N-Nitrosopyrrolidine (CASRN 930-55-2)
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0081
N-Nitrosopyrrolidine;
CASRN 930-55-2
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-Nitrosopyrrolidine
File First 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 | 02/01/1994 |
_I. Chronic Health Hazard Assessments for Noncarcinogenic Effects
_I.A. Reference Dose for Chronic Oral Exposure (RfD)
Substance Name — N-Nitrosopyrrolidine
CASRN — 930-55-2
Not available at this time.
_I.B. Reference Concentration for Chronic Inhalation Exposure (RfC)
Substance Name — N-Nitrosopyrrolidine
CASRN — 930-55-2
Not available at this time.
_II. Carcinogenicity Assessment for Lifetime Exposure
Substance Name — N-Nitrosopyrrolidine
CASRN — 930-55-2
Last Revised — 02/01/1994
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 µg/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 Human Carcinogenicity
__II.A.1. Weight-of-Evidence Characterization
Classification — B2; probable human carcinogen
Basis — Tumors at more than one site have been observed in two rodent species administered nitrosopyrrolidine orally.
__II.A.2. Human Carcinogenicity Data
None. 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 these exposures is of limited use in the evaluation of the carcinogenicity of individual nitrosamines.
__II.A.3. Animal Carcinogenicity Data
There is a large database on the carcinogenicity of nitrosamines, most of which pertains to structure-activity relationships rather than to dose- response. Nitrosopyrrolidine produced a 100% incidence of liver carcinomas in MRC rats given an oral dose of 16 mg/kg/day. Male rats also developed papillary mesotheliomas of the testes (Greenblatt and Lijinsky, 1972a). Exposure in drinking water of 0.25 mg (7-8 mg/kg/day) induced a low incidence of lung adenomas in male and female Swiss mice (Greenblatt and Lijinsky, 1972b). Druckrey (1967) noted hepatocarcinogenicity in BD rats fed 10-20 mg/kg/day in the diet.
Equal numbers (12-31) of male and female Sprague-Dawley rats were maintained on water formulated to deliver 0, 0.3, 1, 3, or 10 mg/kg bw/day nitrosopyrrolidine (Preussmann et al., 1977). Animals remained on treatment until they died or became moribund. There was no statistically significant increase in numbers of tumors in the lowest dose group. Dose-related increases in hepatocellular carcinomas and adenomas were observed. Latency periods were also diminished with increasing dose.
__II.A.4. Supporting Data for Carcinogenicity
N-nitrosopyrrolidine is mutagenic for Salmonella typhimurium upon addition of mammalian metabolic enzymes (Montesano and Bartsch, 1976). It is structurally related to carcinogenic nitrosamines.
_II.B. Quantitative Estimate of Carcinogenic Risk from Oral Exposure
__II.B.1. Summary of Risk Estimates
Oral Slope Factor — 2.1E+0 per (mg/kg)/day
Drinking Water Unit Risk — 6.1E-5 per (ug/L)
Extrapolation Method — Linearized multistage procedure, extra risk
Drinking Water Concentrations at Specified Risk Levels:
Risk Level |
Concentration
|
---|---|
E-4 (1 in 10,000) |
2E+0 ug/L |
E-5 (1 in 100,000) |
2E-1 ug/L |
E-6 (1 in 1,000,000) |
2E-2 ug/L |
__II.B.2. Dose-Response Data (Carcinogenicity, Oral Exposure)
Tumor Type — hepatocellular carcinoma and adenoma
Test Animals — Rat/Sprague-Dawley, male and female
Route — diet
Reference — Preussmann et al., 1977
Admin. Dose
(mg/kg/day) |
Human Equiv. Dose (mg/kg/day) |
Tumor Incidence |
---|---|---|
0 |
0 |
0/61 |
0.3 |
0.051 |
3/60 |
1.0 |
0.17 |
17/62 |
3.0 |
0.51 |
31/38 |
10.0 |
1.70 |
14/24 |
__II.B.3. Additional Comments (Carcinogenicity, Oral Exposure)
There was increased mortality because of pneumonia in the highest dose group. Preussmann et al. (1977) indicated that increased susceptibility to respiratory infection may have been due to cumulative nitrosopyrrolidine toxicity.
The unit risk should not be used if water concentrations exceed 200 ug/L, since above this concentration the unit risk may not be appropriate.
__II.B.4. Discussion of Confidence (Carcinogenicity, Oral Exposure)
Tumor incidence was shown to be dependent on the nitrosopyrrolidine dose in the study above. Adequate numbers of animals were treated and observed for their normal lifetime at several lower doses. As incidences of benign and malignant growths were added, it is not possible to ascertain whether any animals were counted more than once.
_II.C. Quantitative Estimate of Carcinogenic Risk from Inhalation Exposure
__II.C.1. Summary of Risk Estimates
Inhalation Unit Risk — 6.1E-4 per (µg/cu.m)
Extrapolation Method — Linearized multistage procedure, extra risk
Air Concentrations at Specified Risk Levels:
Risk Level |
Concentration
|
---|---|
E-4 (1 in 10,000) | 2E-1 µg/cu.m |
E-5 (1 in 100,000) | 2E-2 µg/cu.m |
E-6 (1 in 1,000,000) | 2E-3 µg/cu.m |
__II.C.2. Dose-Response Data for Carcinogenicity, Inhalation Exposure
The inhalation risk estimates were calculated from the oral exposure data in Section II.B.2.
__II.C.3. Additional Comments (Carcinogenicity, Inhalation Exposure)
The unit risk should not be used if air concentrations exceed 20 µg/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 Ambient Water Quality Criteria Document for Nitrosamines (U.S. EPA, 1980) received extensive peer and public review.
__II.D.2. EPA Review (Carcinogenicity Assessment)
Agency Work Group Review — 07/23/1986, 10/14/1986, 10/29/1986
Verification Date — 10/14/1986
Screening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the cancer assessment for N-Nitrosopyrrolidine conducted in November 2001 identified one or more significant new studies. IRIS users may request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or (202)566-1676.
__II.D.3. EPA Contacts (Carcinogenicity Assessment)
Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (202)566-1676 (phone), (202)566-1749 (FAX) or hotline.iris@epa.gov (internet address).
_III.
[reserved]
_IV. [reserved]
_V. [reserved]
_VI. Bibliography
Substance Name — N-Nitrosopyrrolidine
CASRN — 930-55-2
Last Revised — 03/01/1990
_VI.A. Oral RfD References
None
_VI.B. Inhalation RfC References
None
_VI.C. Carcinogenicity Assessment References
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.
Greenblatt, M. and W. Lijinsky. 1972a. Nitrosamine studies: Neoplasms of liver and genital mesothelium in nitrosopyrrolidine-treated MRC rats. J. Natl. Cancer Inst. 48(6): 1687-1696.
Greenblatt, M. and W. Lijinsky. 1972b. Failure to induce tumors in Swiss mice after concurrent administration of amino acids and sodium nitrite. J. Natl. Cancer Inst. 48(5): 1389-1392.
Montesano, R. and H. Bartsch. 1976. Mutagenic and carcinogenic N- nitroso compounds: Possible environmental Hazards. Mutat. Res. 32: 179-228.
Preussmann, R., D. Schmahl and G. Eisenbrand. 1977. Carcinogenicity of N-nitrosopyrrolidine: Dose-response study in rats. Z. Krebsforsch. 90: 161-166.
U.S. EPA. 1980. Ambient Water Quality Criteria Document 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.
_VII. Revision History
Substance Name — N-Nitrosopyrrolidine
CASRN — 930-55-2
Date |
Section |
Description |
---|---|---|
03/31/1987 | IV. | RQ 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 |
02/01/1990 | VI. | Bibliography on-line |
03/01/1990 | VI.C. | Druckrey et al., 1967 title 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 |
08/01/1993 | II.D.2. | Missing work group review date added |
02/01/1994 | II.D.3. | Secondary contact's phone number changed |
08/01/1995 | II.D.2. | EPA's RfD/RfC and CRAVE workgroups were discontinued in May, 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995. |
04/01/1997 | III., IV., V. | Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. |
12/03/2002 | II.D.2. | Screening-Level Literature Review Findings message has been added. |
_VIII. Synonyms
Substance Name — N-Nitrosopyrrolidine
CASRN — 930-55-2
Last Revised — 01/31/1987
- 930-55-2
- 1-nitrosopyrrolidine
- Nitrosopyrrolidine, N-
- N-Nitrosopyrrolidine
- N-N-pyr
- NO-pyr
- NPYR
- Pyrrole, tetrahydro-N-nitroso-
- pyrrolidine, 1-nitroso-
- RCRA waste number U180