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Administrative data

Description of key information

NOAEL sub-acute (rat): 1000 mg/Kg bw

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
1 000 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

The main study is conducted within 2018 on test item with rats of both sexes, as well as any effects of the test item on male and female reproductive performance, such as gonadal function, mating behaviour, conception, development of conceptuses, parturition and early lactation of the offspring were investigated. A 4 week treatment-free period was allowed in order to assess any delayed toxicity or recovery from any adverse effects observed during the dosing phase.

The vehicle was softened water. All doses were administered at a constant volume of 5 ml/kg body weight.

The study design was as follows:

Main groups
Group  Treatment
(mg/kg/day)
Number of animals
1 0 10♂ + 10♀
2 150 10♂ + 10♀
3 500 10♂ + 10♀
4 1000 10♂ + 10♀
Recovery groups
Group  Treatment
(mg/kg/day)
Number of animals
5 0 6♂ + 6♀
6 1000 6♂ + 6♀

Main groups

Males of the main groups were treated for 2 weeks prior to pairing and during pairing with females until the day before necropsy, for a total of 46/47 days. Females were treated for 2 weeks prior to pairing, and thereafter during pairing, post coitum and post partum periods until Day 13 post partum (for at least 51 days).

The following investigations were performed in both sexes of all groups: mortality check, clinical signs, body weight, food consumption, oestrous cycle, mating performance, litter data, sex ratios, macroscopic observations and organ weights. Sperm analysis was performed in all control and high dose males. Histopathological examination was performed in control and high dose groups, as well as on all abnormalities detected during post mortem observation. The identification of the stages of the spermatogenic cycle was also performed in five randomly selected males of the control and high dose groups.

Mortality and fate of females

No mortality occurred throughout the study.

Clinical signs

Main and recovery groups. No signs of toxicity were observed throughout the study, both sexes, both for main and recovery groups.

Body weight and body weight gain

Main and recovery groups. No differences of toxicological relevance were recorded in body weight and body weight gain, both for main and recovery groups respect to the control groups.

Food consumption

Main and recovery groups. No effects on food consumption were observed in either males or females throughout the study, both for main and recovery groups.

Terminal body weight and organ weights

Main and recovery groups

No relevant changes were observed on terminal body weight, absolute and relative organ weight of treated animals that completed the treatment or recovery period, when compared with controls.

Sperm analysis

No relevant differences were observed at sperm analysis including sperm motility and concentration, and cauda weight between the control and the high dose group at the end of treatment.

Macroscopic observations

Main and recovery groups. No remarkable differences were noted at post mortem examination in treated animals sacrificed at the end of treatment and recovery periods, when compared with controls.

Microscopic observations

No treatment-related changes were noted in animals sacrificed at the end of the treatment period. Seminiferous tubules were evaluated with respect to their stage in the spermatogenic cycle and to the integrity of the various cell types within the different stages; regular

layering in the germinal epithelium was noted.

Conclusion

Based on the results of the present study, the NOAEL (No Observed Adverse Effect Level) for general and reproduction/developmental toxicity was considered to be 1000 mg/kg/day.

The 28 days study, performed on a Similar substance 01 and used in Read Across, followed the EU B.7 Guideline Repeated Dose (28 days) Toxicity (oral) and the OECD 407 Guideline, Repeated Dose 28 day Oral Toxicity Study in Rodents.

Based on the results of a 5 day range finding study, the dose levels for the 28 day toxicity study were selected to be 0, 50, 150 and 1000 mgl kg/day.

Treatment-related findings observed were as follows:

50 mg/kg/day:-No treatment-related findings.

150 mg/kg/day:- No treatment-related findings.

1000 mg/kg/day: No treatment-related findings.

From the results presented in this report a No Observed Adverse Effect Level (NOAEL) of 1000mg kg/day was established.

Based on the read-across principle (read-across from supporting substance -structural analogue or surrogate), the results can be considered for the repeated dose toxicity assessment of the substance. Justification for read-across is detailed in the report attached to the IUCLID section 13.

Justification for classification or non-classification

According to the CLP Annex 1: 3.9.2.8: effects considered not to support classification for specific target organ toxicity following repeated exposure are: small changes in clinical biochemistry, haematology or urinalysis parameters and/or transient effects, when such changes or effects are of doubtful or minimal toxicological importance.

28 days repeated oral administration to rats by gavage at the dose levels 50, 150 and 1000 mg/kg/day did not cause mortality. 

No Observed Adverse Effect Level (NOAEL) of 1000mg kg/day was established.

Based on the read-across principle(read-across from supporting substance -structural analogue or surrogate), the result can be considered for the repeated dose toxicity assessment of the substance. Justification for read-across is detailed in the report attached to the IUCLID section 13.

As conclusion the registered substance is not classified for the oral repeated dose toxicity, according to CLP Regulation 1272/2008.