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Description of key information

Repeated dose oral toxicity study in rats dosed for 4 weeks, followed by 2 weeks of recovery:

NOAEL = 40 mg/kg/day, equivalent to ca. 35 mg/kg a.i.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
35 mg/kg bw/day
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Repeated dose toxicity of target substance was assessed in rats dosed daily by oral route for 4 consecutive weeks; recovery from any treatment-related effects was followed during a period of 2 weeks.

Groups of 5/rat/sex were dosed by gavage at 10, 20 and 40 mg/kg/day. A control group received vehicle alone (water). Control and high dose groups included 5 additional animals per sex to be sacrificed after 2 weeks of recovery.

The following observations were done: clinical signs (daily), detailed clinical signs (weekly), evaluation of sensory reactivity to stimuli, assessment of grip strength and motor activity, body weight, food consumption, clinical pathology investigations, terminal body weight, organ weights, macroscopic observations and histopathological examination.

No treatment related mortality was seen.

No clinical signs were observed in animals of the control groups and in those of groups 2 and 3. Rales, ataxia and dyspnoea were individually observed in male animals of group 4 during the treatment or the first days of the recovery period.

No changes of note were found at the weekly clinical examination which included an evaluation of neurotoxicity during treatment and recovery periods.

No differences between treated animals and controls which could be considered treatment-related were observed at functional tests (sensory reactivity, landing footsplay, grip strength) and motor activity measurements performed at the end of treatment and recovery periods.

Very slight reductions in body weight were noted in animals of the treated groups when compared to controls. These decrements were statistically significant on day 22 for males of group 4, on days 22 and 29 for females of groups 2 and 3 and on day 8 up to the end of the treatment and recovery periods for females of group 4.

No changes in food consumption and haematology were noted.

Clinical chemistry, alterations of some biochemical parameters observed during the treatment or recovery phase were considered unrelated to the treatment or, due to their slight entity, they were not deemed to be suggestive of tissue/organ injury or adverse effect.

At final sacrifice, male animals of groups 3 and 4 showed a statistically significant increase in absolute and relative liver weights. In addition, a statistically significant increase in relative liver weight and relative kidney weight was noted in females of group 4 and in males of the same treated group, when compared to controls.

At recovery sacrifice, no remarkable changes in terminal body weight and in absolute/relative organs weight were noted.

As for microscopic observations, at final sacrifice, treatment-related changes, consisting in moderate to marked hyaline droplets accumulation, were noted in kidneys of male animals of group 4. In addition, multifocal centrilobular hepatocellular hypertrophy from minimal to mild degree was observed in the liver of all males of this group.

However, such histopathological lesions showed a complete reversibility at the end of the recovery period.

Alterations of liver and kidney weights in male and/or female animals in the high dose group (40 mg/kg/day) as well as histopathological alterations in kidneys and liver of male animals in the same group showed a complete reversibility at the end of the recovery period. Therefore, a NOAEL of 40 mg/kg/day, corresponding to ca. 35 mg/kg a.i., was established.

Overall, in studies with prolonged exposure general toxicity was seen.

Upon a 28 -day treatment, effects of general toxicity were seen at the highest dose tested of 35 mg/kg a.i.; however, they disappeared by the end of the recovery period.

In a preliminary teratogenicy study (5, 20, 80 mg/kg/day) from day 6 to 15 of gestation, rats dosed at 80 mg/kg/day, equivalent to 68 mg/kg a.i., were terminated before end due to serious adverse responses, e.g. lethargy, tremor, irregular respiration, prone posture... Such effects were caused by the substance after repeated dosing, i.e. 3, 6, 7, 7, and 8 doses.

Justification for classification or non-classification

According to the CLP Regulation (EC 1272/2008), classification in category 1 for repeated dose toxicity applies to substances that have produced significant toxicity in humans or that, on the basis of evidence from studies in experimental animals, can be presumed to have the potential to produce significant toxicity in humans following repeated exposure. Substances are classified in category 1 for target organ toxicity (repeated exposure) on the basis of:

— reliable and good quality evidence from human cases or epidemiological studies; or

— observations from appropriate studies in experimental animals in which significant and/or severe toxic effects, of relevance to human health, were produced at generally low exposure concentrations.

As for classification in category 2, it applies to substances that, on the basis of evidence from studies in experimental animals can be presumed to have the potential to be harmful to human health following repeated exposure. Substances are classified in category 2 for target organ toxicity (repeated exposure) on the basis of observations from appropriate studies in experimental animals in which significant toxic effects, of relevance to human health, were produced at generally moderate exposure concentrations.

For studies of 28-day duration, classification in category 1 applies when toxicity by oral route is seen at concentrations below 30 mg/kg/d, while category 2 applies for toxicity at doses between 30 and 300 mg/kg/d.

Based on available experimental evidences, the substance is classified as H373 within the CLP Regulation (EC 1272/2008), due to general toxicity occurring after repeated dosing at doses between 30 and 300 mg/kg/d by oral route.