Appendices 1-18 to: Report on the Health Effects of Selected Pesticide Coformulants

Appendices 1-18 to: Report on the Health Effects of Selected Pesticide Coformulants

126 Evaluation

The available toxicological data on cyclohexanone suggest that its critical effects are the irritant effect to the skin, the eyes and the respiratory tract, and the depressant effect on the central nervous system.

Cyclohexanone is absorbed by all routes of exposure. It is rapidly metabolised to cyclohexanol, which is either excreted in urine following conjugation with glucuronic acid or metabolised through the P450 oxidation system to cyclohexanediols, and then conjugated to their glucuronides and excreted in urine. The P450-oxidase function appears to be more important in humans than in animals.

Acute toxicity by inhalation is moderate, with LC₅₀-values ranging from 6200-32500 mg/m³ in rats after 4 hours of exposure. CNS depression has been reported in both humans and animals. The substance is classified in the EU as ’Harmful by inhalation’ (Xn;R20). The acute oral and dermal toxicity of cyclohexanone are in a similar range, with oral LD₅₀-values in rats between 1296 and 3460 mg/kg b.w and dermal LD₅₀-values in rabbits between 794 and 3160 mg/kg b.w. Cases of oral poisoning of humans have been reported.

The substance is irritating to eyes, nose and throat in humans from short-time exposure to 306 mg/m³. Skin irritation is also reported from repeated occupational exposure to 162-368 mg/m³ cyclohexanone. Results form animal studies vary from non-irritating to corrosive, but overall confirm that the substance is a skin and eye irritant following short term and long-term exposure.

Only one case of occupational allergic dermatitis has been reported. Sensitisation studies in guinea pigs and mice are negative. The sensitising potential of cyclohexanone is considered to be negligible.

Neurological symptoms in the central nervous system, including cognitive changes, were reported from long-term occupational exposure to cyclohexanone levels of 162-368 mg/m³. Impairment of the peripheric nervous system was also reported, but the robustness of the methodology was questioned, and the findings were not confirmed in animals. In animals, symptoms of CNS-depression were reported in studies in rats and in rabbits after short time and prolonged exposure.

No information on toxicity to reproduction in humans exposed to cyclohexanone was available.

In a two-generation study in rats, fertility of male rats was reported to be reduced at concentrations above 2040 mg/m³, but without details on the parameters leading to this evaluation. No other studies regarding fertility are available and thus, an evaluation of the effect of cyclohexanone on fertility is not possible on this basis.

In rats and mice, developmental toxicity (slight increase in the number of resorptions, skeletal and visceral malformations) was recorded to occur, but only at maternally toxic levels (irritation, CNS effects, reduced body weights). On the basis of the available database, it is considered that cyclohexanone is not a developmental toxicant.

A number of mutagenicity and genotoxicity tests on cyclohexanone have been performed. Most of the in vitro tests on cyclohexanone are negative. A few in vitro tests indicate that the substance may induce cytogenetic effects; these effects have only been reported in assays performed without an exogenous metabolic activation system suggesting that if cyclohexanone has a cytogenetic potential itself, this property disappears following metabolic degradation.

All in vivo studies but one, of poor quality, are negative.

Overall, the available data indicate that cyclohexanone is not a genotoxic or mutagenic substance.

In chronic studies in rats and in mice exposed orally to cyclohexanone in the drinking water, tumours were reported in the lymphatic tissue, the liver, and in the lungs in mice, and in the adrenals and in the thyroid in rats. Thyroid tumours were not considered relevant by the authors; thyroid tumours in rats may, in some cases, not be relevant for humans; however, as the tumourigenic mechanism for cyclohexanone is not elucidated, no conclusion can be drawn on this effect. Some of the other tumour-types found are also of questionable relevance for humans, and the lack of dose-response indicate that the substance is not carcinogenic in these studies. However, no conclusive evaluation on the carcinogenic effect of cyclohexanone can be performed on basis of the available data.

In conclusion, the available data on cyclohexanone indicate that the critical effects of cyclohexanone are CNS depression and irritation of the skin, the eyes and the respiratory tract.