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Diss Factsheets

Administrative data

Description of key information

- Subacute (28-day) study oral (gavage), rat (Sprague-Dawley) m/f: NOAEL = 40 mg/kg bw/day (actual dose received) (male/female) [OECD TG 407, GLP]

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: Guideline study obtained through inquiry process; SNIF file obtained from ECHA.
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
not specified
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: Wistar (Han: WIST)
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
corn oil
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
28 days
Frequency of treatment:
Dosing regime: 7 days/week
Remarks:
Doses / Concentrations:
40, 200 and 1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
Male: 10 animals at 0 mg/kg bw/day
Male: 5 animals at 40 mg/kg bw/day
Male: 5 animals at 200 mg/kg bw/day
Male: 10 animals at 1000 mg/kg bw/day
Female: 10 animals at 0 mg/kg bw/day
Female: 5 animals at 40 mg/kg bw/day
Female: 5 animals at 200 mg/kg bw/day
Female: 10 animals at 1000 mg/kg bw/day
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
In the intermediate and high dose group dose dependend an increased salivation was observed. The animals of the high dose group showed bright feces from the second week and at the end of the treatment reduced activity, skin turgor and righting reflex. Two females of the high dose group did not show the ear reflex.
Mortality:
mortality observed, treatment-related
Description (incidence):
In the intermediate and high dose group dose dependend an increased salivation was observed. The animals of the high dose group showed bright feces from the second week and at the end of the treatment reduced activity, skin turgor and righting reflex. Two females of the high dose group did not show the ear reflex.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
In the males of the high dose group a reduced body weight development was measured at the end of the study.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
In the males of the high dose group the food consumption was reduced during the whole application period, in the females of the high dose group a reduced food consumption was observed during the first two weeks of the treatment.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
In the females of the mid and high dose group an increase of the number of thrombocytes and an enlargement of the prothrombin time in the males in all dose groups (without relation to the doses) and in females of high and low dose group was observed.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
In females of the high dose group the values for giucose and triglycerides were increased and in both sexes the protein values were reduced. In the males of the high dose group increased activities for ALAT was determined.
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
On the animal body white areas and redness of the mucosa of the stomach and a swelling of the duodenum septum in all animals of the high dose groups were seen. One animal of the intermedium dose group showed a swollen duodenum too.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Microscopically in the animals of the intermedium and high dose group a hyperplasy of the mucousa in the duodenum was detected. In the recovery groups no treatment related changes were observed.
Histopathological findings: neoplastic:
not examined
Details on results:
Dose or concentration at which no effect was observed: 200 mg/kg/day. As described above, a complete recovery was present 2 weeks after the end of treatment.
Dose descriptor:
NOAEL
Effect level:
40 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: original NCD unit is mg/kg/day
Dose descriptor:
NOEL
Effect level:
40 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: original NCD unit is mg/kg/day
Critical effects observed:
not specified

Further clinical observations:

The discolouration of the feces was seen in the discovery group till the end of the first week of the recovery period. One male of the low dose group showed a reduced righting reflex at day 15. At the examination on day 26 a reduced righting reflex was observed at one male of the intermediate dose and at two male of the low dose group.

Conclusions:
NOAEL = 40 mg/kg bw/d; at the maximum dose of 1000 mg/kg substance, test-substance related findings were no longer observable after a recovery period of 2 weeks. Hence, the substance is not subject to classification and labelling.
Executive summary:
The oral repeated dose toxicity of the test substance has been determined in a GLP test with rats according to OECD Guideline No. 407 (28-days of oral gavage exposure at doses of 40, 200 and 1000 mg/kg bw/d). Primary effects involved local irritation in the stomach and duodenum which resolved during the two-week recovery period, with hyperplasia of the duodenum in mid and high dose groups. The NOAEL is conservatively set at 40 mg/kg bw/d.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
40 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The data has been extracted from ECHA databases. The files were first migrated from the SNIF (Structured Notification Interchange Format) format (used under Directive 67/548/EEC) into the IUCLID 5 format (used under the REACH Regulation) and represent all of the information that ECHA currently holds on this endpoint, which were submitted in the framework of a notification at least 12 years previously (as per Article 25(3)) for the substance with the same EC number for which you inquired.

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 oral repeated dose toxicity of the test substance has been determined in a GLP test with rats according to OECD Guideline No. 407 (28-days of oral gavage exposure at doses of 40, 200 and 1000 mg/kg bw/d). Primary effects involved local irritation in the stomach and duodenum which resolved during the two-week recovery period, with hyperplasia of the duodenum in mid and high dose groups. The NOAEL is conservatively set at 40 mg/kg bw/d.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
GLP and guideline study

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Inhalation is not a relevant route of exposure. An oral study is available, the oral NOAEL can be extrapolated to an inhalation NOAEC.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Inhalation is not a relevant route of exposure. An oral study is available, the oral NOAEL can be extrapolated to an inhalation NOAEC.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
Oral study is available. The oral NOAEL can be extrapolated to a dermal NOAEL.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
Oral study is available. The oral NOAEL can be extrapolated to a dermal NOAEL.

Justification for classification or non-classification

The NOAEL has been conservatively set at 40 mg/kg bw/d, but the dose/concentration at which no effect was observed is 200 mg/kg/day. Further, a complete recovery was present 2 weeks after the end of treatment. Hence, the test material is not subject to classification and labelling as STOT-RE in accordance with European Regulation (EC) No. 1272/2008.