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

125     Summary

125.1     Description

Cyclohexanone is a colourless or pale yellow liquid. It is has a vapour pressure of 3.38 mmHg and is moderately soluble in water (80 g/l at 20°C).

125.2     Toxicokinetics

Cyclohexanone is absorbed by all three routes of exposure. The substance is rapidly metabolised to cyclohexanol by alcohol dehydrogenase. In humans, the main part is then hydroxylated through the mixed microsomal P-450 function, the resulting cyclohexanedioles conjugated with glucuronic acid. Cyclohexanol may also be conjugated directly and excreted as cyclohexanol glucuronide. Excretion is mainly in urine, with biliary and lung excretion also playing a role.

In a case of acute poisoning, no urinary diol-conjugates, but large amounts of cyclohexanol glucuronides were found. In babies, cyclohexanol was excreted and no conjugates were found in urine.

Animals also metabolise cyclohexanone to cyclohexanol, but they form less diols and thus primarily excrete cyclohexanol glucuronides.

125.3     Human toxicity

CNS effects and metabolic acidosis have been recorded after accidental ingestion of cyclohexanone.

Exposure of workers to 150 - 630 mg/m³ cyclohexanone for 4 years in mixed exposure with other solvents affected the memory and alertness of the workers. Workers in a furniture factory exposed to 162 - 368 mg/m³ cyclohexanone for 14 years reported CNS symptoms (memory and personality alterations) and measurements of periferic nerve conductivity indicated decreased function.

Cyclohexanone is an eye, nose and throat irritant following inhalation of 306 mg/m³ for a few minutes; a concentration of 102 mg/m³ was reported as being tolerable. Cyclohexanone was also reported to be irritating to the eyes, respiratory tract and the skin following occupational exposure to 162 - 368 mg/m³ for 14 years.

One reference has reported a case of sensitisation from occupational exposure to pure cyclohexanone. In another reference, it was reported that cyclohexanone is not sensitising to man, whereas resin of cyclohexanone caused allergic contact dermatitis in 5 painters.

No data on toxicity to reproduction, mutagenicity and genotoxicity, or carcinogenicity were found.

125.4     Animal toxicity

125.4.1     Single dose toxicity

LC₅₀-values reported for rats range from above 6200 to 32500 mg/m³ for 4 hours of exposure. Symptoms of irritation and narcosis were recorded at sub-lethal concentrations.

Oral LD₅₀-values are reported to be between 1296 and 3460 mg/kg b.w. in rats and between 1400 to 3200 mg/kg b.w. in mice. Minimal lethal doses in rabbits were reported to be 1600-1900 mg/kg b.w. Narcosis was reported in rats, mice and rabbits, and damage in the major organs were reported in rabbits as well.

Reported dermal LD₅₀-values for rabbits range from 794 to 3160 mg/kg b.w.

Reports on the skin irritative potential of cyclohexanone vary from non-irritating to corrosive. One study including more details reports cyclohexanone to be a skin irritant with a dose-response relationship in an occlusive test in rabbits.

Eye irritation is reported to be moderate to severe in rabbits eye; concentration dependency of the irritation was demonstrated in a study resulting in severe injury from instillation of 0.02 ml.

Cyclohexanone was not sensitising in the Guinea Pig Maximisation Test and in the Mouse Ear Swelling Test.

125.4.2     Repeated dose toxicity

Continous inhalation exposure of young rats to 8.2 mg/m³ and of adult rats to 32.6 mg/m³ cyclohexanone for 7 or 10 weeks, respectively, resulted in morphological changes of cells in the olfactory bulbs. Rabbits exposed by inhalation to 12120 mg/m³ cyclohexanone for 3 weeks had CNS depression; 2 of the 4 animals died. Irritation of the eyes and respiratory tract were reported from exposure levels of 1210 mg/m³ and the effect was marked from 3082 mg/m³.

Exposure of rats for 6 months in the drinking water at doses up to 6500 mg/l/day (1000 mg/kg b.w./day) caused weight gain depression at the top dose and mild thyroid gland degeneration at 4700 mg/l (660 mg/kg b.w./day).

In a 13-week mice study with concentrations up to 47000 mg/l in the drinking water, 1/3 of the female mice and 2/3 of the male mice of the high dose died. Pathological examination revealed liver necrosis in both sexes and thymus hyperplasia in 2 females of the high dose group. The body weights were reduced in both sexes at 34000 mg/l and at 25000 mg/l in males, but there were only minimal pathological changes at these doses.

Three studies with dermal applications of 0.5 ml cyclohexanone 3 times a day over 3 to 8 weeks resulted in lens clouding in guinea pigs. However, also guinea pigs of the control groups showed the effect, and no effects were seen in rabbits or rats in these studies.

No adverse effects were reported from a 28 days intravenous test in rats with doses up to 100 mg/kg b.w./day of cyclohexanone. In dogs exposed to 284 mg/kg b.w./day of cyclohexanone for 18-21 days, a large number of irritative, CNS, and general intoxication symptoms were recorded. Pathology showed liver insufficiency and haemolysis.

Dose-dependent eye irritation was recorded in rabbits exposed for 10 weeks to cyclohexanone concentrations of 1224 to 16320 mg/m³.

125.4.3     Toxicity to reproduction

A two-generation study in rats exposed by inhalation to cyclohexanone at concentrations up to 5712 mg/m³ did not show any adverse effects in the F₀-generation, but the high dose caused lachrymation, ataxia and body weight depression in the F₁-generation. The fertility of the males in this group was reduced, and their offspring had reduced survival and body weight depression.

An oral multigeneration study in mice dosed with 2000 mg/kg b.w./day showed reduced viability of pups in both treated and control groups in the first, but not in the second generation.

Two inhalation studies in rats exposed on gestation days 6-19 by inhalation to cyclohexanone at concentrations ranging from 1224 to 5712 mg/m³ showed maternal toxicity (reduced maternal body weights, lachrymation, nasal discharge, lethargy) at the highest dose level, but there was no or only slight effects on reproductive parameters (pregnancy rate, uterine implant data, and number of live foetuses). Foetuses from dams at the highest exposure level had significantly reduced body weights and increased number of skeletal variations, but no malformations. In another inhalation study, where the rats were exposed to up to 2040 mg/m³ from day 5-20 of gestation, three foetuses had heart artery malformations and 2 had skeletal malformations at the two highest exposure levels, which were slightly maternally toxic; however, the findings were not statistically significant.

Mice exposed at concentrations up to 5712 mg/m³ from gestation day 6-17 had reduced maternal body weights at the high dose; the number of corpora lutea and live foetuses was also reduced in that dose group whereas no effects were reported at lower dose levels. Oral dosing of mice on gestation days 8-12 with 0, 800 or 2200 mg/kg b.w./day resulted in high mortality of the dams, 2/28 litter resorptions, and birth weight depression in the high dose group; no effects were seen on viability of the pups at this dose level, and no effects in the dams or the pups were seen at the lower dose levels.

125.4.4     Mutagenic and genotoxic effects

Cyclohexanone was negative in three Ames tests with Salmonella typhimurium and in a mouse lymphoma assay. Ambiguous results were reported in one test in Salmonella typhimurium and a positive result in Bacillus subtilis in a forward mutation assay. Mutations were also induced in one test (HGPRT) in CHO cells in vitro without metabolic activation, but not when a metabolic activator was added.

No chromosome aberrations were induced in CHO cells whereas, in another assay in CHO cells, a weak increase in sister chromatid exchanges was seen without metabolic activation, but not with metabolic activation. Chromosome aberrations, DNA repair and unscheduled DNA-synthesis was not observed in human lymphocytes or human diploid fibroblast in vitro.

Three gene mutation tests in Drosophila melanogaster were negative.

In a dominant lethal test in rats, cyclohexanone did not induce chromosomal aberrations in bone marrow cells. Another test of chromosome aberrations in rat bone marrow cells was reported to be positive; however, the test quality was low.

A micronucleus test in mouse bone marrow cells was reported to be negative.

125.4.5     Carcinogenic effects

In a 2-year oral rat study with doses in the drinking water of approximately 0, 330, or 650 mg/kg b.w./day, body weight gain was decreased in a dose-related way and survival was slightly lower in the high dose group. Incidences of adrenocortical adenomas in low-dose males and of thyroid follicular-cell adenomas/carcinomas in high-dose males were significantly increased.

A 2-year oral mice study with concentrations in the drinking water of 0, 6500, 13000 mg/l to both sexes with an extra 25000 mg/l-group in females resulted in a marked decrease in survival rates in the 25000 mg/l and in the 6500 mg/l groups. Body weights were also affected at these two dose levels. The incidence of hepatocellular adenomas/carcinomas was increased in male mice, with statistical significance at the low dose only, and a not dose-related response. Alveolar-bronchiolar tumour incidence was significantly lower in high dose males compared with controls. The incidence of lymphomas was statistically elevated in female mice of the low-dose group.

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