But-3-en-3-olide

Carcinogenicity

Description of key information

NOEL (single implantation, female rat): 1.1 mg/rat (highest dose tested; basic data only)
NOEL (s.c., once  weekly, 20 months, mouse): 1.1 mg/application (highest dose tested)
NOEL (s.c., once  weekly, lifespan, female rat): 4 mg/application (highest dose tested)
NOEL (dermal, three times weekly, lifespan, mouse): 122.5 mg/kg bw/d (highest dose tested)

Justification for classification or non-classification

Diketene does not have to be classified for carcinogenicity according to the criteria laid down in the EU Dangerous Substances Directive (67/548/EEC) and in the EU Classification Labelling and Packaging Regulation (1272/2008/EC) because in several carcinogenicity studies performed with rats and mice it did not show any carcinogenic effect.

Additional information

Several carcinogenicity studies were performed with Diketene:

- Subcutaneous implantation of Gelatine capsules containing 1.1 mg Diketene in 10 mg of Trilaurin-tricaprylin (4:1) were made in the left axillary region in rats. No tumors were observed 20 months after application.Diketene is inactive as a carcinogen in spite of its high chemical activity with nucleophilic and electrophilic reagents such as alcohols, aldehydes, amines, and ketones. This compound, which can be thought of as the anhydride of acetoacetic acid, hydrolyzes in water to this acid. In the presence of catalysts, this hydrolysis is rapid. This factor, combined with its chemical reactivity, may preclude its reaction at in vivo sites important for carcinogenesis. The hydrolysis rate constant for Diketene at 37 °C is given as 120 [min EE -1 X 10 EE 3].

- Subcutaneous injection of Diketene in mice with tricaprylin as vehicle, once weekly. 1.1 mg per injection. No tumors were observed after 20 months.

- Subcutaneous injection in female Sprague-Dawley rats.4 mg Diketene in 0.1 ml tricaprylin was subcutaneously injected once weekly in the left axillary area. The rats were examined regularly for palpable masses and their condition was recorded once a month. They were treated and observed for their lifspans (543 days). No local subcutaneous sarcomas were  found.

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- The backs of female ICR/Ha Swiss mice were freed of hair and applications of close to 100 mg of 10% solutions were made 3 times weekly onto the dorsal skin. Mice were individually weighed and observed regularly and their tumors were charted on appearance. At the time of death all animals were autopsied. All abnormal tissues and tumors were investigated microscopically. Diketene did not cause carcinogenic effects in this study. The lack of effect was so far seen on the rapid hydrolisis of the Diketene. The application of Diketene in Tricaprylin, in which hydrolisis presumably is slower, yielded however also no carcinogenic effects.

-  Male Swiss-Millerton mice were painted 3 times weekly with approx. 100 mg of a 10% Diketene in Acetone solution per application. The entire backs of the animals were painted and the hair clipped when necessary. 4 control groups with 3 times weekly painting of Benzene, Acetone, Benzo[a]pyrene, and no treatment were included . All tumors were excised at death and confirmed microscopically. The median survival time was 561 days. No tumors were observed.