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Administrative data

Description of key information

ECHA has provided a 28 day repeated dose study to rats via oral exposure. No studies assessing inhalation or dermal exposure are available.

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:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Data migrated from NONS with permission to refer granted by ECHA.
Qualifier:
according to
Guideline:
other: 92/69/EEC
GLP compliance:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
corn oil
Duration of treatment / exposure:
28 days
Frequency of treatment:
7 days per week
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
75 mg/kg bw/day (nominal)
Dose / conc.:
225 mg/kg bw/day (nominal)
Dose / conc.:
750 mg/kg bw/day (nominal)
No. of animals per sex per dose:
5 male and female animals at each dose group
Control animals:
yes, concurrent vehicle
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Decreased faeces were observed in all rats that received 750 mg/kg/day and sialorrhea was observed in all treatment groups.
Mortality:
mortality observed, treatment-related
Description (incidence):
In animals that received 750 mg/kg/day 1 male was found dead on Day 3 and 1 male was sacrificed as moribund on Day 11.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
In males that received 750 mg/kg/day, mean bodyweights were significantly lower than in controls.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
effects observed, treatment-related
Description (incidence and severity):
Food consumption for males that received 750 mg/kg/day was reduced on Days 4 and 7.
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Alkaline phosphatase (ALP) and ALAT concentrations were increase in males that received 750 mg/kg/day. A slight, statistically significant increase in ALAT was also observed in males that received 225 mg/kg/day. The slight increases in ALAT and ALP could be related to the changes observed in the pancreas of animals that received 750 mg/kg/day.
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
In males that received 750 mg/kg/day, there were increases in relative adrenal, testes, kidney and liver weights and decreased absolute spleen, kidney and thymus weights. Liver weights were also increased in females that received 750 mg/kg/day. No associated gross or microscopic findings were observed in these organs.
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Mild exocrine cell necrosis of the pancreas was observed in animals that received 750 mg/kgbw.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Dose descriptor:
NOAEL
Effect level:
225 mg/kg bw/day (nominal)
Based on:
not specified
Sex:
not specified
Basis for effect level:
histopathology: non-neoplastic
Dose descriptor:
NOEL
Effect level:
< 75 mg/kg bw/day (nominal)
Based on:
not specified
Sex:
not specified
Basis for effect level:
other: Lack of toxicologically significant effects
Critical effects observed:
yes
Lowest effective dose / conc.:
750 mg/kg bw/day (nominal)
System:
other: Pancreas
Organ:
pancreas
Treatment related:
yes
Dose response relationship:
no
Relevant for humans:
not specified
Conclusions:
Based on information provided by ECHA, the results of a 28 day repeated dose study include a NOAEL of 225 mg/kg/day based on effects observed in the pancreas of high dose animals.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
225 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Study provided by ECHA from NONS dossier.
System:
other: Pancreatic
Organ:
pancreas

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

Justification for classification or non-classification

Based on information provided by ECHA, the results of a 28 day repeated dose study include a NOAEL of 225 mg/kg/day based on effects observed in the pancreas of high dose animals. In animals that received 750 mg/kg/day effects were observed on bodyweight gain, food consumption, liver enzymes and increases in various organ weights. The main effect was observed in males receiving 750 mg/kg/day which included mild exocrine necrosis of the pancreas which may have been related to the change in liver enzymes ALP and ALAT.

The effects on bodyweight, food consumption, organ weights and evidence of minor clinical signs (e.g. decreased faeces) were all considered of low toxicological importance. The organ weight change was present with no evidence histopathologically of organ dysfunction. As the main effect observed in the pancreas was mild and only observed at a high dose (greater than the guidance cut-off values in Tables 3.9.2 and 3.9.3 of the CLP regulation) no classification for STOT RE effects in the pancreas are deemed appropriate in accordance with the CLP Regulation (EC No. 1272/2008, as amended).