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N-Nitrosopyrrolidine (CASRN 930-55-2)

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0081

N-Nitrosopyrrolidine; CASRN 930-55-2

Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data, as outlined in the IRIS assessment development process. Sections I (Health Hazard Assessments for Noncarcinogenic Effects) and II (Carcinogenicity Assessment for Lifetime Exposure) present the conclusions that were reached during the assessment development process. Supporting information and explanations of the methods used to derive the values given in IRIS are provided in the guidance documents located on the IRIS website.

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.

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_I.B. Reference Concentration for Chronic Inhalation Exposure (RfC)

Substance Name — N-Nitrosopyrrolidine
CASRN — 930-55-2

Not available at this time.

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_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.

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_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.

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_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.

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_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).

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_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

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_VI.B. Inhalation RfC References

None

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_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.

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_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.

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_VIII.  Synonyms

Substance Name — N-Nitrosopyrrolidine
CASRN — 930-55-2
Last Revised — 01/31/1987

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