7,14,25,32-tetraazaundecacyclo[21.13.2.2²,⁵.0³,¹⁹.0⁴,¹⁶.0⁶,¹⁴.0⁸,¹³.0²⁰,³⁷.0²⁴,³².0²⁶,³¹.0³⁴,³⁸]tetraconta-1(36),2(40),3,5(39),6,8(13),9,11,16,18,20,22,24,26(31),27,29,34,37-octadecaene-15,33-dione; 7,14,25,32-tetraazaundecacyclo[21.13.2.2²,⁵.0³,¹⁹.0⁴,¹⁶.0⁶,¹⁴.0⁸,¹³.0²⁰,³⁷.0²⁵,³³.0²⁶,³¹.0³⁴,³⁸]tetraconta-1(36),2(40),3,5(39),6,8(13),9,11,16,18,20,22,26(31),27,29,32,34,37-octadecaene-15,24-dione

Endpoint summary

Description of key information

Oral: LD50 (m/f) > 5000 mg/kg bw, rat, according to OECD TG 423, GLP compliant

Inhalation: LC50 (m/f) > 5.2 mg/L air, rat, according to OECD TG 403, GLP compliant

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:

19-OCT-2005 - 17-NOV-200 5

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

Dec 2001

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

Jun 2004

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Version / remarks:

Dec 2002

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Specific details on test material used for the study:

- Physical state: Solid, black powder
- Analytical purity: > 99%
- Storage condition of test material: Room temperature

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: RCC Ltd, Laboratory Animal Services, CH-4414 Fuellinsdorf/Switzerland
- Age at study initiation: 12 to 14 weeks
- Fasting period before study: for approximately 18 to 19 hours (access to water was permitted). Food was provided again 3 hours after dosing.
- Housing: Individually in Makrolon type-3 cages with wire mesh tops and standard softwood bedding.
- Diet: Pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet, batch no .39/05 (Provimi Kliba AG, CH-4303 Kaiseraugst/Switzerland) ad libitum.
- Water: Community tap water from Füllinsdorf ad libitum.
- Acclimation period: Under laboratory conditions, after health examination. Only animals without any visible signs of illness were used for the study .

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 30-70 %
- Air changes (per hr): 10-15 air changes per hour.
- Photoperiod: 12 hours light and 12 hours dark
- music during the daytime light period.

Route of administration:

oral: gavage

Vehicle:

other: aqueous solution of 0.5 % w/v carboxymethyl cellulose

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 0.25 g/mL

MAXIMUM DOSE VOLUME APPLIED: The application volume was 20 mL/kg body weight.

Doses:

5000 mg/kg bw

No. of animals per sex per dose:

3

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 15 days
- Frequency of observations and weighing: All animals were examined for clinical signs at approximately 30 minutes, 1, 2, 3 and 5 hours after treatment on day 1 and once daily during test days 2-15. Mortality/viability was recorded at approximately 30 minutes, 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15.
- Frequency of weighing: Body weights were recorded on day 1 (prior to administration) and on days 8 and 15.
- Necropsy of survivors performed: yes, All animals were killed at the end of the observation period by carbon dioxide asphyxiation and discarded after macroscopic examinations were performed. No organs or tissues were retained.
- Other examinations performed: clinical signs, body weight

Statistics:

No statistical analysis was used.

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:

All animals survived until the end of the study period.

Clinical signs:

other: The first treated animal was noted with slightly ruffled fur from the 2-hour reading to test day 5. Black feces were seen in the cage from the 5-hour reading to test day 4. All clinical signs were reversible and no longer evident from test day 6 to the en

Gross pathology:

No macroscopic findings were recorded at necropsy.

The median lethal dose of the test substance after single oral administration to female rats, observed over a period of 14 days is:

LD50 (female rat): greater than 5000 mg/kg body weight.

Interpretation of results:

GHS criteria not met

Conclusions:

The median lethal dose (LD50) of the test compound after single oral administration to female rats, observed over a period of 14 days is greater than 5000 mg/kg body weight.

Executive summary:

In a GLP compliant OECD guideline study, three female HanRcc :WIST (SPF) rats, were treated with the test substance by oral gavage administration at a dosage of 5000 mg/kg body weight. The test item was diluted in an aqueous solution of 0.5 % w/v carboxymethyl cellulose at a concentration of 0.25 g/mL and administered at a volume dosage of 20 ml/kg, respectively. The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. All animals were examined for clinical signs at approximately 30 minutes, 1, 2, 3 and 5 hours after treatment on day 1 and once daily during test days 2-15. Mortality/viability was recorded at approximately 30 minutes, 1, 2, 3 and 5 hours after administration on test day 1(with the clinical signs) and twice daily during days 2-15. Body weights were recorded on day 1(prior to administration) and on days 8 and 15. All animals were necropsied and examined macroscopically. All animals survived until the end of the study period. The first treated animal was noted with slightly ruffled fur from the 2-hour reading to test day 5. Black feces were seen in the cage from the 5-hour reading to test day 4. All clinical signs were reversible and no longer evident from test day 6 to the end of the observation period. The second treated animal was noted with slightly ruffled fur from the 30-minute to the 3-hour reading. This clinical sign was reversible and no longer evident from the 5-hour reading to the end of the observation period. The third treated animal was noted with slightly ruffled fur from the 30-minute to the 5-hour reading. This clinical sign was reversible and no longer evident from test day 2 to the end of the observation period. The body weight of the animals was within the range commonly recorded for this strain and age. No macroscopic findings were recorded at necropsy. Therefore, the LD50 (female rat) was determined to exceed 5000 mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

5 000 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

Study period:

04 Oct 2005 - 07 Nov 2005

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1300 (Acute inhalation toxicity)

Qualifier:

according to guideline

Guideline:

other: EU Guideline 92/69/EEC and 93/21/EEC

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Specific details on test material used for the study:

- Physical state: Solid, black powder
- Analytical purity: > 99%
- Storage condition of test material: Room temperature
- Homogeneous

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Laboratory Animal Services; Wölfersraße 4, 4414 Füllinsdorf, Switzerland
- Age at study initiation: 9 weeks for males and approx. 11 weeks for females.
- Weight at study initiation: males: 260,5 g (mean); females: 205,3 g (mean)
- Housing: singly in cages type DK III (Becker, Germany) without bedding
- Diet: KLIBA mouse / rat laboratory diet 10 mm pellets "GLP", Provimi Kliba SA, Kaiseraugst, Basel Switzerland, ad libitum
- Water: drinking water ad libitum
- Acclimation period: at least 1 week in which they were adapted to the surroundings

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24°C
- Humidity (%): 30 - 70%
- Photoperiod (hrs dark / hrs light): dark cycle of 12 hours

Route of administration:

other: dust aerosol

Type of inhalation exposure:

nose/head only

Vehicle:

other: 2% (w/w) of Aerosil 200

Mass median aerodynamic diameter (MMAD):

>= 3 - <= 3.1 µm

Geometric standard deviation (GSD):

>= 3.1 - <= 3.3

Details on inhalation exposure:

GENERATION OF THE INHALATION ATMOSPHERE
- The test substance was stirred in its container before a sample for dust generation was taken. The test substance was desagglomerated in a mixer under addition of 2% (w/w) of Aerosil 200 before introduction into the dust generator, in order to improve dust aerosol formation. The dust was produced inside the inhalation system with a dosing-wheel dust generator and compressed air.

EXPOSURE
- The exposure system was located inside an exhaust cabin in an air-conditioned laboratory. A supply air flow (compressed air) of 1.5 m³/h was used for the exposure. The exhaust airflow was set to 1.35 m³/h. An air change of about 27 times per hour can be calculated by dividing the supply air flow by the volume of the inhalation system.
 
- The lower amount of exhaust air, which was adjusted by means of a separate exhaust air system, achieved a positive pressure inside the exposure system . This ensured that the mixture of test substance and air was not diluted with laboratory air in the breathing zones of the animals. The animals were exposed to the inhalation atmosphere for 4 hours plus equilibration time of the inhalation systems (t99 about 10 min).

Measurement of operation conditions
- The flows of supply and exhaust air were adjusted and continuously measured with flowmeters. They were recorded four times in about 1-hour intervals. The temperature in the inhalation system was measured continuously with a digital thermometer and recorded four times in about 1-hour intervals. The humidity in the inhalation system was measured with a dielectric probe four times in about 1-hour intervals.
 
- No surveillance of the oxygen content in the inhalation system was performed. The air change was judged to be sufficient to prevent oxygen depletion by the breathing of the animals, and the concentration of the test substance used could not have a substantial influence on oxygen partial pressure.
 
Gravimetric determination of the inhalation atmosphere concentration:
Equipment: balance Mettler AT 250. Preweighed filters were placed into the filtration equipment. By means of the vacuum pump metered volumes of the dust were drawn through the filter. For each sample the dust aerosol concentration in mg/I was calculated from the difference between the preweight of the filter and the weight of the filter after sampling, with reference to the sample volume of the inhalation atmospheres. Mean and standard deviation were calculated for the concentration from the results of the individual measurements. The mean concentration was corrected for the amount of additive used.
 
Particle size analysis:
Definitions
• EACD 50% (effective aerodynamic cutoff diameter 50%) defines the separation characteristic of each impactor stage. 50% of particles with the EACD given are deposited in the pertinent impactor stage; the remainder has reached one of the following stages.
• MMAD (mass median aerodynamic diameter) is the calculated aerodynamic diameter which divides the size distribution in half when measured by mass.
• Geometrical standard deviation (GSD) is the ratio of the estimated 84 percentile to the 50 percentile and indicates the slope of the cumulative particle size distribution curve.
• Inspirable aerosol
Inspirable aerosols can enter the respiratory system. Aerosols with MMAD <100 Nm are considered inspirable (MAK Commission of the DFG (German Research Society, MAK list 1997).
• Respirable aerosol
Respirable aerosols can enter the alveolar region of the lung. Aerosols with MMAD < 4 Nm are considered respirable (MAK Commission of the DFG (German Research Society, MAK list 1997).

Before sampling, the impactor was assembled with preweighed glass-fiber collecting discs, and a backup particle filter. The impactor was connected to the vacuum pump and two samples were taken from the breathing zone of the animals starting not earlier than 30 minutes after the beginning of the exposure. The sample volume was 6 L. After sampling the impactor was taken apart. The collecting discs and the backup particle filter were re-weighed. The amounts of material adsorbed to the walls of the impactor and in the sampling probe (wall losses) were also determined quantitatively. The results from the particle size analysis were not corrected for the additive.

- Exposure conditions:
Supply air (m³/h): 1.5
Exhaust air (m³/h): 1.35
Substance flow (g/h): 36.1
Temperature (°C): 21.8±0.3
Relative humidity (%): 47.7±2.2

- Analytical concentration:
Mean mg/l: 5.2
Standard deviation: 1.0
Nominal concentration mg/l: 24.1

- Particle size analysis:
MMAD (µm): 3.1 and 3.0
Geometrical standard deviation: 3.1 and 3.3

Analytical verification of test atmosphere concentrations:

yes

Remarks:

Gravimetric determination

Duration of exposure:

4 h

Concentrations:

5.2 mg/l (nominal concentration: 24.1 mg/l)

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: A check for overt clinical signs of toxicity or mortality as well as a check for the presence of feed and drinking water was made twice a day on workdays and once daily on weekends and public holidays. Detailed clinical observations were recorded for each animal separately several times during exposure and at least once on each workday of the observation period.
- Body weights: The body weight of the animals was determined just prior to exposure (day 0), weekly thereafter and at the end of the observation period.
- Necropsy of survivors performed: yes. At the end of the observation period the animals were sacrificed with C02 and were subjected to gross-pathological examination

Statistics:

A binomial test was used for statistical evaluation.

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.2 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

not determinable

Remarks:

(no mortality observed)

Mortality:

No lethality occurred at the tested concentration of 5.2 mg/I during the study period of 14 days.

Clinical signs:

other: Accelerated respiration, pulmonary respiration e sounds, squatting posture, piloerection and smeared fur. Findings were observed from hour 0 of exposure until including study day 3.

Body weight:

The mean body weights of the animals increased throughout the study period.

Gross pathology:

No pathological abnormalities of the organs were observed in all animals at termination of the study.

Other findings:

Contaminated fur was noted during necropsy in all animals.

Analytical concentration:

Mean (mg/l)	standard deviation	nominal concentration (mg/l)
5.2	1	24.1

Particle Size Analysis:

Sample	MMAD (µm)	geometrical standard deviation
1	3.1	3.3
2	3	3.1

Interpretation of results:

GHS criteria not met

Conclusions:

Under the conditions of this study the LC50 for male and female rats after dust inhalation was determined to exceed 5 .2 mg/I.

Executive summary:

For determination of the acute inhalation toxicity (single 4-hour-exposure) of the test substance as dust, a GLP compliant study in male and female Wistar rats was performed according to OECD-Guideline method 403, as well as EEC and EPA guidelines. A measured concentration of 5 .2 mg/I was tested (Limit test). Cascade impactor measurements resulted in particle size distributions with mass median aerodynamic diameters (MMADs) of 3.0 and 3.1 µm, which are well within the respirable range. No mortality occurred at the tested concentration. Clinical signs of toxicity comprised visually accelerated respiration, pulmonary respiration sounds, squatting posture, piloerection and smeared fur. Findings were observed from hour 0 of exposure until including study day 3. Moreover, contaminated fur was observed in all animals from day 0 onward until termination of the study. The mean body weights of the animals increased throughout the study period. No pathological abnormalities of the organs were observed in all animals at termination of the study. Contaminated fur was noted during necropsy in all animals. Under the conditions of this study the LC50 for male and female rats after dust inhalation was > 5 .2 mg/l.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating conc.

Value:

5 200 mg/m³ air

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Oral toxicity

In a limit test performed according to GLP and OECD Guideline 423 (Acute Toxic Class Method), three fasted female HanRcc:WIST (SPF) rats were given a single oral dose (gavage) of the test article at a concentration of 5000 mg/kg bw (RCC, 2005). The test item was diluted in an aqueous solution of 0.5 % w/v carboxymethyl cellulose at a concentration of 0.25 g/mL and administered at a volume dosage of 20 mg/kg b.w., respectively. The animals were observed subsequently for a period of 15 days. All animals were necropsied and examined macroscopically. No mortality occurred during the observation period. Slightly ruffled fur was observed in all three animals which was reversible within 5 days. Black feces were seen in one animal until day 4. The body weight of the animals was within the range commonly recorded for this strain and age. No macroscopic pathologic abnormalities were noted in the animals examined at the end of the observation period.

 

Inhalation toxicity

In an acute inhalation toxicity study performed according to GLP and the OECD Test Guideline 403, the test article was applied as dust for 4 hours at a measured concentration of 5.2 mg/L (Limit test) to 5 Wistar rats /sex (BASF, 2005). Cascade impactor measurements resulted in particle size distributions with mass median aerodynamic diameters (MMADs) of 3.0 and 3.1 µm, which are well within the respirable range. Animals were then observed for 14 days. No mortality was observed during the observation period. Clinical signs of toxicity included visually accelerated respiration, pulmonary respiration sounds, squatting posture, piloerection and smeared fur. Findings were observed from the start of exposure until including study day 3. Moreover, contaminated fur was observed in all animals from day 0 onward until termination of the study. The mean body weights of the animals increased throughout the study period. No pathological abnormalities of the organs were observed in all animals at termination of the study. Contaminated fur was noted during necropsy in all animals. Under the conditions of this study, the acute inhalative median lethal concentration (LC50) of the test item after inhalative exposure was found to be greater than 5.2 mg/L in male and female rats.

 

Further toxicological data of category members:

The test article belongs to the "perylene based organic pigments" category (see attached document for details on category members and for read across justification). According to the category approach, missing toxicity endpoints can be addressed with data available for other category members. Regarding acute toxicity, reliable data are available for the test article and for other members of the "Perylene based pigments category". All of these data are taken into account for the evaluation and assessment of the acute toxicity of the test article.

Additional information is available for the oral and the inhalation route:

In several studies performed with other substances from the Perylene category the potential for oral toxicity was found to be very low. None of these studies raised any concerns regarding acute toxicity after oral application and therefore none of the substances requires classification. The LD50 values observed for these compounds were greater than 5000 mg/kg bw in alle studies performed.

To assess the acute inhalation toxicity, other category members were tested in studies according or similar to OECD 403 guideline. In all studies, rats were exposed to analytically verified dust aerosols for a duration of 4 hours. Except for one study with a single case of mortality all animals survived the procedure. The observed clinical signs included accelerated respiration, pulmonary respiration sounds, squatting posture, piloerection, flight behavior and smeared fur. No pathological abnormalities of the organs were observed at termination in all animals in any of the studies. The LC50 was always greater than tested limit dose respectively.

There are also studies concerning the acute dermal toxicity. In the studies similar to OECD testing guideline 402 no signs for s local or systemic toxicity could be found.

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. No mortality occurred at the limit dose of 2000 mg/kg bw. As a result, the substance is not considered to be classified for acute oral or inhalation toxicity under Regulation (EC) No. 1272/2008, as amended for the fourteenth time in Regulation (EC) No. 2020/217.