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EC number: 700-798-7 | CAS number: 877399-00-3
- 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
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Endpoint summary
Administrative data
Description of key information
A 7-day repeated dose study (Beerens-Heijnen, 2011) is available which is key study. The test substance has toxic potential when administered to rats by daily oral gavage for a period of up to 7 consecutive days at 150 mg/kg bw/day.
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:
- From 04 to 12 October 2010
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Study run to a method comparable with current guidelines and to GLP
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- other: Crl:Wl(Han)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany.
- Age at study initiation: Approximately 10 weeks.
- Weight at study initiation: all animals within ± 20% of the sex mean.
- Fasting period before study:
- Housing: Group housing of 3 animals per sex in Macrolon cages with sterilized sawdust as bedding material and paper as cage-enrichment.
- Diet (e.g. ad libitum): Free access to pelleted rodent diet.
- Water (e.g. ad libitum): Free access to tap water.
- Acclimation period: At least 5 days.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.0 ± 3.0ºC (actual range: 20.1 – 22.2ºC)
- Humidity (%): 40-70% (actual range: 43 - 81%)
- Air changes (per hr): Approximately 15 air changes per hour.
- Photoperiod (hrs dark / hrs light): 12 hours artificial fluorescent light and 12 hours darkness per day.
IN-LIFE DATES: From: 2010-10-04 To: 2010-10-12 - Route of administration:
- oral: gavage
- Vehicle:
- CMC (carboxymethyl cellulose)
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: Formulations (w/w) were prepared daily within 4 hours prior to dosing, and were homogenized to visually acceptable levels. No correction was made for the purity of the test substance.
DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:
VEHICLE
- Justification for use and choice of vehicle (if other than water): Based on trial formulations performed at NOTOX and on information from the sponsor.
- Concentration in vehicle:
- Amount of vehicle (if gavage): 5 mL/kg body weight.
- Lot/batch no. (if required):
- Purity: - Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- 7 days
- Frequency of treatment:
- Once daily
- Remarks:
- Doses / Concentrations:
150, 300 and 1000 mg/kg
Basis:
nominal in diet - No. of animals per sex per dose:
- 3 males and 3 females per dose
- Control animals:
- yes, concurrent vehicle
- Observations and examinations performed and frequency:
- Mortality/Viability: At least twice daily.
Clinical signs: At least once daily, detailed clinical observations were made in all animals. The time of onset, degree and duration was recorded. All symptoms were recorded and graded according to fixed scales:
Maximum grade 1: grade 0 = absent, grade 1 = present
Maximum grade 3 or 4: grade 1 = slight, grade 2 = moderate, grade 3 = severe, grade 4 = very severe
Body weights: On Days 1, 4 and 7.
Food consumption: Over Days 1-4 and 4-7.
Water consumption: Subjective appraisal was maintained during the study, but no quantitative investigation introduced as no effect was suspected.
Clinical laboratory investigations:
Blood samples were collected under anaesthesia using an isoflurane in nitrous oxide/oxygen combination immediately prior to scheduled post mortem examination, between 7.00 and 10.30 a.m. Animals were deprived of food overnight (for a maximum of 20 hours), but water was available. Blood samples were drawn from the retro-orbital sinus and collected into tubes prepared with EDTA for haematological parameters (0.5 mL), with citrate for clotting tests (0.45 mL) and Li-heparin treated tubes for clinical biochemistry parameters (0.5 mL). An additional blood sample (0.25 mL) was collected into untreated tubes for determination of bile acids. - Sacrifice and pathology:
- Necropsy:
Animals surviving to the end of the observation period were deeply anaesthetized using an isoflurane in nitrous oxide/oxygen combination and subsequently exsanguinated and subjected to a full post mortem examination. Samples of the tissues and organs were collected from all animals at necropsy and fixed in 10% buffered formalin.
Histotechnology:
All organ and tissue samples, as defined under Histopathology (following), were processed, embedded in paraffin wax and cut at a thickness of 2-4 micrometers and stained with haematoxylin and eosin.
Histopathology:
The following slides were examined by a pathologist: all tissues collected at the scheduled sacrifice from all group 1 and 4 animals; all tissues from animal No 20 which died spontaneously; all gross lesions.
Based on treatment-related changes in the thymus, liver and kidneys the histological examination was extended to those particular organs of all animals of groups 2 and 3 (males and females).
All abnormalities were described and included in the report. An attempt was made to correlate gross observations with microscopic findings. - Other examinations:
- Organ Weights:
The organ weights (and terminal body weight) were recorded from the animals on the scheduled day of necropsy. - Statistics:
- None stated
- Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- effects observed, treatment-related
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- Observations
Mortality:
One female at 300 mg/kg was found dead on Day 4 prior to dosing. No definite cause of death could be established for this rat histopathologically. The other animals in this dose group and all animals at 1000 mg/kg survived the scheduled study duration. Therefore this death was considered not to be related to treatment with the test substance.
No mortality occurred among the control animals and animals at 150 and 1000 mg/kg.
Clinical Signs:
Hunched posture and/or piloerection were recorded for all males and females at 1000 mg/kg from Day 4 and 3 onwards, respectively. One of these males showed lethargy on Day 7. Hunched posture was also shown by all surviving females at 300 mg/kg from Day 3 onwards.
The female at 300 mg/kg which died on Day 4 showed hunched posture, quick breathing and piloerection on the preceding day.
No clinical signs were shown by males at 150 and 300 mg/kg and in females at 150 mg/kg.
Body Weights:
All animals at 1000 mg/kg showed body weight loss between Days 1 and 4 (up to 9% from Day 1 values). Except for one male and female, body weights of these animals essentially recovered to control levels between Days 4 and 7.
Food Consumption:
Food consumption before or after correction for body weight was lower for males and females at 1000 mg/kg throughout the treatment period when compared to control animals. Females at 300 mg/kg also showed a lower food consumption before or after correction for body weight between Days 1 and 4, which essentially recovered to control levels between Days 4 and 7.
At 150 mg/kg, food consumption before or after correction for body weight was considered to have been unaffected by treatment.
Clinical Laboratory Investigations
Haematology:
The following changes in haematology parameters distinguished treated animals from control animals:
− Lower red blood cell counts in males at 1000 mg/kg,
− Lower haemoglobin levels in males at 1000 mg/kg,
− Lower reticulocyte counts in females at 1000 mg/kg,
− Higher platelet counts in males at 300 and 1000 mg/kg, and in females at 1000 mg/kg,
− Higher prothrombin time in males at 300 and 1000 mg/kg, and in females at 1000 mg/kg,
− Lower partial thromboplastin time in males and females at 1000 mg/kg.
All other changes remained within the range considered normal for rats of this age and strain.
Clinical Biochemistry:
The following changes in clinical biochemistry parameters distinguished treated animals from control animals:
− Higher alkaline phosphatase activity (ALP) in females at 1000 mg/kg,
− Lower total protein levels in females at 1000 mg/kg,
− Lower albumin levels in females at 1000 mg/kg,
− Higher total bilirubin levels in females at 150, 300 and 1000 mg/kg,
− Lower urea levels in females at 1000 mg/kg,
− Higher creatinine level in males at 1000 mg/kg,
− Lower glucose levels in males at 1000 mg/kg,
− Lower cholesterol levels in males at 300 and 1000 mg/kg,
− Lower triglyceride levels in males at 300 and 1000 mg/kg, and in females at 1000 mg/kg,
− Higher chloride levels in males and females at 1000 mg/kg (with a dose-related trend at lower dosages towards an increase),
− Higher potassium levels in females at 1000 mg/kg,
− Lower calcium levels in males at 1000 mg/kg.
One male at 1000 mg/kg (no. 12) showed a lower total protein and albumin level, and higher bilirubin and urea level. Values of other males of this dose group were considered to be normal.
Pathology
Macroscopic Examination:
Macroscopic observations at necropsy that were considered to be related to treatment included:
− Enlarged liver two males each at 300 and 1000 mg/kg, and in two females at 1000 mg/kg,
− Reduced size of the thymus in two males and one female at 1000 mg/kg,
− Purple contents in the gastro-intestinal tract or ileum (with purple discolouration of the ileum wall) each in one male at 1000 mg/kg,
− Enlarged kidneys in two males at 1000 mg/kg,
− (Black-) brown discolouration of the (cortex of) kidneys in all males at 1000 mg/kg,
− Black-brown contents in the urinary bladder of two males at 1000 mg/kg,
− Black discolouration of the skin of the tail in two males at 1000 mg/kg.
The enlarged liver seen in one male and one female at 150 mg/kg had no microscopic correlate.
Organ Weights:
The following changes in mean organ weights and organ to body weight ratios were considered to be related to treatment:
− Higher liver weight and liver to body weight ratio in males and females at 150, 300 and 1000 mg/kg (with a dose-related trend; liver to body weight ratio 104% and 89% higher than controls for males and females at 1000 mg/kg respectively),
− Lower thymus weight and thymus to body weight ratio in males at 1000 mg/kg,
− Higher kidney weight and kidney to body weight ratio in males at 1000 mg/kg.
Other organ weights and organ to body weight ratios among the dose groups were similar to control levels.
Microscopic Examination:
Treatment-related microscopic findings were present in the kidneys, liver and thymus of both sexes.
Kidneys:
− tubular dilatation was present in both male and female Group 2 (male: 3/3 minimal; female: 2/3 minimal), Group 3 (male: 1/3 minimal, 2/3 slight; female: 2/3 slight) and Group 4 (male: 2/3 slight, 1/3 moderate; female: 3/3 minimal) rats. This was the microscopic correlate to the macroscopic enlarged kidneys.
− Tubular degeneration was present in male and female rats at increasing incidence and severity in Group 3 (male: 1/3 slight; female: 1/3 minimal) and Group 4 (male: 3/3 moderate; female: 1/3 minimal, 2/3 moderate) rats.
− Hyaline droplets were present in male rats at increased incidence and severity in Group 2 (1/3 minimal, 2/3 slight) and Group 3 (1/3 slight, 2/3 moderate) compared to Group 1 (2/3 minimal).
− Tubular basophilia, mainly in the cortico-medullary area, was present at increased severity in male and female Group 4 rats (male: 2/3 moderate, 1/3 marked; female: 3/3 moderate).
− Tubular vacuolation was present in female Group 2 (3/3 slight) and Group 3 (1/3 minimal, 1/3 slight) rats.
− Attenuated tubular epithelium was present at slight degree in 1/3 male and at minimal degree in 1/3 female Group 4 rat.
Liver:
− hepatocellular hypertrophy was present in both male and female Group 2 (male: 2/3 minimal; female 1/3 minimal), Group 3 (male: 3/3 minimal; female: 2/3 minimal) and Group 4 (male: 1/3 minimal, 1/3 slight, 1/3 moderate; female: 2/3 slight, 1/3 moderate) rats. This was the microscopic correlate to the macroscopic enlargement. The anatomic distribution of enlarged hepatocytes (hypertrophy) ranged from centrilobular to panacinar (involving the entire liver lobule).
Thymus:
− lymphoid atrophy was present in 2/3 male (1 minimal; 1 moderate) and 1/3 female (1/3 slight) Group 4 rats. This was the microscopic correlate to the macroscopic reduction in size.
− Lymphocytolysis was present in male and female Group 2 (male: 1/3 minimal; female: 2/3 minimal) and Group 3 (male: 2/3 minimal; female: 1/3 minimal) and in male Group 4 (1/3 minimal, 1/3 slight) rats.
All other microscopic findings recorded were considered to be within the normal range of background pathology encountered in rats of this age and strain. - Dose descriptor:
- NOAEL
- Effect level:
- < 150 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: The test substance has toxic potential when administered to rats by daily oral gavage for a period of up to 7 consecutive days at 150 mg/kg.
- Dose descriptor:
- LOAEL
- Effect level:
- < 150 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: The test substance has toxic potential when administered to rats by daily oral gavage for a period of up to 7 consecutive days at 150 mg/kg.
- Critical effects observed:
- not specified
- Conclusions:
- It is considered that the test substance has toxic potential when administered to rats by daily oral gavage for a period of up to 7 consecutive days at 150 mg/kg.
Reference
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 150 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- 1 (reliable without restriction)
Additional information
A 7-day repeated dose study was conducted according to OECD 407 using rats (Beerens-Heijnen, 2011). Key study.
It is considered that the test substance has toxic potential when administered to rats by daily oral gavage for a period of up to 7 consecutive days at 150 mg/kg bw/day.
Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Study run to a method comparable with current guidelines and to GLP
Justification for classification or non-classification
Repeated dose toxicity: A 7-day repeated dose study on rats showed that the test substance has toxic potential when administered at 150 mg/kg bw/day, resulted a LOAEL value < 150 mg/kg bw/day.
Therefore in accordance with Regulation (EC) No. 1272/2008 Table 3.9.3 the test substance is not classfied for repeated dose toxicity endpoint.
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.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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