National Toxicology Program

National Toxicology Program

Abstract for TR-67 - Mixture of Aspirin, Phenacetin, and Caffeine (CASRN 8003-03-0)

Bioassay of a Mixture of Aspirin, Phenacetin, and Caffeine for Possible Carcinogenicity
(CAS No. 8003-03-0)

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Chemical Formula:

APC, an abbreviation often used for mixtures of aspirin, phenacetin and caffeine, is a nonprescription analgesic preparation sold for relief of headache, muscular aches and pains, arthritis, and other common afflictions. APC is also antipyretic and anti-inflammatory and also acts as a central stimulant.

A bioassay of a mixture of aspirin, phenacetin, and caffeine (APC) for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. APC was administered in the feed, at either of two concentrations, to groups of 50 male and 49 or 50 female animals of each species. For each species, 50 animals of each sex were placed on test as controls. The high dose used in the chronic study for the male and female rats and mice was 1.4 percent. The low dose administered to the male and female rats and mice was 0.7 percent. After a 78-week period of compound administration, observation of the rats continued for up to an additional 35 weeks and observation of the mice continued for an additional 16 weeks.

No significant association was established between administration of APC and mortality in rats or female mice; however, there was a significant positive association between treatment and mortality in male mice. For both species the survival in all groups was adequate for statistical analysis of tumor incidence.

In rats, a variety of endocrine tumors were observed with greater frequency in the male rats treated with APC than in the male control rats. These same tumors were not observed with similar frequencies in the female rats or in the mice of either sex. The endocrine tumors observed most frequently in the treated male rats were adenomas and carcinomas of the pituitary gland. The incidences of these tumors proved to be statistically inconclusive.

In rats, a transitional-cell carcinoma of the bladder was observed in one low dose and one high dose females. A tubular-cell adenocarcinoma of the kidney was seen in one low dose female and one low dose male. A fifth neoplasm, a transitional-cell papilloma of the kidney, was seen in one high dose female. The occurrence of these urinary tumors, although considered important, was not statistically significant.

In mice, there was no statistically significant positive association between APC administration and the incidence of tumors in either sex.

Under the conditions of this bioassay evidence was not sufficient for the carcinogenicity of APC in Fischer 344 rats or in B6C3F1 mice.

Levels of Evidence of Carcinogenicity for Aspirin, Phenacetin, and Caffeine Mixture:
Sex SpeciesResults
Male Rats:Negative
Female Rats:Equivocal
Male Mice:Negative
Female Mice:Negative

Synonyms for APC: 2-(acetyloxy)-benzoic acid, mixture with N-(4-ethoxy-phenzl) acetamide and 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione
Synonym for aspirin: acetophenetidine
Synonym for phenacetin: p-acetophenetidide
Synonym for caffeine: theine, 1,3,7-trimethylxanthine

Report Date: 1978

Target Organs from 2-year Studies

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