International Agency for Research on Cancer (IARC) - Summaries & Evaluations
VOL.: 37 (1985) (p. 241)
CAS Nos: 80508-23-2; 16543-55-8; 84237-38-7
Chem. Abstr. Name: Pyridine, 3-(1-nitroso-2-pyrrolidinyl)-;
5. Summary of Data Reported and Evaluation
N'-Nitrosonornicotine (NNN) has been found in a variety of
tobacco products (chewing tobacco, snuff, cigarettes and cigars), in
mainstream and sidestream smoke from cigars and cigarettes, in saliva
of chewers of betel quid with tobacco and in saliva of oral-snuff
users. Some of the NNN in saliva appears to be formed endogenously
from nitrite in saliva and tobacco alkaloids. Thus, there is
widespread exposure to NNN among users of tobacco products and those
exposed to sidestream smoke.
5.2 Experimental data
NNN was tested for carcinogenicity in rats, mice and hamsters by
different routes of administration in multiple experiments. Following
its oral administration, NNN produced carcinomas of the upper
digestive tract, mainly the oesophagus, and of the nasal cavity in
rats and nasal-cavity tumours in hamsters. Following its
subcutaneous administration, NNN produced primarily tumours of the
nasal cavity in rats and tumours of the trachea in hamsters.
Intraperitoneal injection produced lung tumours in mice and tumours of
the nasal cavity and trachea in hamsters. There was evidence of a
dose-response relationship after subcutaneous administration of NNN to
Several metabolites of NNN were tested in mice by intraperitoneal
injection, producing lung tumours. NNN-1-N-oxide was also tested in
rats and hamsters by oral administration; it produced nasal-cavity and
oesophageal tumours in rats.
NNN is mutagenic to Salmonella typhimurium in the presence of an
exogenous metabolic system. It induces unscheduled DNA synthesis in
primary cultures of rat hepatocytes.
5.3 Human data
No case report or epidemiological study of the carcinogenicity of
NNN was available to the Working Group.
There is sufficient evidence for the carcinogenicity of
N'-nitrosonornicotine to experimental animals.
No data on humans were available.
For definition of the italicized terms, see Preamble Evaluation.
Previous evaluation: Vol. 17 (1978)
Subsequent evaluation: Suppl. 7 (1987) (p. 68: Group 2B)
Last updated: 21 April 1998