Registration Dossier

Administrative data

Description of key information

Four studies were performed to evaluate acute oral and inhalative toxicity of the test substance to the rat (according to OECD 401 and 403). The test substance did not induce mortalities, abnormalities or clinical signs when applied oral. Also single administration via the respiratory system did not cause health effects or mortalities. The LD50 for oral toxicity is considered to be > 10.000 mg/kg bw, LC50 is > 5.24 mg/l air.

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:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
there are no data given for test substance, enviromental conditions of test animals and some animal data are missing, post observation period 7 days
GLP compliance:
no
Remarks:
prior to GLP-introduction
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: Tif. RAI
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Ciba-Geigy Ltd, in-house breeding
- Age at study initiation: 6-7 weeks
- Weight at study initiation: 160-180 g
- Fasting period before study: 1 night before administration
- Housing: groups of five
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: /

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 1
- Humidity (%): 50
- Air changes (per hr): /
- Photoperiod (hrs dark / hrs light): /

IN-LIFE DATES: From: To: /
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
2%
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 50%
- Amount of vehicle (if gavage): /

MAXIMUM DOSE VOLUME APPLIED:
DOSAGE PREPARATION (if unusual): weighed into an Erleimieyer flask on a Mettler balance. It was suspended at 50 % with carboxymethyl-cellulose
2 % and administered by oral intubation. Before treatment the suspension was homogeneously dispersed with an Ultra-Turrax and during treatment it was kept stable with a magnetic stirrer.
Doses:
6000 mg/kg bw and 10.000 mg/kg bw
No. of animals per sex per dose:
10 per sex and dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 7 days
- Necropsy of survivors performed: yes
- Other examinations performed: gross necroscopy
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 10 000 mg/kg bw
Remarks on result:
other: no mortality occurred
Mortality:
no mortalities
Clinical signs:
Within 2 hours after treatunent the rats in both dosage groups showed dyspnoea, exophthalmus, curved position and ruffled fur. These symptoms became more accentuated as the dose was increased. The animals had recovered within 3 to 6 days.
Gross pathology:
No substance related gross organ changes were seen
Interpretation of results:
GHS criteria not met
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
10 000 mg/kg bw

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:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
no
Qualifier:
equivalent or similar to
Guideline:
EU Method B.2 (Acute Toxicity (Inhalation))
Deviations:
no
GLP compliance:
yes
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd., Manston, Kent
- Age at study initiation: young adult
- Weight at study initiation: males 274 - 324g, females 244- 260g
- Fasting period before study: /
- Housing: groups of five
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-22
- Humidity (%): 52-67
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12

IN-LIFE DATES: From: To: /
Route of administration:
inhalation: dust
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: cylindrical exposure chamber with continuous flow
- Exposure chamber volume: 30 l
- Method of holding animals in test chamber: a tapered, polycarbonate restraining tube fitted onto a single tier of the exposure chamber and sealed by means of a rubber '0' ring
- Source and rate of air: compressed air was supplied by means of a Gast oil free compressor
- Method of conditioning air: passed through a water trap and respiratory quality filters which removed particulate material above 0.005 pm before
- System of generating particulates/aerosols: produced from the test material using a 'Wright Dust Feed' mechanism located at the top of the exposure chamber and driven by a variable speed motor. The dust feed was connected to a metered compressed air supply.
- Method of particle size determination: determined three times during the exposure period using a Cascade Impactor
- Temperature, humidity, pressure in air chamber: measured by an electronic thermometer/humidity meter (Kane-May Ltd., Welwyn Garden City, Hertfordshire, U.K.) located in a vacant port in the animals' breathing zone of the chamber and recorded every thirty minutes throughout the four-hour exposure period.

TEST ATMOSPHERE
- Brief description of analytical method used: The chamber was maintained under negative pressure. Homogeneity of the test atmosphere within the chamber was not specifically determined during this study, but, chambers of the same design have been fully validated and shown to produce evenly distributed atmospheres in the animals' breathing zone with a wide variety of test materials. (Green J.D. et al. Fundamental and Applied Toxicology 4, 768 - 777, 1984)
- Samples taken from breathing zone: no

VEHICLE
- air

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: particle size of the generated atmosphere of the test material inside the exposure chamber was determined three times during the exposure period using a Cascade Impactor. This device consisted of six impactor stages with stainless steel collection substrates (10, 6, 3.5, 1.6, 0.9 and 0.5 pm cut-off points) and a back up glass fibre filter. collection substrates were weighed before and after sampling and the weight of test material, collected at each stage, calculated by difference. From the results obtained the weight distribution of particles in the size range > 10 pm, 10 - 6 pm, 6 - 3.5 pm, 3.5 -1.6 pm, 1.6 - 0.9 pm and 0.9 - <0.5 pm was calculated.
Analytical verification of test atmosphere concentrations:
no
Remarks:
concentration estimated at regular intervals during the exposure period, gravimetric method used, employed glass fibre filters (Gelman type A/E 25 mm)
Duration of exposure:
ca. 4 h
Concentrations:
5.0 mg/litre
No. of animals per sex per dose:
5 per sex and dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations hourly during exposure, immediately on removal from the restraining tubes at the end of the exposure, one hour after termination of the exposure and subsequently once daily for 14 days, bodyweights were recorded on the day of exposure, days 7 and 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs
Statistics:
Using the mortality data obtained, an estimate of the acute inhalation median lethal concentration (LC50) of the test material was made.
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5.24 mg/L air
Exp. duration:
4 h
Remarks on result:
other: no mortality occurred
Mortality:
no mortalities
Clinical signs:
other: During exposure wet fur, decreased respiratory rate and test material staining of the fur were noted. On removal from the chamber animals additionally showed hunched posture, lethargy and pilo-erection. Laboured respiration and ptosis were common and ther
Body weight:
Expected bodyweight development was noted throughout the study
Gross pathology:
No abnormalities were detected at necropsy
Interpretation of results:
GHS criteria not met
Conclusions:
No deaths occurred in a group of ten rats exposed to a mean achieved concentration of 5.24 mg/litre (range 4.25 - 6.33 mg/litre). It was therefore considered that the acute inhalation median lethal concentration (LC50) of the test material in the Sprague-Dawley strain rat was greater than 5.24 mg/litre.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating conc.
Value:
5.24 mg/m³

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Procedure and observations

To evaluate the acute oral toxicity, single doses (6000 and 10.000 mg/kg bw) of the test article were administrated to groups of 10 male and 10 female rats by oral gavage (Ciba 1973). Following dosing, the animals were observed for 7d. There were no deaths as a result of treatment with the test article. Within 2 hours after treatment rats in both dosage groups showed dyspnoea, exophthalmus, curved position and ruffled fur. These symptoms became more accentuated as the dose was increased. The animals had recovered within 3 to 6 days.

Antoher acute oral toxicity study was conducted in 1993 (Hoechst). A single dose of 2000 mg/kg bw was administrated to groups of 5 rats/sex by gavage. The animals were observed for 14 days and twice daily checked for clinical symptoms or mortalities. All animals survived until scheduled necropsy; gross necropsy did not reveal any findings. Symptoms like hunched posture or stilted gait resolved within 1 day. In addition, red stained feces was observed.

To evaluate the acute inhalative toxicity, male and female rats (5/sex/dose) were exposed for 4h to a dust aerosol (range 4.25 - 6.33 mg/l air, nose only) of the test item (BASF 2010). Following dosing, the animals were observed for 14d. Examination of clinical signs and viability were performed daily, weighing on day 1, 7 and 13 after treatment. There were no deaths as a result of treatment with the test article. Clinical signs of toxicity or changes in body weight gain were not observed during the observation period. Gross necropsy was without any findings.

Similar results were determined in another inhalation study (Hoechst 1993). Animals (rats, 5/sex/dose) were exposed to dust (4.13 mg/l air, nose only) for 4h and observed for further 7 days. One male animal died accidentially during exposure; this death is not considered as treatment related. All other animals survided until scheduled necropsy; gross necropsy did not reveal any findings. Symptoms like irregular respiration, uncoordinated gait or trembling resolved within post observation period.

Discussion

Application of the test substance via oral or inhalative route did not induce any signs of toxicity. None of the animals died due to treatment, viability and bodyweight gain were unaffected by the test article. The test item was not tested for acute dermal toxicity. With regard to the physico-chemical properties of the substance (pH, structure, solubility), the very limited skin penetration and the absence of systemic and local effects in acute oral and acute inhalation studies dermal toxicity is not likely.

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.