Registration Dossier

Administrative data

Description of key information

Acute oral toxicity: LD50 cut off value ≥ 5000 mg/kg bw (OECD 423; GLP compliant)

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:
2015-03-24 to 2015-04-14
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
adopted 2001-12-17
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
yes
Test material information:
Composition 1
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS - Crl:CD(SD)
- Source: ORIENTBIO INC., Korea
- Age: 8 week old
- Weight: 173.6 to 189.5 g
- Fasting period before study: animals were fasted overnight, approximately 16 hours prior to dosing. feed was provided approximately 4 hours post dosing.
- Housing: stainless wire mesh cage (260W x 350D x 210H (mm)); one animal/cage
- Diet (ad libitum, except for a fasting period before the study as described above): pelleted rodent chow (Teklad Certified Irradiated Global 18% Portein Rodent Diet 2918C; Harlan Laboratories, Inc., U.S.A.))
- Water (ad libitum): public tap water in Cheongju-si was filtered and irradiated by ultraviolet light
- Quarantine/Acclimation period: 3 day / 4 days

ENVIRONMENTAL CONDITIONS
- Temperature: 21.0 to 23.8°C
- Relative humidity: 42.2 to 64.8%
- Air changes: 10 to 15 clean, fresh, filtered air changes per hour
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Lot no.: MKBP7039V

MAXIMUM DOSE VOLUME APPLIED: 5 mL/kg bw
Individual doses were calculated based on the animals' body weight recorded just prior to dosing.

DOSAGE PREPARATION:
The required amount of the test substance was weighed on an electronic balance and placed in a bottle. A small amount of vehicle was added and mixed using a vortex mixer until dissolved. The vehicle was gradually added to yield the desired concentration (400 mg/mL). All preparations were conducted just prior to use.

CLASS METHOD
- Rationale for the selection of the starting dose: due to the low expected toxicity of the test substance, based on information supplied by the sponsor, 2000 mg/kg bw was selected as the starting dose for this study.
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
6 female rats (3 female rats per dosing step)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: all animals were observed at 30 minutes after dosing and at 1, 2, 4 and 6 hours after dosing on Day 0 and once daily thereafter for 14 days.
Body weights were recorded prior to dosing (Day 0), on Days 1, 3 and 7 and on the day of necropsy, Day 14.
- Necropsy of survivors performed: yes, all surviving animales were sacrificed on day 14. Complete gross postmortem examinations were performed on all animals.
Statistics:
not applicable
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Sex:
female
Dose descriptor:
LD50
Effect level:
>= 5 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: LD50 cut-off value based on the flow chart according to the OECD guideline 423 .
Mortality:
All animals dosed at 2000 mg/kg survived the duration of the study.
Clinical signs:
Lacrimation and/or salivation were evident in five animals on the day of dosing. Mucous stool and/or soiled perineal region were observed in 3 animals on Day 1, but they returned to a normal appearance on Day 2. One rat presented clinical signs and those were decreased fecal volume or no stool from Day 1 to Day 3, refusal to feed on Day 2 only, decrease in locomotor activity and irregular respiration from Day 2 until Day 4, but all clinical signs returned to normal from Day 5 onwards.
These clinical signs were considered to be test substance-related effects.
Body weight:
A decrease in body weight or a tendency to suppress body weight was evident in five animals on Day 1 and Day 3. Then, five animals retunred to normal appearance on Day 7. These changes were considered to be test substance-related effects.
Gross pathology:
No grossly visible evidence of morphologic abnormalities was evident in any animals.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
LD50 cut-off value (female rats) ≥ 5000 mg/kg bw
According to the Directive 67/548/EEC and its subsequent amendments, the test substance is not acutely toxic via the oral route.
According to the Regulation (EC) No 1272/2008 and subsequent regulations, the test item is not acutely toxic via the oral route.
Executive summary:

The acute oral toxicity of the test substance was investigated according to the OECD guideline 423 (2001). Two dose groups of three females received a single dose of 2000 mg/kg bw in corn oil via gavage. Clinical signs, mortality, and body weight were recorded. All animals were subjected to gross necropsy.

No mortality was observed during the study. Lacrimation and/or salivation were evident in five animals on the day of dosing. Mucous stool and/or soiled perineal region were observed in 3 animals on Day 1, but they returned to a normal appearance on Day 2. One rat presented clinical signs and those were decreased fecal volume or no stool from Day 1 to Day 3, refusal to feed on Day 2 only, decrease in locomotor activity and irregular respiration from Day 2 until Day 4, but all clinical signs returned to normal from Day 5 onwards. These clinical signs were considered to be test substance-related effects. Furthermore, a decrease in body weight or a tendency to suppress body weight was evident in five animals on Day 1 and Day 3. The five animals retunred to normal appearance on Day 7. These changes were considered to be test substance-related effects. Lastly, no grossly visible evidence of morphologic abnormalities was evident in any animals.

Based on these results the LD50 cut-off value was considered to be equal or greater than 5000 mg/kg bw for female rats.

According to the Directive 67/548/EEC and its subsequent amendments, the test substance is not acutely toxic via the oral route.

According to the Regulation (EC) No 1272/2008 and subsequent regulations, the test item is not acutely toxic via the oral route.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
5 000 mg/kg bw

Additional information

Acute oral toxicity

One reliable animal study according to OECD 423 (key_Acute toxicity_2015_RL1) is considered to be reliable without restrictions. The LD50 cut-off value was determined to be equal or greater than 5000 mg/kg bw. The test item is not acutely toxic via the oral route.


Justification for selection of acute toxicity – oral endpoint
GLP guideline study conducted with the test item

Justification for classification or non-classification

Acute oral toxicity

The available guideline-conform study conducted under GLP indicate that test item is not acutely toxic via the oral route. Thus, according to Directive 67/548/EEC and its subsequent amendments and Regulation (EC) No 1272/2008 and its subsequent regulations, no classification or labelling is required.

Specific target organ toxicant (STOT) - single exposure: oral

The classification criteria according to Regulation (EC) No 1272/2008 as specific target organ toxicant (STOT) – single exposure, oral are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value, oral for a Category 1 classification (C≤ 300 mg/kg bw) and at the guidance value, oral for a Category 2 classification (2000 mg/kg bw ≥C > 300 mg/kg bw). No classification required.