TOXICOLOGY
Chlormequat was evaluated by the Joint Meeting in 1970, 1972, and 1994. In 1972, an ADI of 0-0.05 mg/kg bw was established on the basis of the NOAEL in a study of reproductive toxicity in rats. In 1994, the ADI was withdrawn owing to the inadequacy of the database in comparison with acceptable contemporary standards. The compound was reviewed at the present Meeting in response to a request from the manufacturer. New data on the absorption, distribution, excretion, and biotransformation of chlormequat and on its long-term toxicity in rats and dogs, carcinogenicity in mice and rats, reproductive toxicity in rats, and skin sensitization potential in guinea-pigs were reviewed.
In experiments with 14C-labelled chlormequat in rats, absorption was rapid and elimination was essentially complete within 24 h, occurring almost entirely via the urine mainly as unmetabolized chlormequat. Less than 1% of the administered dose remained in the tissues. Accumulation of 15N-labelled material in the kidneys was reported, but the experimental details were incomplete and detailed evaluation was not possible. Studies of the biotransformation of chlormequat suggested that the only metabolites found in rat urine may have been salts of chlorocholine. A polar, unidentified metabolite was found in faeces.
Pharmacological tests in mice, rats, rabbits, and cats given chlormequat intravenously revealed a stimulatory effect on the parasympathetic nervous system and a myoneural blocking action. Further work showed that chlormequat is a partial agonist of the nicotinic acetylcholine receptor; the affinity for muscarinic receptors was low and relatively unselective.
Chlormequat was of moderate acute oral toxicity in rats, mice, hamsters, guinea-pigs, and monkeys (LD50 = 200-1000 mg/kg bw), but rabbits and dogs appeared to be more sensitive (LD50 = 50-80 mg/kg bw) than the other species. The signs of toxicity may have been due to pharmacological activity, and there were no consistent treatment-related findings at autopsy. WHO has classified chlormequat as slightly hazardous.
In a four-week study of toxicity in rats at dietary concentrations of 0, 500, 1500, 3000, or 4500 ppm, the NOAEL was 1500 ppm, equal to 140 mg/kg bw per day, on the basis of reduced body-weight gain and depression of serum creatinine concentration. These results are largely in agreement with those of older studies in rats of up to 90 days' duration. In a 12-month study of toxicity in dogs at dietary concentrations of 0, 150, 300, or 1000 ppm, the NOAEL was 150 ppm, equal to 4.7 mg/kg bw per day, on the basis of diarrhoea, vomiting, and salivation.
In a 110-week study of toxicity and carcinogenicity in mice at dietary concentrations of 0, 150, 600, or 2400 ppm, the NOAEL was 150 ppm, equal to 21 mg/kg per day, on the basis of tubular down-growth in the ovaries and endometrial hyperplasia.
In a 78-week study of toxicity and carcinogenicity in rats at dietary concentrations of 0, 280, 940, or 2800 ppm, the NOAEL was 940 ppm, equal to 43 mg/kg bw per day, on the basis of reduced body weight. Tumour incidences were not enhanced.
The potential carcinogenicity of chlormequat was investigated in a 104-week study in rats at dietary concentrations of 0, 280, 940, or 2800 ppm. No carcinogenicity were observed. The NOAEL was 940 ppm, equal to 42 mg/kg bw per day, on the basis of reduced body weight.
In a multigeneration study of reproductive toxicity in rats at dietary concentrations of 0, 300, 900, or 2700 ppm, the NOAEL for reproductive toxicity was 900 ppm, equal to 69 mg/kg bw per day, on the basis of reduced numbers of pregnancies and of delivered pups and retarded growth and development of the pups.
The developmental toxicity of chlormequat has been investigated in mice after administration by intraperitoneal injection, gavage, or via the diet, in rats by dietary administration, and in hamsters and rabbits by gavage. Many of the study reports were available only in summary form. In a study in mice at dietary concentrations of 0, 1000, or 10000 ppm on days 1-15 of gestation or 25000 ppm on days 11-15 of gestation, the number of malformations in animals fed 10000 ppm or 25000 ppm was reported to be slightly higher than that in controls; however, the significance of this observation was difficult to assess. In hamsters receiving chlormequat at levels of 0, 25, 50, 100, 200, 300, or 400 mg/kg bw once on day 8 of gestation or 100 mg/kg bw per day on days 7-9 of gestation, malformations and evidence of delayed development were seen after three doses of 100 mg/kg bw per day on days 7-9 of gestation or a single dose of 200, 300, or 400 mg/kg bw on day 8. Evidence of maternal and fetal toxicity was also seen at these doses. The study in hamsters could not be fully evaluated, owing to lack of detail in the publication. A full report of a well-conducted study in which rabbits were dosed orally with 0, 1.5, 3, 6 or 12 mg/kg bw per day on days 6-18 of gestation was available. Signs of maternal toxicity were seen at the highest dose, but there was no evidence of developmental toxicity.
Chlormequat has been adequately tested for genotoxicity in vitro and in vivo in a range of assays. The Meeting concluded that it was not genotoxic.
Chlormequat was not irritating to the skin or eye in rabbits. It did not cause delayed contact hypersensitivity when tested in albino guinea-pigs by the method of Buehler or by the method of Magnusson and Kligman.
An ADI of 0-0.05 mg/kg bw was allocated on the basis of the NOAEL of 4.7 mg/kg bw per day for diarrhoea, vomiting, and salivation in a one-year study of toxicity in dogs, and using a safety factor of 100.
An addendum to the toxicological monograph was prepared.
TOXICOLOGICAL EVALUATION
Levels that cause no toxic effect
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Mouse: |
150 ppm, equal to 21 mg/kg bw per day (110-week study of toxicity and carcinogenicity) |
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Rat: |
940 ppm, equal to 42 mg/kg bw per day (104-week study of toxicity and carcinogenicity) |
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900 ppm, equal to 69 mg/kg bw per day (two-generation study of reproductive toxicity) |
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Rabbit: |
6 mg/kg bw per day (maternal toxicity in a study of developmental toxicity) 12 mg/kg bw per day (fetotoxicity and teratogenicity in a study of developmental toxicity) |
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Dog: |
150 ppm, equal to 4.7 mg/kg bw per day (one-year study of toxicity) |
Estimate of acceptable daily intake for humans
0-0.05 mg/kg/bw
Studies that would provide information useful for the continued evaluation of the compound
Developmental toxicity study in rodents that meets current scientific standards.
Toxicological criteria for setting guidance values for dietary and non-dietary exposure to chlormequat
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Human exposure |
Relevant route, study type, species |
Results, remarks |
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Short-term |
Dermal irritation, rabbit |
Not irritating |
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Eye irritation, rabbit |
Not irritating |
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Skin sensitization, guinea-pig |
Non-sensitizing |
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Inhalation toxicity, rat |
LC50 > 5 mg/l air |
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Dermal toxicity, rabbit |
LD50 > 1300 mg/kg bw |
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Oral toxicity, rabbit |
LD50 = 70 mg/kg bw |
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Oral toxicity, cat |
LD50 = 7-50 mg/kg bw |
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Medium-term |
Repeated oral, reproductive toxicity, rabbit |
NOAEL = 6 mg/kg bw per day: maternal toxicity, no reproductive toxicity |
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Long-term |
Repeated oral, one year, dog |
NOAEL = 4.7 mg/kg bw per day: diarrhoea, vomiting and salivation |
