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EC number: 224-618-7 | CAS number: 4430-18-6
- 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
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- From 27 September 1999 to 4 January 2000
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 000
- Report date:
- 2000
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- Adopted : 21st September 1998
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Sodium 4-[(9,10-dihydro-4-hydroxy-9,10-dioxo-1-anthryl)amino]toluene-3-sulphonate
- EC Number:
- 224-618-7
- EC Name:
- Sodium 4-[(9,10-dihydro-4-hydroxy-9,10-dioxo-1-anthryl)amino]toluene-3-sulphonate
- Cas Number:
- 4430-18-6
- Molecular formula:
- C21H15NO6S.Na
- IUPAC Name:
- sodium 2-[(4-hydroxy-9,10-dioxo-9,10-dihydroanthracen-1-yl)amino]-5-methylbenzenesulfonate
- Test material form:
- solid: particulate/powder
- Remarks:
- Dark Red Violet
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Supplied by KAO Corporation, batch No. 0609RA (lot No. AK0709)
- Expiration date of the lot/batch: May 2001
- Purity test date: March 18, 1999
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material:at room temperature, light and humidity protected
- Stability under test conditions: >= 72 hours
- Solubility and stability of the test substance in the solvent/vehicle: soluble in water and stability : >= 72 hours
TREATMENT OF TEST MATERIAL PRIOR TO TESTING
The mixtures of the test article and vahicle were prepared weekly. The test article was weighed into a glass beaker on a tared precision balance and the vehicle was added (w/v). The mixtures were prepared using a magnetic stirrer. During the daily administration period, homogeneity was maintened using a magnetic stirrer.
Test animals
- Species:
- rat
- Strain:
- Wistar
- Remarks:
- HanIbm:WIST (SPF)
- Details on species / strain selection:
- Recognized by international guidelines as a recommended test system
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: RCC Ltd Biotechnology & Animal Breeding Division
- Females (if applicable) nulliparous and non-pregnant: not specified
- Age at study initiation: 6 weeks
- Weight at study initiation: male : mean 146 grams / female ; mean 116 grams
- Fasting period before study: not specified
- Housing: Groups of five animals in Makrolon type-4 cages with sterilized standard softwood bedding ('Lignocel') Schill AG (Switzerland)
- Diet (e.g. ad libitum): Pelleted standard Kliba 3433 rat maintenance diet (Provimi Kliba AG) ad libitum
- Water (e.g. ad libitum): Tap water ad libitum
- Acclimation period: Seven days under test conditions with an evaluation of health status
DETAILS OF FOOD AND WATER QUALITY: Analysis of contaminants in food and water were performed and reported.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3°C
- Humidity (%): 40-70%
- Air changes (per hr): 10-15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12h/12h and at least 8 hours music/light period
IN-LIFE DATES: From: 27 September 1999 To: 4 January 2000
Administration / exposure
- Route of administration:
- oral: gavage
- Details on route of administration:
- Oral ingestion is a possible route of human exposure
- Vehicle:
- CMC (carboxymethyl cellulose)
- Remarks:
- 1% CMC in bi-distilled water
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
The mixtures of the test article and vehicle were prepared weekly. The test article was weighed into a glass beaker on a tared precision balance and the vehicle was added (w/v). The mixtures were prepared using a magnetic stirrer. During the daily administration period, homogeneity was maintened using a magnetic stirrer.
VEHICLE
- Justification for use and choice of vehicle (if other than water): not specified
- Concentration in vehicle: 10, 30 and 100 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg body weight
- Lot/batch no. (if required): not specified
- Purity: not specified - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Stability and homogeneity and content of the test article in the dose formulations was determined with the first test article preparations before treatment start. Intercurrent samples for analysis (homogeneity and content) were drawn at weeks 6 and 12. The analysis was performed according a High Performance Liquid Chromatography HPLC method.
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- Daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Dose / conc.:
- 300 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 10 animals per sex per dose were used
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose levels were selected according to the results of "Ext. D&C Violet 2 : 14 day oral (gavage) toxicity study in the rat" study report No. RCC Project 736290
- Rationale for animal assignment (if not random): Computer-generated random algorithm
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least once daily
- Cage side observations checked : Piloerection, salivation, hunched posture, ataxia, tremore/twitching, prostration, hyperactivity, somnolence, dyspnea, tachypnea, bradypnea
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once before the first test article exposure and once weekly during weeks 1-12
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No
Calculated : G/Animal/Day
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Acclimatization : on all animals, at week 13 on all animals of groups 1 and 4
- Dose groups that were examined: group 1 and 4
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Bloods samples were collected from all animals early in the working day to reduce biological variation caused by circadian rhythms
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: Yes
- How many animals: All animals
- Parameters checked : Erythrocyte count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, reticulocyte count, reticulocyte fluorescence ratios, nucleated erythrocytes, total leukocyte count, differential leukocyte count, red blood cell morphology, thromboplastin time, activated partial thromboplastin time
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Bloods samples were collected from all animals early in the working day to reduce biological variation caused by circadian rhythms, after 13 weeks
- Animals fasted: Yes
- How many animals: all animals
- Parameters checked : plasma color, glucose, urea, creatinie, uric acid, bilirubin, lipids, cholesterol, triglycerides, phospholipids, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, creatine kinase, alkaline phosphatase, gamma glutamyl transferase, calcium, phosphorus, sodium, potassium, chloride, protein total, protein electrophoresis.
URINALYSIS: Yes
- Time schedule for collection of urine: Urine was collected during 18 hours fasting period into a specimen vial. After 13 weeks
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked : Volume (18 hours), specific gravity, osmolality, color, appearance, pH, protein, glucose, ketone, bilirubin, blood, nitrite urobilinogen, urine sediment, white blood cells, crystals (triple phosphate)
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: During week 13
- Dose groups that were examined:
- Battery of functions tested: grip strength / motor activity
IMMUNOLOGY: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
Organ weighed ; Adrenals, ovaries, brain, spleen, heart, kidneys, testes, thyroid, liver, thymus
HISTOPATHOLOGY: Yes
Organs conserved in neutral phosphate buffered formalin:
Adrenals glands, Aorta, Brain, cerebral cortex, femur, cecum, colon, duodenum, epididymides, esophagus, eyes with optic nerve, heart, ileum, jujenum, kifneys, liver, lungs, lymph nodes, mammary gland area, ovaries, pancreas, pituitary gland, prostate gland, rectum, salivary glands, sciatic nerve, seminal vesicles, skeletal muscle, skin, spinal cord, spleen, stomach, testes, thymus, thyroid gland, parathyroid gland, tongue, trachea, urinary bladder, uterus, vagina - Statistics:
- The following statistical methods were used to analyze the body weights, organ weights and all ratios as well as clinical laboratory data:
If the variables were assumed to follow a normal distribution, the Dunett's test (many to one t-test) based on pooled variance estimate was applied for the comparison of the treated groups and the control groups for each sex.
The steel-test (many-one rank test) was applied instead of the Dunnett-test when the data could not be assumed to follow a normal distribution.
Student's T-test was applied to locomotor activity and grip strength
Fisher's exact test was applied to the ophtalmoscopy data and macroscopial data.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Dark respective blue feces were noted in all treated groups with increasing degree depending on time and/or dose level. Discolored feces were noted in some male or female animals treated with 1000 mg/kg/day during week 3 of the study.
- 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:
- no effects observed
- Description (incidence and severity):
- Opacity and pupillary membrane were observed equally in control and test article treated animals and were therefore considered to be not test article related.
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- An increased Tombroplastin Time (PT) and Incresed Activated Partial Thromboplastin Time was observed in male rats from the high dose level group (1000 mg/kg/day). Only red blood cells slight increase was observed in the females of the same group.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- In male treated with 300 and 1000 mg/kg/day, in all test article treated females, statistically significant decreased urea were noted. In addition, creatinine levels in males and females treated with 1000 mg/kg/day were statistically significant increased when compared with the controls.
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- effects observed, treatment-related
- Description (incidence and severity):
- In females with 300 mg/kg/day and 1000 mg/kg/day, respectively, statistically significant decreased locomotor activity was evident after 45 minutes which persisted in females treated with 1000 mg/kg/day until the end of measurement period as well as increases in motor activity in males given 1000 mg active dye/kg bw/day.
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Description (incidence and severity):
- A slight increase of mean kidney weight was observed on male from the group treated with 100 and 300 mg/kg/day.
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- In two males and two females treated with 1000 mg/kg/day, blue discoloration of the mucosal surface of the stomach and / or intestine was observed.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- not examined
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 300 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- behaviour (functional findings)
- haematology
Target system / organ toxicity
- Critical effects observed:
- no
Any other information on results incl. tables
Table 1 :summary of body weight values
BodyWeight |
|
Group 1 |
Group 2 |
Group 3 |
Group 4 |
Week1 |
Male |
184 |
185 |
192 |
187 |
|
SD |
16.8 |
11.7 |
21 |
23 |
|
Female |
118 |
116 |
118 |
114 |
|
SD |
14.3 |
14.1 |
15.5 |
12.4 |
Week13 |
Male |
376 |
398 |
386 |
390 |
|
SD |
34.8 |
39.4 |
38.6 |
27.1 |
|
Female |
244 |
251 |
242 |
239 |
|
SD |
15.1 |
18.6 |
17.2 |
16.1 |
Table 2 :Summary of Results
HaematologyMeanValue |
|
Group 1 |
Group 2 |
Group 3 |
Group 4 |
PT |
Male |
12.5 |
13.1* |
12.7 |
13.0* |
ProthrombinTime |
Female |
12.5 |
12.6 |
12.1 |
12.5 |
APTT |
Male |
22.6 |
23.5 |
23.1 |
24.8** |
Activated Partial Thromboplastin Time |
Female |
23.1 |
22.1 |
23.1 |
23.5 |
Clinical Biochemistry Mean Value |
|
|
|
|
|
Urea |
Male |
6.17 |
5.9 |
5.31* |
5.29* |
|
Female |
7.7 |
6.49** |
6.07** |
5.64** |
Creatinine |
Male |
53 |
55.1 |
55.9 |
59.5** |
|
Female |
59.7 |
59.2 |
63.7 |
66.1* |
Lipids total |
Male |
2.93 |
2.57 |
2.71 |
2.55* |
|
Female |
2.57 |
2.45 |
2.48 |
2.78 |
Cholesterol total |
Male |
1.98 |
1.64 |
1.79 |
1.7 |
|
Female |
1.44 |
1.37 |
1.35 |
1.66 |
Phospholipids |
Male |
1.68 |
1.49 |
1.56 |
1.46* |
|
Female |
1.62 |
1.55 |
1.61 |
1.78 |
Albumin |
Male |
38.4 |
37.42 |
38.24 |
40.13* |
|
Female |
44.61 |
41.87 |
44.79 |
46.25 |
Gamma globulin |
Male |
1.06 |
1.12 |
1.31 |
1.53** |
|
Female |
1.55 |
1.92* |
1.62 |
1.52 |
Firbinogen |
Male |
1.9 |
2 |
2.05 |
1.17** |
|
Female |
1.46 |
2.01** |
1.62 |
2.02** |
Organ weights |
|
|
|
|
|
Kidneys weight |
Male |
2.05 |
2.36** |
2.33* |
2.2 |
|
SD |
0.17 |
0.24 |
0.26 |
0.16 |
|
Female |
1.5 |
1.62 |
1.6 |
1.58 |
|
SD |
0.13 |
0.13 |
0.1 |
0.17 |
Spleen |
Male |
0.729 |
0.77 |
0.749 |
0.732 |
|
SD |
0.075 |
0.09 |
0.125 |
0.1 |
|
Female |
0.526 |
0.605* |
0.543 |
0.55 |
|
|
0.053 |
0.076 |
0.091 |
0.056 |
*p<0.05 **p<0.01
Applicant's summary and conclusion
- Conclusions:
- Under the experimental conditions of this study, the No Observed Adverse Effect Level (NOAEL) of test substance Jarocol Violet 43 was defined as 300 mg/kg/day on repeated toxicity (gavage) on rats for 90 day period of treatment according to the APTT Activated Partial Thromboplastin increased activity in the high dose level group.
- Executive summary:
This GLP compliant study aims the potential toxic effect of the registered item Acide Violet 43 (Jarocol Violet 43) after a 90 days period of treatment on rats by oral gavage. This study was performed following the OECD guideline 408 method for subchronic oral toxicity test on rodent.
Daily oral gavage at 0 (vehicle, 1% aqueous solution of carboxymethylcellulose), 100, 300 or 1000 mg test material substance/kg/day at a dosing volume of 10 ml/kg was performed for 13 weeks. These dose levels were selected on the basis of a previous 14-day oral toxicity study in rats. Evaluations and measurements included mortality, daily cageside observations, weekly body weight, food intake and detailed clinical observations, ophthalmoscopy (on all animals in acclimation period and on control and high dose animals in week 13), as well as functional parameters, haematology, blood clinical chemistry and urinalysis (week 13). At the end of the dosing period, animals were killed and subjected to macroscopic examination, selected organs were weighed, and organs/tissues were preserved. Microscopic examination was performed for specified tissues/organs from control and high dose rats, and for gross anomalies from all animals.
Dark blue feces were observed at all dose levels and were related to the staining properties of the test substance. Statistically significant decreases in motor activity were observed for females given 300 or 1000 mg/kg bw/day as well as increases in motor activity in males given 1000 mg/kg bw/day. In females effects were evident after 45 minutes and persisted in animals treated with 1000 mg/kg bw/day until the end of the observation period. In males effects were observed after 15 minutes only. The dose-dependency of effects in females might give evidence, that effects could be related to the test substance.
Moderate but statistically significant changes in several clinical laboratory parameters including increases in mean clotting time values and in activated partial thromboplastin time in males were reported for the highest dose group. The only findings at necropsy were a blue discolouration of the digestive tract observed for a few animals given 1000 mg/kg/day. No relevant histopathological changes were noted at examination of tissues and organs of treated animals.
Under the experimental conditions of this study, the No Observed Adverse Effect Level (NOAEL) of test substance Jarocol Violet 43 was defined as 300 mg of test material/kg/day on repeated toxicity (gavage) on rats for 90 day period of treatment according to the APTT Activated Partial Thromboplastin increased activity in the high dose level group.
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