Valeric acid

Endpoint summary

Description of key information

A 14-day repeated dose dermal study in rabbits and a chronic skin painting study in mice are available for valeric acid. Both studies are considered to be invalid due to severe deficiencies in the methodology.

Additional information

In a 14 -day dermal toxicity study, valeric acid was applied to the shaved skin of New Zealand White rabbits (5 animals/sex/dose) at dose levels of 0 and 500 mg/kg bw and day, for 5 days/week during a 14-day period. The skin of 50 % of the animals (3 males and 2 females) was abraded. 3 of the 10 animals were selected as satellite group for a 2 weeks post exposure recovery period. All animals exhibited local skin effects (severe erythema, moderate to severe edema, necrosis, eschar formation and other skin reactions) by the second week of treatment. Dermal response subsided in animals held for recovery. With the exception of discolored gastric mucosa in some animals, no significant gross pathological findings were observed. Histological findings were related to the skin irritation of the test substance. Hematological, clinical, and urinary parameters were not examined as well as organ weights.

 

This dermal toxicity study in the rabbit is regarded to be not of acceptable reliability due to important deviations from the OECD TG 410 (low animal number, short treatment period, only one dose level tested, examinations limited).

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.

This chronic 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.

Justification for classification or non-classification

No classification for repeated exposure is warranted for valeric acid as the effects observed in the repeated dose dermal studies are secondary effects of corrosivity and the substance is already classified for corrosivity.