Registration Dossier

Administrative data

Description of key information

Key study: Acute oral: Experimental results: Study performed according to OECD guideline 401 (1981) under GLP-like quality surveillance (QAU statement included)
LD50 = 461 mg/kg bw
Key study: Acute dermal: Experimental results: Similar to OECD guideline 402. Non-GLP study.
LD50 > 4000 mg/kg bw
Acute inhalation: Data waiving: In accordance with column 2 of REACH Annex VIII, the study does not need to be conducted since exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size.

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:
1985
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study performed according to OECD guideline 401 (1981) under GLP-like quality surveillance (QAU statement included)
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
other: Tif:RAIf(SPF), F3-crosses of RII 1/Tif x RII 2/Tif
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: CIBA-GEIGY LTD. Tierfarm, 4334 Sisseln, Switzerland
- Age at study initiation: 7-8 weeks
- Weight at study initiation: 166-221 g
- Fasting period before study: overnight
- Housing: in groups of 5 in Macrolon cages type 4 with standardized soft wood bedding (Societe Parisienne des sciures, Pantin).
- Diet: Rat food, NAFAG No. 890, NAFAG AG, Gossau, SG (Switzerland), ad libitum
- Water: ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 55 +/- 15
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: January 7, 1985 - January 29, 1985
Route of administration:
oral: gavage
Vehicle:
other: Distilled water containing 0.5% carboxymethylcellulose and 0.1% polysorbate 80
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg
Doses:
100, 500, and 1000 mg/kg body weight
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: Mortality: daily; a.m. and p.m. on working days, a.m. on weekend days; Signs and Symptoms: daily; Body weight: on days 1, 7, 14 and at death
- Necropsy: 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 (J. Berkson, J. Am. Stat. Ass. iS (1944), 357-365).
Sex:
male
Dose descriptor:
LD50
Effect level:
515 mg/kg bw
Based on:
test mat.
95% CL:
236 - 2 577
Sex:
female
Dose descriptor:
LD50
Effect level:
365 mg/kg bw
Based on:
test mat.
95% CL:
149 - 765
Sex:
male/female
Dose descriptor:
LD50
Effect level:
461 mg/kg bw
Based on:
test mat.
95% CL:
296 - 779
Mortality:
1000 mg/kg: all animal died within 3 hours after treatment
500 mg/kg: 1 male died 1/5 day after treatment and 3/5 females died within 3 hours after treatment.
100 mg/kg: all animals survived the treatment.
Clinical signs:
Dyspnea, exophthalmos, ruffled fur, and abnormal body positions were seen, being common symptoms in acute tests. Tremor was seen in all dose groups within 24 hours after application. The animals of the two higher dose groups showed sedation on the application day, with a dose-releated increase in severity. In the same groups, clonicotonic convulsions were observed on the application day. Hemorrhagic discharge in the mouth was seen in the animals of the highest dose group on the application day. The surviving animals recovered within 11-12 days.
Body weight:
All surviving animals gained weight.
Gross pathology:
Enlargement of the liver was observed in one male of the 100 mg/kg bw dose group. Hemorrhagic lungs were seen in one male of the 500 mg/kg bw dose group. In one male of the 1000 mg/kg bw dose group, dilatation of the small intestine was observed.
Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Upon an acute oral administration and 14 day post-treatment observation period, the following LD50 were determined: 515 mg/kg bodyweight (males), 365 mg/kg bodyweight (female), 461 mg/kg bodyweight (both sexes).
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
461 mg/kg bw
Quality of whole database:
Klimisch 2. Study performed according to OECD guideline 401 (1981) under GLP-like quality surveillance (QAU statement included)

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:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Similar to OECD guideline 402. Non-GLP study.
Reference:
Composition 0
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
(Limit test requires five animals/sex. However, in the study five abraded rabbits and five intact rabbits were used)
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Test material information:
Composition 1
Species:
rabbit
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: no data reported
- Age at study initiation: no data reported
- Weight at study initiation: 2.937 +/- 0.332 kg
- Housing: no data reported
- Diet (e.g. ad libitum): no data reported
- Water (e.g. ad libitum): no data reported

ENVIRONMENTAL CONDITIONS: no data reported
Type of coverage:
occlusive
Vehicle:
not specified
Details on dermal exposure:
TEST SITE
- Area of exposure: Upper back
- % coverage: Not reported
- Type of wrap if used: rabbits were wrapped with an impervious band

REMOVAL OF TEST SUBSTANCE
- Washing: After removal of the wrapping, the compound residue was gently flushed off.

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 4000 mg/kg
Duration of exposure:
24 hours
Doses:
4000 mg/kg
No. of animals per sex per dose:
10 rabbits
- 5 rabbits Abraded
- 5 rabbits Intact
Control animals:
yes
Details on study design:
- Duration of observation period following administration: At 24 hours after removal of the wrapping and daily for 14 days
- Necropsy of survivors performed: yes - A macroscopic examination of the viscera was conducted on all rabbits survival at day 14.
- Other examinations performed: Body weights were recorded at Day 0, 3, 7, 10 and 14
Preliminary study:
Range finding study:
Six rabbits were prepared for dosing by clipping the fur from the upper back and dermally applying equivalent doses of 1000 mg, 2000 mg or 4000 mg/kg body weight , two rabbits per dose . The rabbits were wrapped with an impervious band which was left in place for 24 hours. Observations for mortality were made for 72 hours
Sex:
not specified
Dose descriptor:
LD50
Effect level:
> 4 000 mg/kg bw
Based on:
test mat.
Mortality:
> 50% of the animals tested survived
Body weight:
Body weight gain over the 14-day observation period was acceptable for all survivors.
Gross pathology:
Macroscopic examination of the viscera revealed no treatment related observations.
Other findings:
Daily observation:
- Three of the 10 rabbits died during the first 48 hours. All of these animals were treated on abraded skin. A fourth rabbit died on day 9. This was the only death observed in an animal with intact skin.
- Three rabbits showed slight erythema at the treatment site at 24 hours. No other dermal or behavioral reactions were noted.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Rabbits were exposed during 24 hours to the test item according to test procedure in accordance with generally accepted scientific standards. The test substance was applied to 5 test animals with abraded skin and 5 test animals with intact skin. 3 of the animals with abraded skin died within the first 48 h indicating that test substance absorption was higher and faster when the skin was damaged. One animal with intact skin died on day 9. As the overall mortality was 40%, the LC50 is considered to be higher than 4000 mg/kg bw. Therefore, a classification for acute dermal toxicity according to Regulation 1272/2008/EC and amendments and Directive 67/548/EEC and amendments is not warranted following the study results.
Executive summary:

Ten rabbits were exposed to a limit dose of 4000 mg/kg bw to the test item under occlusive conditions for 24 h. The dose was chosen after a preliminary dose range finding study. In 5 animals the skin was abraded. The observation period was 14 days. Four of 10 animals died during the study (3 with abraded skin and one with intact skin). The LD50 was therefore > 4000 mg/kg bw. No signs of systemic toxicity and only slight erythema in three animals after 24h only. The results of this study show that the substance should not be classified for acute dermal toxicity following Regulation 1272/2008/EC and amendments and Directive 67/548/EEC and amendments.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
4 000 mg/kg bw
Quality of whole database:
Klimisch 2. Similar to OECD guideline 402. Non-GLP study.

Additional information

Key study: Acute oral: Experimental results: Study performed according to OECD guideline 401 (1981) under GLP-like quality surveillance (QAU statement included)

LD50 = 461 mg/kg bw

 

Key study: Acute dermal: Experimental results: Similar to OECD guideline 402. Non-GLP study.

LD50 > 4000 mg/kg bw

 

Acute inhalation: Data waiving: In accordance with column 2 of REACH Annex VIII, the study does not need to be conducted since exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size.


Justification for selection of acute toxicity – oral endpoint
Only one reliable study available.

Justification for selection of acute toxicity – dermal endpoint
Only one reliable study available.

Justification for classification or non-classification

Based on the available data, the substance is classified for acute oral toxicity:

LD50 oral = 461 mg/kg bw - Acute oral toxicity Category 4, according to CLP Regulation

LD50 dermal > 4000 mg/kg bw (not classified)