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EC number: 473-370-8 | CAS number: -
- 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
Endpoint summary
Administrative data
Description of key information
In a 28-day oral toxicity study rats (5/sex/dose) received the substance at 0, 5, 15 or 50 mg/kg bw in propylene glycol. Analyses of the formulations showed that the doses were prepared accurately. A few slight changes observed in biochemistry (reduced creatinine levels in males, increased total bilirubin and potassium levels in females and reduced sodium and chloride levels in females) were within historical control ranges and not supported by histopathological findings. No treatment related effects were found for clinical signs, functional observations, body weight, food consumption, haematology, organ weights, macroscopy and histopathology. The NOAEL is therefore set at the highest dose tested, 50 mg/kg bw.
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 07 November 2007 to 07 January 2008
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Qualifier:
- according to guideline
- Guideline:
- other: EPA OPPTS 870.3050
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Wistar
- Details on species / strain selection:
- recognised by the international guidelines
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Deutschland, Sulzbach, Germany
- Strain: Crl:WI (Han) (outbred, SPF quality)
- Females nulliparous and non-pregnant: yes
- Age at study initiation: ca 6 weeks
- Weight at study initiation: males 144-171 g; females 125-140 g
- Housing: 5/cage (Macrolon MIV) saw dust bedding, paper as enrichment
- Diet: Pelleted Rodent Diet ad libitum (SM R/M-Z SSNIFF Soest Germany)
- Water: tap water ad libitum
- Acclimation period: at least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.9-23.1 ˚C
- Humidity (%): 29-94%
- Air changes (per hr): ca 15/h
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- oral: gavage
- Vehicle:
- propylene glycol
- Details on oral exposure:
- VEHICLE
- Amount of vehicle (if gavage): <= 5 mL/kg
- Justification for choice of vehicle: laboratory trial
MAXIMUM DOSE VOLUME APPLIED: 5 mL/kg
DOSAGE PREPARATION: prepared within 4 hours before dosing (homogeneity assessed visually) adjusted for specific gravity (1.036)
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Instrument Alliance Separation Module 2695 (Waters, Milford, MA, USA)
Detector Dual lambda Absorbance Detector (Waters)
Column 150 mm X 4.6 mm i.d., Symmetry Shield RP-18 dp, 5 µm (Waters)
Injection volume 10 µL
Mobile phase 45/55 (v/v) methanol/water
Flow 1.0 mL/min
UV detection 210 nm
Sample analysis:
Calibration (range 0.955-25.5 mg/L) based on 4 concentrations Linear with r > 0.99 (no details)
Recovery: at 1 mg/g 99-102% of nominal, at 100 mg/g 95-104% of nominal
Homogenicity: CV at 5 mg/kg bw 2.3%; CV at 50 mg/kg bw 0.88
Stability over 5 hours: rel difference at 5 mg/kg bw 1.9%; at 50 mg/kg bw -0.067%
Accuracy: in controls not detected; treatment groups 96-98% of nominal - Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- once daily
- Dose / conc.:
- 5 mg/kg bw/day (nominal)
- Remarks:
- measured concentration 97% of nominal
- Dose / conc.:
- 15 mg/kg bw/day (nominal)
- Remarks:
- measured concentration 96% of nominal
- Dose / conc.:
- 50 mg/kg bw/day (nominal)
- Remarks:
- measured concentration 98% of nominal
- No. of animals per sex per dose:
- 5/sex/dose group
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
based on 10-day dose range finding study with 3 females at 0, 50, 150, 500 and 1000 mg/kg bw. At 500 and 1000 mg/kg bw all animals were killed in extremis on day 4 and 3 resp. showing a.o. lethargy, piloerection, hunched posture, abnormal gait and/or uncoordinated movements. Macroscopy revealed reddish discoloration of the fore-stomach.
At 150 mg/kg bw animals had breathing rales, piloerection, chromodacryorrhea and/or salivation and weight loss. Macroscopy showed no abnormalities (no effects seen on liver and kidney). At 50 mg/kg bw animals showed hunched posture and salivation. Bodyweight gain was decreased.There were no macroscopic abnormalities. - Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least once daily
MORTALITY: yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: in standard arena weekly
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION: Yes
- Time schedule for examinations: weekly
WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: immediately before scheduled necropsy
- Anaesthetic used for blood collection: No
- Animals fasted: Yes overnight (maximum 20 h)
- How many animals: all
- Parameters checked: White blood cells, Differential leucocyte count (neutrophils, lymphocytes, monocytes, eosinophils, basophils), Red blood cells, Reticulocytes, Red blood cell distribution width, Haemoglobin, Haematocrit, Mean corpuscular volume, Mean corpuscular haemoglobin, Mean corpuscular haemoglobin concentration, Platelets, PT and APTT
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: immediately before scheduled necropsy
- Anaesthetic used for blood collection: No
- Animals fasted: Yes overnight (maximum 20 h)
- How many animals: all
- Parameters checked: Alanine aminotransferase, Aspartate aminotransferase, Alkaline phosphatase, Total Protein, Albumin, Total Bilirubin, Bile acids, Urea, Creatinine, Glucose, Cholesterol, Sodium, Potassium, Chloride, Calcium, Inorganic Phosphate
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: during week 4
- Dose groups that were examined: all
- Battery of functions tested: motor activity, grip strength, hearing ability, pupil reflex, static righting reflex
IMMUNOLOGY: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Ovaries, Adrenal glands, Pancreas, Aorta, Peyer's patches [jejunum, ileum] if detectable, Brain [cerebellum, mid-brain, cortex], Pituitary gland, Caecum, Ileum, Jejunum, Duodenum, Colon, Rectum, Preputial gland, Cervix, Prostate gland, Clitoral gland, Salivary glands - mandibular, sublingual, Sciatic nerve, Skeletal muscle, Epididymides, Seminal vesicles including coagulating gland, Eyes with optic nerve and Harderian gland, Skin, Female mammary gland area, Spinal cord -cervical, midthoracic, lumbar, Femur including joint, Spleen, Heart, Sternum with bone marrow, Stomach, Testes, Kidneys, Thymus, Larynx, Thyroid including parathyroid, Lacrimal gland, exorbital, Tongue, Liver, Trachea, Lung, infused with formalin, Urinary bladder, Lymph nodes - mandibular, mesenteric, Uterus, Nasopharynx, Vagina, Oesophagus, All gross lesions
ORGAN WEIGHTS: Adrenal glands, Spleen, Brain, Testes, Epididymides, Thymus, Heart, Kidneys,
HISTOPATHOLOGY: Ovaries, Adrenal glands, Pancreas, Aorta, Peyer's patches [jejunum, ileum], Brain [cerebellum, mid-brain, cortex], Pituitary gland, Caecum, Ileum, Jejunum, Duodenum, Colon, Rectum, Cervix, Prostate gland, Salivary glands - mandibular, sublingual, Sciatic nerve, Epididymides, Seminal vesicles including coagulating gland, Eyes with optic nerve and Harderian gland, Skin, Female mammary gland area, Spinal cord -cervical, midthoracic, lumbar, Spleen, Heart, Sternum with bone marrow, Stomach, Testes, Kidneys, Thymus, Larynx, Thyroid including parathyroid [if detectable], Liver, Trachea, Lung, infused with formalin, Urinary bladder, Lymph nodes - mandibular, mesenteric, Uterus, Vagina, Oesophagus, All gross lesions - Statistics:
- Dunnett-test, Steel-test, The Fisher Exact-test
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Salivation was observed along females at 15 mg/kg bw and males and females at 50 mg/kg bw.
This is considered related to gavage treatment. - Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Slight changes (within normal ranges) during part of the study in males and females at 5 and 15 mg/kg bw. No relationship with dose
- 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:
- effects observed, non-treatment-related
- Description (incidence and severity):
- females 50 mg/kg bw: sign lower reticulocyte counts
males 15 mg/kg bw: sign lower rel neutrophil counts, sign higher rel. lymphocyte counts, lower MCHC - Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- males 50 mg/kg bw: sign reduced creatine levels
females at 50 mg/kg bw: sign. reduced sodium and chloride level, sign increased total bilirubin and potassium levels
females at 15 mg/kg bw: sign.lower inorganic phosphate levels (no relation with dose) - Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- motor activity, grip strength, hearing ability, pupil reflex and static righting reflex were within normal limits at all doses
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Description (incidence and severity):
- sign increased liver and kidney weights at 50 mg/kg bw in males
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No abnormalities observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- No microscopic findings
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- see table
- Dose descriptor:
- NOAEL
- Effect level:
- 50 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: absence of adverse effects at the highest dose tested
- Critical effects observed:
- no
- Conclusions:
- The NOAEL of the substance in a subacute oral study is 50 mg/kg bw (the highest dose tested)
- Executive summary:
In a 28-day oral toxicity study rats (5/sex/dose) received the substance at 0, 5, 15 or 50 mg/kg bw in propylene glycol. Analyses of the formulations showed that the doses were prepared accurately. A few slight changes observed in biochemistry (reduced creatinine levels in males, increased total bilirubin and potassium levels in females and reduced sodium and chloride levels in females) were within historical control ranges and not supported by histopathological findings. No treatment related effects were found for clinical signs, functional observations, body weight, food consumption, haematology, organ weights, macroscopy and histopathology. The NOAEL is therefore set at the highest dose tested, 50 mg/kg bw.
Reference
Dose (mg/kg bw) |
0 |
|
5 |
|
15 |
|
50 |
|
Treatment related |
|
|
Endpoint |
M |
F |
M |
F |
M |
F |
M |
F |
|
|
|
Mortality |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
0/5 |
no |
|
|
Clinical signs$ Salivation |
|
|
|
|
|
2/5 |
5/5 |
5/5 |
yes (see remark) |
|
|
Body weight |
NTRE |
|
|
||||||||
Body weight gain d 1-28 |
|
|
|
|
↓27 % |
|
|
|
no |
|
|
Food consumption |
NTRE |
|
|
||||||||
Behavioral effects grip strength, hearing ability, pupil reflex, static righting reflex |
NTRE |
|
|||||||||
Motoractivity |
NTRE |
|
|||||||||
Haematology |
|
|
|
|
neutr↓(18%) Lymp↑ (4%) MCHC ↓ (3%)
|
|
|
Ret↓ (16%)
|
no |
|
|
Clinical biochemistry |
|
|
|
|
|
Phos ↓( 18%)
|
Creat ↓( 8%)
|
TB ↑ (28%) Na, Cl ↓(2-3%) K ↑ (11%) |
no |
|
|
Organ weights r= relative to BW |
|
|
|
|
|
|
Kidney r↑ (19%) Liverr↑(8%) |
|
no |
|
|
Macroscopy |
No findings |
|
|
||||||||
Histopathology |
NTRE |
|
|
||||||||
NTRE= no treatment related effects
↑/↓= significantly increased/decreased
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 50 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- System:
- other: no adverse effecst observed at the highest dose tested
Repeated dose toxicity: inhalation - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
Justification for classification or non-classification
Based on the available information the substance does not need to be classified for repeated dose toxicity according to EU Regulation 1272/2008 (CLP).
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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