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Description of key information

LD50 oral rat is > 200 and < 2000 mg/kg bw

LD 50 dermal rat is > 2000 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:
1997
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
of 22th March 1996
Deviations:
no
Qualifier:
equivalent or similar to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Winkelmann, Borchen, Germany
- Age at study initiation: 8-10 weeks
- Weight at study initiation: 173 g (mean females) and 204 g (mean males)
- Housing: 3 animals per cage
- Diet (e.g. ad libitum): yes
- Water (e.g. ad libitum): yes
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2 °C
- Humidity (%): 55 ± 5 °C
- Air changes (per hr): 15 - 20 per hour
- Photoperiod (hrs dark / hrs light): 12 h rhythm

IN-LIFE DATES: From: To: 10 SEPT 1997 to 08 OKT 1997
Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Details on oral exposure:
application volume 10 mL/kg bw
The test substance was formulated in the application vehicle immediately prior to teatment. Therefore analytical investigations of the stability in the vehicle were not performed.
Doses:
2000 mg/kg bw as first dose in males; 200 mg/kg bw as second dose in male and females
No. of animals per sex per dose:
3 males and 6 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: several times on the day of administration, and at least once daily during the following 14 day observation period
- body weights: weekly
- Necropsy of survivors performed: yes
Statistics:
not applicable
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 200 mg/kg bw
Based on:
test mat.
Remarks on result:
other: LD50 between 200 and 2000 mg/kg bw
Mortality:
all 3 female rats died after administration of 2000 mg/kg bw within 1 hour
Clinical signs:
No clinical signs
Body weight:
no effects on weight gain of the surviving animals
Gross pathology:
Severe red discoloration of the stomach and small intestine was observed at necropsy in the intercurrent death animals (2000 mg/kg bw group). None of the sacrificed animals showed any noticable gross pathological findings (200 mg/kg bw group).

Dose (mg/kg bw) sex  toxicological result  mortality  onset of mortality
(1st) 2000 female 3 / 3 100 %  1h
(2nd) 200 female 3 / 0 ---   ---
 (2nd) 200 male  3 / 0  ---  ---

Toxicological results:

number of dead animals / number of animals treated

Interpretation of results:
Category 4 based on GHS criteria
Executive summary:

The acute oral LD50 in rats was determined as > 200 mg/kg bw and < 2000 mg/kg bw based on the results of a limit dose study performed according to OECD TG 423. The test dose of 2000 mg/kg led to mortality of 3/3 females with severe red discoloration of the stomach and small intestine at necropsy. The second dose of 200 mg/kg bw tested in 3 male and 3 female rats was well tolerated without clinical signs or any noticeable gross pathological findings. Since the dose of 200 mg/kg bw turned out as the NOEL for both sexes it can be considered that the LD50 is > 300 mg/kg bw (Acute Tox 4), as shown in the flow chart in Annex 3c of OECD 423 (1996) and Annex 2d of OECD 423 (2001). The test substance should thus be regarded as harmful if swallowed.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
(1987)
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Strain: HsdCpb: Wu
- Source: Harlan Winkelmann GmbH, Borchen, Germany
- Age at study initiation: approximately 9 weeks for males, about 12 weeks for females
- Weight at study initiation: males 237-251 g; females 196-207 g
- Housing: The animals were caged individually in polycarbonate cages on low dust wood granulate bedding.
- Diet and water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 55 +/- 5
- Air changes (per hr): approx. 10
- Photoperiod (hrs dark / hrs light): 12 / 12
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
One day before the start of the treatment the back and flanks of the rats were shorn. For each dose and animal the required amount of the solid test substance was weighed out and applied to a wet gauze-layer (6.0 cm x 5.0 cm = 30.0 cm²) of a "Cutiplast steril" coated with air-tight "Leukoflex". The gauze strip was placed on the rat's back and secured with a "Lomir biomedical Inc rat jacket", which was connected with a safety pin to the stretch tape to ensure that the animals could not ingest the test substance.

REMOVAL OF TEST SUBSTANCE
After approximately 24 hours the dressings were removed and the area was rinsed with water and soap and gently patting the area dry.
Duration of exposure:
24 hours
Doses:
2000 mg/kg bw per 30.0 cm²
Dose range: males 30.1 - 31.9 mg/cm²; females 28.0 - 29.6 mg/cm².
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: at least 14 days
- Frequency of observations and weighing: Clinical signs and mortality rates were determined several times on the day of application and subsequently at least once daily. The weight gain of the animals was checked weekly until the end of the study.
- Necropsy of survivors performed: yes
Statistics:
An assessment of the LD50 was made based on the applied dose and a software program according to Spearman and Kärber, if appropriate.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
No mortalities occurred.
Clinical signs:
No clinical signs were observed.
Body weight:
There were no toxicologically significant effects on body weight or body weight development in males and females.
Gross pathology:
The necropsies performed at the end of the study revealed no particular findings.
Other findings:
one male showed local skin effects (treatment area was partly encrusted on day 11 of the study).
Interpretation of results:
GHS criteria not met
Executive summary:

An acute dermal toxicity study was performed according to OECD TG 402. For the purpose of a limit test 2000 mg/kg of the test item was applied occlusively to the skin of 5 male and 5 female rats for 24 hours. No mortalities, no clinical signs, no effects on weight development and no gross pathological findings were observed during the 14-days observation period. One male showed local skin effects (treatment area was partly encrusted) on day 11 of the study only. The resulting LD50 was thus determined with > 2000 mg/kg bw for both sexes combined.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw

Additional information

The acute oral LD50 in rats was determined as > 200 mg/kg bw and < 2000 mg/kg bw based on the results of a limit dose study performed according to OECD TG 423. The test dose of 2000 mg/kg led to mortality of 3/3 females with severe red discoloration of the stomach and small intestine at necropsy. The second dose of 200 mg/kg bw tested in 3 male and 3 female rats was well tolerated without clinical signs or any noticeable gross pathological findings. The test substance should be regarded as harmful if swallowed.

An acute dermal toxicity study was performed according to OECD TG 402. For the purpose of a limit test 2000 mg/kg of the test item was applied occlusively to the skin of 5 male and 5 female rats for 24 hours. No mortalities, no clinical signs, no effects on weight development and no gross pathological findings were observed during the 14-days observation period. One male showed local skin effects (treatment area was partly encrusted) on day 11 of the study only. The resulting LD50 was thus determined with > 2000 mg/kg bw for both sexes combined.

Justification for classification or non-classification

In an LD50 study on rats following OECD TG 423 of 1996 the oral dose of 2000 mg/kg bw led to death of all 3 treated females. The second dose of 200 mg/kg bw tested in 3 males and 3 females was well tolerated. Since the dose of 200 mg/kg bw turned out as the NOEL for both sexes it can be considered that the LD50 is > 300 mg/kg bw (Acute Tox 4), as shown in the flow chart in Annex 3c of OECD 423 (1996) and Annex 2d of OECD 423 (2001). According to Regulation 1272/2008 the test substance should thus be regarded as harmful if swallowed (Acute Tox 4, H302).  

No classification for acute dermal toxicity is warranted since the dermal LD50 was determined with > 2000 mg/kg bw.