L5178Y/TK +/- cells and Chinese hamster V79 and ovary cells (IARC,
1982; Brooks and Preston, 1981; Ootz and Mitchell, 1981; Jones and Huberman,
1980; Bartsch et al., 1981; Oberly et al., 1984). N-N1trosod1phenylam1ne
also did not Induce sex-Hnked recessive lethal mutations In 0. melano-
qaster. chromosomal aberrations In rat liver cells hi vitro, sister chroma-
tid exchanges in Chinese hamster ovary cells in vitro or mlcronuclei In mice
(IARC, 1982; Purchase and Ray, 1981; Klrkhart, 1981; Oean, 1981; Perry and
Thomson, 1981; Evans and Mitchell, 1981; Vogel et al., 1981; Tsuchlmoto and
Matter, 1981; Salamone et al., 1981; Neal and Probst, 1983).
Although N-n1trosod1phenylam1ne 1s nonactlve 1n the preponderance of
assays, positive responses have been reported In several studies. These
Include several Ut vitro assays with the yeast S. cerevlslae (reversion In
strain XV185-14C, mitotic aneuploldy In strain D6 and ONA repair In rad
mutant) (de Serres and Hoffmann, 1981) and two DNA damage assays with rat
hepatocytes In vitro [unscheduled ONA synthesis (Althaus et al., 1981) and
alkaline elutlon (Slna et al., 1983)]. N-N1trosod1phenylam1ne-1nduced
transformation In Syrian hamster embryo cells (Plenta and Kawalek, 1981), In
BHK cells (Daniel and Dehnel, 1981) and 1n F344 rat embryo cells Infected
with Rauscher murine leukemia virus (Dunkel et al., 1981), but not In BHK
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cells or Syrian hamster embryo cells In different studies (Styles, 1981;
Dunkel et al.t 1981) or Balb/3T3 cells (Dunkel et al., 1981).
In the only study of p-nltrosodlphenylamlne available, the compound did
not produce sex-1Inked recessive lethal mutations In D. melanoqaster when
administered by feeding or Injection (Valencia et al., 1985).
5.3. TERATOGENICITY
N-N1trosod1methylam1ne was administered 1n the drinking water at concen-
trations of 0 and 0.1 ppm to groups of twenty 4-week-old female CD-I mice
(Anderson et al., 1978). The mice were mated after 75 days and treatment
was continued through pregnancy until weaning. All stillborn fetuses and
dead neonates were necropsled, and viscera (liver, kidney, gastrointestinal
tract, spleen, heart, lungs) and brains from at least five were histologi-
cally examined; live newborns were counted and Inspected (not elaborated).
N-N1trosod1methylam1ne treatment caused a doubling of perinatal deaths (20
vs. 9.9% in controls), with stillborn fetuses (19/185) and dead newborns
(19/185) contributing equally. Abnormalities were not found In any of the
stillborn fetuses or dead newborn. Many of the lungs were atelectatic,
Indicating death before commencement of breathing, but other lesions were
not observed. N-N1trosod1methylam1ne treatment was also associated with
Increased conception time (average 3 days longer than controls) and abnormal
sex ratio (-66% males, -34% females) 1n all Utters (Including those with
low perinatal mortality), but weanlings were comparable in size to controls.
Since the sex ratio was significantly different from 1 even 1n Utters with
low perinatal mortality, this effect is probably not due to selective
sensitivity of the female fetuses at term. Maternal Indices other than
conception time were not reported.
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Alexandrov (1967) administered a single maximum tolerated Intragastric
dose of 30 mg N-n1trosod1methylam1ne/kg to rats of unspecified strain on
each day of gestation (one dose/experiment). Treatment caused an Increase
In fetal mortality, particularly when administered on days 3 (-35%) and 12
(-38%) of gestation. Malformations In the surviving fetuses were not
observed. Similar treatment with single Intraperitoneal (30 mg/kg) or
Intravenous (20 mg/kg) doses of N-n1trosod1methylam1ne reportedly produced
the same effect. Intraplacental Injection of the compound (-50 yg Into
each amniotic cavity) on days 12-14 of gestation also only produced
Increased fetal mortality (up to 25-35%) (Alexandrov, 1973). No additional
Information was provided In the English summary of this Russian study.
Single oral doses of 20 mg N-n1trosod1methylam1ne/kg were administered
to Holtzman rats on days 15, 16, 18 or 20 of gestation (Nlshle, 1983).
Fetal weights measured 2 days after treatment were significantly (p<0.05)
lower following treatment on days 15 and 20 than weights of fetuses from
untreated rats. Fetuses were not examined for gross or microscopic
abnormalities or other Indications of toxicity.
Herrman and Schauer (1973) reported that administration of 250 mg
N-nUrosodlmethylamlne/kg bw Into the amniotic fluid of rats on day 15 of
gestation Induced the formation of macrodontla In 15/103 offspring within
the first 14 days.
Neubert and Bluth (1981) Indicated that unspecified teratogenic effects
were demonstrated by In vitro treatment of cultures of limb buds from 11- or
12-day-old mouse embryos with N-n1trosod1methylam1ne If the embryos were
exposed )n utero to monooxygenase Inducers. Teratogenic effects were not
observed In limb buds from embryos not exposed .In utero to the Inducers.
0749p
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Teratogenic effects were not observed 1n rats given single oral or
Intraperitoneal maximum tolerated doses of N-n1trosod1ethylam1ne (200 and
180 mg/kg, respectively) or N-n1trosod1-n-butylamlne (1200 and 1000 mg/kg,
respectively) on Individual days throughout pregnancy (Alexandrov, 1973).
Both nltrosamlnes exerted an embryotoxlc effect similar to that of N-nltro-
sodlmethylamlne, however, with peaks of susceptibility on days 3, 9, 10 and
12 of gestation. Fetal mortality without teratogenicity was also observed
after an Intraplacental Injection of 0.1-0.3 mg N-n1trosod1ethylam1ne to
every amniotic sac of rats on day 13 of gestation (Alexandrov, 1974).
Additional Information regarding these Russian studies were not reported In
the available English summaries.
Intravenous Injection of N-n1trosod1ethylam1ne (70 mg/kg) on day 15 of
gestation reportedly did not produce teratogenic effects In rats, but
additional Information was not reported (Druckrey, 1973a).
P1elst1cker et al. (1967) IntraperUoneally Injected 2-10 mg N-nltroso-
dlethylamlne Into groups of 12-22 hamsters on day 3 of gestation. Similar
size groups of hamsters were Injected with 2 mg on gestation days 5 and 6, 4
mg on gestation on days 7 and 8, 5 mg on gestation days 6 and 7, and 6-9 mg
on gestation days 3 and 4. Miscarriages reportedly occurred at the higher
doses (not specified). Examination of the offspring 6 weeks after birth did
not reveal treatment-related developmental abnormalities. No hamsters were
treated after gestation day 10, examinations of fetuses were not conducted,
and the use of control groups were not specifically Indicated. Additional
Information was not reported.
Pertinent data regarding the teratogenic or embryotoxlc potential of the
other nltrosamlnes could not be located In the available literature as cited
In the Appendix. The absence of teratogenic effects for the nltrosamlnes
0749p
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discussed previously Is possibly attributable to a lack of enzymes respons-
ible for metabolic activation In the embryo at the time when It Is sensitive
to teratogens (Alexandrov, 1973; Oruckrey, 1973b). Although teratogenicity
has not been demonstrated, several of the dialkyln1trosam1nes, particularly
N-n1trosod1methylam1ne and N-nitrosodiethylamine, are weak transplacental
carcinogens when administered late In gestation (Druckrey 1973a,b; Althoff
and Grandjean, 1979) (see Section 5.1.).
Subcutaneous Injection of N-n1trosod1methylam1ne (12.5 mg/kg In 0.9%
NaCl), N-n1trosod1-n-propylam1ne (100 mg/kg in olive oil) and N-n1trosod1-n-
butylamlne (30 mg/kg in 0.9% NaCl) into groups of five Syrian hamsters on
days 8, 10, 12 or 14 of gestation did not produce grossly visible malforma-
tions in the offspring (Althoff and Grandjean, 1979). Additional Informa-
tion relevant to developmental effects were not indicated, but it was noted
that perinatal, neonatal and postnatal mortality were low (not elaborated).
5.*. OTHER REPRODUCTIVE EFFECTS
Intraperitoneal administration of N-nltrosodlmethylamine has been asso-
ciated with necrotic changes 1n the testes of rats (Hard and Butler, 1970).
Single doses of 30 or 60 mg/kg were Injected into Porton strain rats main-
tained on protein-adequate or protein-free diets for 1 week. Rats were
sacrificed at 1, 2, 3, 4, 7, 10 and 14 days after Injection and thereafter
at weekly Intervals, and were returned to standard diets 1 week after treat-
ment. Group sizes and numbers sacrificed at each interval were not speci-
fied, but the testes of 90 rats were histologically examined; sacrifices
appear to have been continued until recovery was complete In most of the
animals. Treatment-related testicular effects were not observed In the rats
treated with 30 mg/kg and adequate protein, but testes of rats treated with
60 mg/kg and adequate protein were missing spermatogonia within 24 hours and
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had mild necrotic alterations; regeneration was progressive after 7 days and
was almost complete by 14 days. Treatment with 30 and 60 mg/kg and protein-
free diet (to diminish liver metabolism) Induced moderate to severe necrosis
of the seminiferous epithelium, which peaked after 4-7 days and occasionally
failed to recover by 8 weeks.
5.5. CHRONIC AND SUBCHRONIC TOXICITY
Information regarding nonneoplastic effects of long-term oral or Inhala-
tion exposure to N-n1trosam1nes 1s limited because Interest In these com-
pounds has focused overwhelmingly on their carcinogenicity. Nonneoplastic
pathological effects often Included apparent preneoplastic alterations
(I.e., liver hyperplasia) or acute-type responses (e.g., hemorrhage,
necrosis), but deaths were usually directly or indirectly due to tumors.
Alterations In body weight and clinical chemistry and hematology Indices
were reported occasionally, but never in the absence of neoplasia.
In a comprehensive study of liver changes, Terraclnl et al. (1967)
summarized the results of various experiments In which groups of 1-69 Porton
rats of both sexes (4-6 weeks old) were exposed to N-n1trosod1methylam1ne In
arachls oil In the diet at concentrations of 0, 2, 5, 10, 20 or 50 ppm for
up to 120 weeks. Large hepatic parenchymal cells with prominent nuclei were
found In the livers of rats In the 50 and 20 ppm groups, both In nontumorous
parts of livers with tumors and 1n livers without tumors, but Incidences
were not reported. Cystic agglomerates occurred 1n many of the rats treated
with 50 and 20 ppm N-n1trosod1methy1am1ne and at levels as low as 5 ppm.
The cysts occurred In rats with and without malignant hepatomas, apparently
developing Independently. The cysts and hepatomas were distinct when they
occurred together, and most frequently occurred together In the 20 and 50
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ppm groups; of 83 rats that received 5 ppm, 16 had cystaglomerates, 2 had
cysts and hepatomas and 6 had tumors alone. The histological description of
these cysts, however, Indicated that they could be Interpreted as benign
neoplasms (Robblns et al., 1984).
Nonneoplastic effects of N-n1trosod1methylam1ne treatment 1n 126 male RF
mice (8-10 weeks old) were described by Clapp et al. (1968). The compound
was administered 1n the drinking water at a concentration of 5 mg/i for
life, and tissues for histological examination were taken from -70% of the
mice. Nonneoplastic lesions In the livers Included Infarcts (12%), throm-
boses (6%), abscesses (3%) and eosinophilic Intranuclear Inclusions In
hepatocytes; these Incidences reportedly were greater than 1n control mice.
Slight to severe glomerulosclerosis developed In 83% of the kidneys examined
histologically; this lesion was seen In nearly all of the control mice but
occurred much later.
Hepatic histological effects In 58 ten-week-old male RF/Un mice treated
with 40 mg N-nltrosod1ethylam1ne/i drinking water for up to 22 weeks In-
cluded microabscesses In 25% of the mice (Clapp and Craig, 1967). Cyst-I1ke
structures were found In all animals after 12 weeks of treatment, but more
frequently and extensively in livers from mice that died late 1n the experi-
ment. Limited histologic Information Indicates that these lesions are not
Inconsistent with those described 1n rats (Terraclnl et al., 1967). Approx-
imately 40% of the livers had numerous hypertrophled hepatic parenchymal
cells that frequently contained eosinophilic Intranuclear Inclusions.
Nonneoplastic effects of chronic oral exposure to N-n1trosod1phenylam1ne
occurred In the NCI (1979) carcinogenesis bloassay (see Section 5.1.). In
this study, groups of 50 F314 rats of each sex were administered diets
containing 1000 and 4000 ppm of the compound for 101 weeks. Groups of 50
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male B6C3F1 mice were similarly exposed to 10,000 or 20,000 ppm (males);
female mice were exposed to TWA concentrations of 2475 or 6139 ppm, accord-
ing to the schedule described previously (see Section 5.1.)- In the rats,
corneal opacity occurred at higher Incidences In the high-dose males (15/50)
and low-dose females (16/50) than 1n corresponding control males (0/20) and
control females (1/20). In the mice, submucosal Inflammation of the urinary
bladder occurred In the treated groups of both sexes; Incidences In the
control, low- and high-dose groups were 0/18, 12/49 and 31/48, respectively,
1n the males and 0/20, 31/49 and 30/38, respectively. In the females.
Epithelial hyperplasia of the bladder occurred at low Incidences In treated
male (0/20, 2/49, 7/46) and female (0/18, 3/47, 5/38) mice, but Incidences
of bladder neoplasms were not significantly elevated.
5.6. OTHER RELEVANT 1NF0RHATI0N
Acute oral LQ,ns of various nltrosamlnes administered by stomach tube
DU
are tabulated In Table 5-13 (Oruckrey et al., 1967). The dlalkyl N-nltros-
amlnes are characteristically hepatotoxlc, producing hemorrhagic centrllobu-
lar necrosis (Hagce et al., 1976). Organs other than the liver are much
less severely affected; other acute effects primarily Include peritoneal and
pleural exudates, which may contain a high proportion of blood and a
tendency to hemorrhage Into the lungs and other organs.
Ten human cases have been reported In which exposure to N-n1trosod1-
methylamlne produced acute effects (liver damage and diffuse Internal bleed-
ing) similar to those observed 1n animals (Freund, 1937; Barnes and Magee,
1954; Fussgaenger and Dltschunert, 1980; Cooper and Klmbrough, 1980; Pedal
et al., 1982). The primary effects were hemorrhagic/necrotic alterations In
the liver that subsequently developed Into cirrhosis. Four of the subjects
were exposed while In a laboratory and six were poisoned; In four of the
cases, the acute liver Injury was fatal.
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TABLE 5-13
Acute Oral LO50 Values of Selected N-Nltrosamlnes*
Compound LDcn
(mg/kg)
N-N1trosod1methylamine
40
N-Nitrosomethyl ethyl amine
90
N-Nltrosodlethylamine
280
N-N1trosodl-n-propylamine
480
N-N1trosod1-n-butylam1ne
1200
N-Nltrosomethylvinyl amine
24
N-N1trosod1ethanolamine
7500 (not lethal)
N-NHrosodlphenylamlne
3000
p-Nltrosodlphenylamlne
NR
*Source: Oruckrey et al., 1967
NR = Not reported
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5,7. SUMMARY
Numerous chronic and subchronlc oral studies primarily conducted with
rodents have unequivocally demonstrated the carcinogenicity of N-nltrosodl-
methylamlne, N-n1trosodtethylam1ne, N-nltrosodl-n-propyl amine and N-nltroso-
d1-n-butylam1ne (IARC, 1978; Druckrey et al., 1967; Aral et al., 1979;
L1J1nsky and Reuber, 1981, 1983, 1984a; Lljlnsky et al.. 1981b; Lljlnsky and
Taylor, 1978, 1979; Peto et al., 1984). Numerous additional studies have
demonstrated that these d1-n-alkyln1trosam1nes are carcinogenic following
more limited oral exposures as well as by Injection {subcutaneous, Intra-
peritoneal or Intravenous) In all species that have been tested. Generally,
high Incidences of malignant and benign tumors occur primarily In the liver,
bladder, esophagus, forestomach or nasal cavity depending upon chemical,
species and routes. The carcinogenicity of N-n1trosomethylethylamlne,
N-nltrosomethylvinyl amine and N-nHrosodlethanol amine have been less exten-
sively Investigated In chronic and subchronlc oral studies with rats and
mice, but Information Indicating noncarclnogenlcHy has not been reported
(Druckrey et al., 1967; Lljlnsky and Reuber, 1980, 1981, 1984b; Lljlnsky et
al., 1980, 1982, 1983; Lljlnsky and Kovatch, 1985; Preussmann et al., 1982).
These nltrosamlnes primarily Induced tumors 1n the 11 ver and nasal cavities.
Chronic dietary administration of N-n1trosod1phenylamine Induced bladder
carcinomas 1n rats but not mice (NCI, 1979), but carcinogenicity was not
demonstrated In less adequate drinking water or gavage studies (Druckrey et
al., 1967; Argus and Hoch~L1get1, 1961; BRL, 1968) or by weekly Intraperi-
toneal Injections (Boyland et al., 1968). The carcinogenicity of p-nltroso-
dlphenylamlne does not appear to have been assessed.
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Mutagenicity, clastogenlclty and DNA-damaglng ability of N-n1trosod1-
methylamlne, N-n1trosod1ethylam1ne, N-nltrosodl-n-propylamlne and N-nltroso-
d1-n-butylamlne have been demonstrated In numerous bacterial and mammalian
cell assays hi vitro and In several in vivo mammalian systems. The other
d1-n-alkyln1trosam1nes have been evaluated 1n several studies and appear to
have similar effects; N-n1trosomethylethylam1ne was mutagenic 1n S. typhl-
mur1um (Kerklaan et al., 1983; PhllUpson and Ioannldes, 1985) and Chinese
hamster V79 cells (Jones and Huberman, 1980), N-n1trosomethylv1nylam1ne
Induces sex-Hnked recessive lethal mutations In D. melanoqaster (Pasternak,
1964) and N-n1trosod1ethanolam1ne was mutagenic In S. typhlmur1um (Hesbert
et al., 1979; McHahon et al., 1979) and £. coll (McMahon et al., 1979).
N-Nltrosodlphenylamlne Is nonactlve In numerous bacterial, mammalian cell
and Intact animal assays, but uncorroborated evidence of reversion and
mitotic aneuploldy In yeast (de Serres and Hoffmann, 1981), DNA damage 1n
yeast (de Serres and Hoffmann, 1981) and rat hepatocytes Wi vitro (Althaus
et al., 1982; Slna et al., 1983) have been reported. N-N1trosod1phenylam1ne
also transformed Syrian hamster embryo cells (Plenta and Kawalek, 1981) BHK
cells, (Daniel and Dehnel, 1981) and rat embryo cells Infected with Rauscher
murine leukemia virus (Dunkel et al., 1981). In the only study of p-nltro-
sodiphenylamlne located, administration to D. melanoqaster did not produce
sex-linked recessive lethal mutations.
N-N1trosod1methylam1ne produced fetotoxlc effects (stUlborns and
neonatal deaths) when administered orally to mice throughout gestation
(Anderson et al., 1978) or to rats on single days during gestation
(Alexandrov, 1967; Nlshle, 1983). Single oral doses of N-n1trosod1ethyl-
amlne or N-n1trosod1-n-butylamlne during gestation also were fetotoxlc In
rats (Alexandrov, 1973). Teratogenicity was not observed 1n any of the
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above studies. Similar effects (fetotoxlclty without teratogenicity)
reportedly resulted from single Intraperitoneal or Intravenous Injections of
N-n1trosod1methylam1ne 1n rats, single Intraperitoneal Injection of N-n1tro-
sodlethylamlne or N-n1trosod1-n-butylamlne In rats, or Intraplacental Injec-
tion of N-n1trosodlmethylam1ne or N-n1trosod1ethylam1ne In rats (Alexandrov,
1973, 1974). Single Intraperitoneal doses of N-n1trosod1methylam1ne caused
reversible mild necrotic alterations 1n the testes of rats (Hard and Butler,
1970).
Limited Information Is available regarding chronic or subchronlc toxic
effects of the nltrosamlnes because Interest In these compounds Is over-
whelmingly related to their carcinogenicity. Effects Included cysts and
hypertrophled parenchymal cells 1n the livers of rats treated with N-nltro-
sodlmethylamlne in the drinking water for up to 120 weeks (Terraclnl et al.,
1967), infarcts, thromboses and abscesses In the livers of mice treated with
N-n1trosod1methylam1ne In the drinking water for 306 days (life) (Clapp et
al., 1968), and microabscesses, cyst-like structures and hypertrophled
parenchymal cells In the livers of mice treated with N-n1trosod1ethylam1ne
In the drinking water for 22 weeks (Clapp and Craig, 1967). Administration
of N-n1trosod1phenylam1ne 1n the diet for life Induced corneal opacity In
rats of both sexes and submucosal inflammation and epithelial hyperplasia In
the bladders of female mice (NCI, 1979).
Case reports of humans that Ingested N-n1trosod1methylam1ne Indicate
that exposure produced acute effects (liver damage and diffuse Internal
bleeding) similar to those observed In animals (Freund, 1937; Barnes and
Magee, 1954; Fussgaenger and Dltschunert, 1980; Cooper and Klmbrough, 1980;
Pedal et al., 1982). The primary effects were hemorrhagic/necrotic altera-
tions 1n the liver that subsequently developed Into cirrhosis. Carcinogen-
icity of the subject nltrosamlnes In humans has not been reported.
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6. AQUATIC
6.1. ACUTE
The available Information concerning acute toxicity of nltrosamlnes to
aquatic organisms 1s presented In Table 6-1. N-N1trosod1ethylam1ne and
N-n1trosod1methylam1ne appear to be about equally toxic to aquatic organ-
Isms. Bresch and Splelhoff (1974) reported that nltrosamlne toxicity to the
sea urchin, Sphaerechinus qranularls. Increased as the number of carbon
atoms Increased, with N-n1trosod1-n-butylam1ne being most toxic and
N-n1trosod1methylam1ne less toxic. The data on other species presented In
Table 6-1 tend to confirm this generalization. The LCcn values for
dU
H-n1trosod1phenylam1ne, 5.85 mg/g. for the blueglll, Lepomls macrochlrus.
and 7.76 mg/8. for Daphnla magna (U.S. EPA, 1978) are much lower than
LC^g values for N-nltrosodlmethylamlne and N-n1trosod1ethylam1ne In other
fish and Invertebrates.
6.2. CHRONIC
There have been several studies Involving long-term exposures of aquatic
organisms to sublethal concentrations of N-n1trosod1methylam1ne and N-n1tro-
sodlethylamlne (lable 6-2). Since carcinogenicity was generally the effect
of concern, most of these studies Involved a period of observation to
monitor tumor development after an exposure period. N-N1trosod1ethylam1ne
and N-nltrosodlmethylamlne were found to be carcinogenic In six and three
fish species, respectively (see lable 6-2), In the grass frog, Rana tempo-
rarla (Khudolel, 1975), and the freshwater mollusk, Unlo plctorum (Khudolel
and Slrenko, 1977, 1978). Among the vertebrates, the liver was the primary
site of tumor development. N-N1trosod1-n-butylam1ne was also reported to
cause liver tumors In one species, rainbow trout, Salmo qalrdner1. when eggs
were exposed to 1000 mg/l for 1 hour (Hendricks et al., 1980).
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TABLE 6-1
Acute Toxicity of Nltrosamlnes to Aquatic Organisms
Species
Compound
Concentration
(mg/l)
Effect
Reference
FISH
Fathead minnow (Plmephales pronelas)
Creek chub (Sewotllus atromaculatus)
Blueglll (Lepomls nacrochlrus)
Hunlchog (fundulus heteroclltus)
Zebraflsh IBrachydanlo rerlo)
N-nltrosodlmethylamlne
N-nKrosodlethylamlne
N-nltrosodlethylamlne
N-nltrosodlphenylamlne
N-nltrosodlmethylamlne
N-nttrosodlethylamlne
940
775
900-1100
~4.2
5.85
<2.2
3300
200-400
96-hour LCjq
96-hour LC50
critical range
24-hour LC50
96-hour LCtn
96-hour N0EC
96-hour LCjq
1-week LC50
Draper and Brewer,
1979
611lette et al.,
1952
Buccafusco et al.,
1981; U.S. EPA. 1978
ferraro et al., 1977
Hatsushlma and
Suglmura, 1976
INVERTEBRATES
Hater flea (Daohnla maqna)
N-nltrosodtphenylamlne
>46
7.76
1.0
24-hour IC50
48-hour LC5Q
N0EC
U.S. EPA. 197B;
leBlanc, 1980
Amohlpod (Gaimarus llmnaeus)
N-nltrosodlmethylamlne
N-nltrosodlethylanlne
330
500
96-hour LCjg
96-hour LC$o
Draper and Brewer,
1979
Flatworm (Ouaesla dorotoceohala)
N-nltrosodlmethylamlne
N-nltrosodlethylanlne
1365
1490
96-hour LC50
96-hour LC50
Draper and Brewer,
1979
Sea urchin (Sohaerechtnus qranularls)
N-nltrosodlmethylamlne
N-nltrosodlethylanlne
N-nltrosodl-n-propylamlne
N-nltrosodl-n-butylamlne
5928
816
104
13
threshold, effects on
enbryonlc development
same as above
same as above
same as above
Bresch and
Splelhoff, 1974
Mussel (Mvtllus edulls)
N-nltrosodlmethylamlne
100
histological effects,
Rasmussen, 19B2
exposure was every
other day for 14 days
-------
TABLE 6-2
Results of Long-Term Studies with Nltrosamlnes and Aquatic Organisms
Species
Compound
Concentration
{mg/l)»
Ouratlon of
E xposure
Effect
Reference
Guppy
Poecllla reticulata
Zebraf1sh
Brachydanlo rerlo
N-nltrosodlethylamlne
N-nltrosodlethylamlne
N-nltrosodlethylamlne
N-n1trosod1ethyl amine
N-nltrosodlethylamlne,
N-nltrosodlmethylamlne
N-nltrosodtethyl amine
N-nltrosodlethylamlne
N-nltrosodlethylamlne
N-nltrosodlethylamlne
N-nltrosodlethylamlne
N-nltrosodlethylamlne
N-nltrosodlmethylamlne
N-nltrosodlmethylamlne
N-nltrosodlmethylamlne
N-nltrosodlmethylamlne
N-nltrosodlmethylamlne
N-nltrosodlethylamlne
N-nltrosodlmethylamlne
N-nltrosodlethylamlne
N-nltrosodlethylamlne
N-n!trosod1methylam1ne
FISH
10-?00 90 days liver degeneration, carcinomas
26, 100 7 months lesions In organs
25, SO hepatocellular carcinomas, bowel
polyps, esophagael papillomatosis
13-100 7-0 weeks hepatocellular carcinomas,
adenomas, cholangloma
13-100 10-64 days liver necrosis, benign and
malignant tumors
13-100 2.5-9 weeks hepatocellular cancer
100 8 weeks liver tumors, 29% Incidence
25 6 weeks 32/45 survived, preneoplastic
liver lesions, no tumors
50 8 weeks 54/95 survived preneoplastic
lesions and tumors
26-33 8-64 days 20-28% mortality, liver tumors
100 8-64 days 40-46% mortality, liver tumors
100 7-8 weeks hepatocellular carcinomas,
adenomas, cholanglomas
13-100 8 weeks hepatocellular cancer
100 56 days liver tumors
0.48% diet 13 months hepatomas
100 8 weeks liver tumors, 22% incidence
50 22-23 weeks hepatomas
50 22-23 weeks hepatomas
10-100 8 weeks hepatomas, cholanglomas
100 8 weeks 62% Incidence of liver tumors
100 8 weeks 76% Incidence of liver tumors
Simon et al.,
1980
Scherf, 1976
Simon et al.,
1902
Khudolel, 1971
Khudolel, 1973
Khudolel, 1975
Khudolel, 1984
Simon and
Lapis, 1984
Simon and
Lapis, 1984
Pllss and
Khudolel, 1975
Khudolel, 1971
Khudolel. 1975
Hatsushtma and
Sugtmura, 1976
Hatsushlma and
Suglmura, 1976
Khudolel, 1984
Aydln et al.,
1983
Aydln et al.,
1983
Natsushlma and
Suglmura, 1976
Khuoolel, 1984
Khudolel. 1984
-------
TABLE 6-? (cont.)
Species
Compound
Concentration
(mg/t)*
Duration of
Exposure
Effect
Reference
FISH {cont.5
Kllllf Ish
Rlvulus marmoratus
N-nltrosodlethylamlne
N-nltrosodlethylamlne
N-n1trosodlethylamlne
N-nltrosodlethylamlne
100-400
10-1000
15-45
15-45
? hours
1 week
1? weeks
5 weeks
liver tumors, dose-related
Incidence
embryos, no neoplasms within
1 year
larvae, liver tumors, up to 77*
incidence
adults, liver tumors, up to 31%
Incidence
Park and Kim,
1984
Koenlq and
Chasar. 1984
Koenlng and
Chasar, 1984
Koenlng and
Chasar, 1984
Live-bearer
PoeclUnoDSls luclda
N-nltrosodlethylamlne
50, 125
24 hours,
3-5 times
liver tumors
Sehult* and
Schulti, 1982,
1984
Sheepshead minnow
C*Dr1nodon varleqatus
N-nltrosodlethylamlne
30-50
several
weeks
liver damage
Couch and
Courtney, 19B4
Nedaka
Orvilas latlpes
N-nltrosodlethylamlne
N-n1trosodlethylamlne
N-n1trosodlethylamlne
N-nltrosodlethylamlne
N-n1trosodlethylamlne
N-nltrosodlethylamlne
50, 100
45
50, 100
25. 50, 100
100
15-135
8 weeks
2-8 weeks
8 weeks
10 days
6-8 weeks
8 weeks
liver tumors
liver tumors, no effects at
exposures <2 weeks
liver tumors
liver lesions and tumors
liver tumors
liver tumors
Egaml et al.,
1981
Ishlwaka and
Takayama, 1979
Kyono and
Egaml, 1977
Klaunlg et al.,
1904
Kyono-
Hamaguchl, 1984
Ishlwaka
et al.. 1975
Rainbow trout
Salmo qalrdnerl
N-nltrosodlmethylamlne
or N-nltrosodlettiylamlne
N-nltrosodlmethylamlne
or N-nltrosodlethylamlne
0.5
1000
30 minutes
1 hour
embryos, hepatocellular carci-
nomas developed within 1 year
eggs, liver tumors developed
Hendricks. 1901
Hendricks
et al., 1980
Rainbow trout
Salmo qalrdnerl
N-nltrosodlmethylamine
N-nltrosodlethylamlne
200-600 ppm
diet
100 ppm diet
52 weeks
1 year
hepatocellular carcinomas
10.2% tumor Incidence
Grleco et al.,
19Vd; U.S. EPA,
1980a
She1 ton et al.,
1904
-------
TABLE 6-? (cont.)
Species
Compound
Concentration Duration of
(mg/l)* Exposure
Effect
Reference
Grass frog
Rana temporarla
N-nltrosodlmethylamlne
N-nltrosodlethylamlne
AMPHIBIANS
5 2-4 weeks
50 2-4 weeks
highly malignant hepatocellular Khudolel, 1975
cancer
same as above Khudolel, 1975
Clam
Unlo plcton
Mussel
Mytllus edulls
Crayfish
Procaatoarus clarkl
N-n1trosod1ethylam1ne or
N-nltrosodlmethylamlne
N-nltrosodtmethylamlne
N-n1trosodlethylamlne
N-nltrosodlmethylamlne
INVERTEBRATES
200-400 40-15? days
0.25-1.0
0.?5-0.5
100, ?00
4-9 weeks
7 weeks
6 months
neoplasms of digestive gland and
hematopoietic system and kidney
degeneration of Intestinal
epithelium, hepatopancreas,
female gonads
histological effects on female
gonads, necrosis of epithelium
degeneration of antennal gland,
hyperplasia of tubular cells of
hepatopancreas
Khudolel and
Slrenko, 1977,
1978
Petit et al..
1964
Aubert et al.,
1982
Harshbarger
et al.. 1971
*mg/t unless otherwise specified
-------
As In the case wKh mammals, nltrosamlnes apparently require metabolic
activation to be carcinogenic 1n fish. This activation probably Involves
dealkylatlon by microsomal enzymes, resulting In the formation of alkylating
agents (Kyono, 1978). Shelton et al. (1984) found that N-nltrosod1ethyl-
amlne carcinogenicity 1n rainbow trout was enhanced when fish were also
exposed to PCBs. In some cases, relatively high temperatures are necessary
for nltrosamlnes to form tumors (Kyono, 1978; Kyono and Egaml, 1977),
possibly because of higher activities of activating enzymes at higher
temperatures, since fish are polkllotherms. In general, fish (gupples and
rainbow trout) seem to be less sensitive to the carcinogenic effects of
nltrosamlnes In the diet than mammals. This Is partly due to the fact that
fish liver metabolizes (activates) nltrosamlnes (N-n1trosod1methylam1ne) at
a much slower rate than mammalian (rat) liver as was shown In JUi vitro
studies (Hatsushlma and Suglmura, 1976). In addition, It has been shown
that Injected doses of nltrosamlnes are rapidly eliminated by fish. The
combination of slow metabolic activation and rapid elimination explains why
fish are less susceptible to the carcinogenicity of oral nltrosamlne doses
than mammals (Hatsushlma and Suglmura, 1976). The same situation (I.e.,
slow metabolic activation and rapid elimination) Is apparently true of
amphibians as was reported by Montesano et al. (1973) for the newt, TrIturus
helvetlcus and by Rao et al. (1979) for the frog, Xenopus sp.
Noncarclnogenlc effects were occasionally reported 1n some studies.
Couch and Courtney (1984) found Hver damage 1n sheepshead minnows,
CyprInodon varleqatus. exposed to 30-50 mg/l N-n1trosod1ethylam1ne for
several weeks. The lowest concentrations reported to cause adverse effects
were 0.25-1.0 mg/i N-n1trosod1methylam1ne or N-n1trosod1ethylam1ne, which
caused histological effects on gonads and other tissues In mussels, HytHus
0750p
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07/09/86
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edulls (Aubert et al.t 1982; Petit et al., 1984). In two studies concerning
sex-related differences In sensitivity, male zebraflsh, Brachvdanlo rerlo,
and gupples, PoeclHa reticulata, were found to be more sensitive than
females; however, female zebraflsh were more susceptible to carcinogenic
effects than males (Matsushlma and Suglmura, 1976).
Parland and Baumann (1985) conducted a study In which gupples were
exposed to 0 or 0.125 mg/l N-n1trosod1ethylam1ne for 24 hours once weekly
for 3 weeks, and the livers were monitored for hlstopathologlcal effects for
the next 12 months. The observed toxic effects of N-n1trosod1ethylam1ne
Included necrotic zones, macrophage centers, lipid deposits and reversible
bile duct proliferation. Some neoplastic changes 1n liver tissue were also
observed.
6.3. PLANTS
Aubert et al. (1981) reported that a single exposure of the alga,
Navlcula Inserta, to 2-200 vg/l N-n1trosod1methylam1ne had no effect on
growth; however, there was a dose-related depression of growth of Tetra-
selmls maculata exposed to 25-100 yg/l N-n1trosod1methylam1ne for 8 days
(Aubert et al., 1981) or to 100 vg/t N-n1trosod1ethylam1ne for 7 days
(Aubert et al., 1982).
6.4. RESI0UES
Jouany et al. (1985) monitored tissue levels of N-n1trosod1methylam1ne
In aquatic organisms exposed to thlram, a dlthlocarbamate fungicide. Thlram
Is degraded to secondary amines such as dlmethylamlne, which can combine
with nitrites to form N-n1trosod1methylam1ne. The alga, Chlorella vulgaris,
produced nitrite from nitrate and then produced N-nltrosodlmethylamlne from
thlram. Carp, Cyprlnus carplo. zebraflsh, Brachvdanlo rerlo. and water
fleas, 0. magna, also synthesized N-n1trosodlmethylam1ne, but nitrite had to
0750p
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07/09/86
-------
be added to the medium. N-N1trosod1methylam1ne residues 1n these species
exposed to 0-1.0 mg/l thlram and 0-20 mg/l nitrite for 24 hours are
presented In Table 6-3. Jouany et al. (1985) also conducted a food chain
experiment using contaminated algae (C. vulgaris) as food for D. magna,
which was then fed to B. rerlo. The study was conducted for 10 days at
which time all the fish fed the contaminated food had died. There were no
differences In N-n1trosod1methylam1ne tissue levels between exposed daphnlds
and fish and controls, suggesting that a thlram metabolite other than
N-n1trosod1methylam1ne might be accumulated and thus responsible for the
fish mortality. N1trosam1nes are not considered to have a high potential
for bloaccumulatlon and bioconcentratlon because they are rapidly degraded
in vivo (Jouany et al., 1985).
The only other study concerning nltrosamlne residues reported a BCF of
217 and a half-time of elimination of <1 day for bluegllls, L. macrochlrus,
exposed to 9.21 yg/i N-n1tros1d1phenylam1ne for 14 days (Barrows et al.,
1980b; U.S. EPA, 1978).
6.5. OTHER RELEVANT INFORMATION
There are several studies available regarding the effects of Injected
nltrosamlnes on aquatic organisms. Spehar et al. (1979) reported a 10-day
LDj-q of 1770 mg/kg for N-n1trosod1methylam1ne injected 1ntraper1toneally
to rainbow trout. N-N1trosod1methylam1ne Injected Into the foot of mussels,
Hvtllus edulls. at doses of 0.1-0.8 mg/mussel caused dose-related Inflamma-
tion and necrosis. Once-weekly Injections of 0.2 mg N-nUrosodlmethylamlne
for 8 weeks caused histological effects (Rasmussen et al., 1983). Single
Injections of 0.25-1.25 mg N-n1trosod1-n-propylam1ne Into the foot of
mussels caused necrosis of the epithelium lining digestive diverticula.
0760p
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TABLE 6-3
N-N1trosod1methylam1ne Levels In Three Species Exposed to
Different Concentrations of Thlram and Nitrite (0-20 mg/i)
For 24 Hours*
Species
Thlram
Concentration
(mg/l)
N-N1trosod1methylamine
Concentration In Tissues
(ng/g)
Hater flea
0
10
Daphnla maqna
0.1
9.3
1.0
6
ZebrafIsh
0
trace-29
Brachydanlo rerlo
0.1
14-29
1.0
18-33
Carp
0
1-3.4
Cyprlnus carplo
0.1
0.7-5.7
1.0
1-11.1
~Source: Jouany et al., 1985
0750p 6-9 04/03/86
-------
Injections of 0.5 rog N-n1trosod1-n-propylam1ne, 4 times/week for 17 weeks
resulted in damage to digestive tubules and diverticula of H. edulls
(Rasmussen et al., 1985).
6.6. SUMMARY
In general, acute toxicity of different nltrosamlnes to aquatic
organisms tends to Increase as number of carbon atoms Increase (Bresch and
Splelhoff, 1974); however, N-n1trosod1methylam1ne and N-n1trosodlethylam1ne,
the two nltrosamlnes for which there Is the most Information, appear to be
roughly equivalent In acute toxicity (see Table 6-1). Of the nltrosamlnes
for which there are data available, the most acutely toxic Is N-nltroso-
dlphenylamlne, which has a 96-hour LC5Q of 5.85 mg/l for bluegIlls
(Buccafusco et al., 1981; U.S. EPA, 1978).
Nltrosamlnes (N-nltrosodlmethylamlne, N-nltrosodlethylamlne and N-n1tro-
sodl-n-butylam1ne) have been found to cause cancer In fish and amphibians.
As 1s the case with mammals, metabolic activation of nltrosamlnes by micro-
somal enzymes Is apparently necessary for carcinogenicity. Factors that
stimulated enzyme activity (Inducers, high temperature) generally enhanced
nltrosamlne carcinogenicity (Kyono, 1978; Kyono and Egaml, 1977; Shelton et
al., 1984).
Noncarclnogenlc effects of long-term sublethal exposures were also
reported. The most sensitive fish species was the guppy, which experienced
hlstopathologlcal effects In liver tissue after three 24-hour exposures to
0.125 mg/l N-n1trosod1ethylam1ne (Parland and Baumann, 1985). The most
sensitive Invertebrate species tested was the mussel, H. edulls, which
experienced adverse histological effects when exposed to 0.25-1.0 mg/l
N-n1trosodlmethylam1ne or N-n1trosod1ethy1amlne for 4-9 weeks (Aubert et
0750p
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04/03/86
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al.( 1962; Petit et al., 1984). Because they are rapidly degraded, nltros-
amlnes do not bloaccumulate or bloconcentrate to high tissue concentrations
In aquatic organisms (Jouany et al.r 1985).
0750p
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMANS
ACGIH (1985) has classified N-n1trosodlroethylam1ne as an Industrial
substance suspect of carcinogenic potential for man, noting that cutaneous
exposure can potentially contribute to overall exposure. NIOSH recommended
or OSHA promulgated occupational exposure limits are not available for any
of the nltrosamlnes discussed 1n this document.
Cancer-based ambient water quality criteria are recommended for N-nltro-
sodlmethylamlne, N-n1trosod1ethylam1ne, N-n1trosod1-n-butylam1ne and
N-n1trosod1phenylam1ne (U.S. EPA, 1980a). The water concentrations corre-
sponding to lifetime cancer risks of 10~s are 14, 8.0, 64 and 49 ng/a.,
respectively. The bases of the carcinogenic potency factors used to calcu-
late these water concentrations are discussed In Chapter 8.
7.2. AQUATIC
Although U.S. EPA (1980a) did not recommend criteria for the protection
of aquatic life from the effects of nltrosamlnes, they stated that acute
toxicity to freshwater and saltwater organisms occurred at concentrations as
low as 5.85 and 3300 mg/i, respectively, and would occur at lower concen-
trations In species more sensitive than those tested. More recent data
Indicate that toxic effects on saltwater species can occur at concentrations
as low as 0.25 mg/l (Aubert et al.. 1982; Petit et al., 1984).
0751 p
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-------
8. RISK ASSESSMENT
The carcinogenicity of most of the N-n1trosam1ne compounds discussed In
this report 1s documented. The carcinogenicity of N-n1trosod1methylam1ne,
N-n1trosod1ethylam1ne, N-n1trosod1-n-propylam1ne and N-n1trosod1-n-butyl-
amlne has been established unequivocally 1n studies with multiple species,
exposure routes and treatment schedules. N-n1trosomethylethylam1ne,
N-n1trosomethylv1nylam1ne and N-n1trosod1ethanolam1ne have been less exten-
sively studied, but Information Indicating noncarclnogenlclty has not been
reported. N-N1trosod1phenylam1ne produced bladder tumors In rats, but Its
carcinogenicity was not corroborated In other studies. The carcinogenicity
of p-n1trosod1phenylam1ne does not appear to have been assessed. Interest
in the toxicology of these compounds Is almost exclusively related to their
carcinogenicity, and only limited Information regarding nonneoplastic
effects of chronic or subchronlc exposure Is available (see Section 5.5.).
Although the carcinogenicity of most of the N-n1trosam1nes covered In
this report Is unequivocally or reasonably well established, as Is the
carcinogenicity of many other N-n1trosam1nes and N-n1troso compounds (Magee
et al., 1976; U.S. EPA, 1980a; 1ARC, 1982), relatively few of the studies
are appropriate for use 1n quantitative risk assessment. Many of the
studies, particularly those of N-n1trosod1methylam1ne, N-n1trosod1ethyl-
amlne, N-n1trosod1-n-propylam1ne and N-n1trosod1-n-butylam1ne, used
parenteral routes of administration (I.e., Intraperitoneal or subcutaneous
Injection), Inappropriate treatment frequencies or durations (Including
single exposures) or lacked control data.
An overview of the most relevant carcinogenicity studies Is presented,
but mutagenic effects are not summarized for most of the compounds because
0752p
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05/29/86
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of demonstrated carcinogenicity, extenslveness of the mutagenicity data base
(see Section 5.2.) and because the responses are consistent with the
carcinogenicity data.
8.1. N-NITROSODIMETHYLAHINE
Chronic and subchronlc studies have been conducted 1n which rats and
mice were exposed to N-n1trosod1methylam1ne In the drinking water or diet.
As detailed 1n Section 5.1. and summarized 1n Table 8-1, tumors were
primarily produced In the livers of rats (hepatocellular carcinomas) and
livers (hemanglosarcomas) and lungs (adenomas) of mice. Twice weekly
exposure to N-n1trosod1methylam1ne vapor (2 or 4 mg/kg for 30 minutes) for
an unspecified chronic duration produced malignant nasal cavity tumors 1n
small groups of rats (Druckrey et al., 1967); controls were not used In this
study, but the average tumor Induction time was 400 days. Numerous addi-
tional studies have demonstrated the carcinogenicity of N-nltrosodlmethyl-
amine 1n shorter duration oral or Injection (subcutaneous and Intraperito-
neal) studies, Including single dose and prenatal treatment, 1n all species
tested (IARC, 1978).
The Druckrey et al. (1967) study was used as the basis for derivation of
a criterion for N-n1trosod1methylam1ne by U.S. EPA (1980a). In this study,
data from experiments using different N-nltroso compounds, Including
d1-n-alkyln1trosam1nes and particularly N-n1trosod1ethylam1ne, were used to
derive a relationship between dally dose (d) and the median time of tumor
Induction (t5Q) 1n days where d(t5Q)n=k. In U.S. EPA (1980a), values
for k of 0.81xl04 mmol/kg/day and n of 2.3 were used to derive a carcino-
genic potency factor (B) using the one-hit model. A constant (k) for
N-n1trosod1methylam1ne Is not reported by Druckrey et al. (1967) or 1n
another analysis of the same data (Druckrey, 1967), however, and 0.81xl04
0752p
8-2
07/09/86
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TABU 8-1
Chronlc/Subchronlc Oral Carcinogenicity Studies of N-NIIrosodlmethylamlne
o
Specles/StraIn Group Size/Sex Method Dose/Exposure Duration of Main lumor Site/Type Comments Reference
•o Treatment/Study*
Rat/Porton
Rat/BD
Rat/Colworth
Rat/Por ton
Rat/Wlstar
CO
CO Rat/f344
Rdt/P 344
Rat/Wlstar
House/ICR
House/RF/Un
House/RF/Un
S House/BALB/c
vO
6/F
20/NR
36 treated/both
14* control/both
5-62/both
7-17/both
20/mlxed
20/f
60/both
17/H
162 or 94/H
17-250/H
30 or 18/H
diet (arachls
oil)
drinking water
drinking water
diet
diet
drinking water
drinking water
drinking water
diet (peanut
oil)
drinking water
drinking water
5. 10 or
20 ppm
4 mg/kg/day.
5 days/week
0-16.896 ppm
(16 levels)
0. 2, 5, 10,
20 or 50 ppm
0. 0.1. 1.0
or 10 ppm
0.66 mg/day.
S days/week
0. 0.11 or
0.26 mg/day,
5 days/week
2-1470
tig/kg/day
9.04 mg/kg/day
0 or 0.94
mg/kg
0, 1.6, 0.40,
0.43 or 0.91
mg/kg/day
102-104 weeks/
102-104 weeks
life
life
104 weeks/
104 weeks
96 weeks/
96 weeks
30 weeks/
SO weeks
30 weeks/
BO weeks
drinking water 1.7 mg/kg/day
life
10 months/
10 months
306 days/
306 days
49-406 days/
12-17 months
177 days
201 days
I ivcr/hepatocellular
carcinoma
II ver/hepatocellular
careInoma
1 Iver/hepatocellular
careInoma
1 Iver/hepatoma
1Iver/hepatocellular
carcinoma, hemanglo-
sarcoma
testes/lnterstltlal
cell
1Iver/hemanglosarcoma
liver hemanglosarcoma
neoplastic nodules
11ver/not specified
1Iver/hemanglosarcoma
1Iver/hemanglosarcoma
lung/adenoma
Hver/hemanglosarcoma
lung/adenoma
1 Iver/hemanglosarcoma
lung/adenoma
small groups, low
IncIdences
no controls, mean
Induction time =
270 days
Welbull analysis
of data
not a single multi-
dose study
small groups, low
Incidences at 1.0
and 10.0 ppm
no controls, life-
time study
lifetime study
preliminary results.
Incidences not re-
ported
no controls, low
IncIdences
lifetime study
lifetime study but
ambiguous durations
lifetime study
Nagee and
Barnes, 1962
Druckrey
et al.. 1967
Peto et al.,
1964
Terraclnl
et al., 1967
Aral et al.,
1979
lljlnsky and
Reuber, 1981
LIJInsky and
Reuber, 1964a
Crampton, 1980
Takayama and
Oota, 196S
Clapp et al.,
1968
Clapp and
Toya, 1970
Clapp et al.,
1971
00
"Specific durations refer to treated groups
NR = Not reported
-------
mM/kg/day appears to have been misread from the N-n1trosomethylethylam1ne
data from Oruckrey (1967). A value for k of ~2.6xl04 mmol/kg/day can be
estimated for N-n1trosod1methylam1ne from plots of k vs. number of C-atoms
for lower d1-n-alkyln1trosam1nes (C<5) 1n Druckrey et al. (1967) or Oruckrey
(1967). The exponent (n) used to calculate the constants (k) was 2.3.
Using k=2.6xl04 mmol/kg/day, n=2.3 and a molecular weight of 74.1
mg/mmol, a dose (d) associated with a lifetime risk of 0.5. (I.e., time to
50% tumors 1n 728 days) 1s calculated as follows (Druckrey et al., 1967;
Druckrey, 1967):
d(t60)n - k
d « k ~ (t5Q)n
d = 2-6x10' mmol/kq/days x 74.1 mq/mmol mg/kg/day
(728)23
This dose can then be used to derive a potency factor for the rat (B^)
from the one-hit model:
P.l-e-6"
0.5 . e"B d
In 0.5 = -B d
- -In 0.5
B = d
Bfl = 9-l£93 _ ^ 28 (mg/kg/day)"1
* 0.503 mg/kg/day a 3
Adjusting B^ by the cube root of the ratio of human body weight (70 kg) to
assumed rat body weight (0.35 kg) gives a carcinogenic potency factor for
humans (B^) of 8.07 (mg/kg/day)"1. Although this relationship
[d(t,.p)n=k] Is valid for a number of dl-n-alkylnltrosamlnes (and other
N-nltrocompounds), particularly N-n1trosod1ethy1am1ne, this potency factor
reflects the limitations of the experimental data for N-n1trosod1methylam1ne
(I.e., single dose uncontrolled study).
0752p 8-4 07/09/86
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An alternative risk estimate for N-n1trosod1methylam1ne can be made from
the study of Peto et al. (1984) In which groups of Colworth rats were
exposed to multiple concentrations of N-n1trosod1methylam1ne 1n drinking
water for -3 years. Although Peto et al. (1984) did not provide Incidence
data for the Individual dose groups, equations relating cumulative Incidence
to both dose and duration of exposure are given, as summarized in Section
5.1.1. Although positive trends 1n tumor Incidence were observed at several
sites, exposure response relationships were quantified only for liver tumors.
Female rats were somewhat more sensitive to the development of liver
tumors and will be used as the basis of this risk assessment. The relation-
ship of the cumulative Incidence (CI) of response to dose (d), In units of
mg/kg/day, and time (t), In units of years, for female mice Is shown below:
CI - 51.45 (d + 0.1)6t7
Using the standard procedures described in U.S. EPA (1980b) to correct for
background response, the Increased risk associated with a dose of 1 wg/kg/
day for an exposure period of 3 years Is 7.8xl0"s, which corresponds to a
potency factor for rats (B^) of 7.8 (mg/kg/day)"1. Estimating the
average body weight of the female rats to be 250 g from data of Peto et al.
(1984), and adjusting by the cube root of the ratio of the human body
weight (70 kg) to the rat body weight, the estimated carcinogenic potency
factor for humans, 8H, 1s 51 (mg/kg/day)"1.
Other studies published since U.S. EPA (1980a) that could be used to
derive carcinogenic potency factors (q-j*) for N-n1trosod1methylam1ne can
be discounted on the basis of data quality. Aral et al. (1979) exposed rats
to three dose levels of N-nltrosodlmethylamlne In the diet (0.1, 1.0 or 10.0
ppm) for 104 weeks, but small groups of animals were used (9-17) and tumor
Incidences were relatively low (—17-22% at the two highest doses). LlJInsky
0752p
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and Reuber (1984a) administered two doses of N-nltrosodlmethylamlne (0.11
and 0.26 mg/day) to rats In the drinking water 5 days/week but the duration
of exposure (210 days) was much shorter than the duration of observation
(770 days 1n low dose, 700 days 1n high dose).
8.2. N-NITROSOHETHYLETHYLAHINE
The carcinogenicity of N-n1trosomethylethylam1ne has been demonstrated
1n chronic and subchronlc drinking water studies with rats. Druckrey et al.
(1967) administered N-n1trosomethy1ethylam1ne at doses of 1 and 2 mg/kg/day
(4 and 11 BD rats, respectively) for an unspecified period that appears to
be life. LIJInsky and Reuber (1980, 1981) and Lljlnsky et al. (1982, 1983)
conducted a series of experiments In which N-n1trosomethylethylam1ne was
administered to groups of 20 F344 rats at various concentrations on S days/
week for 30 weeks with lifetime observation. Tumors were Induced primarily
1n the livers (hepatocellular carcinoma and hemanglosarcomas) In the treated
rats 1n all of these studies (nasal cavity tumors occurred at relatively low
Incidences 1n several studies), with the exception of leukemia In the
Lljlnsky et al. (1983) study. The latter study used a relatively low dose
of the compound, produced equivocal leukemia without significant Induction
of liver or nasal cavity tumors and was the only study of N-n1trosomethyl-
ethylamlne to use a control group.
The most appropriate basis for calculation of a carcinogenic potency
factor for N-n1trosomethylethy1am1ne 1s the relationship between dally dose
(d) and median time of tumor Induction (t^), d(°ruckrey et
al., 1967; Oruckrey, 1967). Using an approach analogous to that for
0752p
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N-n1trosod1methylam1ne {see Section 8.1.) and values of O.SlxlO4 mmol/kg/
day for k and 2.3 for n, the dose associated with a lifetime risk of 0.5 Is
calculated as follows:
d « 0-8"10« nrnol/kq/day x 68.1 nm/mmol _ 0 ,8645 /k /d
{728)2.3
Using a rearrangement of the one-hit model as detailed 1n Section 8.1., the
potency factor for rats ()1s calculated to be 3.72 (mg/kg/day)"1.
Adjusting the by the cube root of the ratio of human body weight (70
kg) to assumed rat body weight (0.35 kg) results In a carcinogenic potency
factor for humans (B^) of 21.75 (mg/kg/day)~J.
A value of 2.1 was specifically reported as the exponent (n) for
N-nUrosomethylethylamlne (Druckrey et al.f 1967). This exponent was not
used In the above calculation because a constant (k) was not reported with n
- 2.1 1n Druckrey et al. (1967). The exponent 2.3 appears to have been used
as a representative value for dlalkylnltrosamlnes 1n Druckrey (1967) and 1n
Druckrey et al. (1967). The potency factor (B^) calculated above, how-
ever, reflects a limitation In the Druckrey et al. (1967) N-n1trosomethyl-
ethylamlne experiment [I.e., no controls and two dose groups with small
numbers (4 and 11) of rats).
The carcinogenicity studies by Lljlnsky and Reuber (1980, 1981) and
LlJInsky et al. (1982, 1983) are Inappropriate bases for risk assessment
because of limitations that Include relatively short treatment durations (30
weeks) and, In all but the most recent study (Lljlnsky et al., 1983), the
lack of a control group. The use of a control group by Lljlnsky et al.
(1983) does not offset, however, other limitations In the study [single
dose, short treatment duration, equivocal leukemogenlc response (12/20 In
controls vs. 18/20 1n treated)].
0752p
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8.3. N-NITROSODIETHYLAMINE
Chronic and subchronlc studies have been conducted In which rats, mice,
guinea pigs, rabbits and dogs were exposed to N-nltrosodlethylamlne In the
drinking water or by gavage. As detailed In Section 5.1. and summarized In
Table 8-2, generally high Incidences of tumors were produced primarily In
the liver of all these species, In the esophagus of rats and mice and In the
forestomach of mice. Hepatocellular carcinomas have been Induced In small
numbers of monkeys by oral treatment with N-n1trosod1ethylam1ne for 14-69
months or by bimonthly or monthly Intraperitoneal Injection for 2-5 years
(Kelly et al., 1966; Ruebner et al., 1976; Adamson and Sleber, 1979, 1983).
Weekly Intratracheal Injections of N-n1trosod1ethylam1ne for 1-6 months
Induced tracheal and bronchial tumors (primarily papillomas) In hamsters
(Yamamoto et al., 1985; Herrold and Dunham, 1963). Secondary reports
Indicate that spray Inhalation of N-n1trosod1ethylam1ne for 4-5 months
produced tumors In the trachea and lungs of hamsters and liver carcinomas
unaccompanied by respiratory system tumors in rats (Oontenwlll et al., 1962;
Dontenwlll and Hohr, 1962). Chronic application of N-nltrosodlethylamlne to
the skin of hamsters and mice reportedly produced high Incidences of nasal
cavity carcinomas and papillomas but no local tumors (Hoffmann and Graff 1,
1964; Herrold, 1964a,b). Numerous additional studies have demonstrated that
N-nltrosodlethylamlne Is carcinogenic by shorter duration oral exposure
(Including single dose), by Injection (subcutaneous, intraperitoneal and
Intradermal) and by prenatal exposure In all species tested. Including
newborns (IARC, 1978).
The report of Oruckrey et al. (1967) was used as the basis for deriva-
tion of a criterion for N-nltrosodlethylamlne In U.S. EPA (1980a). This
derivation uses the relationship d(t^)n=k and the one-hit model to
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TABLE B-?
Chronlc/Subchronlc Oral Carcinogenicity Studies of N-Nltrosodlethylamlne
»\j
¦3
Species/Strain
Group Size/Sex
Method
Dose/Exposure
Duration of
Treatment/Study*
Main Tumor Site/Type
Comments
Reference
Rat/BO
25-80/NR
drinking water
0.075-14.2
mg/kg/day
life
11ver/hepatoCellular
care tnoma
no controls, 100%
Incidences >0.15
mg/kg/day
Druckrey
et al., 1967
Rat/Colworth
35 treated/both
144 control/both
drinking water
0-16.696 ppn
(16 levels)
life
11ver/hepatocellular
carcinoma
esophagus/NR
Metbull analysis of
data
Peto et al..
1984
Rat/f 34*
20/F (12 In one)
drinking water
0-113 ppn,
5 days/week
17-104 weeks/
20-130 weeks
11 ver/hepatocellular
carcinoma
esophagus/basal cell
carcinoma
lifetime study but
only two treatments
>30 weeks
lljtnsky
et al., 1981b
Rat/Sprague •
Dawley
40/N
ga vage
10 mg/kg
twice weekly
201 days/
201 days
liver/unspecified
mal Ignant
esophagus/pap 11lomas
no controls, life-
time study
Habs et al.,
1980
House/RF
42-162/H
drinking water
0. 3.5 or 6
mg/kg/day
223 days/9.7
nonths or 157
days/9.0 months
ltver/hepatoma
lung/adenoma
fores tomach/squamous
cell carcinoma
lifetime study
Clapp et al.,
1970
House/BALB/c
18-82/*
drinking water
0. 3.5 or 6.7
mg/kg/day
143 days/201
days or 150
days/161 days
1 Iver/hemanglosarcoma
esophagus/squamous
cell carclnoaa
fores tomach/squamous
cell carcinoma
lifetime study
Clapp et al.,
1971
Guinea p1g/NR
IS/MR
drinking water
1-2 mg/day,
5 days/week
16-51 weeks/NR
11ver/carcinoma
lung/adenoma
no controls, doses
Inadequately reported,
unspecified Intervals
without treatment
Argus and
Hoch-Llgetl,
1963
Rabbits/New
Zealand
13/F
drinking water
0 or 8.4
i»g/day.
6 days/week
52-82 weeks/
52-82 weeks
liver/carcinoma
three controls but
100% tumor Incidence
Rapp et al.,
1965
Dogs/mongrel
14/NR
(total number)
drinking water
50. 100 or
500 ppn
52-70 weeks/
52-175 weeks
liver/neoplasms
no controls; group
sizes not reported but
100% tumor Incidence
Hlrao et al.,
1974
o
«»
s
o
oo ^Specified durations refer to treated groups
MR « Not reported
-------
derive a carcinogenic potency factor (B^) (see Section 8.1.). Values of
k=0.35x10* mmol/kg/day and n=2.3 were calculated from the nine-dose drink-
ing water study summarized 1n Section 5.1.3. (Oruckrey et al., 1963) and
reported by Druckrey et al. (1967) and Druckrey (1967). Using these param-
eters and a N-n1trosod1ethylam1ne molecular weight of 102, the dose asso-
ciated with a lifetime risk of 0.5 (I.e., time to 50% tumors 1n 728 days)
was calculated as follows:
d . 0-35»10- nrnol/kq/day x 102 mg/mmol _ 0,09323 mgAg/ljay
(728)'*^
Using a rearrangement of the one-hit model detailed In Section 8.1., a
potency factor for rats (8^) 1s calculated to be 7.43 (mg/kg/day)'1.
Adjusting the by the cube root of the ratio of human body weight (70
kg) to the assumed rat body weight (0.35 kg) results 1n a carcinogenic
potency factor for humans (Bu) of 43.46 (mg/kg/day)"1.
The above assessment of N-n1trosod1ethylam1ne 1s essentially Identical
to that 1n U.S. EPA (1980a) and Is based on a carcinogenic Index, k, of 3500
mmol/kg/day given 1n Druckrey (1967). In addition, Druckrey (1967) also
gives the exponential term on time as 2.3. Thus, as Indicated above, the
relationship for N-n1trosod1ethylam1ne Is as follows:
3500 mmol/kg/day d t^*^
where d Is 1n units of mmol/kg/day and t, the time to 50% tumor Induction at
dose d, 1s in units of days. The data on which these estimates are based
are summarized by Druckrey (1967) and are reproduced in Table 5-4. These
data have been reanalyzed at SRC using the following rearrangement of the
Druckrey (1967) basic equation:
In d ¦= In k - n (In t)
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and using simple linear regression analysis. Estimates of the parameters
are n = 2.18 and k = 190842 mg/kg/day or 1870 mmol/kg/day. The dally dose
associated with an Incidence of 0.5 would then be recalculated as follows:
d = 190842 mg/kg/day * (728)2,18
d = 0.11 mg/kg/day
Using the same method as U.S. EPA (1980a), the potency factor for the rat
can be calculated as follows:
0.5 . l-e"B
= 6.30 (mg/kg/day)"3
Adjusting by the cube root of the ratio of human body weight (70 kg) to
rat body weight (0.35 kg), the carcinogenic potency factor for humans is
36.8 (mg/kg/day)"1. Thus, while the above analysis may more accurately
reflect the data presented by Druckrey (1967), the final risk estimates are
not substantially different.
An alternative risk estimate for N-n1trosod1ethylam1ne can be made from
the study by Peto et al. (1984) In which groups of Colworth rats were ex-
posed to multiple concentrations of N-n1trosod1ethylam1ne 1n drinking water
for ~3 years. Although Peto et al. (1984) did not provide Incidence data
for the Individual dose groups, equations relating cumulative Incidences
for both dose and duration of exposure are given (see Section 5.1.3.).
Although positive trends 1n tumor incidence were observed at several sites,
exposure-response relationships were quantified only for liver and esoph-
ageal tumors in rats exposed to N-n1trosod1ethylam1ne.
Female mice exposed to N-n1trosodlethylamlne were somewhat more sensi-
tive to liver tumors than male mice exposed to N-n1trosod1ethy1am1net but
male mice were more sensitive to the development of esophageal tumors. In
both sexes, however, the low dose potency for the Induction of esophageal
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tumors Is -1000-fold less than the potency for the Induction of liver
tumors. Thus, esophageal tumors will not be further considered and the risk
assessment will be based on liver tumors In female rats as described by the
following relationship of cumulative Incidence (CI) of response to dose (d),
In units of mg/kg/day, and time (t), 1n units of years:
CI - 32.09 (d ~ 0.04)«t7
Based on this relationship and using the standard procedures described 1n
U.S. EPA (1980b) to correct for background response, the Increased risk
associated with a dose of 1 yg/kg/day for an exposure period of 3 years 1s
2.27x10"*, which corresponds to a potency factor for rats (B^) of 22.7
(mg/kg/day)"1. The average body weight of the female rats Is estimated to
be 250 g from data of Peto et al. (1984). Adjusting the 8^ by the cube
root of the ratio of the human body weight (70 kg) to the rat body weight
yields an estimated carcinogenic potency factor for humans, BH, of 150
(mg/kg/day)"1.
Other studies that could be considered for derivation of carcinogenic
potency factors for N-n1trosod1ethylam1ne are limited by deficiencies that
primarily Include short treatment durations, short study durations and lack
of control data (see Table 8-2). L1J1nsky et al. (1981b) exposed F344 rats
to a variety of combinations of doses 1n drinking water and treatment
durations, but only one regimen (0.45 mg/l, 5 days/week for 104 weeks,
130-week study duration) had lifetime exposure, effectively making this a
single dose study.
8.4. H-NITR0S001-N-PROPYLAMINE
Carcinogenicity of N-n1trosod1-n-propylam1ne has been demonstrated In
several drinking water studies In rats. Druckrey et al. (1967) administered
N-nHrosod1-n-propylam1ne at doses of 4, 8, 15 or 30 mg/kg/day to a total of
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48 rats (group sizes ambiguously reported but Inferred to be 16, 16, 15 and
1, respectively) for an unspecified duration that appears to be life.
LlJInsky and Taylor (1970, 1979) and L1J1nsky and Reuber (1981, 1983)
conducted four studies 1n which various doses of N-n1trosod1-n-propylam1ne
(0.9-4.4 mg/day) were administered to groups of 12-20 F344 rats 5 days/week
for 30 weeks. The rats In these studies were observed for life, but 100%
mortality occurred by 50 or 60 weeks In most of the treatment groups and
most of the studies did not use controls. In the only one of these studies
that used controls (UJInsky and Reuber, 1983), males treated with 4.4
mg/day and females treated with 2.2 mg/day for 30 weeks died by weeks 80 and
100, respectively, but only 12 rats were Included in the female group. High
Incidences of liver carcinomas, nasal cavity carcinomas esophageal carci-
nomas and papillomas occurred in the treated rats in the above studies.
Weekly subcutaneous Injections of N-nitrosodl-n-propylamine for life
produced high Incidences of carcinomas, primarily 1n the nasal cavities,
laryngobronchlal tract, lungs and livers of hamsters (Reznlk et al., 1975;
Pour et al., 1973, 1974; Althoff et al., 1973). Evidence for the trans-
placental carcinogenicity of single subcutaneous doses of 100 mg N-n1troso-
di-n-propylam1ne during gestation In hamsters has been reported (Althoff and
Grandjean, 1979). Weekly intraperitoneal Injections of 40 mg N-nltroso-
dl-n-propylamlne/kg for an average total dose of 7.0 g reportedly produced
hepatocellular carcinomas In monkeys (Adamson and Sleber, 1979, 1983).
The most appropriate basis for derivation of a carcinogenic potency
factor for N-n1trosod1-n-propylam1ne 1s the relationship between dally dose
(d) and median time of tumor induction (^50^' wf,ere d(
(Oruckrey et al., 1967; Druckrey, 1967). A value of ~1.7xl04 mmol/kg/day
for k can be estimated for N-nltrosodl -n-propylamlne from plots of k vs.
0752p
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number of C-atoms for lower d1-n-a1kyln1trosam1nes (C<5), Including N-n1tro-
sod1-n-propylam1ne (Druckrey et al., 1967; Druckrey, 1967). The exponent
(n) used to calculate the constants (k) for the d1-n-alkyln1trosam1nes was
2.3. Using an approach analogous to that for N-n1trosod1methylam1ne (see
Section 8.1.) with the above parameters and a molecular weight of 130.2
mg/mmol, the dose associated with a lifetime risk of 0.5 1s calculated as
follows:
d . 1-7»1'>' mmol/kq/Jay x 130.2 mq/mnol __ „ 5,B31 Bg/kg/<)ay
(728)'*^
Using a rearrangement of the one-hit model as detailed 1n Section 8.1., the
potency factor for rats Is calculated to be 1.20 (mg/kg/day)-1. Adjusting
the by the cube root of the ratio of human body weight (70 kg) to the
assumed rat body weight (0.35 kg) results In a carcinogenic potency factor
for humans (B ) of 7.02 (mg/kg/day)_1.
H
A value of 2.2 was specifically reported as the exponent (n) for
N-n1trosod1-n-propylam1ne In Druckrey et al. (1967) and 1n Druckrey (1967).
This exponent was not used In the above calculation because a constant (k)
was not reported with n=2.2 1n these studies. The exponent 2.3 appears to
have been used as a representative value for d1alkyln1trosam1nes In both
Druckrey et al. (1967) and Druckrey (1967).
Deficiencies 1n the drinking water studies with rats (L1J1nsky and
Taylor, 1978, 1979; HJInsky and Reuber, 1981, 1983), primarily short treat-
ment durations, short study durations, lack of controls or small group sizes
preclude their use 1n quantitative risk assessment.
8.5. N-NITR0S0D1-N-BUTYLANINE
Chronic and subchronlc carcinogenicity studies have been conducted 1n
which rats, mice, hamsters and guinea pigs were exposed to N-n1trosod1-n-
butylamlne In the diet, drinking water or by gavage. As detailed In Section
0752p
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5.1. and summarized In Table 8-3, generally high Incidences of malignant and
benign tumors were produced primarily 1n the liver, bladder, esophagus or
forestomach, depending upon species. Numerous additional studies have
demonstrated that N-n1trosod1-n-butylam1ne Is carcinogenic following more
limited oral exposures as well as by subcutaneous, Intraperitoneal or
Intravenous Injection In all species tested (IARC, 1978); these Included
single dose, prenatal and neonatal exposures.
The Bertram and Craig (1970) study was used to derive a carcinogenic
potency factor (q-j*) for N-n1trosod1-n-butylam1ne In U.S. EPA (1980a). In
this study, groups of 50 C57BL/6 mice of each sex were continuously adminis-
tered drinking water that provided N-n1trosod1-n-butylam1ne at doses of 7.6
and 29.1 mg/kg/day (males) or 8.2 and 30.9 mg/kg/day (females). A control
group was not used )n this study. Treatment was continued until the mice
became moribund or died, except for -50% of the high-dose males and females
that were given untreated water after 197 days because of hematuria In the
majority of the high-dose males. The durations of the lifetime exposures
were not specifically reported but can be estimated from reported mean total
doses to be 261 days (1986*199 mg/kg) and 216 days (6310+581 mg/kg) In the
low- and high-dose males, respectively, and 255 days (2096^236 mg/kg) and
230 days (7115*710 mg/kg) In the low- and high-dose females, respectively.
As detailed In Table 5-6, high Incidences of bladder and esophageal tumors
occurred In both treatment groups of both sexes.
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1ABLf 8-3
Subchronlc and Chronic Oral Carcinogenicity Studios of N-Nltrosodl-n-butylamlne
u->
Spec les/Straln
Group Size/
Sex
Method
Dose/Exposure
Duration of
Treatment/Study3
Rain Tumor Site/Type
Conments
Reference
Rat/BO
4-16/NR
diet
10, 20. 37 or
75 mg/kg bw/day
life
liver/carcinoma
esophagus/malignant
bladder/squamous
carcinoma
no controls
Druckrey
et al.. 1967
Rat/F344
20/H
gavage
0 or 5.4
mg/antmal,
2 days/week
30 weeks/
130 weeks
1Iver/carcinoma
fores tomach/carclnoma
lung/carcinoma
bladder/carcinoma
lifetime study
LlJInsky and
Reuber, 1983
Rat/ACl/N
9 m
drinking water
44.3 mg/day
20 weeks/
20-22 weeks/
1 lver/cancer
bladder/papllloma
no controls
Okada et al..
1976
Rat/F344
11 or 29/H
drinking water
0 or 0.02%
26 weeks/
26 weeks
1 Wer/hyperplastlc
nodules
tissues other than
liver not examined
Perelra
et al., 1983
Rat/Wlstar
30/F
drinking water
20 mg/kg/day
NR
bladder/papllloma
controls not
reported
Kunze and
Schauer, 1971
Rat/HUtar
12/NR
drinking water
0.05%
26 weeks/
28 weeks
bladder/carcinoma
controls not
reported
I to, 1973
Rouse/C57Bl/6
50/each
drinking water
7.6-6.2 and
29.1-30.9
mg/kg/day
255-261
(low doses)b
216-230
(high doses)'3
bladder/squamous
carcinoma
esophagus/squamous
carcinoma
no controls, life-
time study
Bertram and
Craig, 1970
House/ICR
30 or 39/H
diet
0 or 50 ppi»
12 months/
12 months
forestomach/squamous
carcinoma
liver/adenoma
brief report
Takayama and
lmalzuml, 1969
Hamster/
Syrian golden
100/N
gavage
300 mg/kg,
1 day/week
50 weeks/
50 weeks
bladder/card noma,
papl lloma
trachea/carc1 noma,
papilloma
lungs/carcinoma,
papilloma
fores tomach/papl1loma
no controls; age
3 months at start
Althoff
et al., 1971
o
CO
-------
TABLE 8-3 (cont.)
Species/Strain
Group Size/
Sex
Method
Dose/fxposure
Duration of
Treatment/Study*
Main Tumor Site/Type
Conments
Reference
Hamster/Chinese
66/H
gavage
300 mg/kg,
1 day/week
40 weeks/
40 weeks
bladder/carcinoma
papilloma
forestomach/
carcinoma, papilloma
no controls; age
3 months at start;
no trachea or lung
tumors
Althoff
et al., 1977
Guinea plg/NR
15C/NR
drinking water
40 mg/kg/day,
S days/week
120 weeks/
120 weeks®
11ver/hepatocellular
carcinoma
bladder/squamous
care(noma
no controls
lvankovlc and
Biicheler. 1948
aSpec1f1c duration refers to treated groups
^Estimated from total dose
cNumber that survived >S50 days
NR - Mot reported
-------
U.S. EPA (1980a) used the bladder and esophageal tumor Incidences In the
male mice and the following parameters for calculation of the q^*:
le (low dose) = 630 days
le (high dose) = 414 days
Le = 630 days
L =• 630 days
w = 0.028 kg
A concurrent control group was not used, but historical spontaneous
tumor Incidence In C57B46 mice was reported to be low. The control
incidence used to calculate the q^* was not reported In U.S. EPA (1980a).
Using these parameters the q^* was calculated to be 5.43 (mg/kg/day)~* .
Apparent discrepancies exist, however, In the durations of treatment (le)
and durations of experiment (Le) used by U.S. EPA (1980a) and Indicated In
Bertram and Craig (1970). As mentioned above, the N-n1trosod1-n-butylamlne
treatments were for life, which are estimated from the reported mean total
doses to be 261 and 216 days 1n the low- and high-dose male mice, respec-
tively; the reason for the use of 630 days for the low-dose le and 414 days
for the high-dose le 1s unclear (U.S. EPA, 1980a). The discontinuation of
treatment that occurred after 197 days In 20/45 high-dose males does not
appear to be a basis for adjustment of the high-dose le because tumor
Incidence and latency did not significantly differ from the male mice In
which treatment was continued until death (Bertram and Craig, 1970). The
estimated durations of lifetime exposure for the males [le and Le of 261
days (low dose) and 216 days (high dose)], when considered with the assumed
Dose
(mq/kq/day)
Incidence
7.6
29.1
0
NR
46/47
45/45
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mouse lifespan of 730 days and the lack of concurrent control data, provide
a deficient basis for potency factor calculation. Consideration of a
based on the Bertram and Craig (1970) data 1s therefore not recommended
until the apparent discrepancies In the U.S. EPA (1980a) N-n1trosod1-n-
butylamlne criterion derivation are resolved.
Given the apparent deficiencies In the Bertram and Craig (1970) study,
1t appears to be more appropriate to derive a carcinogenic potency factor on
the basis of the relationship between dally dose (d) and median time of
tumor Induction ^50^ w^ere d(t,jQ)n=k (Druckrey et al., 1967;
Druckrey, 1967). A value of ~105 mmol/kg/day for k can be estimated for
N-n1trosod1-n-butylam1ne from plots of k vs. number of C-atoms for lower
d1-n-alkyln1trosam1nes (C<5), Including N-n1trosod1-n-butylam1ne (Druckrey
et al., 1967; Druckrey, 1967). The exponent (n) used to calculate the
constants (k) for the d1-n-alkyln1trosam1nes was 2.3. Using an approach
analogous to that used for N-n1trosod1methylam1ne (see Section 8.1.) and
U.S. EPA (1980a) and using the above parameters and a molecular weight of
158.2 mg/mmol, the dose associated with a lifetime risk of 0.5 is calculated
as follows:
105 mmol/kq/day x 130.2 mq/mmol .
0 . 17;8);.3 • 3-4018 9^ y
Using a rearrangement of the one-hit model as detailed in Section 8.1., the
potency factor for rats Is calculated to be 0.204 (mg/kg/day)-1. Adjust-
ing the by the cubed root of the ratio of human body weight (70 kg) to
assumed rat body weight (0.35 kg) yields a carcinogenic potency factor for
humans (B^) of 1.19 (mg/kg/day)"1.
Values of 1.6 (Druckrey et al., 1967) and 1.4 (Druckrey, 1967) were
specifically reported as exponents (n) for N-n1trosod1-n-butylam1ne.
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Although substantially <2.3, these exponents were not used 1n the above
calculation because corresponding constants (k) were not reported. The
exponent 2.3 appears to have been used as a representative value for
dialkylnltrosamlnes by Druckrey et al. (1967) and Oruckrey (1967).
The other studies (summarized In Table 8-3 of this report) are Inappro-
priate for quantitative carcinogenic risk assessment because of deficiencies
1n treatment duration, treatment schedule, study duration or lack of
controls.
8.6. N-NITROSOHETHYLVINYLAHINE
Druckrey et al. (1967) reported that N-n1trosomethylv1nylam1ne was
carcinogenic to BD rats when administered continuously 1n drinking water
that provided doses of 0.3 or 0.6 mg/kg/day or by Inhalation twice weekly
for 30 minutes at concentrations of 25 or 50 ppm. Both of these appear to
be lifetime studies (average tumor Inducatlon times In the low and high
treatment groups were 390 and 270 days, respectively, In the oral study and
300 and 270 days, respectively, 1n the Inhalation study) and neither used
controls. Tumors occurred primarily 1n the esophagus as well as pharynx and
tongue 1n the oral study, and In the nasal cavity 1n the Inhalation study.
Although animal studies with N-n1trosomethylv1nylam1ne are flawed 1n the
reporting of the data, general study detail and design provide a notable
amount of evidence for the carcinogenic potential of this compound In rats
when exposed by drinking water and Inhalation. N-n1trosomethylv1nylam1ne
reportedly caused sex-linked recessive lethal mutations 1n Drosophlla
melanogaster (Pasternak, 1964).
The relationship between dally dose (d) and median time of tumor Induc-
tion U50) (Oruckrey et al., 1967; Oruckrey, 1967), where d(t^Q)n=k,
has been used as the basis for calculation of a carcinogenic potency factor
for other dl-n-alkylnltrosamlnes 1n this report. This approach 1s precluded
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for N-n1trosomethylv1nylam1ne, however, because values for k and the expo-
nent n were not reported (Druckrey, 1967; Oruckrey et al., 1967). Although
the available animal data Is Insufficient to develop a quantitative potency
(risk) estimate, the data together with a recognition of similarity 1n
structure and related carcinogenic activity of similar compounds are
evidence for the carcinogenic potential of this compound.
8.7. N-NITROSOOIETHANOLAHINE
Subchronlc and chronic administration of N-n1trosod1ethanolam1ne In
drinking water has produced carcinogenic effects In rats. As detailed In
Section 5.1. and summarized In Table 8-4, multiple dose studies have demon-
strated that tumors occurred primarily 1n the liver (hepatocellular carci-
noma) and nasal cavities (squamous cell and other types of carcinomas).
Ihrlce weekly topical application of 25 mg N-n1trosodlethanolamlne In
acetone for 36 weeks produced nasal cavity and tracheal tumors In Syrian
hamsters during 20 months of observation (Hoffmann et al., 1983). Malignant
treatment-related tumors In the nasal cavity and trachea of hamsters were
also produced by weekly and biweekly subcutaneous Injections of N-nUroso-
dlethanolamlne (H1lfr1ch et al., 1978; Schmeltz et al., 1978; Pour and
Wallcave, 1981; Hoffman et al., 1983).
lhe lifetime studies of Preussman et al. (1982) and LlJInsky and Kovatch
(1985) provide the best bases for derivation of a carcinogenic potency
factor (q.j*) for humans. In the Preussman et al. (1982) study, male
Sprague-Dawley rats were exposed to drinking water that provided 0, 1.5,
6.0, 25.0, 100.0 or 400 mg N-nltrosod1ethanolam1ne/kg/day 5 days/week for
median survival times of 778, 801, 809, 624, 465 or 351 days, respectively.
Tumors were Induced In the liver and nasal cavities, but the response was
stronger and more clearly related to dose In the liver. The tumor Inci-
dences and data used to calculate a q^* for N-n1trosod1ethanolam1ne from
0752p 8-21 07/09/86
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TABLE 8-4
Subchronlc and Chronic Oral Carcinogenicity Studies oF N-Nltrosodlethanolanlne
Species/Strain
Group Size/
Sex
Method
Dose/Exposure
Duration of
Treatment/Study3
Main Tumor Site/Type
Coonents
Reference
Rat/BO
4 or 16/NR
drinking water
600 or 1000 mg/kg
life
11ver/hepatocellular
carcinoma
no controls
Druckrey
et al.. 1967
Rat/Sprague-
Dawley
36-88/H
drinking water
0. 1.5, 6. 25,
100 or 400 mg/kg/
day, 5 days/week
801-351 days/
801-351 days
11ver/hepatocellular
carcinoma
nasal cavlty/squamous
carcinomas, neuro-
epithelioma
lifetime study
Preussmann
et al., 1982
Rat/F344
16 or 20/each
drinking water
0, 400, 1000
or 2500 mg/t.
5 days/week
75-45 weeks/
110-50 weeks
11ver/hepatocellular
carcinoma
nasal cavlty/adeno-
carclnomas, squamous
carcinomas, olfactory
carcinomas
lifetime study
LlJInsky and
Reuber, 1984b
Rat/f344
20-39/each
drinking water
0, 28, 64, 160
mg/t, 5 days/week
100 and/or 50
weeks/120 or
130 weeks
11ver/hepatocellular
carcinoma, neoplastic
nodules
lifetime study
LlJInsky and
Kovatch, 1985
Rat/F344
10/each
drinking water
0. 3900, 7800,
15,600 or
31,250 mg/lb
54 weeks/
54 weeks
11ver/hepatocellular
carcinoma, cholanglo-
carclnoma
NC
LlJInsky and
et al.. 1980
House/B6C3F1
10/each
drinking water
195-312.5 mg/day,
5 days/week
32 weeks/NR
liver/hyperplastic
nodules, cholangto-
flbrosls, cirrhosis
no tumors
LlJInsky
et al., 1980
'Specific durations refer to treated groups
bAd 1Ibltum 7 days/week for 1? weeks and 20 mi/day, 5 days/week for the following 22 weeks
NC ¦ No conment; NR • not reported
-------
this study are presented In Table 8-5. The Incidences from the two highest
dose groups (100 and 400 mg/kg/day), however, were not used In the calcula-
tion because of the particularly short lifespans. The doses were multiplied
by 5/7 to adjust for partial weekly exposure and for the 25 mg/kg/day
groups, multiplied by (624/800)' to adjust for the shortened lifespan.
The animal was calculated using the computerized multistage linear
model which was adopted by the U.S. EPA (Howe and Crump, 1982). The factor
used to convert the animal to a q^ for humans was the cube root of
the ratio of assumed human body weight (70 kg) to assumed rat body weight
(0.35 kg). The human q^* obtained using these data 1s 0.97 (mg/kg/day)"1.
Lljlnsky and Kovatch (1985) exposed F344 rats of both sexes 5 days/week
to drinking water containing N-nltrosod1ethanolamlne at concentrations of 0
mg/l for 130 weeks, 28 mg/a for 100 weeks, 64 mg/a for 50 weeks, 64
mg/a for 100 weeks or 160 mg/a for 50 weeks with lifetime (120 or 130
weeks) observation. Treatment-related neoplasms of the liver (hepato-
cellular carcinoma, cholanglocellular carcinomas and adenomas, neoplastic
nodules) occurred In both sexes, but the females were most sensitive. It
appears to be most appropriate to calculate a potency factor using only the
Incidence data from the 28 and 64 mg/a groups treated for 100 weeks since
the 100-week treatment provides a more appropriate basis for risk estimation
than the 50-week treatment. Dally dosages are calculated by using reported
water consumption data (20 ml/day) and correcting for partial weekly
exposure by multiplying by 5/7. Animal and human q^*s are calculated with
the data presented In Table 8-6 by the methodology used with the Preussman
et al. (1982) study. The human q^ calculated from the lljlnsky and
Kovatch (1985) 100-week treatment Incidence data Is 2.81 (mg/kg/day)~J.
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TABLE 8-5
Cancer Data Sheet for Derivation of q-|*
Compound: N-n1trosod1ethanolamine
Reference: Preussman et al., 1982
Species, strain, sex: rat, Sprague-Dawley, male
Body weight: 0.35 kg, assumed
0 1.5 6.0 25.0
mq/kq/day mq/kq/day mq/kq/day mq/kq/day
Length of Exposure (1e) 778 days 801 days 809 days 624 days
Length of Experiment (Le) 778 days 801 days 809 days 624 days
Lifespan of Animal (L) 778 days 801 days 809 days 800 days
Tumor site and type: liver, all malignant and benign
Route, vehicle: oral, drinking water
Experimental Doses
or Exposures*
(mq/kq/day. 5 days/week)
0
1.5
6.0
25.0
Transformed Oose
(mq/kq/day)
0
1.1
4.3
8.5
Incidence
No. Responding/No. Tested
or Examined
0/88
7/72
43/72
33/36
~Lengths of exposure (In median survival time) were 778, 801, 809 or 624 days
for experimental doses 0, 1.5, 6.0 or 25.0 mg/kg/day, respectively.
Unadjusted q^* from study = 0.602925xl0"4 (mg/kg/day)"1
Human q^* = 0.970 (mg/kg/day)"1
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TABLE 8-6
Cancer Data Sheet for Derivation of q-|*
Compound: N-n1trosod1ethanolam1ne
Reference: Lljlnsky and Kovatch, 1985
Species, strain, sex: rat, F344, female
Body weight: 0.35 kg, assumed
0 mq/kq/day 28 mq/kq/dav 64 mq/kq/dav
Length of Exposure (le)
(weeks): 130 100 100
Length of Experiment (Le)
(weeks): 130 130 130
Lifespan of Animal (L)
(weeks): 130 130 130
lumor site and type: Hver/hepatocellular carcinoma, cholanglocellular
carcinoma and adenoma or neoplastic nodules
Route, vehicle: oral, drinking water
Experimental Doses Incidence
or Exposures* Transformed Dose No. Responding/No. Tested
(mq/l. 5 days/week) (mq/kq/day) or Examined
0
28
64
0
0.88
2.01
1/20
10/39
14/20
*Cages of 4 rats completely consumed 80 ml/day (20 ml/rat).
Unadjusted qi* from study = 0.208428x10"* (mg/kg/day)"1
Human q-|* = 2.81 (mg/kg/day)"1
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Similar calculations using the Incidence data from both the 100- and 50-week
treatment groups or only the two 50-week treatment groups resulted 1n some-
what lower but comparable q^s, 2.2 and 1.67 (mg/kg/day)""1, respectively.
Use of the other oral carcinogenicity studies of N-n1trosod1ethanolam1ne
summarized 1n Table 8-4 for calculation of carcinogenic potency factors 1s
precluded by deficiencies 1n experimental design that Include short treat-
ment durations or relatively small groups of animals. The Druckrey (1967)
study was used as the basis for the risk assessments of other dlalkylnltros-
amlnes In this report because better data were not available. Since the
q.|* of 2.81 (mg/kg/day)"1 calculated from the L1J1nsky and Kovatch
(1985) study 1s greater than the q^* of 0.97 (mg/kg/day)-1 calculated
from the Preussman et al. (1982) study and since the quality of these
studies 1s not substantially different, the q^* of 2.81 (mg/kg/ day) 1
Is recommended for estimating the Increased lifetime cancer risk for
exposure to N-n1trosod1ethanolam1ne.
8.8. N-NITROSODIPHENYLAHINE
N-NUrosod1phenylam1ne was administered 1n the diet of F344 rats of each
sex at concentrations of 0, 1000 or 4000 ppm for 100 weeks (NCI, 1979).
Sacrifice at the end of the treatment period showed that transitional-cell
carcinomas of the urinary bladder occurred 1n the high-dose groups of both
sexes at Incidences that were highly significant {p<0.001). Flbromas of the
Integumentary system occurred In male rats at Incidences that were dose
related (p=0.003); however, in direct comparisons, the Incidences of these
tumors In the Individual dose groups were not significantly higher than
those 1n the control group. Similar administration of N-n1trosod1phenyl-
amlne at concentrations of 10,000 or 20,000 ppm to male B6C3F1 mice or 2475
or 6139 ppm (TWA concentrations) to female mice for 101 weeks did not Induce
1
significantly elevated Incidences of tumors. (NCI, 1979).
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Or Inking water and gavage studies have not demonstrated a carcinogenic
effect of N-n1trosod1phenylam1ne. These Include uncontrolled studies
Involving administration of N-n1trosod1phenylam1ne to 20 BD rats of unspeci-
fied sex In the drinking water at a dally dose of 120 mg/kg for -541 days
(Druckrey et al., 1967), and treatment of 25 male Wlstar rats by gavage (In
1% aqueous methylcellulose) 5 days/week for 45 weeks with 8 weeks of obser-
vation (Argus and Hoch-L1get1, 1961). Statistically Increased Incidences of
tumors were not demonstrated 1n groups of 12-18 B6C3F1 or B6AKF1 mice of
either sex by dally Intubation of 1000 mg/kg 1n DMS0 from days 7-28 of age
followed by dietary administration of 3769 ppm for 77-79 weeks (BRL, 1968;
Innes et al., 1969). Treatment related neoplasms also were not Induced by
N-nUrosodlphenylamlne In female hairless hr/hr Oslo strain mice by single
weekly topical applications (0.1 ml of 1.0% solution) for 20 weeks with 80
weeks observation (Iversen, 1980), In male CB rats by single weekly Intra-
peritoneal Injections of 2.5 mg In polyethylene glycol 400 for 6 months with
18 months observation (8oyland et al., 1968) or In female 86C3F1 mice or
B6AKF1 mice of either sex by a single subcutaneous Injection of 1000 mg/kg
In DHS0 on day 28 of age with -18 months observation (BRL, 1968). Similar
treatment of male B6C3F1 mice, however, produced a significantly Increased
Incidence of reticulum cell sarcomas (4/16 vs. 0/24 In vehicle controls)
(BRL, 1968).
It 1s appropriate to use carcinogenicity as the basis for risk assess-
ment of N-nHrosodlphenylamlne since Induction of bladder tumors was
unequivocally demonstrated in F344 rats of both sexes (NCI, 1979). The
apparent lack of carcinogenicity 1n the other studies with rats may be
attributable to differences In method of oral exposure (I.e., nondlet),
route, dose, duration of treatment or length of observation period. NCI
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(1979) noted that the actual mechanism by which bladder tumors were Induced
(for example, calculi formation or nltrosatlon of amines present In feed) 1s
unknown.
Using the bladder carcinoma Incidences In the female rats from the NCI
(1979) bloassay, U.S. EPA (1980a) calculated a human q^* of 4.92xl0~a
(mg/kg/day)"1 for N-n1trosod1phenylam1ne.
8.9. p-NITROSODIPHENYLAMINE
Information regarding the carcinogenicity or noncarclnogenlclty of
p-n1trosod1phenylam1ne could not be located In the available literature as
cited 1n the Appendix. p-N1trosod1phenylam1ne did not produce sex-11nked
recessive lethal mutations 1n Drosophlla melanoqaster when administered In
the feed or by Injection (Valencia et al., 1985).
8.10. SUHMARY
The human carcinogenic potency factors calculated 1n Chapter 8 for the
nltrosamlnes and the water concentration associated with 10~5, 10~* and
10"7 risk levels are summarized In Table 8-7.
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TABLE 8-7
Potency Factors and Water Concentrations Associated
with Increased Lifetime Risks of Exposure to Nltrosoamlnes
Risk
Levels {mq/O
Chemical
BH or Ql*
(mg/kg/day) J
10"5
10"6
10"7
N-n1trosod1methylam1ne
51
6.86x10'*
6.86x10"7
6.86x10"9
N-nltrosomethylethylamlne
21.75
1.61xl0~s
1.61x10"'
1.61xl0 7
N-n1trosod1ethylam1ne
150
2.33x10 6
2.33x10"7
2.33x10"8
N-n1trosod1-n-propylam1ne
7.0 2
4.99x10"s
4.99x10"'
4.99x10"7
N-n1trosod1-n-butylam1ne
1.19
2.94xl0~4
2.94xl0~5
2.94x10"*
N-n1trosomethylv1ny1am1ne
ND
ND
ND
NO
N-nltrosodlethanolamlne
2.81
1.25x10*
1.25x10"*
1.25x10"'
N-n1trosod1phenyl amine
4.92x10"8
7.11x10*
7.11X10"3
7.11xl0~«
p-N1trosod1phenyl amine
ND
ND
ND
ND
ND = Not derived
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9. REPORTABLE QUANTITIES
9.1. REPORTABLE QUANTITIES (RQ) RANKING BASED ON CHRONIC TOXICITY
Information regarding nonneoplastic effects of N-n1trosam1nes adminis-
tered chronically or subchronlcal ly by natural routes Is limited, probably
because Interest In these compounds Is overwhelmingly related to carcinogen-
icity. Nonneoplastic effects often Included apparent preneoplastic altera-
tions {I.e., liver hyperplasia) or acute-type responses (e.g., hemorrhage,
necrosis), and deaths were usually (directly or Indirectly) due to tumors.
Alterations in body weight and clinical chemistry and hematology Indices
were occasionally reported, but never In the absence of neoplasia.
Limited Information is available that can be used to Identify MEDs for
N-n it r os odi methyl amine, N-n1trosod1ethyl amine and N-nUrosod1 phenyl amine for
the purpose of RQ classification.
lerraclni et al. (1967) summarized the results of various experiments in
which groups of 1-69 Porton rats of both sexes (4-6 weeks old) were exposed
to N-nitrosodlmethylamine in the diet (arachis oil vehicle) at concentra-
tions of 0, 2, 5, 10, 20 or 50 ppm for up to 120 weeks. Cystic agglomerates
occurred In the livers of many of the rats treated with 50 and 20 ppm
N-n1trosod1raethylam1ne, and occurred at concentrations as low as 5 ppm. The
cysts occurred In rats with and without malignant hematomas, apparently
developing Independently. The cysts and hepatomas reportedly were quite
distinct when they occurred together, and occurred together most frequently
in the 20 and 50 ppm groups. Of 83 rats that received 5 ppm N-nltrosodi-
methylamlne, 16 had cyst agglomerates, 2 had cysts and 6 had tumors alone.
Terracini et al. (1967) considered the cysts to be noncancerous and not
indicative of Impending malignant transformation, but the histological
description of the cysts suggests that they can be interpreted as benign
0753p
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neoplasms (Robblns et al., 1984). Large hepatic parenchymal cells with
prominent nuclei also occurred 1n the livers of rats In the 50 and 20 ppm
groups, both In nontumorous parts of livers with tumors and In livers with-
out tumors, but Incidences were not reported. Consideration of the above
effects Indicates that 20 ppm can be regarded as the MED for histological
alterations In the Hver. This exposure level minimizes uncertainties
associated with the use of a potentially Inappropriate effect (cysts that
are possibly neoplastic) as the only endpolnt at 5 ppm.
Clapp et al. (1968) treated 126 eight- to 10-week-old male RF mice with
N-n1trosod1methylam1ne 1n the drinking water at a concentration (5 mg/i)
that provided 0.94 mg/kg/day for 306 days (life). Histological examinations
were conducted on tissues from -70% of the mice. Nonneoplastic lesions In
the livers Included Infarcts (12%), thromboses (6%), abscesses (3%) and
eosinophilic Intranuclear Inclusions In hepatocytes; these Incidences
reportedly were greater than In control mice. Slight to severe glomerulo-
sclerosis developed 1n 83% of the kidneys examined histologically; this
lesion was seen 1n nearly all of the control mice but occurred much later.
The 5 ppm level In the drinking water can therefore be considered an MED for
hepatic alterations 1n mice. However, high Incidences of liver tumors
(primarily hemanglosarcomas) and lung adenomas also occurred 1n these mice.
Administration of N-n1trosod1methylam1ne In the drinking water at
concentrations of 0 or 0.1 ppm to groups of 20 female CD-I mice for 75 days
before mating and through pregnancy until weaning caused fetotoxlc effects
1n the offspring of the treated group (Anderson et al., 1978). Effects
Included Increased perinatal deaths (20.0% In treated vs. 9.9% In controls)
with stlllborns and neonatal deaths (<48 hours after birth) contributing
equally, and abnormal sex ratios (~66% males, ~34% females) 1n all Utters,
0753p
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Including those with low perinatal mortality. Abnormalities were not found
in any of the stlllborns or dead newborns. N-N1trosodlmethylam1ne treatment
was associated with Increased conception time (average 3 days longer than
controls), but other maternal Indices were not examined. Fetotoxlc effects
(fetal mortality or reduced fetal weight) without teratogenic effects have
been reported 1n other studies In which single doses of N-n1trosod1methyl-
amlne were administered by gavage during pregnancy (Alexandrov, 1967;
Nlshle, 1983). Fetal mortality without teratogenicity also occurred 1n rats
1n single dose oral studies with N-n1trosod1ethylam1ne and N-n1trosod1-n-
butylamlne (Alexandrov, 1973). The 0.1 ppm exposure level 1n the Anderson
et al. (1978) study can be considered an MED for fetotoxlc effects of
N-n1trosod1methylam1ne because exposure was continuous throughout gestation
and because maternal toxicity was not clearly Indicated.
Administration of N-n1trosod1ethylam1ne in the drinking water of 42,
10-week-old male RF/Un mice at a concentration (40 mg/8.) providing 6
mg/kg/day for 22 weeks produced microabscesses In the livers of 25% of the
mice (Clapp and Craig, 1967). Cyst-I1ke structures occurred 1n the livers
of all mice after 12 weeks of treatment, but more frequently and extensively
In livers from mice that died late In the experiment. Approximately 40% of
the livers had numerous hypertrophled hepatic parenchymal cells that
frequently contained eosinophilic Intranuclear Inclusions. Limited histo-
logical descriptions Indicate that the above lesions are not Inconsistent
with those described previously In rats (Terraclnl et al., 1967). The 6
mg/kg/day N-n1trosod1ethylam1ne dose can be considered an MED for non-
neoplastic hepatic alterations In mice, but high Incidences of tumors
occurred concurrently In the livers (hepatomas) and other tissues (stomach
and lungs).
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Nonneoplastic effects of chronic oral exposure to N-nitrosodlphenylamlne
occurred In the NCI (1979) carcinogenesis bloassay (Section 9.2.8.). In
this study, groups of 50 F344 rats of each sex were administered diets
containing 1000 and 4000 ppm N-n1trosod1phenyl amine for 101 weeks. Corneal
opacity occurred at higher Incidences 1n the high-dose males (15/50) and
low-dose females (16/50) than In the control males (0/20) and control
females (1/20). Although a clear dose-response was not demonstrated and the
mechanism of action (I.e., local or systemic) 1s unknown. It 1s appropriate
to score this effect because of the low spontaneous Incidences. Therefore,
1000 ppm 1s considered the HED for corneal opacity 1n the rats.
Groups of 50 male B6C3F1 mice were similarly exposed to 10,000 or 20,000
ppm N-nltrosodlphenylamlne in the diet for 101 weeks (NCI, 1979); female
B6C3I 1 mice were exposed to TWA concentrations of 2475 or 6139 ppm. Sub-
mucosal Inflammation of the urinary bladder occurred In the treated groups
of both sexes; Incidences 1n the control, low- and high-dose groups were
0/18, 12/49 and 31/48, respectively, In the males, and 0/20, 31/49 and
30/38, respectively, 1n the females. Epithelial hyperplasia of the bladder
occurred at low Incidences 1n treated male (0/20, 2/49 and 7/46) and female
(0/18, 3/47, 5/38) mice, but Incidences of bladder neoplasms were not
significantly elevated. The TWA concentration of 2475 ppm N-nltrosodl-
phenylamlne can be considered the HED for submucosal 1rr1tat1on/eplthel1 a 1
hyperplasia because the females appear to be more sensitive.
The data used to calculate CSs and RQs along with the HEDs and effects
are presented In Table 9-1. The animal dosages were converted to human HEDs
by multiplying mg/kg/day dosages by the cube root of the ratio of the animal
weight to human weight (70 kg) and by 70 kg to adjust to units of mg/day.
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TABLE 9-1
Composite Scores for Toxicity of N-N1trosodlmethylam1ne, N-NHrosodlethylamlne and N-N1 trosodlptienylamlne
Compound Route Species/ Dose/Exposure Human HED RVj Effect RVe CS RQ Reference
Strain (mg/day)
N-N1trosodtnethy1amtne
oral (drInking
water)
rat/Porton
20 ppm for 1?0 weeks
18.9
3.6
cystic agglomerates and
hypertrophled paren-
chymal cells In liver
6
21.6
100
Terraclnl
et al., 1967
N-Nltrosodlmethylamlne
oral (drinking
water)
mouse/RF
0.94 mg/kg/daya for
30b days (life)
5.5
4.4
Infarcts, thromboses and
abscesses In liver
6
26.4
100
Clapp
et al., 1968
N-Nltrosodlmethylamlne
oral (drinking
water)
mouse/CD-I
0.1 ppm for 75 days
prior to mating and
throughout gestation
0.1
7.0
Increased stlllboms and
neonatal deaths, abnormal
sex ratio
B
56
10
Anderson
et al., 1978
N-Nltrosodlethylamlne
oral (drinking
water)
mouse/RF/Un
6 mg/kg/dayb for
22 weeks
3.2
4.7
microabscesses, cyst-like
structures and hyper -
trophled parenchyman
cells in liver
6
28.2
100
Clapp and
Craig, 1967
N-Nltrosodlphenylanlne
oral (diet)
rat/F344
1000 pprtt for
101 weeks
535.0
1.4
corneal opacity
6
8.4
1000
NCI, 1979
N-Nltrosodlphenylamlne
oral (diet)
mouse/B6C3Fl
2475 ppai (TMA)d
for 101 weeks
1787.6
1
submucosal Inflammation
and epithelial hyper-
plasia of bladder
4
4
5000
NCI, 1979
Reported
body
weight
0.04 kg
^Reported
body
weight
0.032 kg
cReported
body
weight
0.25 kg
^Reported
body
weight
0.035 kg
-------
Standard dally water consumption (0.078 l/kg bw for rats, 0.17 t/kg bw
for mice) and food consumption (0.05 kg food/kg bw for rats, 0.13 kg food/kg
bw for mice) estimates were used to estimate animal mg/kg/day dosages when
exposures were reported, and assumed (0.35 kg for rats, 0.03 kg for mice) or
measured body weights as reported In Table 9-1 were used for the Inter-
species conversion. Since the animal HE0 for N-n1trosod1ethylam1ne (Clapp
and Craig, 1967) Is based on a subchronlc exposure, a chronic animal ME0 was
estimated by dividing the subchronlc dally dose by 10.
The histological effects In the livers of the N-n1trosod1methylam1ne-
treated rats (Terraclnl et a!., 1967), N-n1trosod1methylam1ne-treated mice
(Clapp et al., 1968) and N-n1trosod1ethylam1ne-treated mice (Clapp and
Craig, 1967) were assigned an RV& of 6, which primarily reflects altera-
tions that may not be reversible (e.g., cysts, Infarcts). The RVg for
fetotoxlcity is 8 (N-nltrosodimethylamine-treated mice; Anderson et al.,
1978). Corneal opacity (N-n1trosod1phenylam1netreated rats; NCI, 1979) was
assigned an RV& of 6 because this effect may not be reversible. The
submucosal inflammation and epithelial hyperplasia in the bladders of the
N-n1trosod1phenylam1ne-treated mice are likely to be Irritative but revers-
ible effects, and are most appropriately represented by an RVft of 4.
Multiplying the RV^s by the corresponding RVgs yields CSs as
presented In Table 9-1. The highest CS for N-nltrosodlmethylamlne, 56, Is
based on the evidence of fetotoxlcity In mice (Anderson et al., 1978) and
corresponds to an RQ of 10. The only effects for N-nUrosodlethylamlne,
hepatic cysts and hypertrophy (Clapp and Craig, 1967), resulted In a CS of
28.2, which corresponds to an RQ of 100. The highest CS for N-n1trosod1-
phenylamlne Is based on the corneal opacity in rats (NCI, 1979) and corre-
sponds to an RQ of 1000. These RQs, which should be used for the ranking of
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N-nltrosodlmethylamlne, N-n1trosod1ethylam1ne and N-n1trosod1phenylam1ne,
are summarized 1n Tables 9-2, 9-3 and 9-4. An RQ for N-nltrosodlmethylamlne
based on fetotoxlclty mitigates concern about basing an RQ on liver altera-
tions since N-n1trosod1methylam1ne-1nduced liver carcinogenesis has been
demonstrated In many species (Section 9.2.). Similarly, an RQ for N-n1tro-
sodlphenylamlne based on corneal opacity mitigates concern about basing an
RQ on effects In the bladder, since treatment of rats caused bladder
carcinomas.
9.2. WEIGHT OF EVIDENCE AND POTENCY FACTOR (F=1/ED1Q) FOR CARCINOGENICITY
The carcinogenicity of N-n1trosodlmethylamlne, N-n1trosod1ethylam1ne,
N-n1trosod1-n-propylam1ne and N-n1trosod1-n-butylam1ne has been demonstrated
unequivocally In numerous studies with multiple species, exposure routes and
treatment schedules. The carcinogenicity of N-n1trosomethylethylam1ne,
N-nHrosomethylv1nylam1ne and N-n1trosod1ethanolam1ne has been less exten-
sively studied, but Information Indicating noncarc1nogen1c1ty has not been
reported. N-N1trosod1phenylam1ne was carcinogenic 1n one species when
administered by diet. The carcinogenicity of p-nltrosodlphenylamlne does
not appear to have been assessed.
Although the carcinogenicity of most of the N-n1trosam1nes covered In
this report Is unequivocally or reasonably well-established, only relatively
few of the studies are appropriate for use 1n quantitative risk assessment.
Many studies, particularly those of N-n1trosod1methylam1ne, N-nUrosodl-
ethylamlne, N-nltrosodl-n-propylam1ne and N-n1trosod1-n-butylam1ne, used
parenteral routes of administration (Intraperitoneal or subcutaneous Injec-
tion), Inappropriate treatment frequencies or durations (Including single
exposures) or lacked control data.
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TABLE 9-2
N-Nltrosodlmethylamlne
Minimum Effective Dose (MEO) and Reportable Quantity (RQ)
Route: oral (drinking water)
Dose*: 0.1 mg/day
Effect: fetotoxiclty {stUlborns, neonatal deaths)
Reference: Anderson et al., 1978
RVd: 7
RVe: 8
Composite Score: 56
RQ: 10
^Equivalent human dose
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TABLE 9-3
N-N1trosod1ethylara1ne
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral (drinking water)
Dose*: 3.2 mg/day
Effect: liver microabscesses, cyst-like structures and hyper-
trophled parenchymal cells
Reference: Clapp and Craig, 1967
RVd: 4.7
RVe: 6
Composite Score: 28.2
RQ: 100
'Equivalent human dose
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TABLE 9-4
N-Nttrosodtphenylamlne
Minimum Effective Dose (HEO) and Reportable Quantity (RQ)
Route:
Oose*:
Effect:
Reference:
RVd:
RVe:
Composite Score:
RQ:
oral (diet)
535 mg/day
corneal opacity
NCI, 1979
1.4
6
8.4
1000
~Equivalent human dose
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An overview of the evidence of carcinogenicity, with emphasis on the
most relevant studies (such as chronic and subchronlc oral), 1s presented
with ED.|q determinations (when possible) for each of the N-n1trosam1nes.
Mutagenicity data are not reviewed for most of the compounds because of the
evidence of carcinogenicity, extenslveness of the mutagenicity data base and
because the responses are consistent with the carcinogenicity data.
9.2.1. N-N1trosodlmethylamlne. Chronic and subchronlc studies have been
conducted 1n which rats and mice were exposed to N-n1trosod1methylam1ne 1n
the drinking water or diet. As summarized 1n Table 8-1, tumors were primar-
ily produced 1n the livers of rats (hepatocellular carcinomas) and livers
(hemanglosarcomas) and lungs (adenomas) of mice. Twice weekly exposure to
N-n1trosod1methylam1ne vapor (2 or 4 mg/kg for 30 minutes) for an unspeci-
fied chronic duration produced malignant nasal cavity tumors In small groups
of rats (Druckrey et al., 1967); controls were not used tn this study, but
the average tumor Induction time was 40 days. Numerous additional studies
have demonstrated the carcinogenicity of N-n1trosod1methylam1ne In shorter
duration oral or Injection (subcutaneous Intraperitoneal) studies, Including
single dose and prenatal treatments. In all species tested (IARC, 1978)
Druckrey et al. (1967) derived a relationship between dally dose (d) and
the median time of tumor Induction U^g) 1" days, where d(t^g)n=k.
This relationship was derived using data from experiments with many differ-
ent N-nltroso compounds, Including dl-n-alkyln1trosam1nes and particularly
N-n1trosod1ethylam1ne, and Is the basis for a criterion for N-n1trosod1-
methylamlne In the U.S. EPA (1980a). Incidence data specifically reported
for N-n1trosod1methylam1ne could not be used directly for derivation of a
criterion because of limitations In experimental design reporting; N-n1tro-
sodlmethylamlne was administered to 20 BD rats of unspecified sex In the
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drinking water at a dose of 4 mg/kg/day, 5 days/week for an unspecified
duration that appears to be life (Druckrey et al., 1967). Hepatocellular
carcinomas developed 1n 11/20 rats after an average Induction time of 270
days (average total dose to Induce tumors In 50% of the animals, 0.4 g/kg),
but control data were not reported.
In U.S. EPA (1980a), values for k of 0.81x10* mmol/kg/day and n of 2.3
were used to derive a carcinogenic potency factor (B) using the one-hit
model. A constant (k, carcinogenic Index) for N-n1trosod1methylam1ne 1s not
reported by Druckrey et al. (1967) or 1n an analysis of the same data
(Druckrey, 1967), however, and 0.81xl04 mmol/kg/day appears to have been
misread from the N-nltrosomethylethylamlne listing from Druckrey (1967). A
value for k of -2.6x10" mmol/kg/day can be estimated for N-n1trosod1-
methylamlne from plots of k vs. number of C-atoms for lower d1-n-alkyl-
nltrosamlnes (C<5), Including N-n1trosod1methylam1ne (Druckrey et al., 1967;
Druckrey, 1967). The exponent (n) used to calculate the constants (k) for
the d1-n-alkyln1trosam1nes was 2.3.
Using k «- 2.6xl04 mmol/kg/day and n-2.3 In the Druckrey et al. (1967)
relationship, a dose (d) associated with a lifetime risk of 0.5 (I.e., time
to 50% tumors 1n 728 days) can be calculated as follows:
d
-------
In 0.5
8 = - —
B = = 1.38 (mg/kg/day)"1
0.503 mg/kg/day
By using the relationship P = Bd, the unadjusted 1/ED-jq calculated as
follows:
cn O-1
EDlO « ~b~
EDio = — =0.07 mg/kg/day
,u 1.38 (mg/kg/day)"1
1 1 = 13.8 (mg/kg/day)"1
E D-] o mg/kg/day
An F factor of 83.57 (mg/kg/day)"1 1s calculated by multiplying the
unadjusted 1 /E^ by the cube root of the ratio of the human body weight
(70 kg) to assumed rat body weight (0.35 kg). Although the Druckrey et al.
(1967) relationship appears In general to be valid for the d1-n-alkyln1tros-
amines, this F factor reflects the limitations of the experimental data for
N-n1trosod1methylam1ne (I.e., single dose uncontrolled study).
An F factor for N~n1trosod1methylam1ne can also be based on the study of
Peto et al. (1984) In which groups of 36 six-week-old Colworth rats of each
sex were exposed to 0.033, 0.066, 0.132, 0.264, 0.528, 1.056, 1.584, 2.112,
2.640, 3.168, 4.224, 5.280, 6.336, 8.448 or 16.896 ppm N-n1trosodlmethyl-
amine 1n the drinking water for life (~3 years). Untreated control groups
consisted of 144 rats of each sex. Tumors were Induced primarily In the
liver (hepatocellular carcinoma), but Incidence data for the Individual dose
groups were not reported as the purpose of this report was Vlelbull analysis
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of the liver tumor dose-response relationship. The following equations
relating cumulative Incidence (CI) to dose (d) In mg/kg/day and duration of
exposure (t) In years were derived:
CI = 37.43 (d * 0.1)*t7 (males)
CI = 51.45 (d = 0.1)*t7 (females)
Using the relationship for female mice (the more sensitive sex) and the
standard procedure described In U.S. CPA (1980b) to correct for background
response, the Increased risk associated with a dose of 1 yg/kg/day for an
exposure period of 3 years is 7.8x10"®, which corresponds to a potency
factor for rats (B^) of 7.8 (mg/kg/day)"1.
By using the relationship EO^q = 0.1/B, the unadjusted Is
calculated to be 78 (mg/kg/day)"1. Multiplying by the cube root of the
ratio of human body weight (70 kg) to measured female rat body weight (0.25
kg) gives an F factor of 510 (mg/kg/day) 1.
Studies published since U.S. EPA (1980a) that could be used to derive F
factors for N-n1trosodlmethy1am1ne using the computerized multistage linear
model (Howe and Crump, 1982) can be discounted on the basis of data quality.
Aral et al. (1979) exposed rats to three dose levels of N-nltrosodlmethyl-
amine In the diet (0.1, 1.0 or 10.0 ppm) for 104 weeks, but small groups of
animals were used (9-17) and tumor Incidences were relatively low (-17-22%
at the two highest doses). LlJInsky and Reuber (1984a) administered two
doses of N-nltrosod1methylamlne (0.11 and 0.26 mg/day) to rats In the drink-
ing water 5 days/week, but the duration of exposure (210 days) was much
shorter than the duration of observation (770 days In low dose, 700 days In
high dose).
The F factor from the Peto et al. (1984) data Is the most appropriate
value for potency ranking of N-n1trosod1methylam1ne because 1t 1s higher
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than the value calculated from the Druckrey et al. (1967) relationship and
because 1t 1s based on N-n1trosod1methylamlne data exclusively from a well-
designed study. An F factor of 510 (mg/kg/day)-1 Indicates that N-nltro-
sodlmethylamlne should be placed In potency group 1. The evidence for
carcinogenicity In animals Indicates that N-n1trosod1methylam1ne should be
classified as EPA Group B2. A potency group 1 and an EPA Group B2 chemical
has a HIGH hazard ranking under CERCLA.
9.2.2. N-N1trosomethylethylam1ne. Druckrey et al. (1967) administered
N-n1trosomethylethylam1ne to 4 and 11 BD rats In drinking water at doses of
1 and 2 mg/kg/day, respectively, for an unspecified duration that appears to
be for life. Controls were not Included 1n this study. Nine of the 15 rats
developed hepatocellular carcinomas. The average Induction times and
average total doses to Induce tumors In 50X of the animals were 500 days and
0.42 g/kg, respectively (1 mg/kg/day) and 360 days and 0.75 g/kg, respec-
tively (2 mg/kg/day). Carcinogenicity of N-n1trosomethylethylam1ne has also
been reported In subchronlc drinking water studies with rats. Lljlnsky and
Reuber (1980, 1981) and L1J1nsky et al. (1982, 1983) conducted a series of
experiments In which N-n1trosomethylethylam1ne was administered to groups of
20 F344 rats at various concentrations, 5 days/week for 30 weeks with life-
time observation. Tumors were Induced primarily 1n the livers (hepatocellu-
lar carcinoma and hemanglosarcomas) of the treated rats In all of these
studies (nasal cavity tumors occurred at relatively low Incidences In
several studies), with the exception of leukemia 1n the Lljlnsky et al.
(1983) study. The latter study used a relatively low dose of N-nltrosodl-
methylamlne, produced an equivocal leukemogenlc response without significant
Induction of liver or nasal cavity tumors and was the only N-nltrosomethyl-
ethylamlne carcinogenicity study to use a control group.
0753p
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The most appropriate basis for calculation of an F factor for N-n1troso-
methylethylamlne Is the relationship between dally dose (d) and median time
of tumor induction (t^J r d(t^)n=k (Druckrey et al., 1967; Druckrey,
1967). Using an approach analogous to that for N-nUrosod1methylamine (see
Section 9.2.1.) and values of 0.81xlQ4 mmol/kg/day for k and 2.3 for n
(Druckrey, 1967; Druckrey et al., 1967), the dose associated with a lifetime
risk of 0.5 1s calculated as follows:
i = mmol/Ka/day « 88.1 m3/«o1 _ /k /d
(728)^:*,3
Using a rearrangement of the one-hit model, the potency factor for rats 1s
calculated to be 3.72 (mg/kg/day)-1. By using the relationship ED1Q =
0.1/B, the unadjusted l/ED-jp calculated to be 37.2 (mg/kg/day)"1. An
f factor of 217.5 (mg/kg/day)-1 Is calculated by multiplying the unadjust-
ed I/ED-jq by the cube root of the ratio of human body weight (70 kg) to
assumed rat body weight (0.35 kg).
A value of 2.1 was specifically reported as the exponent (n) for
N-n1trosomethylethylamine In Druckrey et al. (1967). This exponent was not
used In the above calculation because a constant (k) was not reported with n
= 2.1 1n Druckrey et al. (1967). The exponent of 2.3 appears to have been
used by Druckrey as a representative value for dialkylnltrosamlnes In
Druckrey (1967) and In Druckrey et al. (1967). Furthermore, the F factor
calculated above reflects a limitation In the Druckrey et al. (1967)
N-n1trosomethylethylam1ne experiment 11.e., two dose groups with small
numbers (4 and 11) of rats).
The carcinogenicity studies by Lljlnsky and Reuber (1980, 1981) and
Lljlnsky et al. (1982, 1983) are Inappropriate bases for risk assessment
because of limitations that Include relatively short treatment durations (30
weeks) and, In all but the most recent study (Lljlnsky et al., 1983), the
0753p
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lack of a control group. The use of a control group by LlJInsky et al.
(1983) does not offset, however, other limitations 1n this study [single
dose, short treatment duration, equivocal leukemogenlc response (12/20 1n
controls vs. 18/20 1n treated)].
The F factor of 217.5 (mg/kg/day)"1 derived from the Druckrey et al.
(1967) relationship Indicates that N-n1trosomethylethylam1ne should be
placed 1n potency group 1. The evidence of carcinogenicity Indicates that
the compound should be classified as an EPA Group B2 chemical. A potency
group 1 and an EPA Group B2 chemical has a HIGH hazard ranking under CERCLA.
9.2.3. N-N1trosod1ethylam1ne. Chronic and subchronlc studies have been
conducted in which rats, mice, guinea pigs, rabbits and dogs were exposed to
N-n1trosod1ethylam1ne in the drinking water or by gavage. As summarized in
Table 8-2, generally high Incidences of tumors were produced primarily 1n
the livers of all these species, In the esophagus of rats and mice and 1n
the forestomach of mice. Hepatocellular carcinomas have been Induced In
small numbers of monkeys by oral treatment with N-n1trosod1eihylam1ne for
14-69 months or by bimonthly or monthly Intraperitoneal Injection for 2-5
years (Kelly et al., 1966; Reubner et al., 1976; Adamson and Sleber, 1979,
1983). Weekly Intratracheal Injections of N-n1trosod1ethylam1ne for 1-6
months Induced tracheal and bronchial tumors (primarily papillomas) 1n
hamsters (Yamamoto et al., 1985; Herrold and Dunham, 1963). Spray Inhala-
tion of N-n1trosod1ethylam1ne for 4-5 months produced tumors In the trachea
and lungs of hamsters and liver carcinomas without respiratory system tumors
1n rats (Dontenwlll et al., 1962; Dontenwlll and Hohr, 1962). Chronic
application of N-nltrosod1ethylam1ne to the skin of hamsters and mice
reportedly produced high Incidences of nasal cavity carcinomas and papil-
lomas, but no local tumors (Hoffmann and Graffl, 1964; Herrold, 1964a,b).
0753p
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Numerous additional studies have demonstrated that N-n1trosod1ethylam1ne Is
carcinogenic by shorter duration oral exposure (Including single dose), by
injection (subcutaneous, Intraperitoneal and intradermal) and by prenatal
exposure 1n all species tested, Including newborns (IARC, 1978).
The report of Druckrey et al. (1967) was used as the basis for deriva-
tion of a criterion for N-n1trosod1ethylam1ne 1n U.S. EPA (1980a). This
derivation uses the relationship d(t^0)n=k and the one-hit model to
derive a carcinogenic potency factor (Bu) (see Section 9.2.1.). Values of
k=0.35xl04 mmol/kg/day and n=2.3 were calculated from the nine-dose drink-
ing water study summarized In Table 5-4 (Druckrey et al., 1963) and reported
by Druckrey et al. (1967) and Druckrey (1967). Using these values and a
N-n1trosod1ethylam1ne molecular weight of 102, the dose associated with a
lifetime risk of 0.5 (I.e., time to 5054 of tumors 1n 728 days) is calculated
as follows:
0.35xl04 mmol/kq/day x 102 mq/mmol .. ..
d = (728)2-3 51 = 0.09328 mg/kg/day
Using a rearrangement of the one-hit model, a potency factor for rats 1s
calculated to be 7.43 (mg/kg/day)"1. By using the relationship E0^Q =
0.1/B, the unadjusted 1/E^q Is calculated to be 74.3 (mg/kg/day)"1.
Multiplying by the cube root of the ratio of human body weight (70 kg) to
assumed rat body weight (0.35 kg) yields an F factor of 434.5 (mg/kg/day)"1.
An F factor for N-n1trosod1ethylam1ne can also be based on the study by
Peto et al. (1984), in which groups of 36 s1x-week-old Colworth rats of each
sex were exposed to 0.033, 0.066, 0.132, 0.264, 0.528, 1.056, 1.584, 2.112,
2.640, 3.168, 4.224, 5.280, 6.336, 8.448 or 16.896 ppm N-n1trosod1ethylam1ne
In the drinking water for life (~3 years). Untreated control groups con-
sisted of 144 rats of each sex. Tumors were Induced primarily 1n the liver
and esophagus, but evidence data for the Individual dose groups were not
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reported as the purpose of this report was Welbull analysis of the dose-
response relationships of these tumors. The following equations relating
cumulative Incidence (CI) to dose {d) 1n mg/kg/day and duration of exposure
(t) 1n years were derived:
liver (males) CI = 18.70(d ~ 0.04)«t7
liver (females) CI = 32.09(d * 0.04)«t7
esophagus (males) CI = 21.17dat7
esophagus (females) CI = 11.16dat7
The female mice were somewhat more sensitive to liver tumors and the male
mice were more sensitive to esophageal tumors. In both sexes, however,
low-dose potency for the induction of esophageal tumors 1s -1000-fold less
than the potency for the Induction of liver tumors. Using the relationship
for liver tumors in female rats and the standard procedures described In
U.S. EPA (1980b) to correct for background response, the Increased risk
associated with a dose of 1 pg/kg/day for an exposure period of 3 years 1s
2.27xl0~2, which corresponds to a potency factor for rats (B^) of 22.7
(mg/kg/day)"1. By using the relationship E0^Q = 0.1/B, the unadjusted
1/ED.jg 1s calculated to be 227 (mg/kg/day)"1. Multiplying by the cube
root of the ratio of human body weight (70 kg) to reported rat body weight
(0.25 kg) results 1n an F factor of 1485 (mg/kg/day)"1.
Other studies that could be considered for derivation of F factors for
N-n1trosod1ethylam1ne are limited by deficiencies that primarily Include
short treatment durations, short study durations or lack of control data
(see Table 8-2). L1J1nsky et al. (1981b) exposed F344 rats to a variety of
combinations of doses In drinking water and treatment durations, but only
one regimen (0.45 mg/l, 5 days/week for 104 weeks, 130-week study
duration) had lifetime exposure, effectively making this a single dose study.
0753p
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The F factor calculated from the Peto et al. (1984) study, 1485 (mg/kg/
day)"1. Is more appropriate for potency ranking of N-nttrosod1ethylam1ne
because It 1s higher than the value calculated from the Druckrey et al.
(1967) relationship, 435 (mg/kg/day)-1. The F factors from both of these
studies, however, Indicate that N-n1trosod1ethylam1ne should be placed In
potency group 1. The evidence for carcinogenicity of N-n1trosod1ethylam1ne
1n animals Indicates that N-n1trosod1ethylam1ne should be classified as an
EPA Group 82 chemical. A potency group 1 and an EPA Group B2 chemical has a
HIGH hazard ranking under CERCLA.
9.2.4. N-N1trosod1-n-propylam1ne. In the only chronic carcinogenicity
study available, Druckrey et al. (1967) administered N-n1trosod1-n-propyl -
amine to BD rats of unspecified sex In the drinking water at doses of 4, 8,
15 or 30 mg/kg/day for an unspecified period that appears to be for life.
The total number of rats tested was 48, but the size of each treatment group
was not specifically reported; 1t Is Inferred that 16, 16, 15 and 1 rats
were treated In the low- to high-dose groups, respectively. Controls were
not Included In the study but 45/48 treated rats developed liver carcinomas.
The average Induction times and average total doses to Induce tumors 1n 5054
of the animals were 300 days and 1.15 g/kg (4 mg/kg/day), 202 days and 1.52
g/kg (8 mg/kg/day), 155 days and 1.86 g/kg (15 mg/kg/day), and 300 days and
3.2 g/kg (30 mg/kg/day), respectively. Paplllomas/carclnomas of the esoph-
agus and carcinomas of the tongue occurred In eight and six rats, respec-
tively, that were treated with 8 or 15 mg/kg/day.
Carcinogenicity of N-n1trosod1-n-propylam1ne has also been demonstrated
In subchronlc drinking water studies with rats. LlJInsky and Taylor (1978,
1979) and L1j1nsky and Reuber (1981, 1983) conducted four studies In which
0753p
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various doses of N-n1trosod1-n-propylamlne (0.9-4.4 mg/day) were adminis-
tered to groups of 12-20 F344 rats on 5 days/week for 30 weeks. The animals
In these studies were observed for life but 100% mortality occurred by 50 or
60 weeks In most of the treatment groups, and most of the studies did not
use controls. In the only study that used controls (L1J1nsky and Reuber,
1983), males treated with 4.4 mg/day and females treated with 2.2 mg/day for
30 weeks died by weeks 80 and 100, respectively, but only 12 rats were
Included In the female group. High Incidences of liver carcinomas, nasal
cavity carcinomas, esophageal carcinomas and papillomas occurred 1n the
treated rats In the above studies.
In other carcinogenicity studies, weekly subcutaneous Injections of
N-n1trosod1-n-propylamlne for life produced high Incidences of carcinomas,
primarily in the nasal cavities, laryngobronchlal tract, lungs and liver of
hamsters (Reznlk et al., 1975; Pour et al., 1973, 1974; Althoff et al.,
1973). Evidence for the transplacental carcinogenicity of single subcuta-
neous doses of 100 mg N-n1trosod1-n-propylam1ne during gestation In hamsters
has been reported (Althoff and Grandjean, 1979). Weekly Intraperitoneal
Injections of 40 mg N-n1trosod1-n-propylam1ne/kg for an average total dose
of 7.0 g reportedly produced hepatocellular carcinomas In monkeys (Adamson
and Sleber, 1979, 1983).
The most appropriate bases for derivation of a F factor for N-n1trosod1-
n-propylam1ne 1s the relationship between dally dose (d) and median time of
tumor Induction U50)' where d(t&0)n=k (Druckrey et al., 1967;
Druckrey, 1967). A value of ~1.7xl04 mmol/kg/day for k can be estimated
for N-n1trosod1-n-propylam1ne from plots of k vs. number of C-atoms for
lower dl-n-alkylnltrosamtnes (C<5), Including N-n1trosod1-n-propylam1ne
(Druckrey et al., 1967; Druckrey, 1967). The exponent (n) used to calculate
0753p
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the constants (k) for the d1-n-alkyln1trosam1nes was 2.3. Using an approach
analogous to that for N-n1trosod1methylam1ne (see Section 9.2.1.) with the
above values and a molecular weight of 130.2 mg/mmol, the dose associated
with a lifetime risk of 0.5 Is calculated as follows:
1.7x10* mmol/kq/day x 130.2 mq/mmol „
d = (728)2.3 = mg/kg/day
Using a rearrangement of the one-hit model, the potency factor for rats Is
calculated to be 1.20 (mg/kg/day). By using the relationship E0^ =
0.1/B, the unadjusted 1 /ED-jq Is calculated to be 12.0 (mg/kg/day)'1. An
F factor of 70.2 (mg/kg/day)"1 1s calculated by multiplying the unadjusted
1 /ED-j0 by the cube root of the ratio of human body weight (70 kg) to
assumed rat body weight (0.35 kg).
A value of 2.2 was specifically reported as the exponent (n) for
N-nltrosodl-n-propylamlne 1n Druckrey et al. (1967) and Oruckrey (1967).
This exponent was not used In the above calculation because a constant (k)
was not reported with n=2.2 In these studies. The exponent 2.3 appears to
have been used as a representative value for dlalkylnltrosamlnes (Oruckrey
et al., 1967; Druckrey, 1967).
Deficiencies In the drinking water studies with rats (Hjlnsky and
Taylor, 1978, 1979; LlJInsky and Reuber, 1981, 1983), primarily short treat-
ment duration, short study durations, lack of controls and small group
sizes, preclude their use In quantitative risk assessment.
The evidence of carcinogenicity 1n animal studies Indicates that the
compound should be classified as an EPA Group B2 chemical. The F factor of
70.2 (mg/kg/day)"1 Indicates that N-n1trosod1-n-propylam1ne should be
placed 1n potency group 2. A potency group 2 and an EPA Group B2 chemical
has a MEDIUM hazard ranking under CERCLA.
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9.2.5. N-N1trosod1-n-buty1ai»1ne. Chronic and subchronlc carcinogenicity
studies have been conducted In which rats, mice, hamsters and guinea pigs
were exposed to N-n1trosod1-n-butylam1ne 1n the diet, drinking water or by
gavage. As summarized in Table 8-3, generally high Incidences of malignant
and benign tumors were produced primarily 1n the liver, bladder, esophagus
or forestomach, depending upon species. Numerous additional studies have
demonstrated that DBN Is carcinogenic following more limited oral exposure
as well as by subcutaneous, Intraperitoneal or Intravenous Injection In all
species tested (IARC, 1978); these Included single dose, prenatal and
neonatal exposures.
The Bertram and Craig (1970) study was used to derive a carcinogenic
potency factor (*) for N-n1trosod1 -n-butylam1ne In U.S. EPA (1980a). As
detailed in Table 5-6, groups of 50 C57BL/6 mice of each sex were continu-
ously administered drinking water that provided N-n1trosodl-n-butylam1ne at
doses of 7.6 and 29.1 mg/kg/day (males) or 8.2 and 30.9 mg/kg/day (females).
A control group was not used 1n this study. Treatment was maintained until
the mice became moribund or died, except for -50% of the high-dose males and
females that were given untreated water after 197 days because of hematuria
In the majority of the high-dose males. The durations of the lifetime
exposures were not specifically reported, but can be estimated from reported
mean total doses to be 261 days (1986+199 mg/kg) and 216 days (6310+581
mg/kg) 1n the low- and high-dose males, respectively, and 255 days (2096*236
mg/kg) and 230 days (7115+710 mg/kg) 1n the low- and high-dose females,
respectively. As Indicated In Table 5-6, high Incidences of bladder and
esophageal tumors occurred In both treatment groups of both sexes.
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U.S. EPA (1980a) used the bladder and esophageal tumor Incidences 1n the
male mice and the following parameters for calculation of the q^*:
le (low dose) = 630 days
1e (high dose) =414 days
Le = 630 days
L = 630 days
w - 0.028 kg
Using these parameters, the q^* was calculated to be 5.43 (mg/kg/day)"1.
A concurrent control group was not used, but the historical spontaneous
tumor Incidence In C57BL/6 mice was reported to be low. The control
Incidence used to calculate the q^* was not reported (U.S. EPA, 1980a).
Apparent discrepancies exist, however, 1n the durations of treatment (le)
and durations of experiment (Le) used by U.S. EPA (1980a) and Indicated In
Bertram and Craig (1970). As mentioned above, the N-n1trosod1-n-butylam1ne
treatments were for life, which are estimated from the reported mean total
doses to be 261 and 216 days 1n the low- and high-dose male mice, respec-
tively; the reason for the use of 630 days for the low dose (le) and 414
days for the high dose (le) by U.S. EPA (1980a) Is unclear. The discontinu-
ation of treatment that occurred after 197 days In 20/45 high-dose males
would not appear to be a basis for adjustment of the high-dose le because
tumor Incidence and latency did not significantly differ from the male mice
1n which treatment was continued until death (Bertram and Craig, 1970). The
estimated durations of lifetime exposure for the males [le and Le of 261
days (low dose) and 216 days (high dose)], when considered with the assumed
mouse lifespan of 730 days and the lack of concurrent control data, provide
Dose
(mq/kq/day)
Incidence
0
7.6
29.1
NR
46/47
45/45
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a deficient basis for potency factor calculation. Consideration of an F
factor based on the Bertram and Craig (1970) data 1s therefore not recom-
mended until the apparent discrepancies In the U.S. EPA (1980a) N-n1trosod1-
n-butylam1ne criterion derivation are resolved.
Given the apparent deficiencies In the Bertram and Craig (1970) study,
1t appears to be more appropriate to derive an F factor for N-n1trosod1-n-
butylamlne on the basis of the relationship between dally dose (d) and
median time of tumor Induction (*59). where d(tgg)n=k (Druckrey et
al., 1967; Druckrey, 1967). A value of -10s mmol/kg/day for k can be
estimated for N-n1trosod1-n-butylam1ne from plots of k vs. number of C-atoms
for lower d1-n-alkyln1trosam1nes (C<5), Including N-n1trosod1-n-butylam1ne
(Druckrey et al., 1967; Druckrey, 1967). The exponent (n) used to calculate
the constants (k) for the d1-n-alkyln1trosamlnes was ?.3. Using an approach
analogous to that used for N-n1trosod1methylam1ne (see Section 9.2.1.) and
using the above parameters and a molecular weight of 158.2 mg/mmol, the dose
associated with a lifetime with a risk of 0.5 1s calculated as follows:
10s mmol/kq/day x 130.2 mg/mmol
d = * (728)2.3 = 3.4018 mg/kg/day
Using a rearrangement of the one-hit model, the potency factor for rats Is
calculated to be 0.204 (mg/kg/day)-1. By using the relationship ED^Q -
0.1/B as detailed In Section 9.2.1., the unadjusted 1/EO-jq 1s calculated
to be 2.04 (mg/kg/day)"1. An F factor of 11.9 (mg/kg/day)"1 Is calcu-
lated by multiplying the unadjusted 1/E0-|0 by the cube root of the ratio
of human body weight (70 kg) to assumed rat body weight (0.35 kg).
Values of 1.6 In Druckrey et al. (1967) and Druckrey (1967) were specif-
ically reported as exponents (n) for N-nUrosod1n-butylam1ne. Although
substantially lower than 2.3, these exponents were not used 1n the above
calculation because corresponding constants (k) were not reported. The
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exponent 2.3 appears to have been used as a representative value for
dlalkylnltrosamlne {Druckrey et al.f 1967; Oruckrey, 1967).
The other studies summarized 1n Table 8-3 of this report are Inappro-
priate for quantitative carcinogenic risk assessment because of deficiencies
In treatment duration, treatment schedule, study duration or lack of
controls.
The evidence of carcinogenicity 1n animal studies indicates that
N-n1trosod1-n-butylam1ne should be classified as an EPA Group B2 chemical.
The F factor of 11.9 (mg/kg/day)-1 Indicates that N-n1trosod1-n-butylam1ne
should be placed In potency group 2. A potency group 2 and an EPA Group B2
chemical has a MEDIUM hazard ranking under CERCLA.
9.2.6. N-N1trosomethylv1nylam1ne. N-N1trosomethylv1nylam1ne was adminis-
tered in the drinking water at doses of 0.3 and 0.6 mg/kg bw/day to groups
of 14 and 5 BD rats of unspecified sex, respectively (Druckrey et al.,
1967). The duration of treatment was not specifically stated but appears to
be life. Of the 19 rats, 17 had squamous cell carcinomas of the esophagus,
5 had carcinomas of the pharynx and 4 had carcinomas of the tongue. In
addition, two rats developed papillomas of the esophagus and eight showed
bile-duct proliferation and cysts in the liver. Incidences of these tumors
at each dose were not, however, reported. The average total dose that
caused tumors In 50% of the animals and the average time for tumor Induction
In 50% of the animals were 0.11 g/kg and 390 days, respectively (0.3 mg/kg/
day), and 0.16 g/kg and 270 days, respectively {0.6 mg/kg/day).
Ten of 18 B0 rats of unreported sex that were exposed to 25 or 50 ppm
N-n1trosomethylv1nylam1ne In air for 30 minutes (~1 or 2 mg/kg, respec-
tively) twice weekly for an unspecified chronic period died early (not
elaborated) from severe respiratory tract Inflammation (Druckrey et al..
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1967). Of the remaining eight rats, five developed nasal cavity tumors
(three squamous cell carcinomas, two cholesteatomas). Aesthes1oneuroep1the-
1loma of the ethmoturblnals, carcinoma of the pharynx and papillomas of the
esophagus occurred 1n one, one and two of the animals, respectively. The
tumor Incidences were not tabulated by dose, but the average total dose that
caused tumors In 5054 of the animals and the average time for tumor Induction
In 5054 of the animals were 0.05 g/kg and 300 days (1 mg/kg), respectively,
and 0.09 g/kg and 270 days (2 mg/kg), respectively. Two rats that survived
a single vapor exposure to 18 mg/kg (duration not specified) died 277 and
374 days later with carcinomas of the nasal cavities (Druckrey et a!., 1967).
Additional Information regarding the above uncontrolled studies of
N-nitrosomethyl vinyl amine were not reported by Druckrey et al. (1967).
Although Indicative of N-nUrosomethylvlnylamlne carcinogenicity, additional
evidence (corroborating or noncorroboratlng) has not been reported.
N-N1trosomethylvlnylamlne reportedly caused sex-linked recessive lethal
mutations In D. melanoqaster (Pasternak, 1964).
The relationship between dally dose (d) and median time of tumor Induc-
tion (tgp) (Druckrey et al., 1967; Druckrey, 1967), where d(t^Q)n=k,
has been used as the basis for calculation of f factors for other d1 -n-
alkylnltrosamlnes In this report. This approach Is precluded for N-n1troso-
methylvlnylamlne, however, because values for (k) and the exponent (n) were
not reported by Druckrey. Although the animal studies with N-nitrosomethyl-
vlnylamlne are flawed In the reporting of the data, the general study detail
and design provide a notable amount of evidence for the carcinogenic
potential of this compound In rats by drinking water and Inhalation. This
evidence together with a recognition of the similarity 1n structure and
related carcinogenic activity of similar compounds 1s of a sufficient level
to classify N-nltrosomethylvlnylamlne as a U.S. EPA Group B2 chemical.
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Group B2 means that the agent Is "probably" carcinogenic to humans. For
quantitative purposes the data are Insufficient to develop a potency (risk)
estimate. Similarly, 1t 1s reasonable to assign an Interim hazard ranking
of high to this compound. This ranking 1s based on the observation that on
a molecular weight scaling basis this compound might have a cancer potency
similar to those estimated for N-n1trosod1methylam1ne and N-nltrosomethyl-
ethylamlne when comparing the hazard rankings of all eight nltroso com-
pounds, thus the equivalent high hazard ranking 1s warranted.
9.2.7. N-N1trosod1ethano1amtne. Subchronlc and chronic administration of
N-n1trosod1ethanolam1ne 1n drinking water has produced carcinogenic effects
in rats. As summarized In Table 8-4, multiple dose studies have demonstrat-
ed that tumors occurred primarily In the liver (hepatocellular carcinoma)
and nasal cavities (squamous cell and other types of carcinomas). Thrice
weekly topical application of 25 mg N-n1trosodlethanolamlne In acetone for
36 weeks produced nasal cavity and tracheal tumors In Syrian hamsters during
20 months of observation (Hoffmann et al., 1983). Malignant treatment-
related tumors In the nasal cavity and trachea of hamsters were also pro-
duced by weekly or biweekly subcutaneous Injections of N-n1trosod1ethanol-
amlne (Hllfrlch et al., 1978; Schmeltz et al., 1978; Pour and Wallcave,
1981; Hoffman et al., 1983).
The lifetime studies by Preussman et al. (1982) and lljlnsky and Kovatch
(1985) provide the best bases for derivation of F factors for N-nltrosodl-
ethanolamlne. In the Preussman et al. (1982) study detailed In Table 5-9,
male Sprague-Dawley rats were exposed to drinking water that provided 0,
1.5, 6.0, 25.0, 100.0 or 400 mg/kg/day, 5 days/week for median survival
times of 778, 801, 809, 624, 465 or 351 days, respectively. Tumors were
Induced In the liver and nasal cavities, but the response was stronger and
more clearly related to dose In the liver. Using the Incidence data for
0753p 9-28 07/09/86
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liver tumors and the computerized multistage linear model adopted by the
U.S. EPA (Howe and Crump, 1982), the unadjusted 1/EO^Q 1s calculated to be
0.965 (mg/kg/day)"1 (Table 9-5). The Incidences from the two highest dose
groups (100 and 400 mg/kg/day) were not used 1n this calculation because of
particularly short lifespans. Multiplying by the cube root of the ratio of
human body weight (70 kg) to assumed rat body weight (0.35 kg) gives an F
factor of 5.64 (mg/kg/day)"1.
L1j1nsky and Kovatch (1985) exposed F344 rats of both sexes 5 days/week
to drinking water containing N-n1trosod1ethanolam1ne at concentrations of 0
mg/l for 130 weeks, 28 mg/l for 100 weeks, 64 mg/l for 50 weeks, 64
mg/l for 100 weeks or 160 mg/l for 50 weeks with lifetime (120 or 130
weeks) observation. As detailed In Table 5-10, treatment-related neoplasms
of the liver (hepatocellular carcinoma, cholanglocellular carcinomas and
adenomas, neoplastic nodules) occurred in both sexes, but the females were
most sensitive. It 1s most appropriate to calculate an unadjusted 1/E0^^
using only the Incidence data from the 28 and 64 mg/l groups treated for
100 weeks. Using the data presented In Table 9-6 and the computerized
multistage linear model (Howe and Crump, 1982), the unadjusted 1/EO-jq
calculated to be 1.82 (mg/kg/day)"1. Multiplying by the cube root of the
ratio of human body weight (70 kg) to assumed rat body weight (0.35 kg)
gives an F factor of 10.64 (mg/kg/day)"1. Calculations using the
Incidence data from all four treatment groups or only the 50-week treatment
groups resulted 1n comparable F factors, 11.50 and 11.85 (mg/kg/day)"1,
respectively.
Use of the other oral carcinogenicity studies of N-n1trosod1ethanolam1ne
summarized In Table 8 4 for calculation of F factors 1s precluded by
deficiencies 1n experimental design that Include short treatment durations
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TABLE 9-5
Derivation of Potency Factor (F)
Agent: N-N1trosod1ethanolam1ne
Reference:
Preussman et al., 1982
Exposure route:
oral
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Vehicle or
Physical state:
drinking water
Body weight:
0.35 kg (assumed)
Duration of treatment
(days):
7/8 801 809
624
Duration of study
(days):
7/8 801 809
624
Lifespan of animal
(days):
7/8 801 809
800 (estimated)
Target organ:
liver
Tumor type:
all malignant and benign
Experimental doses/
exposure (mg/kg/day):
0 1.5 6.0
25.0
Transformed doses
(mg/kg/day)*:
0 1.1 4.3
8.5
Tumor incidence:
0/88 7/72 43/72
33/36
Unadjusted 1 /E D-j q :
0.965 (mg/kg/day)-1
1/ED-jg (F Factor):
5.64 (mg/kg/day)'1
^Experimental doses were
exposure and In the 25
shortened lifespan.
multiplied by 5/7 to adjust for
mg/kg/day, multiplied by (624/800)
partial weekly
3 to adjust for
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TABLE 9-6
Derivation of Potency Factor (F)
Agent: N-N1trosod1ethanolam1ne
Reference:
Hjlnskl and Kovatch,
1985
Exposure route:
oral
Species:
rat
Strain:
F344
Sex:
female
Vehicle or
physical state:
drinking water
Body weight:
0.35 kg (assumed)
Duration of treatment
(weeks):
130 100
100
Duration of study
(weeks):
130 130
130
Lifespan of animal
(weeks):
130 130
130
Target organ:
11ver
Tumor type:
hepatocellular carcinoma, cholanglocellular
carcinoma and adenoma, and/or neoplastic
nodules
Experimental doses/
exposure (mg/i):
0 28
64
transformed doses
(mg/kg/day)*:
0 0.88
2.01
Tumor Incidence:
1/20 10/39
14/20
Unadjusted l/EO^o*
1.82 (mg/kg/day)"1
1/E0]o (f Factor):
10.64 (mg/kg/day)-1
*Exposures were transformed by using a reported average dally water consump-
tion of 0.02 t/rat and multiplying by 5/7 to adjust for partial weekly
exposure.
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and relatively small groups of animals. The Druckrey (1967) study was used
as the basis for the risk assessments of other dlalkylnltrosamlnes 1n this
report, because data of better quality were not available.
Since the F factor of 10.64 (mg/kg/day)'x calculated from the Lljlnsky
and Kovatch (1985) study Is greater than the F factor of 5.64 (mg/kg/
day)-1 calculated from the Preussman et al. (1982) study, 10.64 (mg/kg/
day)"1 1s recommended for use In hazard ranking of N-n1trosod1ethanol-
amlne. The evidence of carcinogenicity 1n animal studies Indicates that
N-n1trosod1ethanolam1ne should be classified as an EPA Group B2 chemical.
The F factor of 10.64 (mg/kg/day)"1 Indicates that N-n1trosod1ethanolam1ne
should be placed 1n potency group 2, particularly when the corroborating
alternative data analyses (I.e., combined 50- and 100-week treatment groups,
50-week treatment groups) are considered. A potency group 2 and an EPA
Group B2 chemical has a MEDIUM hazard ranking under CERCLA.
9.2.8. N-N1trosod1phenylam1ne. An NCI (1979) bloassay was conducted 1n
which N-n1trosod1phenylam1ne was administered In the diet of F344 rats of
each sex at concentrations of 0, 1000 or 4000 ppm for 100 weeks (see Table
5-11). Sacrifice at the end of the treatment period showed that transi-
tional cell carcinomas of the urinary bladder occurred 1n the high-dose
groups of both sexes at Incidences that were highly significant {p<0.001).
Flbromas of the Integumentary system occurred In male rats at Incidences
that were dose-related (p=0.003); however, In direct comparisons the Inci-
dences of these tumors In the Individual dose groups were not significantly
higher than those 1n the control group. Similar administration of the com-
pound at concentrations of 10,000 or 20,000 ppm to male B6C3F1 mice or 2475
or 6139 ppm (TWA concentrations) to female mice for 101 weeks did not Induce
significantly elevated Incidences of tumors (NCI, 1979) (see Table 5-11).
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Drinking water and gavage studies have not demonstrated a carcinogenic
effect of N-n1trosod1pheny1am1ne. These Include uncontrolled studies
Involving administration of N-n1trosod1phenylam1ne to 20 BD rats of unspeci-
fied sex In the drinking water at a dally dose of 120 mg/kg for -541 days
(Druckrey et al., 1967), and treatment of 25 male Wlstar rats by gavage (In
1% aqueous methylcellulose), 5 days/week for 45 weeks with 8 weeks of obser-
vation (Argus and Hoch-L1get1, 1961). Statistically Increased Incidences of
tumors were not demonstrated 1n groups of 12-18 B6C3F1 or B6AKF1 mice of
either sex by dally Intubation of 1000 mg/kg 1n DMS0 from days 7-28 of age
followed by dietary administration of 3769 ppm for 77-79 weeks (BRL, 1968;
Innes et al., 1969).
Treatment-related neoplasms also were not Induced by N-n1trosod1phenyl-
amine In female hairless hr/hr Oslo strain mice by single weekly topical
applications (0.1 ml of 1.0% solution) for 20 weeks with 80 weeks of
observation (Iversen, 1980), In male C8 rats by single weekly Intraperito-
neal Injections of 2.5 mg In polyethylene glycol 400 for 6 months with 18
months of observation (Boyland et al., 1968) or In female B6C3F1 mice or
B6AKF1 mice of either sex by a single subcutaneous Injection of 1000 mg/kg
In 0MS0 on day 28 of age with -18 months of observation (BRL, 1968).
Similar treatment of male B6C3F1 mice, however, produced a significantly
Increased Incidence of reticulum cell sarcomas (4/16 vs. 0/24 In vehicle
controls) (BRL, 1968). It 1s appropriate to use carcinogenicity as the
basis for risk assessment of N-n1trosod1phenylam1ne since Induction of
bladder tumors was unequivocally demonstrated In F344 rats of both sexes
(NCI, 1979). The apparent lack of carcinogenicity Is the previous studies
with rats may be attributable to differences In method of oral exposure
(I.e., nondlet), route, dose, duration of treatment of length of observation
0753p
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period. NCI (1979) noted that the actual mechanism by which bladder tumors
were Induced (I.e., calculi formation or nltrosatlon of amines present In
feed) 1s unknown.
Using the bladder carcinoma Incidences In the female rats from the NCI
(1979) bloassay and the computerized multistage linear model (Howe and
Crump, 1982), the unadjusted calculated to be 0.019 (mg/kg/
day)"1 (Table 9-7). Multiplying by the cube root of the ratio of human
body weight (70 kg) to measured rat body weight (0.25 kg) results In an F
factor of 0.124 (mg/kg/day)-1. The evidence for carcinogenicity 1n rats
Indicates that N-n1trosod1phenylam1ne should be classified as an EPA Group
B2 chemical. The F factor of 0.124 (mg/kg/day)"1 Indicates that N-n1tro-
sodiphenylamlne should be placed In potency group 4. A potency group 4 and
an EPA Group B2 chemical has a LOW hazard ranking under CERCLA.
9.2.9. p-NUrosodlphenylamine. Pertinent data regarding the carcinogen-
icity or noncarclnogenlclty of p-n1trosod1phenyl amine could not be located
1n the available literature as cited in the Appendix. p-N1trosod1phenyl-
amlne did not produce sex-linked recessive lethal mutations 1n D. melano-
qaster when administered In the feed or by Injection (Valencia et al., 1985).
9.3. SUMMARY
The information used to rank the nltrosamlnes according to degree of
carcinogenic hazard 1s summarized 1n Table 9-8.
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TABLE 9-7
Derivation of Potency Factor (F)
Agent: N-N1trosod1phenylam1ne
Reference:
Exposure route:
Species:
Strain:
Sex:
Vehicle or
physical state:
Body weight:
Duration of treatment:
Duration of study:
Lifespan of animal:
Target organ:
Tumor type:
Experimental doses/
exposure (ppm):
Transformed doses
(mg/kg/day):
lumor Incidence:
Unadjusted 1 /E D-) q :
1/EDio (F Factor):
NCI, 1979
oral
rat
F344
female
diet
0.25 kg
700 days
700 days
700 days
bladder
transitional cell carcinoma
0 1000 4000
0 50 200
0/18 0/48 40/49
0.019 (mg/kg/day)"1
0.124 (mg/kg/day)-1
07 53p
9-35
07/09/86
-------
TABLE 9-8
Ranking of N1trosam1nes According to Degree of Carcinogenic Hazard
N1trosam1ne
F-Factor
(mg/kg/day)"1
Potency
Group
EPA
Group
CfcRCLA
Hazard
Ranking
N-N1trosod1methylam1ne
510
1
B2
HIGH
N-NUrosomethyl ethyl amine
?17.5
1
B2
HIGH
N-N1trosod1ethyl amine
1485
1
B2
HIGH
N-N1trosod1-n-propylam1ne
70.2
7
B?
MEDIUM
N-N1trosod1-n-butylamine
11.9
2
B2
MEDIUM
N-N1trosomethylvlnylamlne
NC
NA
NA
NA
N-N1trosod1ethanolamine
10.6
2
82
ME0IUM
N-N1trosod1phenyl amine
0.12
4
B2
LOW
p-N1trosod1phenylam1ne
NC
NA
NA
NA
NC = Not calculated; NA = not applicable
0753p
9-36
07/09/86
-------
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killing test using Escher1ch1 a col1 strains WP2, WP67 (uvrA polA) and CM871
(uvrA lexA recA). Prog. Hutat. Res. 1: 199-209.
U.S. EPA. 1977. Computer print-out of nonconfidential production data from
TSCA Inventory. OPTS, CID; U.S EPA, Washington, DC.
U.S. EPA. 1978. In-depth studies on health and environmental Impacts of
selected water pollutants. Prepared under Contract No. 68-01-4646. U.S.
EPA, Washington, DC.
U.S. EPA. 1980a. Ambient Water Quality Criteria for Nltrosamlnes. ECAO,
U.S. EPA, Cincinnati, OH. EPA 440/4-80-064. NTIS PB81-117756.
U.S. EPA. 1980b. Guidelines and Hethodology used in the Preparation of
Health Effects Assessment Chapters of the Consent Decree Water Criteria
Documents. Fed. Reg. 45: 79347-79357.
0754p 10-48 05/29/86
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Valencia, R., J.M. Mason, R.C. Woodruff and S. Z1mmer1ng. 1985. Chemical
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325-348.
Venltt, S. and C. Crofton-Slelgh. 1981. Mutagenicity of 42 coded compounds
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Prog. Mutat. Res. 1: 351-360.
Vogel, E., W.G.H. BUJleven, M.O.H. Kortsellum and O.A. Zljlstra. 1981.
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559-565.
Yordy, J.R. and M. Alexander. 1981. Formation of N-n1trosod1ethanolam1ne
from dlethanolamlne In lake water and sewage. J. Environ. Qual. 10(3):
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Zvelg, G., S. Sellm, R. Hummel, et al. 1980. Analytical survey of
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0754p
10-51
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APPENDIX
LITERATURE SEARCHED
This profile Is based on data Identified by computerized literature
searches of the following:
CASR online (U.S. EPA Chemical Activities Status Report)
CAS online STN International
TOXLINE
TOXBACK 76
TOXBACK 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
These searches were conducted In October, 1985. In addition, hand searches
were made of Chemical Abstracts (Collective Indices 6 and 7), and the
following secondary sources were reviewed:
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1980. Documentation of the Threshold Limit Values. 4th ed. (In-
cludes Supplemental Documentation, 1981, 1982, 1983). Cincinnati,
OH. 486 p.
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1985. TLVs: Threshold Limit Values for Chemical Substances and
Physical Agents In the Workroom Environment with Intended Changes
for 1985-1986. Cincinnati, OH. 114 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed.. Vol. 2A. John Wiley and
Sons, NY. 2878 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2B. John Wiley and
Sons, NY. p. 2879-3816.
0755p
A-l
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Clayton, 6.0. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2C. John Wiley and
Sons, NY. p. 3817-5112.
Grayson, M. and D. Eckroth, Ed. 1978-1983. K1rk-0thmer Encyclo-
pedia of Chemical Technology, 3rd ed. John WHey and Sons, NY. 23
Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc., Littleton, HA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. WHO, IARC, Lyons, France.
IT 11 (International Technical Information Institute). 1982. Toxic
and Hazardous Industrial Chemicals Safety Manual for Handling and
Disposal with Toxicity and Hazard Data. ITII, Tokyo, Japan. 700 p.
NTP (National Toxicology Program). 1984. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Ouellette, R.P. and J.A. King. 1977. Chemical Week Pesticide
Register. McGraw-Hill Book Co., NY.
Sax, N.I. 1979. Dangerous Properties of Industrial Materials, 5th
ed. Van Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1984. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1985. Status Report on Rebuttable Presumption Against
Registration (RPAR) or Special Review Process. Registration Stan-
dards and the Data Call In Programs. Office of Pesticide Programs,
Washington, DC.
U.S. EPA. 1985. CSB Existing Chemical Assessment Tracking System.
Name and CAS Number Ordered Indexes. Office of Toxic Substances,
Washington, DC.
US1TC (U.S. International Trade Commission). 1983. Synthetic
Organic Chemicals. U.S. Production and Sales, 1982, US1TC Publ.
1422. Washington, DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co.,
Inc., Rahway, NJ.
0755p
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In addition, approximately 30 compendia of aquatic toxicity data were
lewed, Including the following:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington, DC.
Johnson, W.W. and H.T. Flnley. 1980. Handbook of Acute Toxicity
of Chemicals to Fish and Aquatic Invertebrates. Summaries of
Toxicity Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior, Fish and Wildlife
Serv. Res. Publ. 137, Washington, DC.
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed.
Prepared for the Resources Agency of California, State Water
Quality Control Board. Publ. No. 3-A.
Plmental, 0. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. PB-269605.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876.
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