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Description of key information

Repeated dose toxicity has been investigated in oral sub-chronic and chronic studies in rats, mice and dogs and in a sub-acute dermal toxicity study in rats. There was no evidence of specific target organ toxicity in any of the studies that would warrant classification or labelling for this end-point.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
4.33 mg/kg bw/day
Study duration:
chronic
Species:
rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat

Additional information

Repeated dose toxicity has been evaluated in key subchronic and chronic dietary toxicity studies in the rat, mouse and dog. Based on the intended use as a plant protection product exposure of humans is most likely to arise from residues in food and hence this is the most relevant route of exposure for mammalian toxicity studies.

In the rat the key study addressing subchronic exposures (90 day dietary exposure; Fankhauser, 1989) showed increased water consumption, pathological effects in the bladder and kidney and associated clinical chemistry findings at high doses (1000 ppm and above). The NOAEL was 150 ppm, equivalent to a mean daily intake of 9.66 mg/kg in males and 10.2 mg/kg in females.

Following chronic dietary exposure (2 year study; Fankhauser, 1992) toxicologically significant effects were hyperplastic changes in the thymus of males at 2000 ppm (approximately 73 mg/kg/day in males; 81 mg/kg/day in females) and of the thyroid gland (follicular epithelial hyperplasia) in females at 2000 ppm and 1000 ppm (approximately 36 mg/kg/day in males; 41 mg/kg/day in females). No treatment-related effects were seen at 100 ppm (3.77 or 4.33 mg/kg/day in males and females, respectively).

Dermal administration to rats was tolerated without any local or systemic effects at a limit dose of 1000 mg/kg/day (6 hrs/day, 5 days/week for 4 weeks) (Schneider, 1988).

In the mouse subchronic and chronic toxicity studies treatment-related findings were limited to increased water consumption and chronic inflammatory changes in the urinary bladder at 18 months. The subchronic NOAEL was 2400 ppm, equivalent to 357 and 470 mg/kg/day in males and females, respectively (Fankhauser, 1989) and the chronic NOAEL was 1000 ppm (111 or 102 mg/kg/day in males and females).

Diets containing concentrations of cloquintocet-mexyl of 15000 ppm and greater were unpalatable to dogs leading to significant body weight loss and a number of effects considered to result from general stress and emaciation. In the subchronic toxicity study, liver cell necrosis in one female and thymic atrophy in one male at 1000 ppm (30.2 mg/kg/day) were both considered to be treatment-related (Allen, 1989). However, 1500 ppm (approximately 44 mg/kg/day) administered for 52 weeks was without effect (Corney, 1991).

Justification for classification or non-classification

No evidence of significant target organ toxicity was seen in repeat dose oral studies in rats, mice and dogs of up to 1 year duration or in a rabbit repeat dose dermal toxicity study at dose levels below regulatory thresholds. No classification is necessary in relation to repeated dose toxicity:

- under Directive 67/548/EEC, as amended for the 28th time in Directive 2001/59/EC.

- under Regulation (EC) 1272/2008.

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