Registration Dossier

Administrative data

Description of key information

All studies were performed using methodologies comparable to recognised testing guidelines.

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:
Aug. 20, 1981 to Sep. 8, 1981
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
not specified
GLP compliance:
no
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
other: Tif:RAIf (SPF)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Ciba-Geigy premises
- Age at study initiation: 7-8 weeks old
- Weight at study initiation: 182-200 g for males and 168-178 g for females
- Fasting period before study: overnight before treatment
- Housing: groups of 5 in Macrolon cages (type 3), marked individually
- Diet (e.g. ad libitum): NAFAG No. 890, NAFAG, Gossau SG ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: minimum of 4 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22+/-2°C
- Humidity (%): 55+/-10%
- Air changes (per hr): not mentioned
- Photoperiod (hrs dark / hrs light): 12h/12h
Route of administration:
oral: gavage
Vehicle:
other: distilled water containing 0.5% carboxymethyl-cellulose + 0.1% Polysorbat 80
Details on oral exposure:
Animals were treated orally, with a single dose by means of a stomach tube.
Doses:
1000, 2500, and 5000 mg/kg body wieght
No. of animals per sex per dose:
5
Control animals:
yes
Details on study design:
Clinical signs of toxicity, physical condition, and rate of death was monitored throughout the 14-day observation period.
The animals were submitted to a necropsy whenever they died, survivors at the end of the observation period.
Body weights were recorded immediately prior to dosing (control weights) and at days 7 and 14.
Statistics:
No statistics were performed.
Preliminary study:
Not applicable.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 500 mg/kg bw
Mortality:
1 male in high-dose group died 2 days after treatment. 5 (all) females in the high dose group died (4 at 24 hours and 1 on day 3).
Clinical signs:
Clinical signs observed were dyspnea, exophthalmos, ruffled fur and curved body position. These clinical signs are common ef¬fects in this type of study. Beside that, some cases of sedation were observed within the first day after treatment. Additionally, convulsions were detected in animals treated with 5000 mg/kg bw. All surviving animals recovered within seven days
Body weight:
No significant changes reported.
Gross pathology:
No test-article related changes were reported.
Interpretation of results:
GHS criteria not met
Conclusions:
Acute oral LD50 was reported to be 2500 mg/kg body weight. The authors reported the test article to be slightly toxic to the rat by this route of adminstration.
Executive summary:

In this guideline (OECD 401) comparable study, the acute LD50 of the test material to rats was determined to be 2500 mg/kg bw via the oral route. A single dose of the test material was given to each animal (5 male, 5 female) via gavage. Animals were observed for 14 days from dosing. The result of the test does not trigger classification of the test material as acutely toxic under the criteria of the EU Classification, Labelling, and Packaging (CLP) regulation (1272/2008).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 500 mg/kg bw
Quality of whole database:
1

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Mar. 11, 1980 to Apr. 10, 1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
4-day acclimatization period, 10-hour light cycle, and dose selected, no autopsy data for single animals
GLP compliance:
no
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
other: TiF:RAIf (SPF)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Ciba-Geigy premises
- Age at study initiation: young adults
- Weight at study initiation: 204-211 g for males and 184-193 g for females
- Housing: 10 animals per cage, males and females segregated and kept in Macrolon cages, type 4
- Diet (e.g. ad libitum): NAFAG, Gosaau AG, Switzerland ad libitum
- Water (e.g. ad libitum): asd libitum
- Acclimation period: minimum of 4 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22+/-2°C
- Humidity (%): 55+/-10%
- Air changes (per hr): not mentioned
- Photoperiod (hrs dark / hrs light): 10 h light/14 h dark
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
other: ethanol 94% + 1% cyclohexane
Details on inhalation exposure:
Inhalation:
Rats were kept in separate PVC tubes positioned so that only snout and nostrils were exposed. Temperature, relative humidity, and oxygen content were monitored thoughout the 4-hour exposure period.

Preparation of aerosol:
A 30% suspension of TK 12599 in ethanol 94% + 1% cyclohexane, Ciba-Geigy Batch No. 7741 was generated by injecting the test material at a rate of 60 mL/hour into an air stream which was discharged into the exposure chamber through a spray nozzle under a pressure of 2 atm. at a rate of 10 L/min.
The control animals were exposed to 60 mL/hour of ethanol 94% + 1% cyclohexane under the same conditions as decribed above.

The concentration and the particle size distribution of the aerosol in the vicinity of the animals were monitored at regular intervals throughout the aerosol exposure. The concentration was determined 5 times gravimetrically by sampling the test atmosphere through a selectron filter of 50 mm diameter and with a pore size of 0.2 ym (Schleicher and Schuell, Feldbach, Switzerland) at an air flow rate of 10 L/min. The size distribution of the particles was measured twice with a 4 stage Cascade Impactor with selectron filters of 25 mm diameter and with a pore size of 0.2 pm (Schleicher and Schuell) at an air flow rate of 17.5 L/min.
Analytical verification of test atmosphere concentrations:
no
Duration of exposure:
4 h
Concentrations:
935 +/- 49 mg/m3 (limit test)
No. of animals per sex per dose:
10
Control animals:
yes
Details on study design:
During the exposure period the following parameters were controlled once at half time of the study inside the inhalation cylinder: temperature (with a THERM 2104 contact thermometer, Ahlborn Messund Regeltechnik, 815 Holzkirchen, Germany), relative humidity (with a VASALA Humidity Indicator HMI 11, Kelag AG, 8057 Zurich, Switzerland) and oxygen content (with a DRAEGER E 15 stationary control system, Draegerwerk AG, Lübeck, Germany) .

After a 4 hour inhalation the rats were returned to their cages. Physical condition and incidence of death were monitored throughout an observation period of 14 days.
Statistics:
LC50 including 95% confidence limits are calculated by the logit model.
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 1 000 mg/m³ air (nominal)
Exp. duration:
4 h
Mortality:
No deaths occured.
Clinical signs:
Dyspnoea, exophthalmos, ruffled fur, and curved and ventral body positions were reported from 2 hours to 4 days after exposure. (Sex and number of animals displaying these clinical signs not reported).
All animals recovered within four days
Body weight:
No significant change throughout 14 day observation period.
Gross pathology:
Autopsy revealed “partially haemorrhages in the lungs” of treated animals. No details are given whether that means that only part of the lungs or part of the animals were affected. (Number and sex of animals not reported).

The control rats did not show any symptoms.

Particle size distribution analysis showed that approximately 80% were < 7µm.

Interpretation of results:
GHS criteria not met
Conclusions:
LC50 reported to be greater than 1000 mg/cubic-meter air.
Executive summary:

In this guideline (OECD 403) comparable study, the acute (4 hour) LC50 of the test material to rats was determined to be >1000 mg/m³. 20 rast (10 male, 10 female) were exposed to the test material at a test concentration of 935 ± 49 mg/m³ in a 95% ethanol 1 % cyclohexane aerosol (nose only). No mortality was reported in the study, although adverse effects (which are not reported as treatment related) were reported in some animals. The result of the test does not meet the criteria of the EU Classification, Labelling, and Packaging (CLP) regulation (1272/2008) for the test material to be classified as acutely toxic.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
1 000 mg/m³
Quality of whole database:
1

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:
From Aug. 26, 1981 to Sep. 8, 1981
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Tif: RAIf (SPF strain)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Random bred rats raised on the premises (CIBA-GEIGY Limited, Exp. Toxicology Sisseln GU 2.1)
- Age at study initiation: 7 to 8 weeks old
- Weight at study initiation: 208 +/-6.7 g for males and 174 +/- 13.8 g for females
- Fasting period before study: Not reported
- Housing: Housed individually in Macrolon cages (type 2)
- Diet (e.g. ad libitum): ad libitum, rat food (NAFAG No. 880, NAFAG, Gossau SG)
- Water (e.g. ad libitum): ad libitum
- Acclimation period: minimum of 4 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 55 ± 10
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
occlusive
Vehicle:
other: Distilled water containing 0.5% carboymethylcellulose and 0.1% Tween 80
Details on dermal exposure:
TEST SITE
- Area of exposure: on the back of the animals
- % coverage: Not reported
- Type of wrap if used: For treatment the test material was evenly dispersed on the skin with a syringe and was covered with an occlusive dressing which was fastened around the trunk with an adhesive elastic bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): After 24 hours the dressing was removed, the skin was cleaned with lukewarm water and the reaction of the skin was appraised.
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 20 mL/kg body weight
- Concentration (if solution): Not reported

Duration of exposure:
24 hours
Doses:
5,000 mg/kg
No. of animals per sex per dose:
5 males and 5 females
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Signs and symptoms, mortality, and skin irritation parameters (erythema, edema, and necrosis) were observed at 1, 2, 3, 5, and 24 hours, and then daily each day up to a period of 14 days. Body weights were recorded immediately prior to dosing and at 7 and 14 days.
- Necropsy of survivors performed: yes
Statistics:
No statistical analysis was performed.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Remarks on result:
other: no deaths reported
Mortality:
No deaths were reported.
Clinical signs:
Dyspnea, exophthalmos, ruffled fur and curved body position. These clinical signs are common effects in this type of study. All animals recovered within nine days.
Body weight:
Mean body weights were provided but were not discussed.
Gross pathology:
No gross organ changes were observed.
Interpretation of results:
GHS criteria not met
Conclusions:
LD50 > 5000 mg/kg bw
Executive summary:

In this guideline (OECD 402) comparable study, the acute, dermal LD50 of the test material to rats was determined to be >5000 mg/kg bw. 10 rats (5 male, 5 female) were exposed dermally to the test material (occlusive conditions) for 24 hours, and then observed for 14 days. No mortality was observed, and no treatment related effects were reported. Based upon this test result the test material does not meet the criteria for classification as acutely toxic under the EU Classification, Labelling, and Packaging (CLP) regulation (1272/2008).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
5 000 mg/kg bw
Quality of whole database:
1

Additional information

A single dose of the test item was administered by gavage to female Wistar rats at concentrations of 1000, 2500 and 5000 mg/kg bw, respectively. The animals were observed for 14 days. Mortality, body weight and clinical signs were recorded continuously. Organ weighing and gross necropsy was performed after scheduled sacrifice. Mortality occured in the high-dose group at day 2 after treatment (one male) and from days 1 to 3 after treatment (all females). Clinical signs observed were dyspnea, exophthalmos, ruffled fur and curved body position. Beside that, some cases of sedation were observed within the first day after treatment. Additionally, convulsions were detected in animals treated with 5000 mg/kg bw. All surviving animals recovered within seven days. The LD50 for acute oral toxicity is considered to be > 2500 mg/kg bw.

A single dose of the test item was applied onto skin of male and female Wistar rats at concentrations of 5000 mg/kg bw. The animals were observed for 14 days. Mortality, body weight and clinical signs were recorded continuously. Organ weighing and gross necropsy was performed after scheduled sacrifice. Dyspnea, exophthalmos, ruffled fur and curved body position were observed. All animals recovered within nine days. The LD50 for acute dermal toxicity is considered to be > 5000 mg/kg bw.

Male and female rats were exposed to an aerosol of the test item at a concentration of 935 mg/m3 for four hours. During the exposure period the following parameters were controlled once at half time of the study inside the inhalation cylinder: temperature, relative humidity and oxygen content. Physical condition and incidence of death were monitored throughout an observation period of 14 days. Dyspnoea, exophthalmos, ruffled fur, and curved and ventral body positions were reported from 2 hours to 4 days after exposure.

All animals recovered within four days. Autopsy revealed “partially haemorrhages in the lungs” of treated animals. No details are given whether that means that only part of the lungs or part of the animals were affected. The LD50 for acute inhalation toxicity is considered to be > 1000 mg/m3.

Justification for classification or non-classification

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

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance is not considered to be classified for acute toxicity under Regulation (EC) No. 1272/2008.