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EC number: 201-375-5 | CAS number: 81-77-6
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data

Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2016-2017
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 017
- Report date:
- 2017
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- 6,15-dihydroanthrazine-5,9,14,18-tetrone
- EC Number:
- 201-375-5
- EC Name:
- 6,15-dihydroanthrazine-5,9,14,18-tetrone
- Cas Number:
- 81-77-6
- Molecular formula:
- C28H14N2O4
- IUPAC Name:
- 6,15-dihydroanthrazine-5,9,14,18-tetrone
- Test material form:
- solid: nanoform, no surface treatment
- Details on test material:
- Batch: P 112045
Appearance: violet/dark blue solid
stable at room temperature
Purity according to elementary analysis: 100.2g/100g
Water content 0.24 g/100g
BET = 36.4m2/g
Constituent 1
- Specific details on test material used for the study:
- Batch: P 112045
Purity: The elementary analysis shows 100.2g/100g.
Expiry date: February 2021
Storage conditions: room temparature
Test animals
- Species:
- rat
- Strain:
- other: Crl:WI (Han)
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH
- Age at study initiation: 11-13 weeks
- Weight at study initiation: average 165 g (gestation day 0), average 196g (beginning of treatment period)
- Housing: single caging
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: six days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30 - 70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 2016-05-11 To: 2016-06-02
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: The specific amount of test substance was weighed, topped up with vehicle in a graduated flask and intensely mixed. The mixture was continuosly stirred until dosing.
VEHICLE
- Justification for use and choice of vehicle (if other than water): The test item can be suspended in the vehicle. It is not soluble in water.
- Amount of vehicle (if gavage): 10 ml/kg body weight - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The stability of the test substance preparations was demonstrated over a period of 7 days at room temperature.
The homogeneous distribution of the test substance in the vehicle (drinking water) was confirmed.
The correctness of the prepared concentrations was shown. - Details on mating procedure:
- - Impregnation procedure: purchased timed pregnant
The day of evidence of mating (= detection of vaginal plug/sperm) was referred to as GD 0. The animals arrived on the same day (GD 0) at the experimental laboratory. - Duration of treatment / exposure:
- gestation days 6- 19
- Frequency of treatment:
- daily
- Duration of test:
- 14 days
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 300 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 25
- Control animals:
- yes
- Details on study design:
- - Dose selection rationale: Based on the results of the OECD 422 study.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Mortality/Morbidity, pertinent behavioral changes and/or signs of overt toxicity. were checked twice daily from Mondays to Fridays and once daily on Saturdays, Sundays and public holidays (GD 0 to 20).
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: Yes
- Time schedule for examinations: GD 0, 1, 3, 6, 8, 10, 13, 15, 17, 19 and 20.
POST-MORTEM EXAMINATIONS: Gross pathology
- Sacrifice on gestation day: GD 20 - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: Site of implantations in the uterus - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
In the present study the glossary of WISE et al. (1997) and its updated version of MAKRIS et al. (2009) was essentially used to describe findings in fetal morphology. Classification of these findings was based on the terms and definitions proposed by CHAHOUD et al. (1999) and SOLECKI et al. (2001, 2003):
Malformation
A permanent structural change that is likely to adversely affect the survival or health.
Variation
A change that also occurs in the fetuses of control animals and/or is unlikely to adversely affect the survival or health. This includes delays in growth or morphogenesis that have otherwise followed a normal pattern of development.
The term "unclassified observation" was used for those fetal findings, which could not be classified as malformations or variations. - Statistics:
- DUNNETT's test: Food consumption, body weight, body weight change, DUNNETT's test
corrected body weight gain, carcass weight, weight of the unopened uterus, weight of the placentas and
fetuses, corpora lutea, implantations, pre- and postimplantation losses, resorptions and live fetuses
FISHER's exact test
Number of pregnant animals at the end of the study, FISHER's exact test mortality rate (of the dams) and number of litters with fetal findings
WILCOXON test
Proportion of fetuses with findings per litter - Indices:
- sex ratio
conception rate (in %)
preimplantation loss (in %)
postimplantation loss (in %) - Historical control data:
- Historical control data is included in the study report.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food efficiency:
- no effects observed
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
- Details on results:
- The test item is a blue colorant. This caused the feces of the high dose group animals to be stained blue. At necropsy, the content of the gastrointestinal tract was blue; this reflects presence of the blue test item as expected for oral dosing.
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed - Changes in number of pregnant:
- no effects observed
- Other effects:
- no effects observed
Effect levels (maternal animals)
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: no adverse effects observed at the limit dose
Maternal abnormalities
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed - Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Skeletal malformations:
- no effects observed
- Visceral malformations:
- no effects observed
- Other effects:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- Individual skeletal malformations
One male control fetus had a shortened humerus. One low dose male fetus had a severely malformed vertebral column and/or ribs. There were no skeletal malformations in the mid and high dose fetuses.
Individual skeletal variations (Table 8)
High dose group fetuses had an incidence of a hole in the tuberositas deltoidea which slightly exceeded the historical control (2.6% versus a range of 0.2 - 2.3%). The incidence of supraoccipital hole(s) was not dose-related and within the historical control group range.
Effect levels (fetuses)
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: absence of adverse effects at the limit dose.
Fetal abnormalities
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Developmental effects observed:
- no
Any other information on results incl. tables
Table 1 (FC = Food consumption; BW = Body weight; BWC = Body weight change)
Parameter | Test group 0 0 |
Test group 1 100 mg/kg bw |
Test group 2 300 mg/kg bw |
Test group 3 1000 mg/kg bw |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Females mated/ pregnant/ animals with viable fetuses: | 25/24/24 | 25/25/25 | 25/24/24 | 25/23/23 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Clinical observations: | no adverse effects |
no adverse effects |
no adverse effects |
Feces discolored (blue) (25/25) |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
FC (0 - 6) FC (6 - 19) FC (0 - 20) |
16.5 g 21.1 g 19.9 g |
16.3 g (99%) 20.9 g (99%) 19.6 g (99%) |
16.1 g (98%) 20.9 g (99%) 19.6 g (99%) |
15.9 g (96%) 20.4 g (97%) 19.2 g (97%) |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
BW (0) BW (6) BW (19) BW (20) |
167.3 g 201.6 g 276.6 g 287.4 g |
165.5 g (99%) 198.9 g (99%) 276.8 g (100%) 288.4 g (100%) |
167.8 g (100%) 201.5 g (100%) 282.7 g (102%) 295.4 g (103%) |
165.2 g (99%) 195.0 g (97%) 273.8 g (99%) 286.5 g (100%) |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
BWC (0 - 6) BWC (6 - 19) BWC (0 - 20) BWC (0 - 1) BWC (17 - 19) |
34.3 g 75.1 g 120.2 g 14.9 g 20.0 g |
33.4 g (97%) 78.0 g (104%) 123.0 g (102%) 13.2 g (88%) 22.5 g (113%) |
33.7 g (98%) 81.1 g (108%) 127.6 g (106%) 14.3 g (96%) 23.1 g (116%)* |
29.8 g (87%)** 78.7 g (105%) 121.3 g (101%) 12.3 g (83%)* 22.6 g (113%) |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Uterus weight: | 48.9 g | 53.4 g (109%) | 55.7 g (114%) | 55.6 g (114%) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Carcass: | 238.6 g | 235.1 g (99%) | 239.8 g (101%) | 230.9 g (97%) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Corrected body weight gain: | 37.0 g | 36.2 g (98%) | 38.2 g (103%) | 35.8 g (97%) |
Necropsy findings (dams): | no effects observed | Stomach: content discolored (5/25) Caecum: content discolored (1/25) Large intestine: content discolored (1/25) Dilated renal pelvis (1/25) |
Stomach: content discolored (9/25) Small intestine: content discolored (2/25) Caecum: content discolored (3/25) Large intestine: content discolored (4/25) |
Stomach: content discolored (6/25) Small intestine: content discolored (1/25) Caecum: content discolored (13/25) Large intestine: content discolored (5/25) Rectum: content discolored (11/25) |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Postimplantation loss: | 9.0% | 9.5% | 8.3% | 2.3% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Total Resorptions: | 0.9 | 1.0 | 0.9 | 0.3 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Live fetuses/dam: | 8.5 | 9.2 | 9.7 | 9.7 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Placental weights: | 0.50 g | 0.52 g (104%) | 0.50 g (99%) | 0.51 g (102%) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Fetal weights: | 3.6 g | 3.7 g (101%) | 3.7 g (102%) | 3.7 g (101%) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Total external malformationsFetuses: Litter: Affected fetuses/litter: |
0/204 (0.0%) 0/24 (0.0%) 0.0% |
0/230 (0.0%) 0/25 (0.0%) 0.0% |
0/233 (0.0%) 0/24 (0.0%) 0.0% |
0/223 (0.0%) 0/23 (0.0%) 0.0% |
Table 3
Group 0 | Group 1 | Group 2 | Group 3 | |
0 | 100 mg/kg bw | 300 mg/kg bw | 1000 mg/kg bw | |
Pregnant | 24 | 25 | 24 | 23 |
Aborted | 0 | 0 | 0 | 0 |
Premature birth | 0 | 0 | 0 | 0 |
Dams with viable fetuses | 24 | 25 | 24 | 23 |
Dams with all resorptions | 0 | 0 | 0 | 0 |
Pregnant at terminal sacrifice | 24 | 25 | 24 | 23 |
Corpus Lutea (mean) | 10.5 D | 10.9 | 11.2 | 10.6 |
SD | 1.14 | 1.86 | 1.28 | 1.92 |
Total | 253 | 272 | 269 | 244 |
Implantation sites (mean) | 9.4 D | 10.2 | 10.6 | 10 |
SD | 2.19 | 2.3 | 1.77 | 2.14 |
Total | 226 | 256 | 254 | 229 |
preimplantation loss (mean) | 10.6 D | 6.8 | 5.7 | 6.8 |
SD | 19.38 | 14.41 | 11.03 | 10.18 |
postimplantation loss (mean) | 9 D | 9.5 | 8.3 | 2.3 |
SD | 12.21 | 11.54 | 9.58 | 4.75 |
Early resorptions (mean) | 0.8 D | 1 | 0.9 | 0.3 |
SD | 1.02 | 1.31 | 1.08 | 0.54 |
total | 19 | 24 | 21 | 6 |
Late resorptions (mean) | 0.1 D | 0.1 | 0 | 0 |
SD | 0.45 | 0.28 | 0 | 0 |
total | 3 | 2 | 0 | 0 |
Dead fetuses | 0 | 0 | 0 | 0 |
% female fetuses | 53.4 | 54.8 | 55.8 | 52.5 |
% male fetuses | 46.6 | 45.2 | 44.2 | 47.5 |
D = Dunnett-test (two-sided)*: p<=0.05
Table 4: Total soft tissue malformations
|
|
Test group 0 0 mg/kg bw/d |
Test group 1 100 mg/kg bw/d |
Test group 2 300 mg/kg bw/d |
Test group 3 1000 mg/kg bw/d |
Litter |
N |
24 |
25 |
24 |
23 |
Fetal incidence |
N (%) |
0.0 |
1 (0.9) |
0.0 |
0.0 |
Litter incidence |
N (%) |
0.0 |
1 (4.0) |
0.0 |
0.0 |
Affected fetuses/litter |
Mean% |
0.0 |
0.8 |
0.0 |
0.0 |
mg/kg bw/d = milligram per kilogram body weight per day; N = number; % = per cent
Table 5: Total soft tissue variations
|
|
Test group 0 0 mg/kg bw/d |
Test group 1 100 mg/kg bw/d |
Test group 2 300 mg/kg bw/d |
Test group 3 1000 mg/kg bw/d |
Litter |
N |
24 |
25 |
24 |
23 |
Fetal incidence |
N (%) |
3 (3.2) |
5 (4.6) |
4 (3.6) |
4 (3.8) |
Litter incidence |
N (%) |
3 (13) |
5 (20) |
4 (17) |
2 (8.7) |
Affected fetuses/litter |
Mean% |
2.7 |
4.4 |
4.7 |
3.2 |
mg/kg bw/d = milligram per kilogram body weight per day; N = number; % = per cent
Table 6: Total fetal skeletal malformations
|
|
Test group 0 0 mg/kg bw/d |
Test group 1 100 mg/kg bw/d |
Test group 2 300 mg/kg bw/d |
Test group 3 1000 mg/kg bw/d |
Litter |
N |
24 |
25 |
24 |
23 |
Fetal incidence |
N (%) |
1 (0.9) |
1 (0.8) |
0.0 |
0.0 |
Litter incidence |
N (%) |
1 (4.2) |
1 (4.0) |
0.0 |
0.0 |
Affected fetuses/litter |
Mean% |
2.1 |
1.0 |
0.0 |
0.0 |
mg/kg bw/d = milligram per kilogram body weight per day; N = number; % = per cent
Table 7: Total fetal skeletal variations
|
|
Test group 0 0 mg/kg bw/d |
Test group 1 100 mg/kg bw/d |
Test group 2 300 mg/kg bw/d |
Test group 3 1000 mg/kg bw/d |
Litter |
N |
24 |
25 |
24 |
23 |
Fetal incidence |
N (%) |
109 (99) |
116 (95) |
120 (98) |
109 (92) |
Litter incidence |
N (%) |
24 (100) |
25 (100) |
24 (100) |
23 (100) |
Affected fetuses/litter |
Mean% |
99.2 |
95.7 |
98.3 |
91.9 |
mg/kg bw/d = milligram per kilogram body weight per day; N = number; % = per cent
Table 8: Occurrence of statistically significantly increased fetal skeletal variations (expressed as mean percentage of affected fetuses/litter)
Finding |
Test group 0 0 mg/kg |
Test group 1 100 mg/kg bw/d |
Test group 2 300 mg/kg bw/d |
Test group 3 1000 mg/kg bw/d |
Historical control data Mean % (range) |
Supraoccipital hole(s) |
0.0 |
4.7* |
1.9 |
0.0 |
6.5 (0.0 – 30.1) |
Hole in tuberositas |
0.0 |
0.0 |
0.0 |
2.6* |
0.2 (0.0 – 2.3) |
mg/kg bw/d = milligram per kilogram body weight per day; % = per cent* = p <= 0.05 (Wilcoxon-test [one-sided]) ** = p <= 0.01 (Wilcoxon-test [one-sided])
Table 9: Total unlassified cartilage observations
|
|
Test group 0 0 mg/kg bw/d |
Test group 1 100 mg/kg bw/d |
Test group 2 300 mg/kg bw/d |
Test group 3 1000 mg/kg bw/d |
Litter |
N |
24 |
25 |
24 |
23 |
Fetal incidence |
N (%) |
62 (56) |
62 (51) |
70 (57) |
62 (53) |
Litter incidence |
N (%) |
22 (92) |
23 (92) |
22 (92) |
22 (96) |
Affected fetuses/litter |
Mean% |
55.1 |
49.2 |
56.8 |
51.0 |
mg/kg bw/d = milligram per kilogram body weight per day; N = number; % = per cent
Applicant's summary and conclusion
- Conclusions:
- The substance does not cause developmental toxicity or teratogenicity in rats.
- Executive summary:
In a prenatal developmental toxicity study the test substance was administered to pregnant Wistar rats daily by gavage from implantation to one day prior to the expected day of parturition (GD 6-19) to evaluate its potential maternal and prenatal developmental toxicity. Analyses confirmed the correctness of the prepared concentrations, the homogeneous distribution and the stability of the test substance in the vehicle. Generally, clinical observations including food consumption and body weight gain revealed no toxicologically relevant difference between the animals receiving 100, 300 or 1000 mg/kg bw/d test substance and controls. No differences of toxicological relevance between the control and the treated groups (100, 300 or 1000 mg/kg bw/d) were determined for any reproductive parameters, such as conception rate, mean number of corpora lutea, mean number of implantations, as well as pre- and postimplantation loss. Similarly, no influence of the test substance on fetal weight and sex distribution of the fetuses was noted at any dose. Overall, there was no evidence for toxicologically relevant adverse effects of the test substance on fetal morphology at any dose.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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