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N-Nitroso-N-methylethylamine
CASRN 10595-95-6
Contents
0179
N-Nitroso-N-methylethylamine; CASRN 10595-95-6
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-Nitroso-N-methylethylamine
File On-Line 03/31/1987
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-Nitroso-N-methylethylamine
CASRN -- 10595-95-6
Not available at this time.
__I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
Substance Name -- N-Nitroso-N-methylethylamine
CASRN -- 10595-95-6
Not available at this time.
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name -- N-Nitroso-N-methylethylamine
CASRN -- 10595-95-6
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 -- Increased incidence of tumors of the liver and other sites in two
rat strains
___II.A.2. HUMAN CARCINOGENICITY DATA
Inadequate. 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 are of limited use in the evaluation of carcinogenicity of individual
nitrosamines.
___II.A.3. ANIMAL CARCINOGENICITY DATA
Sufficient. As part of a survey of 65 N-nitroso compounds, Druckrey et
al. (1967) administered N-nitrosomethylethylamine to 4 or 11 BD rats in
drinking water at doses of 1 or 2 mg/kg/day, respectively. Treatment was
continuous for life. A total of 9/15 rats developed hepatocellular carcinomas
with average induction times and total doses to produce tumors in 50% of the
animals of 500 days and 0.42 g/kg for the low-dose group and 360 days and 0.75
g/kg for the high-dose group.
Male and female F344 rats receiving 3.0 mg N-nitrosomethylethylamine/day
in drinking water for 30 weeks showed a high incidence of hepatocellular
carcinomas (19/20) as well as lung metastases and esophageal papillomas or
carcinomas (Lijinsky and Reuber, 1981). Male rats receiving 600 ug or 3000
ug/week in drinking water for 30 weeks likewise developed tumors: 3/20
hepatocellular carcinomas in the low-dose group and 12/20 hepatocellular
carcinomas, nasal tumors and esophageal papillomas in the high-dose group
(Lijinsky and Reuber, 1980). Tumors of the liver (9/20) and nasal cavity
(4/20) were also observed in male F344 rats receiving approximately 0.12
mg/rat/day in drinking water over a 30-week period (Lijinsky et al., 1982).
By contrast, female rats receiving drinking water containing 6 mg N-nitroso-
methylethylamine/L developed leukemias (18/20 as compared with 12/20 in
controls) as the only observed treatment-related neoplastic response (Lijinsky
and Reuber, 1983). Michejda et al. (1984) reported that all of a group of 20
F344 rats administered 8 mg/kg N-nitrosomethylethylamine in drinking water for
15 weeks had died of liver tumors with a median time to death of 45 weeks.
___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
N-nitrosomethylethylamine is mutagenic to Salmonella typhimurium
(Kerklaan et al., 1983; Phillipson and Ioannides, 1985) and to V79 cells
(Jones and Huberman, 1980).
__II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
___II.B.1. SUMMARY OF RISK ESTIMATES
Oral Slope Factor -- 2.2E+1/mg/kg/day
Drinking Water Unit Risk -- 6.3E-4/ug/L
Extrapolation Method -- One-hit
Drinking Water Concentrations at Specified Risk Levels:
Risk Level Concentration
-------------------- -------------
E-4 (1 in 10,000) 2E-1 ug/L
E-5 (1 in 100,000) 2E-2 ug/L
E-6 (1 in 1,000,000) 2E-3 ug/L
___II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE)
Tumor Type -- hepatocellular carcinomas
Test Animals -- Rat/BD, sex not specified
Route -- drinking water
Reference -- Druckrey, 1967; Druckrey et al., 1967
Information in the references cited was used in quantitation of risk using the
following relationship:
Ck/(t50)** n = d
where: C = conversion between mmol and mg = 88.1 mg/mmol
k = empirically derived constant = 0.81E+4 mmol/kg/day
t50 = median time of tumor induction = 728
n = representative value for dialkylnitrosamines as published by
Druckrey = 2.3
d = daily dose of test compound, calculated from the above to be
0.18645 mg/kg/day
The slope factor for rats (BA) was calculated from a rearrangement of the one-
hit model:
BA = -ln (0.5/day) = 3.72/mg/kg/day
Adjusting this value by the cube root of the assumed human body weight (70 kg)
to the assumed rat body weight (0.35 kg) gives the human slope factor
21.8/mg/kg/day.
___II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE)
A reported value of n=2.1 for N-nitrosomethylethylamine was not used in
the calculations, since a k value for this n was not reported.
The unit risk should not be used if the water concentration exceeds 20
ug/L, since above this concentration the slope factor may differ from that
stated.
___II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE)
Small numbers of rats were treated at only two doses, and there was no
control group.
__II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
Not available.
__II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
___II.D.1. EPA DOCUMENTATION
Source Document -- U.S. EPA, 1986
The values in the 1986 Health and Environmental Effects Profile have received
an Agency review.
___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
Agency Work Group Review -- 02/11/1987
Verification Date -- 02/11/1987
___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-Nitroso-N-methylethylamine
CASRN -- 10595-95-6
Last Revised -- 12/01/1989
__VI.A. ORAL RfD REFERENCES
None
__VI.B. INHALATION RfD REFERENCES
None
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
Druckrey, H. 1967. Quantitative aspects in chemical carcinogens. In:
Potential Carcinogenic Hazards from Drugs. UICC Monograph, Series 7. Berlin
Springer-Verlag. p. 60-78.
Druckrey, H., R. Preussmann, S. Ivankovic and D. Schmael. 1967. Organotropic
carcinogenic effects of 65 different N-Nitroso-compounds on BD-rats. Z.
Kerbsforsch. 69(2): 103-201.
Jones, C.A. and E. Huberman. 1980. A sensitive hepatocyte-mediated assay for
the metabolism of nitrosamines to mutagens for mammalian cells. Cancer Res.
40(2): 406-411.
Kerklaan, P., S. Bouter and G. Mohn. 1983. Activation of nitrosamines and
other carcinogens by mouse-liver S9, hepatocytes and in the hostmediated assay
produces different mutagenic responses in salmonella. Mutat. Res. 110(1):
9-22.
Lijinsky, W. and M.D. Reuber. 1980. Carcinogenicity in rats nitroso-
methylethylamines labeled with deuterium in several postions. Cancer Res.
40(1): 19-21.
Lijinsky, W. and M.D. Reuber. 1981. Comparative carcinogenesis by some
aliphatic nitrosamines in Fischer rats. Cancer Lett. 14(3): 297-302.
Lijinsky, W. and M.D. Reuber. 1983. Carcinogens in Fischer rats by
nitrosodipropylamine, nitrosodibutylamine and nitrosobis(2-oxopropyl)amine
given by gavage. Cancer Lett. 19: 207-213.
Lijinsky, W., J.E. Saavedra, M.D. Reuber, et al. 1982. Esophageal
carcinogenesis in F344 rats by nitrosomethylethylamines SUBSTituted in the
ethyl group. J. Natl. Cancer Inst. 68(4): 681-684.
Michejda, C.J., M.B. Krueger-Koepke and R.M. Kovatch. 1984. Carcinogenic
effects of sequential administration of two nitrosamines to rats. Proc. of
AACR. 25: 126.
Phillipson, C.E. and C. Ioannides. 1985. Metabolic activation of
nitrosamines to mutagens by various animal species including man. Biochem.
Pharmacol. 34(3): 441-442.
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.
_VII. REVISION HISTORY
Substance Name -- N-Nitroso-N-methylethylamine
CASRN -- 10595-95-6
-------- -------- --------------------------------------------------------
Date Section Description
-------- -------- --------------------------------------------------------
03/01/1988 II.B.1. Oral unit risk changed
03/01/1988 II.B.4. Confidence statement revised
03/01/1988 II.D.3. Contacts switched
12/01/1989 II.A.3. Lijinsky et al. (1983) changed - Lijinsky&Reuber, 1983
12/01/1989 VI. Bibliography on-line
01/01/1992 IV. Regulatory actions updated
07/01/1993 II.D.3. Secondary contact's phone number changed
VIII. SYNONYMS
Substance Name -- N-Nitroso-N-methylethylamine
CASRN -- 10595-95-6
Last Revised -- 03/31/1987
10595-95-6
Ethanamine, N-methyl-N-nitroso-
Ethylamine, N-methyl-N-nitroso-
Ethylmethylnitrosamine
Methylethylnitrosamine
Methylethylnitrosoamine
Nitrosomethylethylamine
Nitroso-N-methylethylamine, N-
N-Methyl-N-nitrosoethanamine
N-Methyl-N-nitrosoethylamine
N-Nitrosoethylmethylamine
N-Nitrosomethylethylamine
N-Nitroso-N-methylethylamine
Last updated: 5 May 1998
URL: http://www.epa.gov/iris/SUBST/0179.HTM
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