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Administrative data

Description of key information

In a study comparable to OECD Guideline 401, the LD50 of the test item was determined to be 685 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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Gassner
- Weight at study initiation: males: 222 (170 - 252) g; females: 176 (153 - 188) g

ENVIRONMENTAL CONDITIONS
not reported
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 2 - 30 % aqueous suspension with carboxymethyl cellulose and 2 - 3 drops of Cremophor EL.

MAXIMUM DOSE VOLUME APPLIED: 21.4 mL/kg bw
Doses:
6400; 3200; 1600; 800; 400; 320; 200 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 7 days
- Frequency of observations and weighing: Body weight was measured on the application day, on day 3 and 4, respectively, and on day 7. Observation of clinical signs was several times on the day of administration and once daily afterwards with the exception of weekends and on holidays.
- Necropsy of survivors performed: yes
Statistics:
Calculation of LD50 by method of Litchfield and Wilcoxon.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
685 mg/kg bw
Based on:
test mat.
95% CL:
>= 486 - <= 966
Remarks on result:
other: mortality was observed in doses of 320 mg/kg bw and higher
Mortality:
see table "any other information on results incl. tables"
Clinical signs:
Convulsions, dyspnea, apathy, tremors, salivation, eye discharge, partial exophthalmus, ventral or lateral body position, staggering, exsiccosis, paresis of hind limbs.

6400 and 3200 mg/kg bw:
15 minutes after application convulsions, dyspnea, cower position.
Hours later apathy, tremors, cower position, at 6400 mg/kg bw additionally gasping for breath, partial exophtalmus.
During observation period lateral position, dyspnea, apathy, partially secretion out of eyes and mouth, cower position.

1600 mg/kg bw:
Hours after application dyspnea, cower position, apathy, lateral body position, staggering, clonic convulsions.
Symptoms stable for the following days, additionally tremors and secretion out of mouth and eyes.

800 - 320 mg/kg bw:
Hours after application staggering, partially cower position and creeping, at 800 and 400 mg/kg bw additionally convulsions, latero-abdominal position, dyspnea, aggressiveness, partially weakness of hind limbs, biting convulsions, partially tremors, salivation.
Amelioration of symptoms during the following days, 800 mg/kg additionally exsiccosis.
Animals free of symptoms around day 4.

200 mg/kg bw:
Hours after application cower position, slight apathy.
Animals free of symptoms on day 2.
Body weight:
Body weight gain stagnated during observation period in survivors of all dose groups.
Gross pathology:
Hyperemia, dilatation of heart and gastroesophageal vestibule, fine ulcerations, diarrhoeic intestinal content, discoloration of kidneys and liver in animals that died.
Nothing abnormal found in sacrificed animals.

Mortality 

Dose [mg/kg bw]

Concentration in vehicle [%]

Number of animals and sex

1 h

24 h

48 h

7 d

6400

30

5 M

0/5

5/5

5/5

5/5

 

 

5 F

0/5

5/5

5/5

5/5

3200

30

5 M

0/5

4/5

5/5

5/5

 

 

5 F

0/5

3/5

4/5

5/5

1600

16

5 M

0/5

2/5

2/5

5/5

 

 

5 F

0/5

5/5

5/5

5/5

800

8

5 M

0/5

1/5

1/5

2/5

 

 

5 F

0/5

2/5

4/5

4/5

400

4

5 M

0/5

0/5

0/5

0/5

 

 

5 F

0/5

0/5

1/5

2/5

320

4

5 M

0/5

0/5

0/5

0/5

 

 

5 F

0/5

0/5

1/5

1/5

200

2

5 M

0/5

0/5

0/5

0/5

 

 

5 F

0/5

0/5

0/5

0/5

 

 

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
In a study comparable to OECD Guideline 401, the LD50 of the test item was determined to be 685 (95 % CL: 486 - 966) mg/kg bw.
Executive summary:

The acute oral toxicity of the test item was assessed in a study comparable to OECD Guideline 401 (Acute Oral Toxicity, standard acute method). Male and female rats of the Sprague-Dawley strain (weight at study initiation: males: 222 (170 - 252) g; females: 176 (153 - 188) g; number of animals per sex per dose: 5) were exposed by gavage to doses of 6400; 3200; 1600; 800; 400; 320; 200 mg test item/kg bw over a test duration of 7 days. As vehicle carboxymethyl cellulose  (2 - 30 % aqueous suspension with carboxymethyl cellulose and  2 - 3 drops of Cremophor EL) was used. No control was performed. Body weight was measured on the application day, on day 3 and 4,  respectively, and on day 7. Observation of clinical signs was performed several times on the day of administration and once daily afterwards with the exception of weekends and on holidays. In addition, necropsy of survivors was conducted. The LD50 was calculated by method of Litchfield and Wilcoxon.The following clinical signs were observed: Convulsions, dyspnea, apathy, tremors, salivation, eye discharge, partial  exophthalmus, ventral or lateral body position, staggering, exsiccosis,  paresis of hind limbs. At 6400 and 3200 mg/kg bw, 15 minutes after application convulsions, dyspnea and cower position occurred. Hours later apathy, tremors, cower position, at 6400 mg/kg bw  additionally gasping for breath and partial exophtalmus was observed. During observation period lateral position, dyspnea, apathy, partially secretion out of eyes and mouth and cower position was noted. For level of 1600 mg/kg bw, dyspnea, cower position, apathy, lateral body position, staggering and clonic convulsions was reported. The symptoms were stable for the following days (additionally tremors and secretion out of mouth and eyes). At 800 - 320 mg/kg bw, staggering, partially cower position and creeping, at 800 and 400 mg/kg bw additionally convulsions, latero-abdominal position, dyspnea, aggressiveness, partially weakness of hind limbs, biting convulsions, partially tremors and salivation was observed. During the following days all symptoms ameliorated; at 800 mg/kg  additionally exsiccosis occurred. Animals were free of symptoms around day 4. At 200 mg/kg bw, hours after application animals were in cower position and slightly apathic. Animals were free of symptoms on day 2. The body weight gain stagnated during observation period in survivors of all dose groups. By gross pathology, hyperemia, dilatation of heart and gastroesophageal vestibule, fine ulcerations, diarrhoeic intestinal content, discoloration of kidneys and  liver in animals that died was detected. Nothing abnormal was found in sacrificed animals. Mortality was observed in doses of 320 mg/kg bw and higher. In result, the LD50 of the test item was determined to be 685 (95 % CL: 486 - 966) mg/kg bw. Based on this result, the test item is considered to be classified as category 4 based on GHS criteria.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
685 mg/kg bw
Quality of whole database:
The study data is considered sufficient for conclusion.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

There are data on acute oral toxicity of the test item in five different species (rat, rabbit, dog, cat and hen) available.

Key study

The acute oral toxicity of the test item was assessed in a study comparable to OECD Guideline 401 (Acute Oral Toxicity, standard acute method). Male and female rats of the Sprague-Dawley strain (weight at study initiation: males: 222 (170 - 252) g; females: 176 (153 - 188) g; number of animals per sex per dose: 5) were exposed by gavage to doses of 6400; 3200; 1600; 800; 400; 320; 200 mg test item/kg bw over a test duration of 7 days. As vehicle carboxymethyl cellulose  (2 - 30 % aqueous suspension with carboxymethyl cellulose and  2 - 3 drops of Cremophor EL) was used. No control was performed. Body weight was measured on the application day, on day 3 and 4,  respectively, and on day 7. Observation of clinical signs was several times on the day of administration and once daily afterwards with the exception of weekends and on holidays. In addition, necropsy of survivors was conducted. The LD50 was calculated by method of Litchfield and Wilcoxon. Mortality was observed in doses of 320 mg/kg bw and higher. In result, the LD50 of the test item was determined to be 685 (95 % CL: 486 - 966) mg/kg bw.

Supporting study

The acute oral toxicity of the test item was assessed in a study comparable to OECD Guideline 401 (Acute Oral Toxicity, standard acute method). Male and female rats of the Wistar strain (weight at study initiation: ca. 180 g; number of animals per sex per dose: 5) were exposed by gavage to a limit dose of 2000 mg test item/kg bw over a test duration of 14 days. As vehicle carboxymethyl cellulose  (0.5% aqueous solution) was used. No control was performed. Body weight was measured on the application day, on day 3 and 4,  respectively, and on day 7. Toxicological symptoms were recorded several times on the day of administration and at least once each day. In addition, necropsy of survivors was conducted. Acclimation to test conditions (temperature: 20-24 °C; humidity: 30-70 %; photoperiod: 12 dark/12 light) was for at least 1 week. One female died within 2 d, but no further mortalities were observed. In result, the LD50 of the test item was determined to be > 2000 mg/kg bw.

Other information

In a study similar to OECD Guideline 401 (BASF AG, 1959), male and female rats (number of animals per sex per dose: 10) were exposed by gavage to 1000, 1260, 1600, 2000 and 2500 mg/kg bw over a test duration of 7 days. The LD50 of the test item was 1330 mg/kg bw (95 % CL 1168 - 1519).

To determine the acute oral toxicity of the test item in cats by the standard acute method (BASF AG, 1976), male and females (one animal per dose) were exposed by gavage to doses of 464; 215; 100 and 46.4 mg test item/kg bw at a test duration of 14 days. 50 % of the animals died within 4 to 8 days upon treatment with 215 mg/kg or more. In result, the LD50 of the test item was determined to be ca. 215 mg/kg bw.

In a study to assess the acute/ subacute toxicity and neurotoxicity of the test item, male and female dogs (strain:Beagle; 2 animals per dose level) were exposed by gavage to doses of 50 and 100 mg test item/kg bw (BASF AG, 1981). The LD50 of the test item was > 100 mg/kg bw.

Moreover, the acute oral toxicity of the test item was assessed in a GLP-complaint 21-day Acute Delayed Neurotoxicity Test according to the proposed guidelines of the United States Environmental Protection Agency (E.P.A) 163 (1978). The test item was administered by gavage at dose levels of 0 (vehicle only), 2778, 3727, 5000, 6708 and 9000 mg/kg bw to female hens (10 animals per dose, 5 in the "protected" trial, 5 in the "unprotected" trial). In result, the LD50 of the test item was determined to be 7400 mg/kg bw (BASF AG, 1981).

In a study similar to OECD Guideline 401 (BASF AG, 1976), male and female rabbits (number of animals per sex per dose: 2; 215 mg/kg bw: 3) were exposed by gavage to 2150; 1000; 464; 215 and 100 mg test item/kg bw over a test duration of 14 days. The LD50 of the test item was ca. 215 mg/kg bw.

Conclusion

Based on a worst-case-approach and using the most reliable information (BASF AG, 1974), the LD50 of the test item is considered to be 685 mg/kg bw. In another study with rats comparable to OECD Guideline 401 (BASF AG, 1988) the LD50 of the test item was determined to be much higher (> 2000 mg/kg bw). This result is supported by an older study with rats similar to OECD 401 (BASF AG, 1959), according to which the LD50 is reported to be 1330 mg/kg bw. The toxicity to cats (BASF AG, 1976), dogs (BASF AG, 1992) and rabbits (BASF AG, 1976) was established to be much higher. In contrast, the highest LD50 was determined for hens (BASF AG, 1981; LC50 = 7400 mg/kg bw).

Following the principle of minimising/avoiding unnecessary animal testing, the performance of a new guideline study is not indicated. According to Regulation EC No 1907/2006, Annex XI available data are regarded as suitable to cover the endpoint 7.2.1 acute oral toxicity.

Justification for classification or non-classification

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

The available data are suitable for classification purposes under Regulation 1272/2008 (CLP). As a result the test item is considered to be classified for acute oral toxicity Category 4 (H302: Harmful if swallowed) under Regulation (EC) No 1272/2008, as amended for the 12th time in Regulation (EU) 2019/521.