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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
830 mg/kg bw/day
Additional information

The reproductive toxicity of cloquintocet-mexyl has been evaluated in a two-generation (one litter per generation) study in the rat in a key guideline study (OECD 416, 1983) conducted to GLP. This study was supported by a dose range-finding study in which five groups of 7 males and 14 females were fed cloquintocet-mexyl continuously in the diet at concentrations of 0 (control), 40, 400, 4000 or 8000 ppm. After a pre-mating period of 14 days, each male was mated with 2 females and the females were allowed to litter and rear the offspring to weaning. Administration of 8000 ppm revealed slightly toxic effects on parental animals (reductions in body weight gain and food consumption during the premating period) but no toxic effects on the offspring. On the basis of this result, the highest dose level selected for the two-generation study was 10000 ppm.

For the two-generation study, groups of 25 male and 25 female rats were fed cloquintocet-mexyl continuously in the diet at nominal concentrations of 0, 50, 500, 5000 or 10000 ppm. After a 14 week pre-mating period, the P parental animals were mated and allowed to litter and to rear the F1a pups to weaning. After a 14 week post weaning maturation period the selected F1 parental animals were mated and allowed to litter and to rear the F2a pups to weaning.

At 10000 ppm, effects in the P and Fl parental animals included reduced body weight and food consumption, the death of four Fl males and histological changes in the kidney and urinary bladder of the Fl animals. For pups, mean body weight was significantly reduced on day 21 for both F1a and F2a pups and the incidence of renal pelvic dilatation was increased in F1a pups but not in F2a pups. There were no adverse effects of 50, 500 or 5000 ppm cloquintocet-mexyl. The NOAEL for toxicity was 5000 ppm, corresponding to a mean daily intake of 420 mg/kg bw/day.

There was no effect on fertility or general reproductive performance in either of the two generations at any dietary concentration of cloquintocet-mexyl in this study and thus the NOAEL for fertility was 10000ppm corresponding to a mean daily intake of 830 mg/kg bw/day.

The study was not conducted to current guidelines which require evaluation of estrous cyclicity and sperm together with extended histopathology and organ weight information for both parents and offspring. It is however, considered to be robust evaluation with no indication of adverse effects on reproduction hence no further testing is warranted.


Short description of key information:
The fertility and general reproductive performance of cloquintocet-mexyl has been evaluated in a two-generation study (OECD 416, 1983) conducted to GLP. No effect of cloquintocet-mexyl on reproduction was detected at the highest dose level tested, 10000 ppm, equivalent to 830 mg/kg bw/day. At this dose level, parental toxicity was observed and mean pup weight at weaning was decreased. The overall NOAEL for toxicity was 5000 ppm, corresponding to a mean daily intake of 420 mg/kg bw/day. Although the study was not conducted to current guidelines, it is considered to be robust and no further testing is warranted.

Effects on developmental toxicity

Description of key information
The developmental toxicity of cloquintocet-mexyl has been evaluated in the rat and rabbit, in two key guideline studies (OECD 414, 1981) conducted to GLP and found not to be teratogenic at dose levels that induce maternal toxicity. Developmental toxicity, described as a reduction in mean foetal weight and a slight delay in development, was observed only in the presence of maternal toxicity i.e. at dose levels of 400 and 300 mg/kg bw/day, in the rat and rabbit respectively.  The NOAEL for maternal and developmental toxicity is 100 mg/kg bw/day in the rat and 60 mg/kg bw/day in the rabbit. Although the studies were not conducted to current guidelines, they are considered to be robust and no further testing is warranted.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
60 mg/kg bw/day
Additional information

The developmental toxicity of cloquintocet-mexyl has been evaluated in the rat and rabbit, in two key guideline studies (OECD 414, 1981) conducted to GLP.

Groups of 24 time-mated female rats were administered cloquintocet-mexyl by oral gavage on days 6 -15 of pregnancy at dose levels of 0, 10, 100 or 400 mg/kg bw/day. Foetuses were obtained by caesarean section on day 21 of pregnancy and examined for external, visceral and skeletal malformations and anomalies. 

The dose level of 400 mg/kg bw/day was toxic to the pregnant female resulting in increased water consumption, increased wet bedding and odorous urine, reduced body weight and reduced food consumption. Lower mean foetal weight was seen in the presence of this maternal toxicity but there was no increase in incidence of external, visceral or skeletal malformations or anomalies. The NOAEL for maternal and developmental toxicity was 100 mg/kg bw/day. There was no evidence of teratogenicity at any dose level of cloquintocet-mexyl.

Groups of 20 mated female rabbits were administered cloquintocet-mexyl by oral gavage on days 7 -19 of pregnancy at dose levels of 0, 10, 60 or 300 mg/kg bw/day. Foetuses were obtained by caesarean section on day 29 of pregnancy and examined for external, visceral and skeletal malformations and anomalies. 

The dose level of 300 mg/kg bw/day was toxic to the pregnant female resulting in the premature death of 5 animals (between days 12 and 18 of pregnancy) although no effect on body weight or food consumption was observed in the surviving rabbits. There was no effect of 300 mg/kg bw/day on mean foetal weight. There was no increase in incidence of external, visceral or skeletal malformations or anomalies although a slight delay in development was ascribed to 300 mg/kg bw/day. There was no evidence of teratogenicity at any dose level of cloquintocet-mexyl.

On the basis of these studies, it is concluded that cloquintocet-mexyl is not teratogenic to either rats or rabbits at dose levels that induce maternal toxicity. Developmental toxicity, described as a reduction in mean foetal weight or a slight delay in development, was observed only in the presence of maternal toxicity i.e. at dose levels of 400 and 300 mg/kg bw/day, in rats and rabbits respectively. The NOAEL for maternal and developmental toxicity is 100 mg/kg bw/day in the rat and 60 mg/kg bw/day in the rabbit.

The studies were not conducted to current guidelines which require an extended dosing period to cover the period from implantation through to the day before termination. However, the studies are considered to be robust and no further testing is warranted.

Justification for classification or non-classification

There is adequate information available from which to assess the potential of cloquintocet-mexyl to induce reproductive or developmental effects and to conclude that classification under the DSD or CLP is not warranted:

- under Directive 67/548/EEC, as amended for the 28th time in Directive 2001/59/EC, Annex VI, 4.2.3.

- under Regulation (EC) 1272/2008, Annex I, Part 3, 3.7.2.

Additional information