For definition of Groups, see Preamble Evaluation.
Supplement 7: (1987) (p.310)
Chem. Abstr. Name: Acetamide, N-(4-ethoxyphenyl)-
A. Evidence for carcinogenicity to humans (limited for phenacetin; sufficient for analgesic mixtures containing phenacetin)
There have been many case reports of renal pelvic and other urothelial tumours in patients who had used large amounts of phenacetin-containing analgesics [ref: 1-13]. Case-control studies have been consistent in showing a positive association between cancer of the renal pelvis and cancer of the bladder and use of phenacetin-containing analgesics, with relative risks varying from 2.4 to over 6; these associations have not been explained by confounding with other causes of urothelial cancer and, where looked for, a positive dose-response relationship has been evident [ref: 14-19]. In one study [ref: 14], use of nonphenacetin-containing analgesics appeared to increase the risk of cancer of the renal pelvis to the same extent as did phenacetin-containing analgesics. This result was not obtained in other studies [ref: 15,17,18].
B. Evidence for carcinogenicity to animals (sufficient for phenacetin; limited for analgesic mixtures containing phenacetin)
Phenacetin given orally induced benign and malignant tumours of the urinary tract in mice [ref: 20] and rats [ref: 1,21] and of the nasal cavity in rats [ref: 1]. When given in combination with aspirin and caffeine to rats or mice, no significant association was found between the administration of the mixture and the incidence of tumours [ref: 1]. In rats, phenacetin alone or in combination with phenazone slightly increased the incidences of renal-cell and renal-pelvic tumours; rats treated with phenacetin, phenazone and caffeine in combination developed hepatomas [ref: 22]. In rats, phenacetin enhanced the incidence of urinary bladder tumours induced by N-nitrosobutyl-N-(4-hydroxybutyl)amine [ref: 1], and prevented the induction of hepatocellular carcinomas by 2-acetylaminofluorene [ref: 23].
C. Other relevant data
No data were available on the genetic and related effects of phenacetin in humans.
The results of studies on the induction of chromosomal aberrations, sister chromatid exchanges and micronuclei in rodents treated with phenacetin in vivo were equivocal. Phenacetin induced chromosomal aberrations in Chinese hamster cells in vitro but not DNA strand breaks in rat hepatocytes. It did not induce sex-linked recessive lethal mutations in Drosophila. Phenacetin was mutagenic to bacteria when tested in the presence of a metabolic system derived from hamster but not mouse or rat liver. The urine from phenacetin-treated Chinese hamsters, but not that from rats, was mutagenic to bacteria [ref: 24].
Phenacetin is probably carcinogenic to humans (Group 2A).
Analgesic mixtures containing phenacetin are carcinogenic to humans (Group 1).
For definition of the italicized terms, see Preamble Evaluation.
Also see previous evaluations: Vol. 13 (1977); Vol. 24 (1980)
1. IARC Monographs, 24, 135-161, 1980
2. Christensen, T.E. & Ladefoged, J. (1979) Carcinomata in the urinary tract in patients with contracted kidneys and massive abuse of analgesics (phenacetin) (Dan.). Ugeskr. Laeg., 141, 3522-3524
3. Gonwa, T.A., Corbett, W.T., Schey, H.M. & Bukalew, V.M., Jr (1980) Analgesic-associated nephropathy and transitional cell carcinoma of the urinary tract. Ann. intern. Med., 93, 249-252
4. Mihatsch, M.J., Manz, T., Knüsli, C., Hofer, H.O., Rist, M., Guetg, R., Rutishauser, G. & Zollinger, H.U. (1980) Phenacetin abuse. III. Malignant urinary tract tumours with phenacetin abuse in Basel, 1963-1977 (Ger.). Schweiz. med. Wochenschr., 110, 255-264
5. Orell, S.R., Nanra, R.S. & Ferguson, N.W. (1979) Renal pelvic carcinoma in the Hunter Valley. Med. J. Aust., 524, 555-557
6. Blohmé, I. & Johansson, S. (1981) Renal pelvic neoplasms and atypical urothelium in patients with end-stage analgesic nephropathy. Kidney int., 20, 671-675
7. Syré, G. & Matejka, M. (1981) Phenacetin abuse and renal pelvis carcinomas (Ger.). Wien. klin. Wochenschr., 93, 420-423
8. Porpáczy, P. & Schramek, P. (1981) Analgesic nephropathy and phenacetin-induced transitional cell carcinoma - analysis of 300 patients with long-term consumption of phenacetin-containing drugs. Eur. Urol., 7, 349-354
9. Mihatsch, M.J., Brunner, F.P., Korteweg, E., Rist, M., Dalquen, P. & Thiel, G. (1982) Phenacetin abuse. VII. Tumours of the urinary tract in haemodialysis and kidney transplant patients (Ger.). Schweiz. med. Wochenschr., 112, 1468-1472
10. Novák, J. & Zidek, I. (1983) Phenacetin as a carcinogen for the renal pelvis (Czech.). Cas. Lék. ces., 122, 1149-1152
11. Mihatsch, M.J. & Knüsli, C. (1982) Phenacetin abuse and malignant tumors. An autopsy study covering 25 years (1953-1977). Klin. Wochenschr., 60, 1339-1349
12. Marek, J. & Hradec, E. (1985) Chronic sclerosing ureteritis and nephrogenic adenoma of the ureter in analgesic abuse. Pathol. Res. Pract., 180, 569-573
13. Kliment, J. (1979) Renal pelvis tumours and abuse of analgesics (Czech.). Bratisl. lék. Listy, 72, 641-764
14. McCredie, M., Ford, J.M., Taylor, J.S. & Stewart, J.H. (1982) Analgesics and cancer of the renal pelvis in New South Wales. Cancer, 49, 2617-2625
15. McCredie, M., Stewart, J.H., Ford, J.M. & MacLennan, R.A. (1983) Phenacetin-containing analgesics and cancer of the bladder or renal pelvis in women. Br. J. Urol., 55, 220-224
16. McCredie, M., Stewart, J.H. & Ford, J.M. (1983) Analgesics and tobacco as risk factors for cancer of the ureter and renal pelvis. J. Urol., 130, 28-30
17. McLaughlin, J.K., Mandel, J.S., Blot, W.J., Schuman, L.M., Mehl, E.S. & Fraumeni, J.F., Jr (1984) A population-based case-control study of renal cell carcinoma. J. natl Cancer Inst., 72, 275-284
18. Piper, J.M., Tonascia, J. & Matanoski, G.M. (1985) Heavy phenacetin use and bladder cancer in women aged 20 to 49 years. New Engl. J. Med., 313, 292-295
19. Piper, J.M., Matanoski, G.M. & Tonascia, J. (1986) Bladder cancer in young women. Am. J. Epidemiol., 123, 1033-1042
20. Nakanishi, K., Kurata, Y., Oshima, M., Fukushima, S. & Ito, N. (1982) Carcinogenicity of phenacetin: long-term feeding study in B6C3F1 mice. Int. J. Cancer, 29, 439-444
21. Muradyan, R.Y. (1986) Experimental studies of phenacetin carcinogenicity (Russ.). Vopr. Onkol., 32, 63-70
22. Johansson, S.L. (1981) Carcinogenicity of analgesics: Long-term treatment of Sprague-Dawley rats with phenacetin, phenazone, caffeine and paracetamol (acetamidophen). Int. J. Cancer, 27, 521-529
23. Yamamoto, R.S., Frankel, H.H. & Weisburger, E.K. (1979) Effect of phenacetin and N-alkylacetanilides on N-2-fluorenylacetamide hepatocarcinogenesis. Cancer Lett., 8, 183-188
24. IARC Monographs, Suppl. 6, 448-450, 1987
Synonyms for Phenacetin
See Also: Toxicological Abbreviations