2,9-bis(p-methoxybenzyl)anthra[2,1,9-def:6,5,10-d'e'f']diisoquinoline-1,3,8,10(2H,9H)-tetrone

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

13 Oct 1982 - 27 Oct 1982

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1983

Report date:

1983

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

GLP compliance:

no

Test type:

standard acute method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

2,9-bis(p-methoxybenzyl)anthra[2,1,9-def:6,5,10-d'e'f']diisoquinoline-1,3,8,10(2H,9H)-tetrone

EC Number:

280-472-4

EC Name:

2,9-bis(p-methoxybenzyl)anthra[2,1,9-def:6,5,10-d'e'f']diisoquinoline-1,3,8,10(2H,9H)-tetrone

Cas Number:

83524-75-8

Molecular formula:

C40H26N2O6

IUPAC Name:

7,18-bis[(4-methoxyphenyl)methyl]-7,18-diazaheptacyclo[14.6.2.2²,⁵.0³,¹².0⁴,⁹.0¹³,²³.0²⁰,²⁴]hexacosa-1(23),2,4,9,11,13,15,20(24),21,25-decaene-6,8,17,19-tetrone

Details on test material:

Test materials used in this dossier are all considered to fall under the definition of nano-materials according to the European Commission Recommendation 2011/696/EU as the synthesis and manufacturing of this pigment always yields particulate material with a fine particle size distribution.

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: THOM; Zuchtbetrieb: Dr. K. Thomae GmbH, 7950 Biberach
- Age at study initiation: 8 weeks
- Weight at study initiation: 245 g (males) and 179 g (females)
- Housing: type DIII (Fa. Becker)
- Diet: SSNIFF R 10 mm Pellet, Ssniff-Versuchstierdiäten GmbH, 4770 Soest, ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20- 24
- Humidity (%): 30 - 70
- Air changes (per hr): Fully airconditioned room
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:

inhalation: dust

Type of inhalation exposure:

nose/head only

Vehicle:

clean air

Mass median aerodynamic diameter (MMAD):

1.9 µm

Geometric standard deviation (GSD):

3.9

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Head-nose inhalation system INA 20 (glass-steel construction, BASF Aktiengesellschaft)
- Exposure chamber volume: ca. 55 L
- Method of holding animals in test chamber: the animals were restrained in tubes and their snouts projected into the inhalation chamber
- Source and rate of air: 1500 L/h, supply air
- Method of conditioning air: The exposure system was placed in an air-conditioned laboratory. Temperatures in the exposure system were 19-25 °C
- System of generating particulates/aerosols: A dust aerosol air mixture was generated by means of a dust generator.
- Method of particle size determination: Stack Sampler Mark III (Andersen)

TEST ATMOSPHERE
- Brief description of analytical method used: The preweighed filter was placed into the filtration equipment. By means of a vacuum compressed air pump a volume of the dust aerosol was drawn through the filter. The dust concentration in mg/l 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 atmosphere. The concentration was corrected for the amount of the added excipient.
- Samples taken from breathing zone: yes

Analytical verification of test atmosphere concentrations:

yes

Remarks:

gravimetric determination

Duration of exposure:

4 h

Concentrations:

5.4 mg/L

No. of animals per sex per dose:

10

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: daily
- Body weights: at the beginning of the study, after 7 days and at the end of the study
- Necropsy of survivors performed: yes

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.4 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

None of the animals died during the observation period

Clinical signs:

other: Erratic breathing, slight nasal excretion, ruffled fur during the first 4 days of the observation period, no abnormal findings were observed from day 5 onward.

Body weight:

Normal weight gain.
Day 7, mean weight (g): males: 267; females 201
Day 14, mean weight (g): males: 316; females 211.

Gross pathology:

No abnormal findings.

Any other information on results incl. tables

Results of analytical measurements:

Sample No	Analyt. Conc. (mg/l)
1	5.31
2	5.07
3	5.40
4	5.65
Mean	5.4
standard deviation of the mean	0.33
Nominal concentration	39

Particle size analysis:

Stage	EACD 50% [µm]	[mg]	percentage distribution [%]	cummulative distribution [%]
pre-impactor	26.6	9.35	2.502	97.498
0	29.5	0.618	2.032	95.466
1	18.2	0.502	6.133	89.333
3	8.5	1.515	13.209	76.124
4	5.5	3.263	18.22	57.904
5	2.8	4.501	18.755	39
7	1.2	4.633	39.149	149
backup filter	< 1.2	9.671
Sum		34.053

The MMAD 50% = 1.9 µm (geometrical standard deviation =3.9) was calculated from the results of the particle size analysis.

A respirable dust aerosol fraction that might reach the alveolar region of 89% was obtained from the results of the particle size analysis.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

According to the EU and GHS classification criteria, no classification is warranted as to acute inhalation toxicity for the test substance.

Executive summary:

In an acute inhalation toxicity study, 10 male and 10 female Wistar rats were exposed to the test substance as a dust aerosol at a concentration of 5.4 mg/L for 4 hours. The animals were observed for 14 days after exposure.

No mortality occurred at the tested concentration. Clinical signs observed after treatment were erratic breathing, slight nasal excretion, ruffled fur during the first 4 days of the observation period, no abnormal findings were observed from day 5 onward. The body weight gain of the test group was normal and compareable with the control group. No gross pathological abnormalities were noted during the necropsy at termination of the post exposure observation period.

Cascade impactor measurements resulted in particle size distributions with mass median aerodynamic diameters (MMADs) of 1.9 µm.