Valeric acid

Carcinogenicity

Description of key information

A chronic dermal toxicity study in mouse is available for valeric acid.

Justification for classification or non-classification

With respect to the chemical structure of valeric acid and together with its corrosive action, it can be concluded that the initially observed weak carcinogenic potency results from skin repair mechanisms (treated skin showed ulceration, scar formation), rather than from an inherent carcinogenic potential of the substance. Hence, valeric acid should not be classified for carcinogenicity.

Additional information

In a carcinogenicity study, valeric acid was dermally administered twice weekly to 50 male C3H mice at dose levels of 0 (controls) and 25 mg/application for 80 weeks. For the first four application (first two weeks) the dose was 50 mg which was reduced to 25 mg due to apparent toxic effects of the test substance. There were two negative controls groups, one with no treatment, the other with application of vehicle only (50 mg of corn oil). A positive control group received 0.05% benzo(a)pyrene in mineral oil. In the valeric acid group marked pathological skin reactions (ulceration, scare formation) were observed. The mean survival time was reduced to 90 % compared to controls. The valeric acid treatment group showed average body weights below those of the negative controls throughout the study (approx. 83% at the termination or the study). The increased mortality was related to severe systemic toxicity. Tubular necrosis was seen in kidneys of 3 mice out of 19 examined; this lesion was not seen in controls (0/49). Regarding neoplasms, there was an increase in tumor incidence in treated animals (squamous cell carcinomas of the skin in 4 mice, fibrosarcomas in 6 mice, fibromas in 3 mice, and keratoacanthoma in 1 mouse, no statistical comparision to controls). Histopathological re-examintion revealed, however, that with the exception of 3 tumors the observed neoplasms were related to scar tissue or off the application site (Celanese/Kettering, 1985). With respect to the chemical structure of valeric acid and together with its corrosive action, it can be concluded that the initially observed weak carcinogenic potency results from skin repair mechanisms (treated skin showed ulceration, scar formation), rather than from an inherent carcinogenic potential of the substance. Therefore, a NOAEL of 400 mg/kg bw and day may be derived for carcinogenicity from this dermal mouse study. This carcinogenicity study in the mouse is assessed as not acceptable. The test system, i.e. chronic dermal aplication of a corrosive test substance, is not suitable and in accordance with the current OECD TG 451, because cutaneous exposure to valeric acid is not regraded to represent a main route of human exposure, and because corrosive test substances do not represent a suitable model system for induction of tumorigen skin lesions.

The main study is considered invalid due to significant methodological deficiencies: only one dose used which exceeded the maximum tolerated dose; significant mortality observed in control (48%) and treated animals (64%); abnormal skin observed in majority of no-treatment and mineral oil controls, identity of test material not verified; purity and stability of test material not specified.