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EC number: 263-417-9 | CAS number: 62121-75-9
- 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
Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 23. Oktober 2019 to 10. July 2020
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 020
- Report date:
- 2020
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)
- Version / remarks:
- adopted to 2016
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- p-[4,5-dihydro-4-[[2-methoxy-5-methyl-4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-3-methyl-5-oxo-1H-pyrazol-1-yl]benzenesulphonic acid, sodium salt
- EC Number:
- 263-417-9
- EC Name:
- p-[4,5-dihydro-4-[[2-methoxy-5-methyl-4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-3-methyl-5-oxo-1H-pyrazol-1-yl]benzenesulphonic acid, sodium salt
- Cas Number:
- 62121-75-9
- Molecular formula:
- C20H22N4O11S3.xNa C20H(22-x)N4NaxO11S3; x<=2
- IUPAC Name:
- sodium 4-[4-(2-{2-methoxy-5-methyl-4-[2-(sulfonatooxy)ethanesulfonyl]phenyl}diazen-1-yl)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]benzene-1-sulfonate
- Test material form:
- solid: particulate/powder
- Details on test material:
- Name of test substance: Reactive Yellow 15
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Batch number of test material: 145/AD/0615
- Expiration date of the lot/batch: August, 31st, 2021
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temeprature (10 - 30°C)
- Stability of the test substance in the vehicle: 8 days at 2-8°C
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on species / strain selection:
- Wistar rats are commonly used and recommended to assess toxicity. A large number of publications on the subject are available as well as historic data and firsthand experience at the test facility.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Germany
- Females: nulliparous and non-pregnant
- Age at study initiation: 11-12 weeks
- Weight at start of administration: Main: 380-450 g (males), 205-246 g (females); Recovery: 357-442 g (males), 212-258 g (females)
HOUSING
- During acclimatization, pre-exposure and pre-mating, male animals, as well as female recovery animals, were caged in groups of two to three animals per cage (open macrolon cages type 2000P, Techniplast (size slightly larger than GV-SOLAS Type IV)). Individually housed females (main groups), paired animals and single dams with their litters were housed in open macrolon cages type III. Throughout the mating period, animals were kept in pairs of one female and one male rat. The female was placed with the same male until pregnancy occurred or two weeks have elapsed. After the mating period, male rats were housed in groups of three, which were originally formed during the pre-mating phase; female rats were housed individually.
- Diet (ad libitum): Maintenance diet for rats and mice, No. 1324 TPF (Altromin Spezialfutter GmbH & Co. KG); dams: breeding diet for rats and mice, No 1314 TPF (Altromin Spezialfutter GmbH & Co. KG).
- Water (ad libitum): sterilized community tap water.
- Acclimation period: 6-9 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 30-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From 11. November 2019 to 31. January 2020
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on exposure:
- Concentration in vehicle:
200 mg/ml (females 100 mg/ml from study day 38-41 onwards)
60 mg/ml
20 mg/ml
Application volume: 5 ml per kg bodyweight - Details on mating procedure:
- - M/F ratio per cage: 1/1
- Length of cohabitation: until proof of copulation (vaginal plug or sperm in the vagial swab) or 14 days
- Mating indices: 100% for all dose groups - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- In the quantitative re-analysis, the recovered test item content in the test item/water solutions was compared with the target test item content in the preparations. Analysis was conducted by Liquid Chromatography-Diode Array Detector (LC-DAD).
The concentration of the test item in the solutions was determined once within pre-mating phase, within the gestation phase and at the end of gestation/ beginning of lactation phase.
Recovery rates between 90-110 % were set. All criteria were fulfilled. - Duration of treatment / exposure:
- Main groups: Males were dosed daily for 41-43 days (depending on cohort), including the day before the scheduled termination of the in-life phase. This included a minimum of two weeks of dosing prior to mating and continued throughout the mating period until approximately two weeks post-mating.
Females were dosed two weeks prior to mating, covering at least two complete oestrus cycles, the variable time to conception, the duration of pregnancy and 15-17 days after delivery, up to and including the day before scheduled termination of the in-life phase. Therefore, the duration of the study following acclimatization and pre-dosing oestrus cycle evaluation, was depending on the female performance and was between 53 and 66 days: 14 days pre-mating, up to 14 days until mating, an average of 22 days of gestation, and a minimum of 13 days of lactation.
Recovery groups: Male and female animals were dosed daily for 49 days followed by an observation periode of 14 days post treatment. - Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 1 000 mg/kg bw/day
- Remarks:
- MAIN GOUP: high dose; for females reduced to 500 mg/kg bw/day from study day 38-41 onwards
- Dose / conc.:
- 300 mg/kg bw/day
- Remarks:
- MAIN GROUP; medium dose
- Dose / conc.:
- 100 mg/kg bw/day
- Remarks:
- MAIN GROUP; low dose
- Dose / conc.:
- 0 mg/kg bw/day
- Remarks:
- MAIN GROUP; vehicle
- Dose / conc.:
- 1 000 mg/kg bw/day
- Remarks:
- RECOVERY GOUP: high dose; for females reduced to 500 mg/kg bw/day from study day 38-41 onwards
- Dose / conc.:
- 0 mg/kg bw/day
- Remarks:
- RECOVERY GROUP; vehicle
- No. of animals per sex per dose:
- 12/sex/dose (main groups)
5/sex/dose (recovery groups) - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: According to the available literature, no toxic effects of the test item has been observed at a dose of 500 mg/kg bw during a 20-day oral administration with a total of 14 administrations. In addition, the LD50 value (oral) for mice was reported to be >10.000 mg/kg bw, the LD50 for rats is specified as greater 2000 mg/kg bw. Based on this information, it was decided to test 1000 mg/kg bodyweight per day as the highest dose. An interval of approximately 3 has been chosen for the two subsequent doses resulting in 300 mg/kg bw/day for the medium dose and 100 mg/kg bw/day for the low dose group.
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly (IRWIN test) in a standard arena, on all animals (main and recovery groups)
- Time schedule: at the end of the the in-life phase (grip-strength and beam-walking test), on 5 randomly selected male and female animals per dose group (main groups) and all recovery animals.
BODY WEIGHT: Yes
- Time schedule for examinations: At least once weekly (including once before beginning of application)
FOOD CONSUMPTION: Yes
- Time schedule for examinations: At least once weekly
WATER CONSUMPTION: Yes
- Time schedule for examinations: At least once weekly
HAEMATOLOGY: Yes
On randomly selected male and female animals per dose group (main groups):
- 5 females at the end of the pre-mating period
- 5 males at the end of the treatement period.
On all recovery animals at the end of the treatment period (recovery groups).
Leukocytes, Erythrocytes, Haemoglobin, Haematocrit, Mean corpuscular volume (MCV), Mean corpuscular Haemoglobin (MCH), Mean corpuscular haemoglobin conc. (MCHC), Thrombocytes, Reticulocytes, Neutrophil granulocytes, Lymmphocytes, Monocytes, Eosinophils, Basophils, Blood clotting time.
CLINICAL CHEMISTRY: Yes
On randomly selected male and female animals per dose group (main groups):
- 5 females at the end of the pre-mating period
- 5 males at the end of the treatment period.
On all recovery animals at the end of the treatment period (recovery groups).
Alkaline Phosphatase (AP), Aspartate aminotransferase (AST); Alanine aminotransferase (ALT), Gamma-glutamyl-transferase (GGT), Cholesterol, Urea, Sodium, Potassium, Calcium, Chloride, Glucose, Total protein, Albumin, Globulin, A/G ratio, Creatinine, Bile acids, T4-hormone levels
REPRODUCTIVE PARAMETERS: Yes
- Females showing evidence of copulation, Females achiving pregnancy, no. of conceiving days, no. of days of pregnancy,
- No. of dams with live young born/with live young at day 4 post partum (pp),
- Implants/dam, Live pups/dam at birth/at day 4,
- Sex ratio (m/f) at birth/ at day 4,
- Loss of offspring: pre-natal/post-implantation (implantation sites minus live birth); post-natal (live births minus alive on day 4; live birth minus alive at day 13) - Oestrous cyclicity (parental animals):
- - daily by vaginal swabs for a 14-days pre-exposure period, throughout the pre-mating and mating period until evidence of mating
- frequency and mean length of irregular cycles - Litter observations:
- PARAMETERS EXAMINED
The following parameters were examined in offspring:
number and sex of pups at birth, day 4 and day 13, stillbirths, live births, postnatal mortality, presence of gross anomalies, physical or behavioural abnormalities, anogenital distance (AGD), litter weight at birth/day 4/day 13, mean pup weight at birth/day 4/day 13, individual pup weight on the day of AGD, presence of nipples/areolae in male pups. T4-hormone levels at day 4 and day 13. - Postmortem examinations (parental animals):
- SACRIFICE
An animal was euthanized when it was found to be moribund or at the end of the in-life phase at the latest:
- Male animals: All surviving animals [as soon as possible after the last litters in each generation were produced]
- Maternal animals: All surviving animals [describe when, e.g. after the last litter of each generation was weaned]
GROSS NECROPSY
All adult animals were sacrificed humanely by asphyxiation in a CO2/O2 atmosphere and were examined macroscopically. All occurring lesions were recorded on checklists for each individual animal. Special attention was paid to the organs of the reproductive system. The number of implantation sides was recorded. Organs were surgically extracted from adult male animals (testes, epididymis, prostate and seminal gland vesicles with coagulating gland as a whole, LABC muscle, Cowper’s gland, glans penis) and from all adult female animals (uterus including cervix, ovaries) and were weighed as soon as possible after dissection. The thyroid glands were surgically extracted from both, male and female animals and weighed before fixation. Paired organs were weighed individually. The ovaries, testes, epididymis, accessory sex organs (cervix, prostate etc.), thyroid and all other organs showing macroscopic lesions of all adult animals were preserved in the appropriate fixative.
From all recovery animals and 5 randomly selected male and female animals per dose group (main groups), additional organs were preserved in the appropriate fixative/s. Organs to be weighed were trimmed of any adherent tissue and their wet weight was taken as soon as possible after dissection. Paired organs were weighed individually.
Modified Davidson solution was used for testis and epididymis; Davidson solution was used for the eyes. All other organs/tissues were fixed in formalin.
ADDITIONAL ORGAN WEIGHTS (5 randomly selected male and female animals per dose group (main groups), all recovery animals):
Brain, heart, liver, spleen, thymus, kideny, adrenal glands
HISTOPATHOLOGY (selected animals)
A detailed histological examination was performed on selected organs and tissues of the animals and pups of the main high dose and the vehicle control group. The thyroid glands of the remaining animals were included in the histology panel, due to test item-related findings from the T4-analysis.
The tissues were embedded in paraffin wax, sectioned, and stained with hemalum and eosin. - Postmortem examinations (offspring):
- Dead pups and pups humanely sacrificed by asphyxiation in a CO2/O2 atmosphere at day 13, or shortly thereafter, were examined externally for gross abnormalities. External reproductive genitals were examined for signs of altered development. Immediately after death, the thyroid gland from one male and one female pup per litter was preserved.
- Statistics:
- Anova with Dunnett's t-test
- Reproductive indices:
- Copulatory Index
Fertility Index
Pre-Coital Interval - Offspring viability indices:
- pre-natal loss
post nalat loss D4 and D13
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Salivation after test item administration as well as wiping the mouth in the cage bedding was observed for individual male animals of the high dose groups (main and recovery). Signs of salivation were considered related to the lack of palatability of the administered test item and were rated as neglectable or mild under consideration of intensity and frequency of incidence, and with no adversity associated.
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- Five female animals treated with the high dose of the test item (four of the main groups, one of the recovery group) and one animal of the medium dose group died soon after gavage, showing signs of reflux. The test item solutions showed viscous, not yet described physical characteristics. A gavage related reflux was assumed as most likely cause of death for those animals. A physicochemical relationship is therefore assumed rather than a toxicological property of the substance.
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Water consumption and compound intake (if drinking water study):
- effects observed, treatment-related
- Description (incidence and severity):
- Male main group animals of the high dose as well as female animals of the recovery groups showed test-item related increase in water consumption during treatment period, when compared to the respective vehicle control group, but below amounts considered to be adverse. A secondary effect related to the increase in salivation and/or the high concentration of the formulation might be conceivable.
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- T4-analysis of parental animals revealed significant increase of the T4 hormone level in the high dose groups (male and female) and the medium dose animals (males only) when compared to the respective vehicle control group. The values for the pups (day 4pp and day 13 pp) showed no difference between test item treated animals and controls. After 14 days recovery, no significant changes for the T4 hormone levels have been observed.
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- no effects observed
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive performance:
- no effects observed
Effect levels (P0)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Target system / organ toxicity (P0)
- Key result
- Critical effects observed:
- no
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Sexual maturation:
- no effects observed
- Anogenital distance (AGD):
- no effects observed
- Nipple retention in male pups:
- no effects observed
- Gross pathological findings:
- no effects observed
- Other effects:
- no effects observed
Effect levels (F1)
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- >= 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Target system / organ toxicity (F1)
- Key result
- Critical effects observed:
- no
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- The NOAEL based on repeated dose and reproduction toxicity is set at >= 1000 mg/kg body weight for the female and male animals.
- Executive summary:
A daily oral administration of the test item Reactive Yellow 15 to male and female Wistar rats at dose levels of 1000 mg (500 mg from study day 38 to 41 onwards for the female animals), 300 mg and 100 mg/kg body weight over a time period of 41-43 days for males and 54-66 days for females resulted in some minor animal behavioral changes observed in male and female animals predominately of the high dose groups, alterations in water consumption in male (main) and female (recovery) high dose groups and changes in T4 hormone levels in the high dose group. Findings for T4 levels could not be seen after a 14-day recovery period. The findings were not considered adverse. As the findings could not be associated with a substantial impact on the animal’s health, the NOAEL regarding the repeated dose toxicity was set to 1000 mg/kg body weight for the male and female animals when administered for at least 41 days.
All results show that the physicochemical properties of the substance are responsible for the deaths within the female dose groups. Toxicological properties, which should have been taken into account for the determination of the NOAEL, have not been observed in those animals.Furthermore, no pathological evidence for toxic effects on the reproduction performance of female and male rats was found. Regarding the overall time period of gestation/lactation and after birth until end of in-life phase no evidence for a toxic effect on the pup development could be detected. The NOAEL regarding reproduction and development of Reactive Yellow 15 under these study conditions was set to be >= 1000 mg/kg body weight for the female and male animals.
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