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Description of key information

Oral (OECD 401), rat: LD50: > 20 mL/kg bw (corresponding to > 18000 mg/kg bw based on a density of 0.9 g/cm³; limit test)

Dermal (OECD 402), rat: LD50 > 2000 mg/kg bw (limit test)

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:
1977
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
No information on test substance purity was given, limited documentation
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
no information about test substance purity, limited documentation
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Remarks:
SPF
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Females nulliparous and non-pregnant: not specified
- Weight at study initiation: 145 - 190 g (7 days prior to dosage)
- Fasting period before study: approx. 16 h prior to dosage
- Housing: groups of five in plastic cages (42 x 26 x 14 cm), wood chip bedding
- Diet: pelleted Sniff Standard diet, ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): approx. 20
- Humidity (%): 50
- Photoperiod (hrs dark / hrs light): 12 / 12
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 20 mL/kg bw


Doses:
20 mL/kg bw (corresponding to 18000 mg/kg bw based on a density of 0.9 g/cm³)
No. of animals per sex per dose:
10
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: All animals were observed closely for gross signs of systemic toxicity and mortality at frequent intervals during the day of dosage, and at least once daily thereafter for a total of 14 days. Body weights were recorded on the day of administration and on day 14 thereafter.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
Statistical analysis of the mortality data was performed by the Litchfield & Wilcoxon in combination with the Gaussian Integral.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 18 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: The original LD50 value of > 20 mL/kg bw was recalculated based on the density of 0.9 g/cm3.
Mortality:
No mortality occurred during the study period.
Clinical signs:
All animals exhibited disturbances in coordination, diarrhea and piloerection beginning within 3 h after dosage and persisting for 24 h. At the 48 h evaluation and throughout the remainder of the study all the animals generally exhibited normal appearance and behavior.
Body weight:
No effect on body weight was noted.
Gross pathology:
Necropsies performed on the animals at termination exhibited no gross pathological findings.
Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No 1272/2008
Conclusions:
In this acute oral toxicity study a LD50 value > 20 mL/kg bw (corresponding to > 18000 mg/kg bw based on a density of 0.9 g/cm³) in male and female rats was found.
Executive summary:

The acute oral toxicity of the test substance was assessed in a study similar to OECD Guideline 401 (1977). A total dose of 20 mL/kg bw (equivalent to 18000 mg/kg bw based on a density of 0.9 g/mL; limit test) test substance was administered to 10 male and 10 female rats by gavage. Animals were observed for mortality and general clinical condition on the day of administration and once daily thereafter for 14 days. Body weights were recorded on the day of administration and on day 14 thereafter. Gross necropsy was performed at the end of the observation period at terminal sacrifice. None of the animals died during the study and the body weight gain was not affected by the administration of the test substance. All animals exhibited disturbances in coordination, diarrhea and piloerection beginning within 3 h after dosage and persisting for 24 h. No pathological findings were observed at necropsy. Based on the results of this study, the oral LD50 value was determined to be > 20 mL/kg bw (equivalent to > 18000 mg/kg bw based on a density of 0.9 g/mL) in rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 2) and consistent studies, and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via inhalation route

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:
05 - 19 Nov 1992
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
missing information about environmental conditions and acclimatisation period; occlusive instead of semi-occlusive dressing
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
adopted February 24, 1987
Deviations:
yes
Remarks:
missing information about environmental conditions and acclimatisation period; occlusive instead of semi-occlusive dressing
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Females nulliparous and non-pregnant: not specified
- Weight at study initiation: 2.0 - 2.6 kg (males) and 2.1 - 2.4 kg (females)
- Housing: individually in suspended wire mesh cages
- Diet: Purina Rabbit Chow (Diet #5321), provided daily
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12 / 12

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: clipped skin of the dorsal area of the trunk
- % coverage: 10%
- Type of wrap if used: plastic wrap secured with non-irritating tape

REMOVAL OF TEST SUBSTANCE
- Washing: The residual test article was gently washed off with distilled water prior to dermal observations.
- Time after start of exposure: 24 h
Duration of exposure:
24 h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The test sides were scored for dermal irritation at 24 hours post dose and on days 7 and 14 using the numerical Draize scale. The animals were observed 1, 2 and 4 hours post dose and once daily for 14 days for toxicity and pharmacological effects. The animals were observed twice daily for 14 days for mortality. Body weights were recorded pretest, weekly and at death or termination.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross pathology with preservation of abnormal tissues in 10% buffered formalin
Statistics:
LD50, 95% Confidence Limits, dose response curve and slope were calculated by method of Litchfield and Wilcoxon.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
One male animal died at day 11 post-dose.
Clinical signs:
Diarrhea occured in 2/5 males and 1/5 females within day 8 -14 post-dose. Male animal which died on day 12 post-dose showed predeath physical signs of diarrhea and lethargy, which is attributed to stress-induced gastrointestinal abnomalities common in New Zeeland White rabbits.
Body weight:
Body weight gains were within the normal ranges during the whole study period.
Gross pathology:
Necropsy of the dead animal revealed abnomalities in the intestines (filled with fluid) and treated skin, as well as soiling of the anogenital area. Necropsy results of survivors revealed treated skin abnormaties in 8/9 animals, two of which also exhibited liver abnormalities (nodules on liver). One animal appeared normal at necropsy.
Other findings:
Dermal reactions, well defined to moderate on day 1, were absent to severe on day 7 and absent on day 14.

Table 1. Results of acute dermal toxicity

Dose

[mg/kg bw]

Mortality

Clinical signs

 

n = 5

n = 5

Males

2000

1/5

2/5

Females

2000

0/5

1/5

Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No 1272/2008
Conclusions:
In this acute dermal toxicity study thre LD50 value was > 2000 mg/kg bw in male and female rabbits.
Executive summary:
The acute dermal toxicity of the test substance was assessed in a limit test performed in 5 male and 5 female new Zealand White rabbits according to OECD Guideline 402 and in compliance with GLP (1993). The test substance was applied at a single dose of 2000 mg/kg bw to the clipped dorsal area of the trunk of the animals and held in contact to the skin with a gauze patch and a plastic wrap around the torso for 24 hours. Animals were observed for mortality, general clinical condition and alterations of the administration area (erythema and/or edema) for a 14-day period. Body weights were recorded on the day of administration and on days 7 and 14 thereafter. Macroscopic examination was performed at the end of the observation period at terminal sacrifice. Nine of ten animals survived the 2000 mg/kg bw dermal application. One male died on day 11 after physical signs of diarrhea and lethargy which were attributed to stress-induced gastrointestinal tract abnormalities common in New Zealand White rabbits. Necropsy of the dead animal revealed abnormalities of intestine and treated skin, as well as soiling of the anogenital area. Diarrhea was the only abnormal physical sign noted in the survivors. Body weight gain was not affected by test substance administration. Erythema (grade 2-3) and edema (grade 2-3) of treated skin areas were observed on day 1 and was absent for on day 7. Erythema was fully regressed on day 14. Necropsy of survivors revealed treated skin abnormalities in 8/9 animals, two of which also exhibited liver abnormalities. Based on the results of this study, the dermal LD50 value for acute toxicity was determined to be > 2000 mg/kg bw in rabbits.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 2) and consistent studies, and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

Additional information

Oral

The acute oral toxicity of the test substance was assessed in a study similar to OECD Guideline 401 (1977). A total dose of 20 mL/kg bw (equivalent to 18000 mg/kg bw based on a density of 0.9 g/mL; limit test) test substance was administered to 10 male and 10 female rats by gavage. Animals were observed for mortality and general clinical condition on the day of administration and once daily thereafter for 14 days. Body weights were recorded on the day of administration and on day 14 thereafter. Gross necropsy was performed at the end of the observation period at terminal sacrifice. None of the animals died during the study and the body weight gain was not affected by the administration of the test substance. All animals exhibited disturbances in coordination, diarrhea and piloerection beginning within 3 h after dosage and persisting for 24 h. No pathological findings were observed at necropsy. Based on the results of this study, the oral LD50 value was determined to be > 20 mL/kg bw (equivalent to > 18000 mg/kg bw based on a density of 0.9 g/mL) in rats.

Dermal

The acute dermal toxicity of the test substance was assessed in a limit test performed in 5 male and 5 female new Zealand White rabbits according to OECD Guideline 402 and in compliance with GLP (1993). The test substance was applied at a single dose of 2000 mg/kg bw to the clipped dorsal area of the trunk of the animals and held in contact to the skin with a gauze patch and a plastic wrap around the torso for 24 hours. Animals were observed for mortality, general clinical condition and alterations of the administration area (erythema and/or edema) for a 14-day period. Body weights were recorded on the day of administration and on days 7 and 14 thereafter. Macroscopic examination was performed at the end of the observation period at terminal sacrifice. Nine of ten animals survived the 2000 mg/kg bw dermal application. One male died on day 11 after physical signs of diarrhea and lethargy which were attributed to stress-induced gastrointestinal tract abnormalities common in New Zealand White rabbits. Necropsy of the dead animal revealed abnormalities of intestine and treated skin, as well as soiling of the anogenital area. Diarrhea was the only abnormal physical sign noted in the survivors. Body weight gain was not affected by test substance administration. Erythema (grade 2-3) and edema (grade 2-3) of treated skin areas were observed on day 1 and was absent for on day 7. Erythema was fully regressed on day 14. Necropsy of survivors revealed treated skin abnormalities in 8/9 animals, two of which also exhibited liver abnormalities. Based on the results of this study, the dermal LD50 value for acute toxicity was determined to be > 2000 mg/kg bw in rabbits.

Justification for classification or non-classification

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

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