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Description of key information

Acute oral toxicity (OECD guideline 401): LD50 = 2356 mg/kg bw (CIBA-GEIGY Ltd., 850292, 1985)


Acute dermal toxicity (OECD guideline 402): LD50 > 2000 mg/kg bw (CIBA-GEIGY Ltd., 850295, 1985)

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:
May-June, 1985
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes
Remarks:
Conducted under GLP-like quality assurance with QAU statement included
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: TIF:RAIf (SPF), F3-crosses of RII 1/Tif x RII 2/Tif
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: CIBA-GEIGY LTD. Tierfarm, 4334 Sisseln, Switzerland
- Age at study initiation: 7-8 weeks
- Weight at study initiation: 165 - 220 g
- Fasting period before study: overnight fasting
- Housing: caged in groups of 5 in Macrolon cages type 4 with standardized soft wood bedding
- Diet: Rat food, NAFAG No. 890, NAFAG AG, ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3° C
- Humidity (%): 55+15%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12
Route of administration:
oral: gavage
Vehicle:
other: Distilled water containing 0.5% carboxymethylcellulose and 0.1% polysorbate 80
Details on oral exposure:
DOSE VOLUME APPLIED
10 mL/kg bw
Doses:
1000, 2000, and 5000 mg/kg bw
No. of animals per sex per dose:
5 males and 5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations:
Mortality: daily; a.m. and p.m. on working days, a.m. on weekend days
Signs and symptoms: 1, 2, 3 and 5 hours post dose and then daily
Body weight: on days 1, 7, 14 and at death
- Necropsy of survivors performed: yes; spontaneously dying animals were submitted to a gross necropsy as soon as possible; survivors at the end of the observation period.
Statistics:
From the body weights, the group means and their standard deviations were calculated.
The LD50 values (including their 95% confidence limits) were computed by the logit model.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
2 356 mg/kg bw
Based on:
test mat.
95% CL:
1 810 - 3 307
Sex:
male
Dose descriptor:
LD50
Effect level:
2 505 mg/kg bw
Based on:
test mat.
95% CL:
1 616 - 5 058
Sex:
female
Dose descriptor:
LD50
Effect level:
2 238 mg/kg bw
Based on:
test mat.
95% CL:
1 375 - 4 014
Mortality:
0/10 mortality occurred in the 1000 mg/kg bw group. 3/10 animals died in the 2000 mg/kg bw group (1 male and 2 females), and all (10) animal died in the 5000 mg/kg bw group.
Clinical signs:
Dyspnea, exophthalmos, ruffled fur, and abnormal body positions were seen, being common symptoms in acute tests.

Additionally, diarrhea was observed in the two lower dose groups on the administration day, in the highest dose group up to four days after the administration.

In the 2000 and 5000 mg/kg dose groups, sedation was detected up to day 4 after the administration and chromodacryorrhea between days 2 and 4 after the administration.

Tremor was seen in the 2000 mg/kg bw dose group on the administration day and on day 1.

The surviving animals recovered within 10 - 12 days.
Body weight:
Not impaired
Gross pathology:
No deviations from normal morphology were found in the 1000 mg/kg bw dose group.

Gastrointestinal dilatations were observed in two females of the 2000 mg/kg bw dose group and in six animals of the 5000 mg/kg bw dose group. Hemorrhagic lungs were detected in one male each of the 2000 and 5000 mg/kg bw dose groups. In one female of the 5000 mg/kg bw dose group, fluid contents of the thoracic cavity was found.

In the 2000 mg/kg bw dose group, in one female haemorrhagic contents were found in the abdominal cavity.
Interpretation of results:
GHS criteria not met
Conclusions:
Upon an acute oral administration and a 14 day post-treatment observation period, the LD50 (with 95% confidence limits calculated, where possible) was determined to be 2356 (1810-3307) mg/kg bw.
Executive summary:

In an acute oral toxicity test according to OECD guideline 401 and performed under GLP-like quality control, groups of 5 male and 5 female rats were treated with the test substance by oral gavage administration at dosage levels of 1000, 2000 and 5000 mg/kg body weight. The test item was diluted in distilled water containing 0.5% carboxymethylcellulose and 0.1% polysorbate 80. All animals were observed 1, 2, 3 and 5 hours postdose and then once daily for 14 days for signs and symptoms. The animals were observed twice daily for mortality and body weights were recorded on days 1, 7, 14 and at death. All animals were necropsied and examined macroscopically. No mortality occurred in the 1000 mg/kg body weight group. In the 2000 mg/kg bw group, 1 male and 2 females died and all animal died in the 5000 mg/kg bw group. Dyspnea, exophthalmos, ruffled fur, and abnormal body positions were seen, being common symptoms in acute tests. Additionally, diarrhea was observed in the two lower dose groups on the administration day and in the highest dose group up to four days after the administration. Tremor was seen in the 2000 mg/kg bw dose group on the administration day and on day 1. In the 2000 and 5000 mg/kg dose groups, sedation was detected up to day 4 after the administration and chromodacryorrhea between days 2 and 4 after the administration. The surviving animals recovered within 10 - 12 days. During necropsy, no deviations from normal morphology were found in the 1000 mg/kg bw dose group. Gastrointestinal dilatations were observed in two females of the 2000 mg/kg bw dose group and in six animals of the 5000 mg/kg bw dose group. In addition, hemorrhagic content was found in the abdominal cavity in one female of the 2000 mg/kg bw dose group. Hemorrhagic lungs were detected in one male each of the 2000 and 5000 mg/kg bw dose groups. In one female of the 5000 mg/kg bw dose group, fluid contents of the thoracic cavity was found. The resulting LD50 values with 95% confidence limits were calculated to be 2505 (1616-5058) mg/kg bw in males, 2238 (1375-4014) mg/kg bw.in females and 2356 (1810-3307) mg/kg bw.in both sexes.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
2 356 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because the substance is classified as corrosive to the skin
Endpoint conclusion
Endpoint conclusion:
no study available

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:
May - July, 1985
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
no
Remarks:
GLP-like quality assurance
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Tif:RAIf (SPF), F3-crosses of RII 1/Tif x RII 2/Tif
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: CIBA-GEIGY LTD. Tierfarm, 4334 Sisseln, Switzerland
- Age at study initiation: 7-8 weeks
- Weight at study initiation: 193 - 236 g
- Housing: caged individually in Macrolon cages type 2 with standardized soft wood bedding
- Diet: Rat food, NAFAG No. 890, NAFAG AG, ad libitum.
- Water: ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 55 +/- 15
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12

IN-LIFE DATES:
From: May 8, 1985 To: May 22, 1985
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: back of the rat
- % coverage: at least 10 %
- Type of wrap if used: covered with a gauze-lined semiocclusive dressing, which was fastened around the trunk with an adhesive elastic bandage.

REMOVAL OF TEST SUBSTANCE
- Washing: After an exposure period of 24 hours the dressing was removed and the skin was cleaned with lukewarm water.

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2 mL/kg bw
- Concentration (if solution): undiluted
- Constant volume or concentration used: yes
Duration of exposure:
24h
Doses:
One single dose (2000 mg/kg bw).
No. of animals per sex per dose:
5 males and 5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations:
Mortality: daily, a.m. and p.m. on working days, a.m. on weekends
Signs and Symptoms: 1, 2, 3 and 5 hours post dose, then daily
Body weight: on days 1, 7, and 14
- Necropsy of survivors performed: yes, at the end of observation period
Statistics:
From the body weights, the group means and their standard deviations were calculated.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Sex:
male
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
All animals survived.
Clinical signs:
Dyspnea, exophthalmos, ruffled fur, and abnormal body positions were seen, being common symptoms in acute tests. Additionally, sedation was observed 5 hours after application. Slight erythema was observed on day 1. The animals recovered within 9 days.
Body weight:
Body weight development was not impaired.
Gross pathology:
No deviations from normal morphology were found.
Interpretation of results:
GHS criteria not met
Conclusions:
Upon an acute dermal administration and a 14 day post-treatment observation period, the LD50 (with 95% confidence limits calculated where possible) was determined to be greater than 2000 mg/kg body weight.
Executive summary:

In an acute dermal toxicity study following OECD guideline 402 and under quality controlled conditions, 5 male and 5 female rats were dermally exposed to the test item for 24 hours at a limit dose of 2000 mg/kg body weight. The test article was used undiluted and applied at a volume of 2 ml/kg body weight to the clipped back of the animals. It was covered with a gauze-lined semiocclusive dressing, which was fastened around the trunk with an adhesive elastic bandage. After an exposure period of 24 hours the dressing was removed and the skin was cleaned with lukewarm water. All animals were observed 1, 2, 3 and 5 hours postdose and once daily for 14 days for signs and symptoms. The animals were observed twice daily for mortality. Body weights were recorded on days 1, 7 and 14. All animals were submitted to a gross necropsy at the end of the observation period. All animals survived the 2000 mg/kg dermal application. Dyspnea, exophthalmos, ruffled fur, and abnormal body positions were seen, being common symptoms in acute tests. Additionally, sedation was observed 5 hours after application. Slight erythema was observed on day 1. The animals recovered within 9 days. No deviations from normal morphology were found during necropsy. Based on these observations, the dermal LD50 value of the test item was greater than 2000 mg/kg body weight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
> 2 000 mg/kg bw

Additional information

Acute oral toxicity:

The acute oral toxicity of the test substance was assessed in a GLP-like quality controlled study following OECD guideline 401 (CIBA-GEIGY Ltd, 850292, 1985). Groups of 5 male and 5 female rats were treated with the test substance by oral gavage administration at dose levels of 1000, 2000 and 5000 mg/kg body weight followed by an observation period of 14 days. The test item was diluted in distilled water containing 0.5% carboxymethylcellulose and 0.1% polysorbate 80. No mortality occurred in the 1000 mg/kg body weight group. In the 2000 mg/kg bw group, 1 male and 2 females died and all animal died in the 5000 mg/kg bw group. Dyspnea, exophthalmos, ruffled fur, and abnormal body positions were seen, being common symptoms in acute tests. Additionally, diarrhea was observed in the two lower dose groups on the administration day and in the highest dose group up to four days after the administration. Tremor was seen in the 2000 mg/kg bw dose group on the administration day and on day 1. In the 2000 and 5000 mg/kg dose groups, sedation was detected up to day 4 after the administration and chromodacryorrhea between days 2 and 4 after the administration. The surviving animals recovered within 10 - 12 days. During necropsy, no deviations from normal morphology were found in the 1000 mg/kg bw dose group. Gastrointestinal dilatations were observed in two females of the 2000 mg/kg bw dose group and in six animals of the 5000 mg/kg bw dose group. In addition, hemorrhagic content was found in the abdominal cavity in one female of the 2000 mg/kg bw dose group. Hemorrhagic lungs were detected in one male each of the 2000 and 5000 mg/kg bw dose groups. In one female of the 5000 mg/kg bw dose group, fluid contents of the thoracic cavity was found. The resulting LD50 values with 95% confidence limits were calculated to be 2505 (1616-5058) mg/kg bw in males, 2238 (1375 -4014) mg/kg bw in females and 2356 (1810-3307) mg/kg bw in both sexes.

This result was confirmed in a second acute oral toxicity study conducted according OECD guideline 401 but without QAU surveillance (CIBA-GEIGY Ltd, 840601, 1984). Groups of 5 male and 5 female rats were treated with the test substance by oral gavage administration at dosage levels of 1000, 2000 and 5000 mg/kg body weight followed by a 14 day observation period. The test item was diluted in distilled water containing 0.5% carboxymethylcellulose and 0.1% polysorbate 80. The following mortalities occurred: all animals of the 5000 mg/kg group, 4/5 females and 0/5 males in the 2000 mg/kg group, and 0 animals in the 100 mg/kg group. Dyspnoea, exophthalmus, ruffled fur and curved body position were observed, being symptoms commonly seen in acute tests. In addition, the following symptoms were considered to be test item related: in all dose groups, sedation, which was severe in all but one animal of the 5000 mg/kg dose group (preceding death), was seen. Slight diarrhea in animals of all dose groups, and a slight tremor in animals of the intermediate dose group were noted. During necropsy, no gross organ changes were observed, that were considered to be due to the administration of the test compound. The resulting LD50 values with 95% confidence limits were calculated to be 2789 (1778-6457) mg/kg bw in males, 1786 (786-2863) mg/kg bw in females and 2217 (1691-3022) mg/kg bw in both sexes. These values are in a similar range as observed in the above described study. The study from 1985 was selected as the key study, because it was performed under QAU surveillance and revealed effects related to treatment during necropsy examination.

Acute dermal toxicity:

An acute dermal toxicity study was performed according to OECD guideline No. 402 with 5 male and 5 female rats (CIBA-GEIGY Ltd, 850295, 1985). In the limit test, the undiluted test article was applied semiocclusively to the back of the test animals for 24 hours at a dose level of 2000 mg/kg body weight followed by an observation period of 14 days. No mortality occurred within the timeframe of the study. Dyspnea, exophthalmos, ruffled fur, and abnormal body positions were seen, being common symptoms in acute tests. Additionally, sedation was observed 5 hours after application. Slight erythema was observed on day 1. The animals recovered within 9 days. No deviations from normal morphology were found during necropsy. Based on these observations, the dermal LD50 value of the test item was greater than 2000 mg/kg body weight.

Acute inhalation toxicity:

No data available.


Justification for selection of acute toxicity – oral endpoint
Most relevant guideline study

Justification for selection of acute toxicity – dermal endpoint
guideline study

Justification for classification or non-classification

Classification, Labeling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for the purpose of classification under Regulation (EC) No.1272/2008. Based on the data, classification for acute toxicity is not warranted under Regulation (EC) No.1272/2008.