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Description of key information

The acute oral toxicity and the acute dermal toxicity of the test substance were investigated in Wistar rats, both studies were performed according to the respective OECD guidelines. 
- oral: LD50 (rat) > 2200 mg/kg bw
- dermal: LD50 (rat) > 4000 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:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP Guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: DR. K. Thomae GmbH, D-W7950 Biberach
- Age at study initiation: young adults
- Weight at study initiation: 150-300 g
- Fasting period before study: 16 hrs
- Housing: individual
- Diet: Kliba laboratory diet, Klingenthalermühle, Kaiseraugst, Switzerland ad libitum
- Water: Tap water ad libitum
- Acclimation period: at least 1 week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
oral: gavage
Vehicle:
other: solution in olive oil DAB 9
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 20 and 44 g/100 ml
- Amount of vehicle (if gavage): 5 ml/kg
- Justification for choice of vehicle: test substance is insoluble in water


MAXIMUM DOSE VOLUME APPLIED: 5 ml/kg

Doses:
1000, 2200 mg/kg
No. of animals per sex per dose:
5 males and females per dose level
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: at least once daily on working days, recordings of signs and symptoms several times/day; once on weekends
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 200 mg/kg bw
Mortality:
no death occurred in any of the dosing groups
Clinical signs:
In male animals no clinical signs were noted in the 1000 mg/kg dosing group, female animals showed dyspnoea, apathy, abdominal position, staggering, piloerection exsiccosis and exophthalmos and poor general state in the first 4 hours after dosing.

In the 2000 mg/kg dosing group dyspnoea, apathy, lateral position, staggering, atonia, paresis, narcotic like state, absent pain reflex, absent corneal reflex, cyanosis, piloerection, exsiccosis and red adhesive snout were noted in male and female animals
Body weight:
normal body weight gain was observed for all animals
Gross pathology:
no pathologic findings noted
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 200 mg/kg bw
Quality of whole database:
GLP, OECD guideline study

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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP Guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: DR. K. Thomae GmbH, D-W7950 Biberach
- Age at study initiation: young adults
- Weight at study initiation: 150-300 g
- Fasting period before study: 16 hrs
- Housing: individual
- Diet: Kliba laboratory diet, Klingenthalermühle, Kaiseraugst, Switzerland ad libitum
- Water: Tap water ad libitum
- Acclimation period: at least 1 week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: dorsal and dorsolateral parts of the trunk; about 50 cm²
- % coverage: 25-17 (calculated with a body surface area of 300-400 cm² depending on a body weight of 200-300 g as specified above)
- Type of wrap if used: semiocclusive dressing


REMOVAL OF TEST SUBSTANCE
- Washing (if done): warm water
- Time after start of exposure: 24 hours


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.43, 2.17, 4.34 ml/kg bw, respectively
- Concentration (if solution):
- Constant volume or concentration used: yes
Duration of exposure:
24 hours
Doses:
400, 2000, 4000 mg/kg
No. of animals per sex per dose:
5 males and females per dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: at least once daily on working days, recordings of signs and symptoms several times/day; once on weekends
- Necropsy of survivors performed: yes
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 4 000 mg/kg bw
Mortality:
In the highest dosing group 2 female animals died after one day and another female on day 2 after substance application.
Clinical signs:
Signs of toxicity noted in the 4000 mg/kg group comprised poor general state, dyspnoea, apathy, abdominal or lateral position, atonia, paresis, narcotic-like state, absent corneal and pain reflex, red-coloured urine and red-smeared fur in the anogenital area. The animals of the 2000 and 400 mg/kg dose group did not show any systemic signs of toxicity. After removal of the patches very slight to well-defined erythema, slight to moderate edema and hemorrhage could be observed in the high dose group. 7 days after application almost all animals showed scaling and one hemorrhage. Only scaling could be observed in almost all animals 14 days after application. In the mid dose group very slight to well-defined erythema and very slight edema were noticed after removal of the patches. 7 days after application a few animals exhibited very slight to well-defined erythema, very slight edema, scaling and severe scaling. 14 days after application only scaling was observed in 3 animals. In the low dose group no local effects could be seen.
Body weight:
all animals showed normal body weight gain
Gross pathology:
Animals that died (females)
4000 mg/kg (3 females)
general congestion
Liver intensified grayish-brown lobule liver pattern, partly confluent
Kidneys: black-brown tinge urine, bloody coloured

Histopathology:
4000 mg/kg (1 female):
Liver: increased lipid storage in the lobular periphery
Kidneys: acute necrosis of tubular cells in the cortex, focal fatty degeneration of tubular cells, diffuse
Urinary bladder: blood filled

Sacrificed animals: no pathologic findings noted
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
4 000 mg/kg bw
Quality of whole database:
GLP, OECD guideline study

Additional information

Acute oral toxicity:

The acute oral toxicity of the test substance was investigated in two groups of 5 male and 5 female rats, given a dose of 2200 and 10 female rats given a dose 1000 mg/kg bw as gavage (GLP OECD401 study, 1992_RL1). Signs of toxicity noted in the higher dosing group included poor and impaired general state, dyspnoea, apathy, lateral position staggering, paresis narcotic-like state, absent pain and corneal reflex cyanosis exsiccosis, chromodacryorrhea and red adhesive snout. Signs of toxicity of the lower dose included poor general state, dyspnoea, apathy, abdominal position staggering and exophthalmos. No death occurred and all animals appeared to be normal within 3 days after application. No abnormalities were noted at necropsy. under the conditions of the study the acute oral median lethal dose was found to be greater than 2200 mg/kg bw for male and female animals.

In a supporting study (GLP, similar to OECD guideline, 1986_RL1) the oral LD50 in rats was 2050 mg/kg bw.

Acute inhalation toxicity

Appropriate data to assess the acute inhalation toxicity of the test article are not available.

Acute dermal toxicity

The acute dermal toxicity of the test substance was investigated in three groups of 5 male and 5 female rats (OECD guideline 402, 1992_RL1). The test material was applied unchanged to the clipped epidermis of each animal at dose levels of up to 4000 mg/kg bw under semiocclusive conditions for 24 hours. Signs of toxicity were only noted for the highest dosing group including poor general state, dyspnoea, apathy, abdominal or lateral position, atonia, paresis, narcotic like state, absent corneal and pain reflex and red coloured excrements. After removal of the patch signs of skin irritation were visible. Signs of general toxicity was not observed for the lower dosing groups. In the highest dosing group 3 females died 1 or 2 days after application of the test substance wile no deaths were recorded for the lower dosing groups. Necropsy findings included general congestion, intensified grayish-brown partly confluent lobule marking of the liver black-brown colouring of the kidneys and bloody coloured urine. Histopathological examination identified the kidney and the urinary tract as the main targets of toxicity in one female animal. Under the conditions of the study conducted, the median LD50 of the test material was found to be greater than 4000 mg/kg bw for male animals, while the LD50 for female animals was found to be about 4000 mg/kg bw.

In a supporting study (similar to OECD guideline, 1986_RL1) the dermal LD50 in rabbits was > 2000 mg/kg bw.

Justification for classification or non-classification

According to EC/1272/2008, the test substance needs not to be labelled for acute toxicity.