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EC number: 235-920-3 | CAS number: 13047-13-7
- 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
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 986
- Report date:
- 1986
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- May 12, 1981
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Version / remarks:
- 84/449/EC
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 4-(hydroxymethyl)-4-methyl-1-phenylpyrazolidin-3-one
- EC Number:
- 235-920-3
- EC Name:
- 4-(hydroxymethyl)-4-methyl-1-phenylpyrazolidin-3-one
- Cas Number:
- 13047-13-7
- Molecular formula:
- C11H14N2O2
- IUPAC Name:
- 4-(hydroxymethyl)-4-methyl-1-phenylpyrazolidin-3-one
- Test material form:
- solid
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Animal Production, Ciba-Geigy, Stein Switzerland
- Strain: Tif: RAIf
- Females (if applicable) nulliparous and non-pregnant: no data
- Housing: individually in Macrolon type 3 cages with granulated soft wood bedding
- Age at study initiation: 7-8 weeks
- Weight at study initiation: males 171-195 g; females 160-182 g
- Diet : pelleted standard diet (Nafag. 890 Tox) ad libitum (quality checks on regular basis)
- Water: drinking water ad libitum (quality check under routine investigations)
- Acclimation period: 8 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2 °C
- Humidity (%): 55 ± 10 %
- Air changes (per hr): 16-20
- Photoperiod (hrs dark / hrs light):12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: water with 0.5% CMC and 0.1% Tween 80
- Details on oral exposure:
- VEHICLE
- Justification for use and choice of vehicle: necessary to make suspension
- Concentration in vehicle: 1 mg/mL, 4 mg/mL, 10 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg bw - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- LC with UV detection:
pump: Perkin Elmer Series 4
sampler: Perkin Elmer ISS 100
detector: Kratos Spectroflow 773 (λ = 250 nm)
integrator: Spectra-Physics (SP 4270) 5 mm/min
Column: Hypochrome (250 mm Ø 4.6 mm) packed with Nucleosil C18 (5 um)
Mobile phase: acetonitrile/acetate buffer (22/78%)
column temperature: 40 °C
flow rate: 2.0 mL/min
substance retention time: 3.6 min
Accuracy
method suitable between 1 and 15 mg/L (no recovery samples reported)
Stability
stability over a 4 hr period is measured at 1 mg/mL and 50 mg/mL in samples prepared at nominal concentrations in the vehicle and diluted after 4 hours with methanol (final nominal concentration 0.4 and 40 mg/L) . Thereafter the samples were measured (standard 4 mg/L).
stability : 91-92% at 1 mg/ml and 100.2-100.8% at 50 mg/mL
In the tests for accuracy of preparation (on day 1 and 19) the results after storage at room temperature for (17 days and 1 day) were 1.5 and 68% at 1 mg/mL; 12.0 and 87.5% at 4 mg/mL; 54.4 and 93.6% at 15 mg/mL. When stored on dry ice for 1 day all samples (taken on day 23 and 28) were within 84.5 to 98.5% of nominal - Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 10 mg/kg bw/day (nominal)
- Remarks:
- measured concentration when stored on ice 84.5-92.5% of nominal
- Dose / conc.:
- 40 mg/kg bw/day (nominal)
- Remarks:
- measured concentration when stored on ice 89.8-91.8% of nominal
- Dose / conc.:
- 150 mg/kg bw/day (nominal)
- Remarks:
- measured concentration when stored on ice 95.3-98.5% of nominal
- No. of animals per sex per dose:
- 5 males and 5 females
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- standard 28 day study
- Positive control:
- NA
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily for mortality and clinical signs
DETAILED CLINICAL OBSERVATIONS: No outside cage examinations
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION: Yes
- Time schedule: weekly
WATER CONSUMPTION: Yes
- Time schedule: weekly
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: pre-test and on day 27
- Dose groups that were examined: controls and high dose group
HAEMATOLOGY: Yes
- Time schedule for collection of blood: on day 28
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: Yes for 18 hours
- How many animals: all
- Parameters checked: White blood cells, Differential leucocyte count (neutrophils, lymphocytes, monocytes, eosinophils, basophils, plasma cells), Red blood cells (including morphology), Reticulocytes, Red blood cell distribution width Haemoglobin, Haematocrit, Mean corpuscular volume, Mean corpuscular haemoglobin, Mean corpuscular haemoglobin concentration, Heinz bodies, Platelets and PT
CLINICAL CHEMISTRY: Yes / No / Not specified
- Time schedule for collection of blood: on day 28
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: Yes for 18 hours
- How many animals: all
- Parameters checked: Alanine aminotransferase, Aspartate aminotransferase, Alkaline phosphatase, Total Protein, Albumin, Globulin, A/G ratio, Urea, Glucose, Cholesterol, Sodium, Potassium, Calcium, Inorganic Phosphate
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
IMMUNOLOGY: No - Sacrifice and pathology:
- ORGAN WEIGHTS: from all animals:
Adrenal glands, Spleen, Brain, Testes, Thymus, Heart, Kidneys, Liver, Ovaries
GROSS PATHOLOGY: in all animals:
Skin, mammary gland area, spleen, mesenteric lymphnode, axillary lymphnode, popliteal lymphnode, sternum with bone marrow, femur with joint, skeletal muscle, trachea, lung, heart, aorta, submandibular salivary gland, liver, pancreas, oesophagus, stomach, small intestine, large intestine, kidney, urinaty bladder, prostate, seminal vesicle, testis, epididymus, vagina, uterus, ovary, pituitary gland, adrenal gland, thyroid with parathyroid gland, thymus, peripheral nerve, brain, spinal cord, eye with optic nerve, orbital gland, extra orbital lacrimal gland, zymbal gland, muzzle with tongue
HISTOPATHOLOGY: in control and high dose animals:
Skin, mammary gland area, spleen, mesenteric lymphnode, axillary lymphnode, sternum with bone marrow, femur with joint, skeletal muscle, trachea, lung, heart, aorta, submandibular salivary gland, liver, pancreas, oesophagus, stomach, small intestine, large intestine, kidney, urinaty bladder, prostate, seminal vesicle, testis, epididymus, uterus, ovary, pituitary gland, adrenal gland, thyroid with parathyroid gland, thymus, peripheral nerve, brain, spinal cord, eye with optic neree, orbital gland, extra orbital lacrimal gland
in animals dosed at 15 and 40 mg/kg bw: liver, spleen, kidneys, testes and epididymus
For kidneys in addition a PAS screen was included. - Statistics:
- included uni-variate statistical analytics (Jonckhere 1954, Lepage, 1971)
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- small wounds due to scratching
- 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):
- no effects observed
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Females at 150 mg/kg bw: sign. increased numbers of Heinz bodies, sign decreased number of erythrocytes and haemoglobin, sign increased MCV and MCH, sign increase of number of reticulocytes
Females at 40 and 150 mg/kg bw: non-treatment related changes in white blood cells
Males at 150 mg/kg bw: sign increase of number of reticulocytes - Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Females at 150 mg/kg bw: increased ALAT and increased glucose
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Males at 40 and 150 mg/kg bw: increased spleen weights (abs and rel to BW), increased kidney weights (abs)
Females at 150 mg/kg bw: increased spleen weights (abs and rel to BW) - Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Males at 150 mg/kg bw:
spleen: congestion and (extramedulary) hemosiderosis increased (incidence and severity) -> dose related
kidneys: eosinic bodies in the proximal tubulus
epididymus: cellular debris and spermatic granuloma
testis: Leydig cell hyperplasia
Males at 40 mg/kg bw:
spleen: congestion and (extramedulary) hemosiderosis increased (incidence and severity) -> dose related
kidneys: eosinic bodies in the proximal tubulus
epididymus: cellular debris in 1/5 males
Females at 150 mg/kg bw
spleen: congestion and (extramedulary) hemosiderosis increased (incidence and severity) -> dose related
Liver: hemosiderosis
Females at 40 mg/kg bw:
spleen: congestion and (extramedulary) hemosiderosis increased (incidence and severity) -> dose related - Histopathological findings: neoplastic:
- not examined
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 10 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- haematology
- histopathology: non-neoplastic
- Remarks on result:
- other: the effects on the testes were observed at the same dose levels, thus the derived NOAEL also protects for these male specific effects
Target system / organ toxicity
open allclose all
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 40 mg/kg bw/day (nominal)
- System:
- haematopoietic
- Organ:
- spleen
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 150 mg/kg bw/day (nominal)
- System:
- male reproductive system
- Organ:
- cauda epididymis
- Leydig cells
- testes
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
Applicant's summary and conclusion
- Conclusions:
- The NOAEL as derived from this study is 10 mg/kg bw
- Executive summary:
Rats (5/sex/dose) received the substance by gavage at 0, 10, 40 and 150 mg/kg bw during 28 days. No treatment related effects were reported related to mortality, clinical signs, body weight, food and water consumption, clinical chemistry and macroscopy. Effects seen were related to the the maturation of red blood cells (reduction of number of red blood cells, reduction of hemoglobin, increased number of reticulocytes, increased spleen weights and spleen congestion and (extramedulary) hemosiderosis) at 40 and 150 mg/kg bw in both males and females. In addition eosinophylic bodies were found in the kidneys of males at 40 and 150 mg/kg bw. The male reporductive systenm (testes (hyperplasia of Leydig cells) and epididymus (debris and granuloma)) was also affected at 150 mg/kg bw (and very slightly at 40 mg/kg bw).
Based on these findings the NOAEL for males and females is considered to be 10 mg/kg bw.
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