For definition of Groups, see Preamble Evaluation.
Supplement 7: (1987) (p.248)
CAS No.:
A. Evidence for carcinogenicity to humans (inadequate)
Three cases of brain tumour (gliomas) and one of colon cancer have been reported from a genetics laboratory over a 13-year period. All the subjects were likely to have been exposed to MNNG for at least six to 15 years prior to death, but other carcinogens had been used in the laboratory [ref: 1,2].
B. Evidence for carcinogenicity to animals (sufficient)
MNNG has been tested for carcinogenicity in mice, rats, hamsters, rabbits and dogs, producing tumours at many sites. It has a predominantly local carcinogenic effect and is carcinogenic in single-dose experiments. Following its oral administration, papillomas and squamous-cell carcinomas of the oesophagus and forestomach, adenocarcinomas of the stomach, small intestine and large bowel, and sarcomas of the gastrointestinal tract were reported [ref: 3]. These findings have been extended in more recent studies after oral administration to rats [ref: 4-7], hamsters [ref: 8,9] and dogs [ref: 10,11]. After subcutaneous injection in mice, it produced lung and liver tumours and haemangioendotheliomas [ref: 12]; after intrarectal instillation in rats and guinea-pigs [ref: 13-15] and after intrauterine and intravaginal application to rats, it produced local tumours [ref: 16].
C. Other relevant data
MNNG is an alkylating agent [ref: 17]. No data were available to evaluate the genetic and related effects of this compound in humans.
MNNG induced DNA strand breaks in various organs of rats treated in vivo. It did not cause dominant lethal mutations in mice, but it gave positive results for mutation in the mouse spot test; it induced chromosomal aberrations and micronuclei in bone-marrow cells of mice and sister chromatid exchanges in bone-marrow cells of mice and Chinese hamsters treated in vivo. It induced chromosomal aberrations, sister chromatid exchanges, DNA strand breaks and unscheduled DNA synthesis in human and rodent cells in vitro and induced mutation in cultured rodent cells. It gave positive results in several assays for cell transformation. MNNG induced somatic and sex-linked recessive lethal mutations in Drosophila. It caused chromosomal aberrations, sister chromatid exchanges and mutation in plants and recombination and mutation in fungi. It was mutagenic to and caused DNA damage in bacteria, and gave positive results in host-mediated assays using bacteria or yeast as indicators and mice as hosts [ref: 17].
Overall evaluation
N-Methyl-N'-Nitro-N-Nitrosoguanidine (MNNG) is probably carcinogenic to humans (Group 2A).
For definition of the italicized terms, see Preamble Evaluation.
Also see previous evaluation: Vol. 4 (1974)
References
1. Pleven, C., Audran, R., Falcy, M., Efthymiou, M.-L. & Philbert, M. (1983) Glioblastomas and chemical mutagenesis in biology laboratories. Report of 3 deaths in the same institute (Fr.). Arch. Mal. prof., 44, 411-418
2. Pleven, C., Falcy, M., Audran, R., Philbert, M. & Efthymiou, M.L. (1984) Occurrence of glioblastomas in people working in research laboratories using nitroso compounds (Fr.). J. Toxicol. med., 4, 249-257
3. IARC Monographs, 4, 183-195, 1974
4. Martin, M.S., Martin, F., Justrabo, E., Michiels, R., Bastien, H. & Knobel, S. (1974) Susceptibility of inbred rats to gastric and duodenal carcinomas induced by N-methyl-N'-nitro-N-nitrosoguanidine. J. natl Cancer Inst., 53, 837-840
5. Kartasheva, L.A. & Bykorez, A.J. (1975) Induction of adenocarcinomas of the stomach in rats by N-methyl-N'-nitroso-N-nitroguanidine (Russ.). Vopr. Onkol., 21, 50-55
6. Habs, M., Deutsch-Wenzel, R., Preussmann, R. & Schmahl, D. (1978) Induction of gastric tumors in BD-IV rats by single application of N-methyl-N'-nitro-N-nitrosoguanidine. Z. Krebsforsch., 91, 183-188
7. Sherenesheva, N.I. (1979) Induction of gastrointestinal tumours in rats by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) (Russ.). Vopr. Onkol., 25, 72-74
8. Kogura, K., Sasadaira, H., Kawachi, T., Shimosato, Y., Tokunaga, A., Fujimura, S. & Sugimura, T. (1974) Further studies on induction of stomach cancer in hamsters by N-methyl-N'-nitro-N-nitrosoguanidine. Br. J. Cancer, 29, 132-142
9. Ketkar, M., Reznik, G. & Green, U. (1978) Carcinogenic effect of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in European hamsters. Cancer Lett., 4, 241-244
10. Fujita, M., Taguchi, T., Takami, M., Usugane, M., Takahashi, A. & Shiba, S. (1974) Carcinoma and related lesion in dog stomach induced by oral administration of N-methyl-N'-nitro-N-nitrosoguanidine. Gann, 65, 207-214
11. Koyama, Y., Omori, K., Hirota, T., Sano, R. & Ishihara, K. (1976) Leiomyosarcomas of the small intestine induced in dogs by N-methyl-N'-nitro-N-nitrosoguanidine. Gann, 67, 241-251
12. Fujii, K. & Nakadate, M. (1977) Tumor induction by a single subcutaneous injection of N-methyl-N'-nitro-N-nitrosoguanidine and its derivatives in newborn mice. Z. Krebsforsch., 90, 313-319
13. Nakano, H. (1973) Histopathological studies on rat colo-rectal carcinoma induced by N-methyl-N'-nitro-N-nitrosoguanidine. Tokohu J. exp. Med., 110, 7-21
14. Chlap, Z. & Przewlocki, F. (1979) A study of colon cancer in rats after rectal administration of N-methyl-N'-nitro-N-nitrosoguanidine (Pol.). Pat. Pol., 30, 475-488
15. Narisawa, T., Wong, C.Q. & Weisburger, J.H. (1976) Large bowel carcinoma in strain-2 guinea pigs by intrarectal instillation of N-methyl-N'-nitro-N-nitrosoguanidine. Gann, 67, 41-46
16. Tanaka, T. & Mori, H. (1983) Experimental induction of uterine cancer in rats by N-methyl-N'-nitro-N-nitrosoguanidine. Pathol. Res. Pract., 178, 20-26
17. IARC Monographs, Suppl. 6, 394-398, 1987
See Also:
Toxicological Abbreviations