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Description of key information

Oral (OECD TG 423), rat: LD50 cut-off value: 2500 mg/kg bw

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
09 Jul 2013 - 02 Aug 2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP- Guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
other: Sprague-Dawley (Crl:CD(SD)), SPF
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Orientbio INC., Korea
- Age at study initiation: 8-9 weeks old
- Weight at study initiation: 170.6 - 227.3 g
- Fasting period before study: overnight, approximately 16 hours prior to dosing
- Housing: stainless wire mesh cages, 260W x 350D x 210H (mm). 1 animal per cage during the study
- Diet: pelleted rodent chow (Teklad Certified Irradiated Global 18% Protein Rodent Diet 2918C). The diet was placed in feeders and provided ad libitum
- Water: public tap water in Cheongju-si was filtered and irradiated by ultraviolet light and provided ad libitum
- Acclimation period: 4 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.0 - 22.3
- Humidity (%): 43.0 - 66.3
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 02 Jul 2013 To: 17 Jul - 02 Aug 2013
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 60 and 400 mg/mL
- Amount of vehicle (if gavage): 5 mL/kg bw

- Lot/batch no.: MKBG0329V and MKBH4894V


MAXIMUM DOSE VOLUME APPLIED: 5 mL/kg bw

DOSAGE PREPARATION: a small amount of corn oil was added and mixed using a vortex mixer until dissolved. Additional vehicle
was gradually added to yield the desired concentration

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: the starting dose level for this study was selected at 300 mg/kg (step 1 and 2) because there was no available information on the toxicity of the test substance. The following sequential dosing steps (step 3 and 4) were based on the mortality and clinical observations of animals three to four days after the previous dose level.
Doses:
300 mg/kg bw (step 1 and step 2) and 2000 mg/kg bw (step 3 and 4)
No. of animals per sex per dose:
6 (3 per step)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations - prior to dosing (day 0), 30 min after dosing, 1 h, 2 h, 4 h, 6h and then once daily thereafter for 14 days (days 1 to 14). Weighing - prior to dosing (day 0), on day 1, 3, and 7 and on the day pf necropsy, day 14.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight and histopathology (in the case of gross findings)
Statistics:
Statistical analysis was not performed. Mean scores and values are presented.
Sex:
female
Dose descriptor:
LD50
Effect level:
2 500 mg/kg bw
Based on:
test mat.
Remarks on result:
other: LD50 cut-off according to OECD TG 423
Mortality:
300 mg/kg bw: 0/6 animals died
2000 mg/kg bw: 2/6 animals died (at 6 h and on day 1 post-dose)
Clinical signs:
300 mg/kg bw: no clinical signs of toxicity were observed in the animals up to the end of the 14-d observation period.
2000 mg/kg bw: in the two animals which died, irregular respiration, lacrimation, loss of locomotor activity, prone position and/or decreased respiration were evident from 30 min to 6 h after dosing. These animals were then found dead in a state of lacrimation and/or prone position at 6 h and on day 1 after dosing respectively. In the four surviving animals, irregular respiration, abnormal gait and/or tremor were evident from 30 min to 6 h after dosing. Decrease of fecal volume, soiled perineal region, no stool and/or irregular respiration were evident on day 1 after dosing. These animals then returned to a normal state on day 2 after dosing.
Body weight:
300 mg/kg bw: no effect on body weight was noted in the animals during the study.
2000 mg/kg bw: a tendency to suppress body weight gain and/or a decrease in body weight was evident in two surviving animals at 2000 mg/kg bw on day 1 after dosing. These animals then returned to normal on day 3 after dosing.
Gross pathology:
No grossly visible evidence of morphologic abnormalities was evident in the animals dosed with 300 and 2000 mg/kg bw of the test substance respectively.
Interpretation of results:
not classified
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
CLP: not classified
DSD: not classified
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfil the standard requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

Additional information

Acute toxicity: oral

The test substance was investigated for acute oral toxicity according to OECD TG 423 and in compliance with GLP (Lee, 2013). The test substance in corn oil was administered by stomach intubation to Sprague-Dawley rats (6/females/dose), at doses of 300 (step 1 and 2) and 2000 mg/kg bw (step 3 and 4). No mortality or clinical signs of toxicity were observed during the 14-day observation period in the animals dosed with 300 mg/kg bw of the test substance. In the animals dosed with 2000 mg/kg bw of the test substance, two mortalities at 6 h and on day 1 after dosing occurred. In the two animals which died, irregular respiration, lacrimation, loss of locomotor activity, prone position and/or decrease respiration were evident from 30 min to 6 h post dosing. These animals were then found dead in a state of lacrimation and/or prone position at 6 h and on day 1 after dosing respectively. In the four surviving animals in the 2000 mg/kg bw dose group, irregular respiration, abnormal gait and/or tremor were evident from 30 min to 6 h after dosing. Furthermore, decrease of fecal volume, soiled perineal region, no stool and/or irregular respiration were evident on day 1 after dosing. These animals then returned to a normal state on day 2 after dosing. A tendency to suppress body weight and/or a decrease in body weight gains was evident in two surviving animals at 2000 mg/kg bw on day 1 after dosing. These animals then returned to normal on day 3 after dosing. No effect on body weight was noted in the animals dosed with 300 mg/kg bw of the test substance. Moreover, no grossly visible evidence of morphologic abnormalities was evident in the animals dosed with 300 and 2000 mg/kg bw of the test substance respectively.Therefore, based on the results of this study, an LD50 cut-off value of 2500 mg/kg bw was derived according to OECD TG 423.

Justification for selection of acute toxicity – oral endpoint

There is only one study available

Justification for classification or non-classification

The available data on acute oral toxicity of the test substance do not meet the criteria for classification according to Regulation EC 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.