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EC number: 223-912-2 | CAS number: 4118-16-5
- 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
Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 30 Mar 2015 - 16 Sep 2015.
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 015
- Report date:
- 2015
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- GLP compliance:
- yes (incl. QA statement)
Test material
- Reference substance name:
- 1,1'-[(6-phenyl-1,3,5-triazine-2,4-diyl)diimino]bisanthraquinone
- EC Number:
- 223-912-2
- EC Name:
- 1,1'-[(6-phenyl-1,3,5-triazine-2,4-diyl)diimino]bisanthraquinone
- Cas Number:
- 4118-16-5
- Molecular formula:
- C37H21N5O4
- IUPAC Name:
- 1,1'-[(6-phenyl-1,3,5-triazine-2,4-diyl)diimino]di(9,10-anthraquinone)
- Details on test material:
- - Physical state: Solid / yellow
- Storage condition of test material: Room temperature
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River UK Limited, Margate, Kent, UK
- Age at study initiation: males: 9-10 weeks; females: 8-9 weeks
- Weight at study initiation: males: 254-298g; females: 152-199g
- Fasting period before study: no
- Housing: Animals were initially housed 2 or 3 per cage by sex (unless reduced by mortality) in appropriately sized suspended polycarbonate/polypropylene cages with stainless steel grid tops and solid bottoms. A few days prior to mating, males were transferred to individual cages with a solid bottom. On the first day of pairing, the individual identity of each female rat was confirmed before being placed into the corresponding male’s cage for mating. Mated females were transferred to individual solid bottomed cages. White paper tissue was supplied as nesting material from Day 20 of gestation. Females with litters were retained in this type of cage until termination. After mating, the males were re-housed with their original cage mates.
- Diet: SDS VRF-1 breeder diet was provided ad libitum
- Water: ad libitum from water bottles
- Acclimation period: 2 weeks
ENVIRONMENTAL CONDITIONS
- Temperature: 19-22°C
- Humidity: 38-57%
- Air changes (per hr): >10
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- CMC (carboxymethyl cellulose)
- Remarks:
- 1% carboxymethylcellulose in Milli Q water
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
The required amount of test item was weighed into a pre-labelled container according to instructions from the formulation data capture system (Dispense 8). The total amount of vehicle was then added to the container, and the formulation was mixed using a magnetic stirrer. Formulations were then mixed using a high shear mixer until a homogenous suspension was achieved. The dosing formulations were prepared at least weekly, stored at ambient temperature and dispensed daily. The dosing formulations were removed from storage and were magnetically stirred for at least 30 minutes prior to dosing and continuously during dosing. Any residual volumes were discarded.
VEHICLE
- Concentration in vehicle: 20, 60 and 200 mg/ml
- Amount of vehicle (if gavage): 5 ml/kg - Details on mating procedure:
- Pairing was on a 1 male to 1 female basis, with the exception of a 1 male to 2 female pairing in Group 2 (203M paired with 253F and 254F) due to the premature death of Animal 204M. During the evening (after 7pm) of Day 15 of dosing, females were housed with their allocated co-group male partner. The animals were paired in ascending numerical order.
Vaginal lavages were taken early each morning from the day of pairing until mating has occurred and the stage of oestrus observed in each vaginal lavage was recorded. The day of detection of a copulatory plug in situ and/or of sperm in the lavage was designated Day 0 of gestation. The pairing period for each pair of animals was a maximum of 14 nights. Evidence of mating was not observed by the end of the pairing period for one animal of the intemediateh dose group, so this animal was separated from the male during the morning following the last night of pairing and treated as if mating had occurred during that night. Procedures for this animal continued as if it had mated on the last night of pairing up to the time of littering where lactation procedures were performed as required. For each female the time taken to show a positive mating sign and the number of failed opportunities to mate (oestruses passed without a sign of mating) was evaluated. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- All Week 1 and 4 formulations were found to be within the concentration acceptance criteria of ±10% of theoretical concentration (actual ranges of -3.5% to +10%) and a low relative standard deviation (<2.1%) indicated that these formulations were also homogenous. The absence of test material from all analysed control formulations was also confirmed.
- Duration of treatment / exposure:
- The males were dosed once daily for at least 4 weeks overall, starting from 2 weeks prior to mating.
The females were dosed once daily from 2 weeks prior to mating, then continuing until the day prior to termination. - Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- 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:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose levels were selected based on the results of a 14 day dose range findings study in which rats received the test compound at dose levels of 300 or 1000 mg/kg/day and no adverse findings were noted.
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily, once at the start and once towards the end of the working day throughout the study
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly, beginning Week -1
BODY WEIGHT: Yes
- Time schedule for examinations: weekly during pretreatment and daily during dosing period.
FOOD CONSUMPTION:
Food consumption was quantitatively measured weekly, starting Week -1, for both sexes until pairing for mating. Consumption was also measured for mated females over the periods Days 0-7, 7-14 and 14-20 of gestation, and Days 0-4 of lactation, with the exception of Animal 251 (Group 2, 100 mg/kg/day) which did not have food consumption measured over Days 14-20 of gestation of Days 0-4 of lactation, in error.
WATER CONSUMPTION: Yes
- Time schedule for examinations: Water consumption was monitored by visual inspection of the water bottles on a regular basis throughout the study. As no inter-group differences were noted, consumption was not measured by weight.
OPHTHALMOSCOPIC EXAMINATION: Yes
The eyes were examined using an indirect ophthalmoscope after the application of a mydriatic agent (1% Tropicamide, Mydriacyl®). The anterior, lenticular and fundic areas were examined in all animals pretreatment (including spare animals), during Week 4 for all males and prior to sacrifice for all females – with the exception of: Animals 154F (Group 1, Control), 253F, 254F and 256F (Group 2, 100 mg/kg/day); 352F, 354F and 355F (Group 3, 300 mg/kg/day) and 453F and 457F (Group 4, 1000 mg/kg/day), where pre-terminal examination was not performed in error.
HAEMATOLOGY: Yes
- Anaesthetic used for blood collection: No data
- Animals fasted: males were fasted overnight
- How many animals: 5 animals per sex and dose group
- Parameters examined: Red blood cell count, Haemoglobin, Haematocrit, Mean cell volume, Mean cell haemoglobin concentration, Mean cell haemoglobin, Reticulocytes, Reticulocyte count (absolute), Red blood cell distribution width, Platelets, White blood cell count, Neutrophils, Lymphocytes,
Monocytes, Eosinophils, Basophils, Large unstained cells, Activated partial thromboplastin time, Fibrinogen, Prothrombin time
CLINICAL CHEMISTRY: Yes
- Animals fasted: males were fasted overnight
- How many animals: 5 animals per sex and dose group
- Parameters examined: Urea, Glucose, Aspartate aminotransferase, Alanine aminotransferase, Alkaline phosphatase, Creatine phosphokinase, Lactate dehydrogenase, Sodium, Potassium, Chloride, Total protein, Albumin, Globulin, Albumin/globulin ratio, Cholesterol, Creatinine, Total bilirubin, Calcium, Inorganic phosphate, Triglycerides, Total Bile Acids
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Detailed Functional Observations were performed pretreatment for all animals (including spare animals) and weekly during the dosing period for all animals. Functional Tests were performed: - Pretreatment (5 selected rats per sex per group); - week 4 (5 selected males per group (prior to blood sampling)); - During Lactation (the first 5 females per group which rear their litter to at least Day 3 of lactation (prior to blood sampling)).
- Battery of functions tested: Cageside Observations, observations in a Standardised Area, sensory activity, grip strength, motor activity - Sperm parameters (parental animals):
- Testes of all Group 1 and Group 4 males, examined for staging of spermatogenesis (qualitative evaluation).
- Litter observations:
- The numbers of live and dead pups born in each litter was recorded as soon as possible after completion of parturition on Day 0 of lactation. The live pups were counted and examined daily for the presence of milk in the stomach and for any externally visible abnormalities. Each litter was weighed en masse (by sex) on Days 1 and 4 of lactation.
Pups that were found dead or killed during lactation were sexed and appropriately examined as above. Any externally abnormal decedent pup was preserved; externally normal pups were discarded. Deficiencies in maternal care were recorded: inadequate construction or cleaning of the nest, pups left scattered and cold, physical abuse of pups, or apparently inadequate lactation or feeding. - Postmortem examinations (parental animals):
- GROSS PATHOLOGY: Yes
Scheduled Euthanasia Day: Males: Day 29; Females: Between Days 5-7 of lactation
Animals were subjected to a complete necropsy examination, which included evaluation of the carcass and musculoskeletal system; all external surfaces and orifices; cranial cavity and external surfaces of the brain; and thoracic, abdominal, and pelvic cavities with their associated organs and tissues. The reproductive tracts of all females were examined for signs of implantation, the number of any implantation sites being recorded. The total number of corpora lutea graviditatis were recorded for each female. The protocol stated that the uteri of all non-pregnant females would be stained using 10% aq (v/v) ammonium sulphide solution and examined for implantation sites, however this was not performed in error prior to histopathology of these tissues.
ORGAN WEIGHTS
The following organs were weighed at necropsy for all scheduled euthanasia animals:
Brain, Epididymisa, Gland, adrenala, Gland, pituitary, Gland, prostate, Gland, thyroidab, Heart, Kidney , Liver, Ovarya, Spleen, Testisa, Thymus, Uterus
HISTOPATHOLOGY: Yes
The following tissues were examined:
- Full tissues of unscheduled deaths
- Full tissues of the 5 male and 5 female Group 1 and Group 4 animals used for laboratory investigations
- The reproductive organs of all Group 1 and Group 4 animals and Animal 254F (Group 2) which failed to produce a litter.
- Testes of all Group 1 and Group 4 males, examined for staging of spermatogenesis (qualitative evaluation).
- Gross lesions of all animals (all groups).
Tissues examined:
Animal identification, Artery, aorta, Bone marrow smear x 2, femur bone marrow, sternum bone marrow, femur (with articulating surface), rib, sternum, Brain, Cervix, Epididymis x 2, Eye x 2, adrenal gland x 2, clitorial gland, hardarian gland x 2, lacrimal gland x 2, mammary gland, parathyroid x 2, pituitary gland, prostate gland, preputial gland, salivary (mandibular) gland x 2, seminal vesicle including coagulating gland, thyroid x 2, Gross lesions/masses, Gut-associated lymphoid tissue (Peyer’s Patches), Heart, Kidney x 2, caecum, colon, rectum, Larynx, Liver, Lung, axillary lymph node x 2, mesenteric lymph node, skeletal muscle, Nasal cavity, optic nerve x 2, sciatic nerve x 2, Oesophagus, Ovary x 2, Oviduct x 2, Pancreas, Pharynx, Skin, duodenum, ileum, jejunum, Spinal cord, Spleen, Stomach, Testis x 2, Thymus, Tongue, Trachea, Ureter x 2, Urinary bladder, Uterus, Vagina - Postmortem examinations (offspring):
- Where practicable, animals found dead or killed were sexed, and then checked for the presence of milk in the stomach and for the presence of any externally visible abnormalities. Any abnormal pups were, where practicable, fixed in 10% formalin or methylated ethyl alcohol, as appropriate, for optional further examination. Externally normal pups were discarded.
- Statistics:
- Unless otherwise stated, all statistical tests were two-sided and performed at the 5% significance level using in-house software. Males and females were analysed separately. Pairwise comparisons were only performed against the control group. The following pairwise comparisons were performed:
Control Group vs Group 2
Control Group vs Group 3
Control Group vs Group 4
Body weight (males throughout the study and females prior to mating), food consumption (prior to mating), selected functional observational battery and motor activity data, haematology, coagulation and clinical chemistry were analysed for homogeneity of variance using the ‘F Max' test. If the group variances appear homogeneous, a parametric ANOVA was used and pairwise comparisons made using Fisher’s F protected LSD method via Student's t test i.e. pairwise comparisons were made only if the overall F test is significant. If the variances are heterogeneous, log or square root transformations were used in an attempt to stabilise the variances. If the variances remain heterogeneous, then a Kruskal-Wallis non-parametric ANOVA was used and pairwise comparisons were made using chi squared protection (via z tests, the non-parametric equivalent of Student's t test).
In circumstances where it was not possible to perform the F Max test due to zero standard deviation in at least one group, the non-parametric ANOVA results are reported.
Organ weights were analysed using ANOVA as above and by analysis of covariance (ANCOVA) using terminal kill body weight as covariate. In addition, organ weights as a percentage of terminal body weight were analysed using ANOVA as above as an exploratory analysis. In circumstances where the variances in the ANCOVA remain heterogeneous following log or square root transformations, the data was subjected to a rank transformation prior to analysis. Where it is not possible to perform the F-Max test due to the small sample size, the untransformed parametric ANCOVA results are reported. - Reproductive indices:
- Fertility Index (male), Fertility Index (female), Gestation Index
- Offspring viability indices:
- Birth Index, Live Birth Index, Viability Index
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no clinical observations, body weight or food consumption effects, or any necropsy or histopathological findings in this animal which were considered to be treatment related. There were no clinical observations which were considered to be related to treatment with the test article. All clinical observations were considered to be incidental background findings commonly observed in this species.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- Animal 204M (Group 2, 100 mg/kg/day) was killed prematurely on Day 9 after biting and swallowing part of the gavage tube during dosing. The death of this animal was considered to be incidental and unrelated to treatment.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Group mean body weights followed similar patterns to Controls in both sexes throughout study.
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- Group mean food consumption was generally comparable to Controls in both sexes prior to mating and in females during gestation and lactation.
On Day 15, mean values in females at 100 or 1000 mg/kg/day were statistically different to Controls; however, as these differences were minor and did not follow a dose related pattern, they were considered to be incidental and unrelated to treatment. - Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Description (incidence and severity):
- There were no ophthalmoscopy findings which were considered to be related to treatment with the test item.
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- In treated males, mean white blood cell and lymphocyte counts were lower than Controls at the end of the treatment period. These findings followed a treatment related pattern, with values at 1000 mg/kg/day being approximately 45% lower than controls and being statistically significant at 300 or 1000 mg/kg/day. There were no other haematology or coagulation findings in males or any findings in females which were considered to be related to treatment. Occasional other statistically significant differences from controls were considered to be incidental and unrelated to treatment since the differences were minor and lacked a dose related response.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- In treated groups, mean lactate dehydrogenase and creatine phosphokinase were lower than Controls at the end of the treatment period. In males, the differences followed a treatment related pattern and were statistically significant, with values at 1000 mg/kg/day being approximately 45% lower than Controls. In females, the changes did not follow a treatment related pattern therefore these findings were not positively attributed to treatment in this sex. There were no other clinical chemistry findings in either sex which were considered to be related to treatment. Higher chloride concentrations in males were considered to be incidental due to the lack of a dose-related response.
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- effects observed, non-treatment-related
- Description (incidence and severity):
- Throughout the study, the type and distribution of neurotoxicity observations did not indicate an association with treatment with test material. Detailed functional observations were generally similar between Controls and treated groups. Slight intergroup difference did not follow dose related patterns and were, therefore, considered to be incidental and unrelated to treatment. There were no differences in motor activity between treated animals and Controls which were considered to be related to treatment. In males at 1000 mg/kg/day, lower mean X and Y ambulation values during Week 4, when compared to Controls, were considered to be incidental as these parameters were also lower than Controls during the pretrial period.
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- There were no treatment related microscopic findings at any dose level, in either sex. All findings were considered to be incidental or of the nature commonly observed in this species, and/or were of similar incidence and severity in controls and treated groups, therefore, they were considered not to be associated with treatment.
- Histopathological findings: neoplastic:
- no effects observed
Reproductive function / performance (P0)
- Reproductive performance:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Mating performance, fertility, duration of gestation and litter size were similar in Controls and treated groups.
One female at 100 mg/kg and one male and female at 1000 mg/kg failed to produce/sire a litter, however, these were considered to be incidental as there was no dose-related pattern or correlating data to suggest any relation to treatment.
Effect levels (P0)
- Dose descriptor:
- NOAEL
- Remarks:
- parental toxicity
- Effect level:
- 1 000 mg/kg bw (total dose)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No treatment related clinical observations, body weight, food consumption, detailed functional observation or ophthalmoscopy changes, or any gross necropsy or histopathological findings.
Results: F1 generation
Details on results (F1)
The type and distribution of observations noted in dams and pups during lactation did not indicate any association with treatment.
Effect levels (F1)
- Dose descriptor:
- NOAEL
- Remarks:
- Fertility
- Generation:
- F1
- Effect level:
- 1 000 mg/kg bw (total dose)
- Sex:
- male/female
- Basis for effect level:
- other: Fertility, mating and pregnancy performance and pup/litter performance were similar between all groups.
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- It was considered that 1000 mg/kg/day was the parental No Observed Adverse Effect Level (NOAEL) and the reproductive/developmental No Observed Effect Level (NOEL).
- Executive summary:
The objective of this study was to assess the toxicity of the test item in the Han Wistar rat after oral administration and aimed to provide initial information on possible effects on reproduction and/or development and neurotoxicity. Three test groups (100, 300 and 1000 mg/kg bw) and one control group (vehicle), each containing 10 males and 10 females were used. Males were treated for 2 weeks prior to mating until necropsy after 4 weeks of treatment. Females were treated for 2 weeks prior to mating, then through mating, gestation and until at least Day 4 of lactation. The following parameters and end points were evaluated in this study: clinical signs, body weights, food consumption, ophthalmology, detailed functional observations, clinical pathology parameters (haematology, coagulation and clinical chemistry), fertility, mating and pregnancy performance, maternal care, pup performance (litter survival and litter/pup weight), gross necropsy findings, organ weights and histopathological examinations. Dosing with the test item at dose levels of up to 1000 mg/kg/day was not associated with any treatment related clinical observations, body weight, food consumption, detailed functional observation or ophthalmoscopy changes, or any gross necropsy or histopathological findings. In addition, fertility, mating performance, pregnancy performance and pup/litter performance were similar between all groups. Clinical pathology findings in treated males of lower white blood cell and lymphocyte counts (up to approximately 40% at 1000 mg/kg/day) and lower lactate dehydrogenase and creatine phosphokinase (up to approximately 45% at 1000 mg/kg/day) were considered not to be adverse as there were no correlating histopathology or organ weight findings and changes were of a small enough magnitude that they may indicate a chance related finding. In conclusion, it was considered that 1000 mg/kg/day was the parental No Observed Adverse Effect Level (NOAEL) and the reproductive/developmental No Observed Effect Level (NOEL)
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