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N-Nitrosodiethylamine
CASRN 55-18-5
Contents
0042
N-Nitrosodiethylamine; CASRN 55-18-5
Health assessment information on a chemical substance is included in IRIS only
after a comprehensive review of chronic toxicity data by U.S. EPA health
scientists from several Program Offices and the Office of Research and
Development. The summaries presented in Sections I and II represent a
consensus reached in the review process. Background information and
explanations of the methods used to derive the values given in IRIS are
provided in the Background Documents.
STATUS OF DATA FOR N-Nitrosodiethylamine
File On-Line 01/31/1987
Category (section) Status Last Revised
----------------------------------------- -------- ------------
Oral RfD Assessment (I.A.) no data
Inhalation RfC Assessment (I.B.) no data
Carcinogenicity Assessment (II.) on-line 07/01/1993
_I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
__I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Substance Name -- N-Nitrosodiethylamine
CASRN -- 55-18-5
Primary Synonym -- Diethylnitrosamine
Not available at this time.
__I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
Substance Name -- N-Nitrosodiethylamine
CASRN -- 55-18-5
Primary Synonym -- Diethylnitrosamine
Not available at this time.
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name -- N-Nitrosodiethylamine
CASRN -- 55-18-5
Primary Synonym -- Diethylnitrosamine
Last Revised -- 07/01/1993
Section II provides information on three aspects of the carcinogenic
assessment for the substance in question; the weight-of-evidence judgment of
the likelihood that the substance is a human carcinogen, and quantitative
estimates of risk from oral exposure and from inhalation exposure. The
quantitative risk estimates are presented in three ways. The slope factor is
the result of application of a low-dose extrapolation procedure and is
presented as the risk per (mg/kg)/day. The unit risk is the quantitative
estimate in terms of either risk per ug/L drinking water or risk per ug/cu.m
air breathed. The third form in which risk is presented is a drinking water
or air concentration providing cancer risks of 1 in 10,000, 1 in 100,000 or 1
in 1,000,000. The rationale and methods used to develop the carcinogenicity
information in IRIS are described in The Risk Assessment Guidelines of 1986
(EPA/600/8-87/045) and in the IRIS Background Document. IRIS summaries
developed since the publication of EPA's more recent Proposed Guidelines for
Carcinogen Risk Assessment also utilize those Guidelines where indicated
(Federal Register 61(79):17960-18011, April 23, 1996). Users are referred to
Section I of this IRIS file for information on long-term toxic effects other
than carcinogenicity.
__II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY
___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION
Classification -- B2; probable human carcinogen
Basis -- Induction of tumors at multiple sites in both rodent and nonrodent
species exposed by various routes
___II.A.2. HUMAN CARCINOGENICITY DATA
Human exposure to nitrosamines results from contact with mixtures
containing these compounds (e.g., cutting oils, tobacco products). Because of
potential confounding by the other substances in these mixtures, data from
human exposure is of limited use in the evaluation of carcinogenicity of
individual nitrosamines.
___II.A.3. ANIMAL CARCINOGENICITY DATA
There is a large data base on the carcinogenicity of nitrosamines, most of
which pertains to structure-activity relationships rather than to dose-
response. Diethylnitrosamine administered by gavage, in drinking water, or by
feeding produces liver tumors in the following species: rats, mice, hamsters,
guinea pigs, rabbits, dogs, and monkeys (Yamamoto et al., 1972; Druckrey et
al., 1967, 1963; Magee et al., 1976; Rajewsky et al., 1966; Tomatis, 1973).
Tracheal and lung tumors have been observed in Syrian golden hamsters upon
administration of diethylnitrosamine by gavage or inhalation (Magee et al.,
1976). Diethylnitrosamine administered to pregnant mice, rats, and hamsters
has been shown to act transplacentally, inducing tumors in the progeny
(Tomatis, 1973; Mohr, 1966; Druckrey, 1973a,b).
Peto et al. (1984) exposed groups of 48 Colworth rats/sex to
diethylnitrosamine in drinking water at 15 concentrations between 0.033 and
16.896 ppm. Six animals/group were sacrificed at 6 and at 12 months and the
remainder kept on treatment until natural death. Water consumption was 41 and
72 mL/kg for adult males and females. Data on tumor incidence was not
reported for each group, but data pooled by sex indicated positive trends for
tumors of the nasopharynx, lower jaw, stomach, kidney, ovaries, seminal
vesicles, liver, and esophagus. Dose-related increases in incidence of upper
GI tumors and liver cell tumors were observed in C57-BO mice, and tracheal and
liver cell tumors were observed in Syrian hamsters (Peto et al., 1984).
___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
Diethylnitrosamine is mutagenic for S. typhimurium, E. coli, and
Neurospora crassa, and produced mitotic recombination in S. cerevisiae,
recessive lethal mutations in D. melanogaster, and chromosomal aberrations in
mammalian cells. Positive responses in bacterial cells are dependent upon the
addition of a mammalian metabolic system (Montesano and Bartsch, 1976).
Diethylnitrosamine is structurally related to known carcinogens.
__II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
___II.B.1. SUMMARY OF RISK ESTIMATES
Oral Slope Factor -- 1.5E+2 per (mg/kg)/day
Drinking Water Unit Risk -- 4.3E-3 per (ug/L)
Extrapolation Method -- Weibull, extra risk
Drinking Water Concentrations at Specified Risk Levels:
Risk Level Concentration
-------------------- -------------
E-4 (1 in 10,000) 2E-2 ug/L
E-5 (1 in 100,000) 2E-3 ug/L
E-6 (1 in 1,000,000) 2E-4 ug/L
___II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE)
Tumor Type -- liver
Test Animals -- rat/Colworth, female
Route -- drinking water
Reference -- Peto et al., 1984
Specific tumor incidences were not published. Data from Peto et al.
(1984) on incidence of liver tumors of all types in female rats were shown to
follow this relationship:
CI = 32.09 (d + 0.04) **4 x t**7
where: CI = cumulative incidence
d = dose (mg/kg/day)
t = time in years
Using procedures described in U.S. EPA (1980) to correct for background
response, the increased risk associated with exposure to 1 ug/kg/day for 3
years = 2.27E-2, corresponding to a slope factor in rats of 22.7 per
(mg/kg)/day. The slope factor was calculated using the cube root of the ratio
of the assumed adult human weight of 70 kg and the reported rat weight of 250
g.
___II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE)
Peto et al. (1984) reported liver and esophageal tumors to be the only
treatment-related cause of death. The unit risk should not be used if the
water concentration exceeds 2 ug/L, since above this concentration the unit
risk may not be appropriate.
___II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE)
Although specific incidences were not reported, it appears that large
numbers of animals were observed for their lifetime. Tumor induction was
dose-related as regards both numbers of animals with tumors and latency. The
study was designed specifically for analysis using the Weibull model. A slope
factor calculated in the Ambient Water Quality Criteria Document for
Nitrosamines (U.S. EPA, 1980) based on data of Druckrey et al. (1963) was
43 per (mg/kg)/day, within a factor of 4 of the above risk estimate.
__II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
___II.C.1. SUMMARY OF RISK ESTIMATES
Inhalation Unit Risk -- 4.3E-2 per (ug/cu.m)
Extrapolation Method -- Weibull, extra risk
Air Concentrations at Specified Risk Levels:
Risk Level Concentration
-------------------- ---------------
E-4 (1 in 10,000) 2E-3 ug/cu.m
E-5 (1 in 100,000) 2E-4 ug/cu.m
E-6 (1 in 1,000,000) 2E-5 ug/cu.m
___II.C.2. DOSE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION EXPOSURE
The inhalation risk estimates were calculated from the oral exposure data
in II.B.2.
___II.C.3. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION EXPOSURE)
The unit risk should not be used if the air concentration exceeds 2E-1
ug/cu.m, since above this concentration the unit risk may not be appropriate.
___II.C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION EXPOSURE)
See II.B.4.
__II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
___II.D.1. EPA DOCUMENTATION
Source Document -- U.S. EPA, 1980, 1986
The values in the Health and Environmental Effects Profile for Nitrosamines
(U.S. EPA, 1986) received Agency review.
___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
Agency Work Group Review -- 07/23/1986, 08/13/1986, 10/29/1986
Verification Date -- 10/29/1986
___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
_VI. BIBLIOGRAPHY
Substance Name -- N-Nitrosodiethylamine
CASRN -- 55-18-5
Primary Synonym -- Diethylnitrosamine
Last Revised -- 03/01/1990
__VI.A. ORAL RfD REFERENCES
None
__VI.B. INHALATION RfC REFERENCES
None
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
Druckrey, H., A. Schildbach, D. Schmahl, R. Preussmann and S. Ivankovic.
1963. Quantitative analyse der carcinogen Wirking von Diathylnitrosamin.
Arzneimittel-Forsch. 13: 841-851.
Druckrey, H., R. Preussmann, S. Ivankovic and D. Schmaehl. 1967.
Organotropism and carcinogenic effects of 65 different N-nitroso compounds in
BD-rats. Z. Kerbsforsch. 69(2): 103-201.
Druckrey, H. 1973a. Chemical structure and action in transplacental
carcinogenesis and teratogenesis. IARC Sci. Publ., Lyon, France. No. 4. p.
45-58.
Druckrey, H. 1973b. Specific carcinogenic and teratogenic effects of
"indirect" alkylating methyl and ethyl compounds, and their dependency on
stages of oncogenic development. Xenobiotica. 3: 271.
Magee, P.N., R. Montesano and R. Preussman. 1976. N-Nitroso compounds and
related carcinogens. ACS Monograph. 173: 491-625.
Mohr, U., J. Althoff and A. Authaler. 1966. Diaplacental effect of the
carcinogen diethylnitrosamine in the golden hamster. Cancer Res. 26:
2349-2352.
Montesano, R. and H. Bartsch. 1976. Mutagenic and carcinogenic N-Nitroso
compounds: Possible environmental hazards. Mutat. Res. 32: 179-228.
Peto, R., R. Gray, P. Brantom and P. Grasso. 1984. Nitrosamine
carcinogenesis in 5120 rodents: Chronic administration of sixteen different
concentrations of NDEA, NDMA, NPYR and NPIP in the water of 4440 inbread rats,
with parallel studies on NDEA alone of the effect of age starting (3, 6 or 20
weeks) and of species (rats, mice, hamsters). IARC Sci. Publ., Lyon, France.
57: 627-665.
Rajewsky, M.F., W. Dauber and H. Frankenberg. 1966. Liver carcinogenesis by
diethylnitrosamine in the rat. Science. 152: 83-85.
Tomatis, L. 1973. Transplacental carcinogenesis. In: Modern Trends in
Oncology, Part I, R.W. Raven, Ed. Butterworths, London.
U.S. EPA 1980. Ambient Water Quality Criteria for Nitrosamines. Prepared by
the Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Water Regulations and
Standards, Washington, DC. EPA 440/5-80-064. NTIS PB 81-117756.
U.S. EPA. 1986. Health and Environmental Effects Profile for Nitrosamines.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste
and Emergency Response, Washington, DC.
Yamamoto, R.S., R. Kroes and J.H. Weisburger. 1972. Carcinogenicity of
diethylnitrosamine in Mystromys albicaudatus (African white-tailed rat).
(36573). Proc. Soc. Exp. Biol. Med. 140: 890.
_VII. REVISION HISTORY
Substance Name -- N-Nitrosodiethylamine
CASRN -- 55-18-5
Primary Synonym -- Diethylnitrosamine
-------- -------- --------------------------------------------------------
Date Section Description
-------- -------- --------------------------------------------------------
03/31/1987 IV. RQ added
09/30/1987 IV. Water Quality Criteria added
03/01/1988 II.A.1. Text clarified
03/01/1988 II.B.1. Number rounded off
03/01/1988 II.B.3. Text revised
03/01/1988 II.B.4. Confidence statement revised
03/01/1988 II.C.1. Number rounded off
03/01/1988 II.C.4. Confidence statement revised
03/01/1988 II.D.3. Secondary contact changed
02/01/1990 II.A.3. Rajewsky et al., 1966 spelling corrected
02/01/1990 VI. Bibliography on-line
03/01/1990 VI.C. Druckrey, Peto and Mohr reference titles clarified
01/01/1991 II. Text edited
01/01/1991 II.C.1. Inhalation slope factor removed (global change)
01/01/1992 IV. Regulatory actions updated
07/01/1993 II.D.3. Secondary contact's phone number changed
VIII. SYNONYMS
Substance Name -- N-Nitrosodiethylamine
CASRN -- 55-18-5
Primary Synonym -- Diethylnitrosamine
Last Revised -- 01/31/1987
55-18-5
DANA: DEN
DENA
diaethylnitrosamin
diethylamine, N-nitroso
Diethylnitrosamine
diethylnitrosoamine
ethylamine, N-nitrosodi-
NDEA
N-ethyl-N-nitroso-ethanamine
nitrosodiethylamine
Nitrosodiethylamine, N-
N,N-diethylnitrosamine
N-Nitrosodiethylamine
RCRA waste number U174
Last updated: 5 May 1998
URL: http://www.epa.gov/iris/SUBST/0042.HTM
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