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EC number: 245-442-7 | CAS number: 23128-74-7
- 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
Endpoint summary
Administrative data
Description of key information
No adverse effects were reported in two subchronic studies with dogs and rats and in a chronic study with rats. the NOAEL in the dog study was 787 mg/kg/day (mean for males and females) and in the rat study 1343 mg/kg/day.
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 409 (Repeated Dose 90-Day Oral Toxicity Study in Non-Rodents)
- Version / remarks:
- (1981-05-12)
- Deviations:
- yes
- Remarks:
- substance purity not reported
- GLP compliance:
- no
- Limit test:
- no
- Species:
- dog
- Strain:
- Beagle
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Olac (Western) Ltd., Llandeilo, Dyfeld, Wales and Balbeggie Kennels, By Kirkaldy, Fife, Scotland
- Age at study initiation: 28 weeks
- Weight at study initiation: 9481 g (mean value)
- Housing: single housing in kennels at Alconburry
- Diet: complete dry diet (Spratt's dog diet), finely ground form, 400 g diet offered per day
- Water: ad libitum
- Acclimation period: 2 months - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- DIET PREPARATION
- Rate of preparation of diet (frequency): Each week
- Mixing appropriate amounts with (Type of food): 915 g of test substance with 1085 g of sieved dry diet - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Representative sample of diets fed were selected in the first and seventh week. The samples were extracted with chloroform and the extracts analyzed by an ultraviolet spectrometer. Experimental reproducibility is ± 10 % or better.
- Duration of treatment / exposure:
- 90 days (all animals in study are included) followed by a recovery period of 4 weeks (1 male and 1 female each of the control and high dose level) without treatment.
- Frequency of treatment:
- each morning animal gets offered 400 g of fresh diet , at the same time the old residues are removed.
- Dose / conc.:
- 5 000 ppm
- Remarks:
- corresponding to 195 mg/kg bw for males and 196 mg/kg bw for females
- Dose / conc.:
- 10 000 ppm
- Remarks:
- corresponding to 368 mg/kg bw for males and 413 mg/kg bw for females
- Dose / conc.:
- 20 000 ppm
- Remarks:
- corresponding to 750 mg/kg bw for males and 825 mg/kg bw for females
- No. of animals per sex per dose:
- control group: 5 animals per sex
group of low and intermediate dose level: 4 animals per sex
group of high dose level: 5 animals per sex - Control animals:
- yes, plain diet
- Details on study design:
- SATELLITE GROUPS:
Formation of a satellite group of 4 animals (consisting of a negative control group (1 male and 1 female dog) as well as a high dose level group (1 male and 1 female dog)). These animals had a treatment-free post exposure period of 4 weeks. - Positive control:
- no positive control
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: No data
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily
BODY WEIGHT: Yes
- Time schedule for examinations: once a week
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 (g food/week) for individual animals
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: during the 4-week predosing period, during weeks 1-4 and 9-12 of dosing, during the 4-week recovery period, measured on weekdays only.
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
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: before dosing, after 4, 8, 12 weeks and after 4 weeks recovery
- Dose groups that were examined: eyes of all dogs were examined
HAEMATOLOGY: Yes
- Time schedule for collection of blood: before dosing, after 4, 8, 12 weeks and after 4 weeks recovery
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes (16 hrs before examination food was removed)
- How many animals: all animals
- Parameters checked:
-Erythrocyte sedimentation rate (ESR)
-Packed cell volume (PCV)
-Haemoglobin (Hb)
-Red blood cell count (RBC)
-Reticulocyte count (Retics)
-Mean corpuscular haemoglobin concentration (MCHC)
-mean cell volume (MCV)
-Total white cell count (WBC) Differential count:
-neutrophils
-lymphocytes
-eosinophils
-basophils
-monocytes
-platelet count
-prothrombin index (PTI)
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: before dosing, after 4, 8, 12 weeks and after 4 weeks recovery
- Animals fasted: Yes (16 hrs before examination food was removed)
- How many animals: all animals
- Parameters checked:
-plasma urea
-plasma glucose
-total serum proteins
-serum protein electrophoresis and AG ratio
-serum alkaline phosphatase (SAP)
-serum glutamic - pyruvic transaminase (SGPT)
-serum bilirubin
-electrolytes (sodium, potassium)
URINALYSIS: Yes
- Time schedule for collection of urine: before dosing, after 4, 8, 12 weeks and after 4 weeks recovery
- Metabolism cages used for collection of urine: Yes (urine was collected in special containers between 5 pm and 9 am the following day)
- Animals fasted: no (wihdrawal of supply of water from the animals at midday at day of examination)
-Parameters checked:
-specific gravity
-pH
-protein
-reducing substances
-glucose
-ketones
-bile pigments
-urobilinogen
-haemoglobin
-specimen of urine was centrifugated and the deposit examined microscopically for:
-epithelial cells
-polymorphonuclear leucocytes
-mononuclear leucocytes
-erythrocytes
-organism
-casts
-abnormal constituents
grading of cell frequency according to following scheme:
- NIL
- few in some fields examined
- few in all fields examined
- many in all fields examined - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
following organs were examined macroscopically
- brain
- liver
- thymus
- thyroids
- pituitary
- spleen
- prostate/ uterus
- adrenals
- heart
- pancreas
- kidneys
- gonads
- lungs
- spinal cord
For histopathology all tissues from gross pathology were observed, additionally pieces of aorta (arch and abdominal), trachea, lymphnodes (cervical and mesenteric), gall bladder, urinary bladder, salivary gland, tongue, oesophagus, stomach, duodenum, jejunum, ileum, colon, skin, mammary gland, skeletal muscle, bone marrow, peripheral nerve, eye and optic nerve) - Statistics:
- Student's t-test for analysis of variances
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No clinical symptoms were observed.
- Mortality:
- no mortality observed
- Description (incidence):
- No mortality was observed.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Test substance has no adverse effect on body weight gain.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Test substance has no adverse effect on food consumption and body weight gain.
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Description (incidence and severity):
- During both the pre-dosing period and the first 4 weeks of dosing, water consumption was satisfactory for all groups. It was noted, however, that on the latter occasion water consumption had increased slightly in the control group, but had remained almost unchanged in the dosed groups. Consequently, it was possible to show statistically significant group differences relating to this parameter, but since the trend was also apparent from the-predosing measurements, it was probably of no toxicological significance.
During weeks 9-12, water consumption had increased in all groups, but no significant group mean differences were demonstrated. Water consumption remained satisfactory during the recovery period. It may be concluded, therefore, that there was no definite adverse effect on water consumption. - Ophthalmological findings:
- no effects observed
- Description (incidence and severity):
- No abnormalities were detected that were considered to be related to ingestion of the test compound.
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No effects were seen that had any toxicological significance, however increased values could be seen for
-platelet count:
no values higher than the accepted limit were seen prior to beginning of the study, after 4, 8 weeks and in the recovery phase. After 12 weeks in one dog of the intermediate dose group a platelet count of 490,000/cm² was measured (accepted upper limit is 450,000/cm²). A further blood sample, taken a few days later, confirmed this finding (550,000/cm²). - Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No effects were seen that had any toxicological significance, however increased values could be seen for
- glucose level:
- prior to beginning of the study in one dog of intermediate dose level (118 mg% vs. 110 mg%). A further blood sample taken a few days later confirmed this finding (112 mg%).
- after 4 weeks in a dog of control group (114 mg% )
- after 12 weeks in a dog of the high dose (116 mg%)
- increased values were seen only in these animals at these time points, especially no increased values were seen in recovery animals
- increase SGPT -level:
After 4 weeks in a dog of control group and of intermediate groups were 86 mU/mL and 50 mU/mL respectively (accepted limit 50 mU/mL) measured. Both findings were confirmed by a further blood sample. Again after 12 weeks in another dog of the intermediate group the value was exceeded (59mU/mL) and confirmed by a further blood sample. Increased values were seen only in these animals at these time points, especially no increased values were seen in recovery animals, consequently this effect is to be considered as reversible.
- increased SAP-level:
after 12 weeks in a dog from control group (43 KA units vs. 35 KA units as accepted limit). Increased values were seen only in these animals at these time points, especially no increased values were seen in recovery animals, consequently this effect is to be considered as reversible. - Urinalysis findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- - after 4 weeks the specimen of urine produced by a dog of the control group had a low specific gravity (1.026 vs. 1.035 as accepted lower limit), this was confirmed by a further probe. Test samples taken after 8 and 12 weeks were in the accepted range.
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no changes that were considered to be related to administration of the test compound.
It was, however, noted that the thyroids for a number of animals from all groups including the controls, were heavier than usually seen at this centre, whilst a number of dogs had liver weights that exceeded our normally accepted upper limit of 4% of the bodyweight this is only valid for the animals obtained from Balbeggie Kennels, and it is, therefore, concluded that these observations represent a difference in the strain of beagle. - Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- One dog of the high dose recovery group showed a linear area of erosion, approximately 10 mm x 2 mm, at the junction of the body and antrum of the stomach, a similar area of erosion in the duodenum together with three nodular haemorrhagic foci in the duodenum. Since this dog had received untreated diet for 4 weeks prior to sacrifice, it seems unlikely that these findings were related to administration of the test compound.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No histopathological abnormality or variation from normal was encountered In the tissues examined which was attributable to treatment with the test substance.
- Trachea: A small focus of mononuclear cells was seen in the subepithelium of 2 dogs (control and low dose group) and also minimal infiltration of mixed inflammatory cells was noted in the epithelial lining and the corresponding subepithelium of one dog (high dose group)
- Lung: Small areas of interstitial pneumonitis and emphysema were encountered in all dogs from both treated and control groups. Also occasional areas of parasitic pneumonitis were seen in 3 dogs each one of the low, intermediate and high dose group. The above changes are not uncommon in the laboratory-maintained dog, and were considered to be of no toxicological significance.
-Liver: A proportion of animals from all groups, including controls showed small foci of mononuclear cells and or eosinophils in sinusoids and periportal regions. Also parasitic granulomota or occasional areas of mixed inflammatory cells were found in dogs (1 of the control group, 2 of the low dose group and 1 of the intermediate group). These minor changes were considered to be of no toxicological importance.
-Kidney: No treatment-related changes were detected. Minor changes which were considered to be of no toxicological importance were recorded as follows:
dystrophic mineralisation in the medullary collecting tubules of a proportion of dogs from both treated and control groups,
cortical parasitic granulomata (1 animal of the control, 3 animals of the low dose, and 1 animal of the intermediate dose group),
occasional small cortical foci or areas of chronic inflammatory cells in dogs (3 in control animals, 1 in low dose, 2 in high dose groups),
occasional lymphoid aggregations in the peripheric regions of one dog (intermediate dose group) and a small cortical area of tubular basophilia in dog of the low dose group. - Dose descriptor:
- NOAEL
- Effect level:
- 787 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: highest dose tested
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Dose descriptor:
- NOAEL
- Effect level:
- 750 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: highest dose tested
- Dose descriptor:
- NOAEL
- Effect level:
- 825 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: highest dose tested
- Critical effects observed:
- no
Reference
Tables of body weights
Table 1: male dogs
Mean weekly body weight |
|||
|
dietary concentration [ppm] |
||
Test group |
|||
week |
5000 |
10000 |
20000 |
1 |
9850 |
10225 |
9940 |
2 |
9850 |
10250 |
10080 |
3 |
9775 |
10300 |
10040 |
4 |
10050 |
10400 |
10050 |
5 |
10150 |
10625 |
10400 |
6 |
10425 |
10850 |
10800 |
7 |
10475 |
10950 |
10900 |
8 |
10650 |
11200 |
11060 |
9 |
10475 |
11200 |
11020 |
10 |
10525 |
11200 |
10900 |
11 |
10550 |
11425 |
11100 |
12 |
10450 |
11375 |
11060 |
13 |
10350 |
11325 |
10920 |
|
|
|
|
control group: 5 male & 5 female animals |
|||
test groups, low and intermediate dose: 4 male & 4 female animals |
|||
test group, high dose: 5 male & 5 female animals |
|||
recovery group: 1 male & 1 female animals were retained from control and high dose group |
|||
Table 2: Female Dogs
Mean weekly body weight |
|||
|
dietary concentration [ppm] |
||
Test group |
|||
week |
5000 |
10000 |
20000 |
1 |
8900 |
8725 |
8980 |
2 |
8925 |
8925 |
9060 |
3 |
8975 |
8975 |
9100 |
4 |
9275 |
9225 |
9320 |
5 |
9525 |
9200 |
9440 |
6 |
9500 |
9500 |
9540 |
7 |
9675 |
9475 |
9580 |
8 |
9775 |
9600 |
9760 |
9 |
9950 |
9675 |
9720 |
10 |
9900 |
9650 |
9740 |
11 |
9975 |
9725 |
9920 |
12 |
10025 |
9600 |
9840 |
13 |
9900 |
9750 |
9680 |
|
|
|
|
control group: 5 male & 5 female animals |
|||
test group, low and intermediate dose: |
|||
test group, high dose: 5 male & 5 female animals |
|||
recovery group: 1 male & 1 female animals were retained from control and high dose group |
|||
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 750 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- dog
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
In a subchronic toxicity study in dogs, the test substance (pure substance) was administered to beagle dogs (low, intermediate dose: 4 animals/ sex/ dose, control, high dose: 5 animals/ sex/dose) in diet at dose levels of 0 (control), 5000, 10000, 20000 ppm, corresponding to 195, 368, 750 mg/kg bw/d for male animals and 196, 413, 825 mg/kg bw/d for female animals. There were no compound related effects in mortality, clinical signs, body weight, food consumption, hematology, clinical chemistry, organ weights, or gross and histological pathology. The mean NOAEL is 787 mg/kg bw for males and females (highest dose applied). This subchronic toxicity study in dogs is acceptable and satisfies the guideline requirement for a subchronic oral study (OECD 409) in dogs with some restrictions (substance purity not given, no GLP study).
In a supporting subchronic toxicity study the test substance (pure substance) was administered to Sprague-Dawley rats (low, intermediate dose: 15 animals/ sex/ dose, controls, high dose: 20 animals/ sex/dose) in diet at dose levels of 5000, 10000, 20000 ppm, corresponding to doses of 339 mg/kg bw/d, 717 mg/kg bw/d, 1343 mg/kg bw/d for males and females. There were no compound related effects in mortality, clinical signs, body weight, food consumption, hematology, clinical chemistry, organ weights, or gross and histological pathology. The NOAEL is 1343 mg/kg bw (highest dose applied). This subchronic toxicity study in rats is acceptable and satisfies the guideline requirement for a subchronic oral study (OECD 408) in rats with some restrictions (no GLP study, substance purity not given).
A further chronic toxicity study also supports the findings of the key study. In this combined chronic/carcinogenic toxicity study test substance, (pure substance) was administered to 70 Crj: CD(SD) rats per sex/dose in diet at dose levels of 0 (control), 500, 1500, 5000 ppm for duration of 105 weeks. This corresponds to 19.0, 57.7, 191.5 mg/kg bw/d for male animals and 24.0, 72.7, 241.3 mg/kg bw/d for female animals. At the highest dose in male animals elevated blood urea concentrations and elevated kidney weights at the same animals were reported. However, inter-group differences were small on all these occasions and were inconsistent between examinations. It was considered therefore that these minor changes in blood urea concentrations could not be unequivocally associated with the administration of the test substance. The only microscopic change in these kidneys was geriatric nephropathy, a finding common in control rats of the same age. Apart from these findings no further compound related effects in mortality, clinical signs, body weight, food consumption, hematology, clinical chemistry, urinalysis, or gross and histological pathology were reported. The NOAEL is 191.5 mg/kg bw/d for males and 241.3 mg/kg bw/d for females based on test material. These values are derived from the highest dose applied for males and females. This chronic/ carcinogenic study in the rats is acceptable and satisfies the guideline requirement for a chronic/carcinogenicity study (OECD 453) in rats with some restrictions (no GLP study).
Justification for classification or non-classification
Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008
The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance is not considered to be classified for repeated dose toxicity under Regulation (EC) No. 1272/2008.
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