Registration Dossier

Administrative data

Description of key information

NOAEL = 1000 mg/kg/day (OECD 422)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
2015
Deviations:
no
Qualifier:
equivalent or similar to guideline
Guideline:
other: EPA OPPTS 870.3650 (2000)*
Version / remarks:
*Note: The study design is similar to OPPTS 870.3650 design, but pups will be kept longer and additional endpoints will
be measured.
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Species:
rat
Strain:
Wistar
Details on species / strain selection:
Crl:WI rats
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
28 days
Frequency of treatment:
7 days a week
Dose / conc.:
100 mg/kg bw/day (nominal)
Remarks:
20 mg/mL, dose volume 5 mL/kg bw
Dose / conc.:
300 mg/kg bw/day (nominal)
Remarks:
60 mg/mL, dose volume 5 mL/kg bw
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Remarks:
200 mg/mL, dose volume 5 mL/kg bw
No. of animals per sex per dose:
15
Control animals:
yes, concurrent vehicle
Positive control:
none
Clinical signs:
effects observed, non-treatment-related
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, non-treatment-related
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, non-treatment-related
Clinical biochemistry findings:
effects observed, non-treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
effects observed, non-treatment-related
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
No endocrine disruptor effect of test item was observed in the study based on the results of thyroid hormone analysis and thyroid gland weights.
Key result
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
behaviour (functional findings)
body weight and weight gain
clinical biochemistry
clinical signs
dermal irritation
food consumption and compound intake
gross pathology
haematology
immunology
mortality
neuropathology
ophthalmological examination
organ weights and organ / body weight ratios
urinalysis
water consumption and compound intake
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Critical effects observed:
no
Conclusions:
Daily administration of the test item by oral gavage to Wistar rats at dose levels of 100, 300 or 1000 mg/kg bw/day (Low, Mid and High dose levels, respectively) during the treatment period under the conditions of this study did not result in test item related mortality, clinical signs, or effects on body weight or body weight gain, food consumption, haematology, coagulation, clinical chemistry or urinalysis parameters.
No test item related effect was detected during neurotoxicity assessment. In case of decreased motor activity results in High dose females, based on the historical control data, shape of the curve, lack of similar results in High dose males and lack of similar indication in the other tests, the observed data were considered as animal variability and not related to the test item treatment.
No test item-related macroscopic findings were recorded in any of the dose groups at necropsy; no microscopic effects were seen at histopathology. There were no test-item related differences among groups in the weights of organs measured when compared to controls.
No test item effect on oestrus cycle of parental females were was noted.
No test item related changes were noted in the reproductive parameters, gestation, parturition and lactation.
There were no adverse effects on the F1 offspring viability, clinical signs, physical or sexual development. No test item related macroscopic finding were was recorded for F1 pups at necropsy.
No endocrine disruptor effect of test item was observed in the study.

In conclusion, under the conditions of this study, the no observed adverse effect level (NOAEL) for the test substance is considered to be 1000 mg/kg bw/day for the female and male parental/adult generation, and also for the F1/pups generation.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat

Mode of Action Analysis / Human Relevance Framework

No test item related toxicity was detected in a 28day rat study.

Additional information

Justification for classification or non-classification

Bases on the available data, the substance is not classified according to Regulation (EC) No 1272/2008.