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EC number: 445-710-5 | CAS number: 108313-21-9
- 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
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2007
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: The study was conducted according to OECD TG 407, EPA OPPTS 870.3050 and in accordance with the Principles of Good Laboratory Practice (GLP).
Cross-referenceopen allclose all
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to other study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 007
- Report date:
- 2007
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- yes
- Remarks:
- Minor deviations (eg. single instance of extension of the 12 hour light/dark cycle and a missing right adrenal gland from one animal at neropsy - omitted from statistical analysis) which did not have an impact on the quality and outcome of the study
- Qualifier:
- according to guideline
- Guideline:
- other: EPA OPPTS Guideline 870.3050
- Deviations:
- yes
- Remarks:
- same as above
- Principles of method if other than guideline:
- not applicable
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- -
- EC Number:
- 445-710-5
- EC Name:
- -
- Cas Number:
- 108313-21-9
- Molecular formula:
- C54H60N4O2
- IUPAC Name:
- 1,4,5,8-tetrakis[(4-butylphenyl)amino]-9,10-dihydroanthracene-9,10-dione
- Test material form:
- solid: particulate/powder
- Remarks:
- migrated information: powder
- Details on test material:
- - Name of test material (as cited in study report): Spectrace MD-710 Marker [solvent stripped]/1,4,5,8-Tetra (4'-n-butylphenylamino) Anthraquinone (TBPAAQ)
- Substance type: very dark green to black powder
- Physical state: solid
- Analytical purity: > 97% active ingredient
- Lot/batch No.: Lot 20070406
- Expiration date of the lot/batch: March 2010
- Stability under test conditions: expected to be stable for the duration of testing
- Storage condition of test material: room temperature
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Raleigh, North Carolina
- Age at study initiation: approximately 7 weeks
- Weight at study initiation: 220 g to 260 g for males and 164 g to 208 g for females
- Housing: individually in clean, stainless steel, wire-mesh cages suspended above cage-board
- Diet (e.g. ad libitum): in accordance with the Guide for the Care and Use of Laboratory Animals (National Research Council, 1996). PMI Nutrition International, LLC, Certified Rodent LabDiet® 5002 (meal)
- Water (e.g. ad libitum): Reverse osmosis-treated (on-site) drinking water, delivered by an automatic watering system, and the basal diet were provided ad libitum throughout the study, except during the period of fasting prior to blood collection when food, but not water, was withheld.
- Acclimation period: 13 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 70.1°F to 71.5°F (21.2°C to 22.0°C)
- Humidity (%): 37.5% to 53.4%
- Air changes (per hr): 10 fresh air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Remarks:
- (lot no. 026K0051, exp. dates: 12 June 2012 and 12 July 2012, and lot no. 126K0117, exp. date: 17 July 2008, both manufactured by Sigma Aldrich)
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: The appropriate amount of test substance for each formulation was weighed into tared, calibrated glass containers. Approximately 70% of the required amount of corn oil was added to each container. The formulation was mixed until uniform using a magnetic stirrer. Corn oil was then added to each container to bring the formulation to the calibration mark, and the formulation was homogenized using a Silverson L4RT or L4RT-A electric homogenizer until a uniform mixture was obtained. The formulation was then mixed using a magnetic stirrer until uniform.
The test substance formulations were prepared approximately weekly as single formulations for each dosage level, divided into aliquots for daily dispensation and stored refrigerated. The daily aliquots were removed from refrigeration, homogenized and stirred at room temperature prior to release for dose administration. The test substance formulations were stirred continuously throughout the preparation, sampling and dose administration procedures.
VEHICLE
- Justification for use and choice of vehicle: Corn oil is a recommended vehicle by various regulatory agencies
- Amount of vehicle (if gavage): 10 ml/kg
- Lot/batch no. (if required): (lot no. 026K0051, exp. dates: 12 June 2012 and 12 July 2012, and lot no. 126K0117, exp. date: 17 July 2008, both manufactured by Sigma Aldrich) - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Prior to the initiation of dose administration, quadruplicate samples (1 mL each) for determination of homogeneity, resuspension homogeneity (3 and 10 days) and stability were collected from the top, middle and bottom strata of the 10 and 100 mg/mL dosing formulations. Due to out-of-specification results for the 3-day stability assessment, which was thought to be the result of resuspension technique, additional samples were collected from the formulations prepared for analysis of 6-day resuspension homogeneity and stability. In addition, quadruplicate samples (1 mL each) for concentration analysis were collected from the
middle strata of the dosing formulations prepared for use during study weeks 0 and 3. Two samples from each set of 4 were analyzed; the remaining 2 samples were stored frozen (approximately -65°C to -85°C) as back-up samples. All analyses were conducted by the Analytical Chemistry Department, WIL Research Laboratories, LLC.
The analyzed dosing formulations were found to contain the amount of Spectrace MD-710 Marker [solvent stripped] (85% to 115% of target), were homogeneous (variability for the mean concentration was ≤10% RSD at a concentration within the acceptable limits) and were stable (post-storage concentration was not less than 90% of the pre-storage value) under refrigerated conditions for up to 10 days with the following exception. The 10 mg/mL formulation stored refrigerated for 3 days was determined to be 89.4% of the pre-storage value. The results were thought to be due to the resuspension technique, which was magnetic stirring for at least 15 minutes. Subsequent to the collection and analysis of the 3-day samples, the resuspension technique was amended to included homogenization with an electric homogenizer; consequently, all formulations resuspended after the 3-day time point met test substance stability criteria. No test substance was detected in the vehicle formulation used for administration to the control group (Group 1). - Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- daily once for 28 days
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
100 mg/kg/day
Basis:
other: nominal concentration
- Remarks:
- Doses / Concentrations:
300 mg/kg/day
Basis:
other: nominal concentration
- Remarks:
- Doses / Concentrations:
1000 mg/kg/day
Basis:
other: nominal concentration
- No. of animals per sex per dose:
- 10 male + 10 female rats/dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: based on the results of the 14-day dose range-finding toxicity study.
- Rationale for animal assignment: random - Positive control:
- not applicable
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily, once in the morning and once in the afternoon for mortality and moribundity. Clinical examinations were performed twice daily fro all animals, at the time of dosing and approximately 1-2 hours after dosing.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to the scheduled necropsy
- Anaesthetic used for blood collection: Yes (inhalation of isoflurane)
- Animals fasted: Yes
- How many animals: all animals
- Parameters examined: Total leukocyte count (White Cells), Erythrocyte count (Red Cells), Hemoglobin, Hematocrit, Mean corpuscular volume (MCV), Mean corpuscular hemoglobin, (MCH), Mean corpuscular hemoglobin concentration (MCHC), Platelet count (Platelet), Prothrombin time (ProTime), Activated partial thromboplastin time (APTT), Reticulocyte count - Percent (Reticulocyte) Absolute (Retic Absolute), Differential leukocyte count - Percent and absolute - Neutrophil, Lymphocyte, Monocyte, Eosinophil, Basophil, Large unstained cell, Platelet estimate, Red cell morphology - (RBC Morphology) and coagulation time
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: prior to necropsy
- Animals fasted: Yes
- How many animals: all animals
- Parameters examined: Albumin, Total protein, Globulin [by calculation], Albumin/globulin ratio (A/G Ratio) [by calculation], Total bilirubin (Total Bili), Urea nitrogen, Creatinine, Alkaline phosphatase (AlkalinePhos’tse), Alanine aminotransferase (Alanine Transfer), Aspartate aminotransferase (AspartatTransfer), Gamma glutamyltransferase (GlutamylTransfer), Glucose, Total cholesterol (Cholesterol), Calcium, Chloride, Phosphorus, Potassium, Sodium, Triglycerides (Triglyceride)
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: study week 3
- Dose groups that were examined: all animals
- Battery of functions tested: sensory activity / grip strength / motor activity - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes - Other examinations:
- The following organs were weighed from all animals at the scheduled necropsy: Adrenal glands, Brain, Epididymides, Heart, Kidneys, Liver, Ovaries (with oviducts), Spleen, Testes, Thymus and Uterus. Paired organs were weighed together and organ-to-final-body-weight ratios were calculated
- Statistics:
- Standard statistical methods were employed
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- CLINICAL SIGNS AND MORTALITY - All animals survived to the scheduled necropsy. There were no adverse test substance-related clinical observations. Test substance-related clinical observations were noted in all test substance-treated groups and consisted of low incidences of wet/dry green material on various body surfaces (mouth, ventral neck, dorsal trunk and head, and anogenital region). These findings did not occur in a dose-responsive manner. The coloration was attributed to the physical properties of the test substance formulations and was characterized as staining, which is not an adverse effect. All other clinical findings in the test substance-treated groups were noted with similar incidence in the control group, were limited to single animals, were not noted in a dose-related manner and/or were common findings for laboratory rats of this age and strain.
BODY WEIGHT AND WEIGHT GAIN - Body weights were unaffected by test substance administration. There were no statistically significant differences when the control and test substance-treated groups were compared.
FOOD CONSUMPTION - There were no test substance-related effects on food consumption. There were no statistically significant differences when the control and test substance-treated groups were compared.
HAEMATOLOGY - Hematology and coagulation parameters were unaffected by test substance administration. The only statistically significant (p<0.05) differences from the control group consisted of higher platelet values for the 100 and 1000 mg/kg/day group males. These group mean differences were not considered to be test substance-related because the values were not observed in a dose-related manner, were observed in males only and were of a magnitude that would be considered to be toxicologically unimportant.
CLINICAL CHEMISTRY - There were no test substance-related effects on serum chemistry parameters. However, some statistically significant (p<0.05) differences were observed when the control and test substance-treated groups were compared. These findings included: lower A/G ratio for 300 mg/kg/day group males, higher globulin for 1000 mg/kg/day group females and lower alkaline phosphatase for 1000 mg/kg/day group females. These group mean differences were not considered to be test substance-related because the values did not show a dose-related response, involved a single sex, were of a magnitude that would be considered toxicologically unimportant and/or involved a change in a direction of no known biological importance.
NEUROBEHAVIOUR -
Home cage observations - Home cage observations were unaffected by test substance administration. There were no statistically significant differences when the test substance-treated males and females were compared to the control group at the study week 3 evaluation.
Handling observations - Handling observations were unaffected by test substance administration. There were no statistically significant differences when the test substance-treated males and females were compared to the control group at the study week 3 evaluation.
Open field observations - Open field observations were unaffected by test substance administration. There were no statistically significant differences when the test substance-treated males and females were compared to the control group at the study week 3 evaluation.
Sensory observations - Sensory observations were unaffected by test substance administration. There were no statistically significant differences when the test substance-treated males and females were compared to the control group at the study week 3 evaluation.
Neuromuscular observations - Neuromuscular observations were unaffected by test substance administration. The 300 mg/kg/day group females were noted to have a significantly higher mean hindlimb footsplay value when compared to the control group; however, the higher hindlimb footsplay noted in the 300 mg/kg/day group females was not considered to be related to test substance administration because a dose-related response was not observed. There were no other statistically significant differences when the test substance-treated males and females were compared to the control group at the study week 3 evaluation.
Physiological observations - Physiological observations were unaffected by test substance administration. There were no statistically significant differences when the test substance-treated males and females were compared to the control group at the study week 3 evaluation.
Locomotor activity - Locomotor activity patterns (total and ambulatory activity counts) were unaffected by test substance administration. Values obtained from the 4 epochs evaluated (0-15 minutes, 16-30 minutes, 31-45 minutes and 46-60 minutes) and the overall 60-minute test session were similar to the concurrent control values. No remarkable shifts in the pattern of habituation occurred in any of the test substance-treated groups when the animals were evaluated.
ORGAN WEIGHTS - Organ weights were unaffected by test substance administration. There were no statistically significant differences when the control and test substance-treated groups were compared.
GROSS PATHOLOGY - Test substance-related macroscopic findings at the scheduled necropsy included green discoloration and/or dark green contents of various segments of the gastrointestinal tract (stomach, jejunum, ileum, cecum and colon). These findings were not observed in a dose responsive manner and were attributed to the color of the test substance formulations and were not considered to be adverse.
HISTOPATHOLOGY - No test substance-related microscopic changes were observed in any of the rats administered 1000 mg/kg/day of Spectrace MD-710 Marker [solvent stripped]. Incidental microscopic findings consisted of foci of mononuclear inflammatory cell infiltrations in the coagulating gland, epididymides, heart, kidneys, lacrimal glands, larynx, liver and trachea. These observations occurred sporadically and were not attributed to the test substance. The data support the conclusion that test substance administration had no effect on the occurrence of this common, spontaneously-occurring lesion in young rats. Other microscopic changes observed in the designated organs and tissues were typical of those that occur spontaneously in laboratory rats of this age and strain and were not test substance-related.
Effect levels
- Dose descriptor:
- NOEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: see 'Remark'
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
None
Applicant's summary and conclusion
- Conclusions:
- Based on the results of this study, the no-observed-effect-level (NOEL) for oral (gavage) administration of Spectrace MD-710 Marker [solvent stripped] to Crl:CD(SD) rats over a period of 28 days was 1000 mg/kg/day.
- Executive summary:
The objective of this study was to evaluate the possible toxic effects of the test substance, Spectrace MD-710 Marker [solvent stripped], also known as 1,4,5,8-tetra (4’-n-butylphenylamino) anthraquinone, or TBPAAQ, when administered orally (by gavage) to rats for 28 days. This study included evaluation of potential neurotoxicity by functional observational battery (FOB) and locomotor
activity (MA) assessment.
Spectrace MD-710 Marker [solvent stripped] in the corn oil vehicle was administered orally by gavage once daily for 28 consecutive days to 3 groups (Groups 2-4) of Crl:CD(SD) rats. Dosage levels were 100, 300 and 1000 mg/kg/day. A concurrent control group (Group 1) received the vehicle on a comparable regimen. The dose volume was 10 mL/kg for all groups. Each group consisted of 10 animals/sex. Study day 0 was designated as the first day of dosing.
All animals were observed twice daily for mortality and moribundity. Clinical examinations were performed at the time of dosing and approximately 1-2 hours after dosing. Detailed physical examinations were performed weekly. Individual body weights and food consumption were recorded approximately weekly. Functional observational battery (FOB) and locomotor activity data were recorded for all animals during study week 3. Clinical pathology evaluations (hematology and serum chemistry) were conducted for all animals on the day of the scheduled necropsy (study day 28). Complete necropsies were conducted on all animals, and selected organs were weighed at the scheduled necropsy. Selected tissues were examined microscopically from selected animals.
All animals survived to the scheduled necropsy. Body weights and food consumption were unaffected by test substance administration. There were no test substance-related functional observational battery or locomotor activity findings or effects on hematology, coagulation and serum chemistry parameters. Organ weights were unaffected by test substance administration, and there were no test substance-related histopathologic findings.
Clinical observations of green material on various body surfaces and macroscopic observations of green discoloration and/or green contents of various segments of the gastrointestinal tract were noted in all test substance-treated groups. These findings were attributed to the presence of Spectrace MD-710 Marker [solvent stripped] and were not an adverse effect.
Daily oral (gavage) administration of Spectrace® MD-710 Marker [solvent stripped] to Crl:CD(SD) rats at dosage levels of 100, 300 and 1000 mg/kg/day for 28 days was well tolerated. There were no effects on body weights, food consumption, hematology or serum chemistry parameters, organ weights or histopathology. There were no indications of neurotoxicity following FOB and locomotor activity assessment. Clinical and macroscopic observations of green material were noted on various body surfaces and in or on various segments of the gastrointestinal tract. These observations were attributed to the presence of Spectrace MD-710 Marker [solvent stripped] and were not an adverse effect. Based on the results of this study, the no-observed-effect-level (NOEL) for oral (gavage) administration of Spectrace MD-710 Marker [solvent stripped] to Crl:CD(SD) rats was 1000 mg/kg/day.
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