Registration Dossier

Administrative data

Description of key information

oral:
In an acute toxicity study conducted on rats, the LD50 after oral intake was determined to be approximately 280 mg/kg bw.
inhalation:
The LC50 after 1 h exposure was found to be between 4.5 and 10.1 mg/L air in rats.
dermal:
The LD50 was found to be greater than 200 mg/kg bw.

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
280 mg/kg bw
Quality of whole database:
The available studies are comparable to guideline studies and sufficient for assessment.

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: scientifically acceptable study report
Reference:
Composition 0
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
exposure time only 1 hour
Principles of method if other than guideline:
Dynamic inhalation method; whole-body - head/nose exposure with analytical and nominal concentration determination.
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Mean body weight: 200 - 300 g
The animals were held in air-conditioned rooms with a room temperature of 22 +/- 2°C and a relative humidity of 55 +/- 10%.
Air changing: 10- to 15-fold
Day/night rhythm: 12 h dark, 12 h light
Type of cage: Makrolon type 3 (23 x 39cm2)
Animals per cage: 2
Animal identification: via ear marks
The animals were offered a standard animal laboratory diet as well as drinking water ad libitum.
TEST ANIMALS
- Weight at study initiation: 200-300 g
- Housing: 2 animals per cage, Makrolon type 3 (23 x 39cm2)
- Diet: standard animal laboratory diet, ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): of 22 +/- 2°C
- Humidity (%): 55 +/- 10%.
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12 h dark, 12 h light

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Makrolon animal tubes
- Exposure chamber volume: 28.5 L
- Source and rate of air: continuous airation, 600 L/h
- System of generating particulates/aerosols: diffuser nozzle

TEST ATMOSPHERE
- Samples taken from breathing zone: yes

Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
1 h
Concentrations:
4.5 and 10.1 mg/L (nominal)
No. of animals per sex per dose:
10
Details on study design:
- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 4.5 - < 10.1 mg/L air
Based on:
test mat.
Exp. duration:
1 h
Remarks on result:
other: by applying Habers' law (c x t = k) for time extrapolation (1 h to 4 h exposure): LC50 > 1.1 < 2.5 mg/L air
Mortality:
4.5 mg/L: no mortality
10.1 mg/L: all animals died
Clinical signs:
During exposure:
In the lowest concentration male and female rats showed a slight reduced spontaneous activity as well as a slight reduced rection of outer stimuli; furthermore slight gasping, slight constricted palpebral fissures and slight increased salivation.
In the highest concentration, male and female animals showed a intense reduced breathing rate and gasping, slight to severe cyanotic skin, constricted palpabral fissures and severe salivation. 4 hours after begin of inhalation all animals were free of symptoms.
During the observiation period:
In the low concentration male and female rats showed a slight reduced spontaneous activity as well as a slight reduced reaction of outer stimuli, furthermore gasping and slight constricted palpebral fissures.
4 hours after study start all animals were without findings.
Body weight:
not examined
Gross pathology:
Animals that died (high concentration): 10 of 20 rats showed the following changes of the lung: alveolar emphysema, petechiae and focal atelectasis.
Sacrificed animals: 1 of 20 rats showed isolated petechia (low concentration).
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Quality of whole database:
Acceptable study report, sufficient for assessment.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:

Additional information

Oral

The acute oral toxicity of the test substance was tested in three different studies on rats, dogs and rabbits.

The substance was administered to rats in concentrations of 2, 4, 8 and 20 % (v/v) in doses of 160, 200, 256, 320, 640 and 1280 mg/kg bw. 10 rats per dose were used. Affected rats showed dyspnoea, convulsions, leaning position, cyanosis and apathy. As a result of the study, the approximate LD50 value was determined to be 280 mg/kg bw.

In a study using dogs (16 males and 3 females) the test substance was administered via gavage in various dose levels in 5 or 10 % aqueous solutions or undiluted or in stomach-soluble and small intestine-soluble gelatine capsules. The applied doses were 8, 40, 200, 400 and 800 mg/kg bw. The lowest concentration was the only concentration not causing any symptoms. All other doses caused vomiting (partially containing blood), panting, dyspnoea, staggering and prone positioning. All dogs of the highest dose group and 2 of 6 dogs of the 400 mg/kg bw dose group receiving an aqueous solution via gavage died within 1-2 hours after application. All surviving animals were symptom free within a few hours. The LD50 value was determined to be >400 and <800 mg /kg bw.

Applied to rabbits, the test substance was administered in concentrations of 1, 2, 2.5, 3 or 5 % in the following doses: 80, 160, 200, 240 and 400 mg/kg bw. No deaths occurred in the lowest two dose groups, in the 200 mg/kg bw dose group 2 of 5 rabbits died and in both the highest dose groups 2 of 2 animals died. Clinical signs were anorexia, trembling, diarrhea and from the 240 mg/kg bw dose group onwards salivation, restlessness, atony and motion spasms. At autopsy of the surviving animals and those that had died no pathological changes were found on the inner organs. The LD50 was determined to be 201 mg/kg bw.

Inhalation

In the first study, 40 rats were exposed to test substance vapour at the nominal concentrations 6 and 25.1 mg/L air. Analytical measurements were also conducted and revealed 4.5 and 10.1 mg/L, respectively. 10 male and 10 female rats were exposed to each concentration for a duration of 1 hour. In the low dosage group, no mortality occurred whereas all animals from the high dose group died. Therefore, the LC50 (1 h) for both male and female animals was found to be >4.5 and <10.1 mg/L air.

In another study 12 rats were exposed to 0.71 mg/L for 1 hour and no mortality occurred. At autopsy, chronic bronchitis was observed in 1 animal. After a 4 minutes exposure time with a vapour concentration of 560 mg/L air all animals (6) died. After 3 minutes exposure with 365 mg test substance per L air also all test animals (12) died.

Dermal

According to Annex VII of REACH, the study does not need to be concucted as studies for oral and inhalation routes are available. Nevertheless, two studies adressing this endpoint are available. The first study was conducted on 5 male and 5 female White Vienna rabbits. Therefore, 200 mg/kg bw of the test substance were applied to the clipped backs and flanks. As a result, the LD50 value was found to be greater than 200 mg/kg bw. In another study the LD50 value was determined to be greater than 160 mg/kg bw. In both studies no mortalities occured up to the highest concentration tested. Classification on the basis of these results is not possible.

Intraperitoneal

The test material was administered peritoneally to male and female mice at concentrations of 1, 2, and 20 % (v/v in water) in the following doses: 40, 100, 128, 160, 1280 mg/kg (original values 50, 100, 125, 160, 200, 1600 mm3/kg, values in mg/kg calculated using a density of 0.8003 g/mL). Clinical signs observed during the 7 days-observation period were dyspnea, spasms, abdominal and lateral position, cyanosis and apathy. Deaths occurred from the 80 mg/kg bw dose group onwards. At autopsy, adherences and adhesions were observed in the abdomen. Based on these findings, the approximate LD50 was determined to be 88 mg/kg bw (original value: ca. 110 mm3/kg, value in mg/kg bw was calculated using the densitiy of 0.8003 g/mL).


Justification for selection of acute toxicity – oral endpoint
Three studies are available for this endpoint which were used in a weight-of-evidence approach.

Justification for selection of acute toxicity – inhalation endpoint
Old but acceptable study report.

Justification for selection of acute toxicity – dermal endpoint
According to Annex VII of REACH, the study does not need to be conducted, as studies for oral and inhalation routes are available. Nevertheless, two study reports are available which show no mortality up to 200 mg/kg bw.

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

The available studies are considered reliable and suitable for classification purposes under 67/548/EEC. As a result the substance is considered to be classified and labelled as Xn, R20/R22 (harmful by inhalation and if swallowed) under Directive 67/548/EEC, as amended for the 31st time in Directive 2009/2/EG.

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

The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. As a result the substance is considered to be classified as acute toxic cat 3 (H301: toxic if swallowed) and acute toxic cat 4 (H332: harmful if inhaled) under Regulation (EC) No 1272/2008, as amended for the sixth time in Regulation No 605/2014.