7,17,28,38-tetraazatridecacyclo[24.16.2.2²,⁵.1⁸,¹².1²⁹,³³.0³,²².0⁴,¹⁹.0⁶,¹⁷.0²³,⁴³.0²⁷,³⁸.0⁴⁰,⁴⁴.0¹⁶,⁴⁶.0³⁷,⁴⁵]octatetraconta-1(42),2(48),3,5(47),6,8,10,12(46),13,15,19,21,23,25,27,29(45),30,32,34,36,40,43-docosaene-18,39-dione; 7,17,28,38-tetraazatridecacyclo[24.16.2.2²,⁵.1⁸,¹².1²⁹,³³.0³,²².0⁴,¹⁹.0⁶,¹⁷.0²³,⁴³.0²⁸,³⁹.0⁴⁰,⁴⁴.0¹⁶,⁴⁶.0³⁷,⁴⁵]octatetraconta-1(42),2(48),3,5(47),6,8,10,12(46),13,15,19,21,23,25,29,31,33,35,37(45),38,40,43-docosaene-18,27-dione

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

July 11, 2005 - Sep. 13, 2005

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

2005

Report date:

2005

Reference 2

Reference Type:

other: Amendment

Title:

Unnamed

Year:

2006

Report date:

2006

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

adopted December 17, 2001

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

GLP compliance:

yes (incl. QA statement)

Remarks:

BASF AG, Experimental Toxicology and Ecology, Ludwigshafen, Germany

Test type:

acute toxic class method

Limit test:

yes

Test material

Test material information

Constituent 1

Test material form:

solid: nanoform, no surface treatment

Details on test material:

- State of aggregation: solid, powder
- Particle size distribution (TEM): 29.1 nm (D50)
- Mass median aerodynamic diameter (MMAD): not specified
- Geometric standard deviation (GSD): not specified
- Shape of particles: plate
- Surface area of particles: 89 m²/g
- Crystal structure: crystalline
- Coating: no
- Surface properties: not applicable
- Density: 1566 kg/m³ at 20°C
- Moisture content: refer to IUCLID chapter 1
- Residual solvent: refer to IUCLID chapter 1
- Activation: not applicable
- Stabilisation: not applicable

Specific details on test material used for the study:

- Physical state: Powder / black
- Storage condition of test material: Room temperature
- Stability: The test substance was stable over the study period (demonstrated by reanalysis). Additionally, the stability of the test substance in the vehicle for the maximum application period was confirmed indirectly by analysis of the correctness of the concentration.
- Homogeneity: The test substance was homogeneous by visual inspection. Additionally, the homogeneity of the test substance preparation in the vehicle used for the first administration was confirmed indirectly by the concentration control analysis.

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: RCC Ltd Laboratory Animal Services, Fuellinsdorf, Switzerland
- Age at study initiation: Young adult animals (female animals approx. 8 - 12 weeks)
- Weight at study initiation: mean (6 female animals): 179 g
- Fasting period before study: Feed was withdrawn from the animals at least 16 hours before administration, but water was available ad libitum.
- Housing: Single housing
- Diet (e.g. ad libitum): Kliba-Labordiaet (Maus / Ratte Haltung "GLP"), Provimi Kliba SA, Kaiseraugst, Basel, Switzerland, ad libitum
- Water: Tap water ad libitum
- Acclimation period: Acclimatization for at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24°C
- Humidity (%): 30 - 70%
- Air changes (per hr): The animals were housed in fully air-conditioned rooms.
- Photoperiod (hrs dark / hrs light): 12 h /12 h

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: 0.5% CMC-solution (cleaned sodium carboxymethylcellulose, Hoechst AG) in doubly distilled water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 25 g/100 ml
- Justification for choice of vehicle: Aqueous formulation corresponds to the physiological medium.

MAXIMUM DOSE VOLUME APPLIED: 20 ml/kg

DOSAGE PREPARATION: The test substance preparation was produced for each administration group shortly before administration by stirring with a high speed homogenizer (Ultra-Turrax) and a magnetic stirrer.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Based on the physical and chemical characteristics of the test substance and its composition, no pronounced acute oral toxicity was expected. Therefore, a starting dose of 5000 mg/kg body weight (limit test) has been chosen.

Doses:

5000 mg/kg bw

No. of animals per sex per dose:

6 female animals

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Individual body weights shortly before administration (day 0), weekly thereafter and at the end of the study. Recording of signs and symptoms several times on the day of administration, at least once each workday for the individual animals. A check for any dead or moribund animal was made twice each workday and once on Saturdays, Sundays and on public holidays.
- Necropsy of survivors performed: yes

Results and discussion

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

No mortality occurred.

Clinical signs:

other: Clinical observation revealed impaired general state, dyspnoea, staggering and piloerection were observed from hour 3 until including hour 4 after administration.

Gross pathology:

No macroscopic pathologic abnormalities were noted in the animals (6 females) examined at termination of the study.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

Under the conditions of this study the median lethal dose of the test article after oral administration was found to be greater than 5000 mg/kg body weight in rats.

Executive summary:

In a GLP compliant OECD 423 guideline study, single doses of 5,000 mg/kg body weight of test material preparations in 0.5% CMC-solution in doubly distilled water were given to two administration groups of three fasted female Wistar rats by gavage in a sequential manner. The animals were observed for a period of 14 days following administration and mortality, viability and clinical signs were recorded daily. Body weights were recorded shortly before administration (day 0), weekly thereafter and at the end of the study. All animals were necropsied and examined macroscopically. All animals survived until the end of the study period. Clinical observation revealed impaired general state, dyspnoea, staggering and piloerection. Findings were observed from hour 3 until including hour 4 after administration. The mean body weights of the administration groups increased throughout the study period. No macroscopic pathologic abnormalities were noted in the animals examined at the end of the observation period. In conclusion, the LD50 (female rat) was determined to exceed 5000 mg/kg body weight.