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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
Carcinogenicity
Administrative data
Description of key information
In a 2-year cancer study no indications of a carcinogenic effect became evident, the NOAELs reported were 191.5 mg/kg bw/d for males rat and 241.3 mg/kg bw/d for females.
Key value for chemical safety assessment
Carcinogenicity: via oral route
Link to relevant study records
- Endpoint:
- carcinogenicity: 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
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
- Version / remarks:
- (1981-05-12)
- GLP compliance:
- no
- Species:
- rat
- Strain:
- Crj: CD(SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River U.K. Ltd., Margate, Kent, England
- Age at study initiation: 4-5 weeks
- Weight at study initiation: 60- 80 g (at day of delivery); 120-121 g ( ± 10; males), 114-115 g (± 11, females) at day 0 of study
- Housing: five rats of one sex were held in each cage
- Diet (e.g. ad libitum): ad libitum, pulverised fat-coated pellets (Spratts Laboratory Animal Diet No.2 ), ad libitum (week 1-30);
from week 30 no coating of pellets with fat (expanded autoclaved diet), no antibiotic, chemotherapeutic or prophylactic agent; it was monitored for organochlorine pesticides, polychlorinated biphenyl, aflatoxin contaminants and from week 65 organophosphorus compounds; additionally each batch of diet was analysed by the manufacturer, a certificate of analysis is available (with beginning of treatment week 40)
- Water (e.g. ad libitum): ad libitum (two polyethylene bottles with chromium plated sipper-tubes)
- Acclimation period: 6 days
- other: Within 6 days of acclimatisation period: any rat that failed to gain weight satisfactorily was discarded
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2
- Humidity (%): 50 ± 10
- Air changes (per hr):15
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- DIET PREPARATION
Pre-mixes were prepared weekly from which the dietary concentrations were obtained by direct dilution with further quantities of diet. Homogeneity was achieved by mixing manually for five minutes in a plastic container, followed by 10 minutes in a Kenwood-Chef mixer and 10 minutes in a rotary double-cone mixer to produce the premix, and finally for 20 minutes in a Gardner (Type 50L 28GM) horizontal interrupted-spiral mixer to produce the required concentrations. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- concentrations of test material in dietary safety were determined by different methods
1.) liquid chromatography (Ciba-Geigy, analytical department, analytical method LC-41)
2.) thin layer chromatography for samples < 1000 ppm (Ciba-Geigy, analytical department, analytical method RJ-24/2)
3.) spectrophotometry for samples ≥ 1000 ppm (Ciba-Geigy, analytical department, analytical method RJ-24/2)
4.) high pressur eliquid chromatography (HPLC) (Ciba-Geigy, analytical department, analytical method RJ-62) - Duration of treatment / exposure:
- 105 weeks
- Frequency of treatment:
- dietary study, food continously available
- Dose / conc.:
- 500 ppm
- Remarks:
- corresponding to 19.0 and 24.0 mg/kg bw/day in males and females, respectively
- Dose / conc.:
- 1 500 ppm
- Remarks:
- corresponding to 57.7 and 71.7 mg/kg bw/day in males and females, respectively
- Dose / conc.:
- 5 000 ppm
- Remarks:
- corresponding to 191.5 and 241.3 mg/kg bw/day in males and females, respectively
- No. of animals per sex per dose:
- 70
- Control animals:
- yes, plain diet
- Details on study design:
- - Rationale for animal assignment: 100 rats were discarded due to extreme lower or upper body weight, the remainder were divided evenly among 4 treatment groups
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
BODY WEIGHT: Yes
- Time schedule for examinations: day of treatment, week 1- 13 (once per week), 14 weeks and higher (each 4th week) and at
weeks 26, 52, 78 and 104
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 but food consumption not related to individual animal instead related to cage (5 animals per cage)
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
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
WATER CONSUMPTION AND COMPOUND INTAKE
- Only visual assessment of water bottle residues, due to absence of inter-group differences no quantitative measurements
were done
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: before treatment, after 12, 26, 51, 77 and 104 weeks
- Dose groups that were examined: all groups (before treatment); control and high dose group (after 12, 26, 51, 77 and 104
weeks)
HAEMATOLOGY: Yes
- Time schedule for collection of blood: after 13, 26, 52, 79 and 103 weeks of treatment
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: No data
- How many animals: 10 animals per group, all groups
- Parameters checked: haemoglobin concentration (Hb), erythrocyte count (RBC), calculation of mean cell haemoglobin
concentration (MCHC) and mean cell volume (MCV) , total leucocyte count (WBC), differential leucocyte count (WBC),
packed cell volume (PCV), platelet count, reticulocyte count (Retics), prothrombin time, microscopic examination for presence
of Howell-Jolly bodies or Heiz bodies
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: after 13, 26, 52, 79 and 103 weeks of treatment
- Animals fasted: No
- How many animals: 10 animals per group, all groups
- Parameters checked: urea concentration, glucose concentration, total protein concentration, electrophoretic protein fractions,
alkaline phosphatase activity, alanine amino-transferase activity (ALT), aspartate amino-transferase activity (AST), sodium and
potassium concentrations - cholesterol concentration
URINALYSIS: Yes
- Time schedule for collection of urine: upon completion of 12, 25, 51, 78 and 103 weeks of treatment
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No, but drinking water was removed 5 hrs prior to urine sampling
- Parameters checked: volume, pH, specific gravity (SG), reducing substances, glucose, protein, ketones, bile pigments,
urobilin, blood pigments, specimen of urine were centrifuged and the deposit examined microscopically for: epithelial cells (E),
polymorphonuclear leucocytes (P), mononuclear leucocytes (M), erythrocytes (R), casts (C), other abnormal components (A).
Grading of cell frequency according to following scheme: - NIL, few in some fields examined, few in all fields examined, many
in all fields examined.
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- All rats survived or being in extremesis were subjected to euthanasia by carbon dioxide.
ORGAN WEIGHTS: weights of following organs were recorded: adrenal glands, brain, heart, kidney, liver, pituitary gland, spleen and testes
GROSS PATHOLOGY: YES
HISTOPATHOLOGY: YES
Following tissues were examined: - adrenal glands, aortic arch, bone (including marrow), brain, caecum, duodenum, epididymides, eyes and optic nerves (one sectioned initially), harderian gland, head (middle ears, nasal cavity and sinuses, nasopharynx, oral cavity, tongue, turbinal bones), heart, ileum, jejunum, kidneys, liver, lungs and mainstem bronchi, lymph nodes (cervical and mesenteric), mammary gland (posterior and anterior), oesophagus, ovaries, pancreas, pituitary gland, prostate gland, salivary gland (submaxillary), sciatic nerve, seminal vesicles, skeletal muscle, skin, spinal cord (in situ), lumbar and cervical, spleen, stomach, testes, thymus, thyroid and parathyroid glands, tissue masses, suspected tumors and regional lymph nodes, tongue, trachea, urinary bladder, uterine cervix, uterus - Statistics:
- The significance of any inter-group differences in growth performance,organ weight analysis and, where considered
necessary, blood composition was assessed by Student's t-test, deriving an overall variance from the individual group
variances, and obtaining from this the standard error of the differences between the means. Analysis of food consumption data
was done by Student's t-test, using the group mean values and computing overall means of means for the periods indicated.
For convenience significant differences between means of means have been attached to the total intakes quoted. Where
appropriate, the significance of inter-group differences in urine composition was assessed by a rank sum test (Mann-
Whitney/Wilcoxon test).
The significance of any inter-group differences in the incidence of palpable swellings detected in vivo or at necropsy, and the
mortality distribution was assessed by 2 x 2 contingency tests with reference to chi-square tables. The inter-group distribution
of neoplastic or non-neoplastic changes was evaluated by 2 x 2 contingency tests, used as a two-tailed test, computing the
exact probability of the observed or more extreme distributions occurring by chance.
Significant differences are depicted in the tables in the following way:
1.) Not significantly different from controls, P > 0.05.
2.) Significantly different from controls, P < 0.05.
3.) Significantly different from controls, P < 0.01.
4.) Significantly different from controls, P < 0.001. - Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Behaviour, appearance, locomotor function and faecal characteristics were similar between treated and untreated rats. A total of 380 rats (142 males, 238 females) had one or more cutaneous or subcutaneous swellings detected visually or by palpation at some time during the course of the study; the group distribution and multiplicity were unrelated to the administration of the test substance (Chi2 test, P > 0.05).
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- Three hundred and fifty rats (185 males and 165 females) died or were killed in extremis during the treatment period. Overall mortality was similar in all groups. Only in females treated with 5000 ppm a reduction in mortality during the first 78 weeks of treatment was seen (p <0.05).
Macropathological observations and the organ weights of animals which died or were killed in extremis and clinical laboratory findings for blood samples taken from rats killed in extremis did not implicate the test substance as a cause of death debility. - Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The bodyweight increments of males receiving 5000 ppm of the test substance were slightly superior to those of the controls during the first year; on most occasions of analysis between weeks 8 and 57 the bodyweight differences (body weight gain from week 17-26 for highest dose group of male rats: 136 g vs. 124 g for control group) attained statistical significance (P < 0.05). This enhanced growth pattern reflected the increased food intake. A similar trend towards superior bodyweight gain was noted in males receiving 500 ppm, but in this case differences from control values failed to reach statistical significance (P > 0.05), bodyweight increments of males receiving 1500 ppm and females receiving 5000 ppm or below were similar to those of their respective controls.
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- The food consumption of male rats receiving the test substance at 5000 ppm was marginally higher (104%) than that of controls throughout the treatment period. Females receiving 5000 ppm and rats of either sex receiving 1500 ppm or below resembled the controls in this respect. Food conversion ratio was similar in all observation groups
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- no effects observed
- Description (incidence and severity):
- The findings did not reveal any treatment-related abnormality.
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- A slightly lower packed cell volume, haemoglobin concentration and erythrocyte count were seen (high dose male animals, after 103 weeks) but no statistical significance was achieved. Shorter prothrombin times were also recorded at this examination, for male and female rats receiving the high dosage. However, the change was not confirmed by repeat blood samples taken three days later. The cellular and coagulation characteristics of the blood of rats receiving 500 or 1500 ppm of the test substance were similar, throughout the treatment period, to those of the respective control rats; those inter-group differences which arose, including a slightly higher erythrocyte count for all male groups after 13 weeks of treatment, were not considered to be of toxicological significance. There were no Howell-Jolly bodies or Heinz bodies observed on any occasion of haematological examination.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Elevated blood urea concentration (P < 0.01) was recorded after 103 weeks of treatment for male rats receiving 5000 ppm of the test substance.This finding was consistent with changes in urine composition and kidney weights for these animals, slightly higher blood urea concentrations, compared with control values, were also recorded on several other occasions during the treatment period amongst rats receiving the test substance. These differences attained statistical significance at week 25, in the case of males receiving 5000 ppm (P < 0.001) or 1500 ppm (P < 0.05) and at week 79 or in the case of females receiving 5000 ppm (P < 0.05). 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.
High plasma sodium concentrations recorded after 52 weeks of treatment for several groups, including the female control, were not confirmed by repeat blood samples taken from the same rats 2 weeks later. Conversely, low potassium concentrations recorded after 103 weeks for all groups were confirmed, although plasma sodium and chloride concentrations assayed at this time were within the normal range of expectancy. Other minor changes in the parameters of blood chemistry which were not considered to be associated with the administration of the test substance, included sporadic and inconsistent changes in serum or plasma glucose concentrations, particularly in rats receiving 5000 ppm, lower total protein concentration during Week 53 for male rats receiving 1500 or 5000 ppm and lower alkaline phosphatase activity after 103 weeks of treatment for male rats receiving 5000 ppm of the test substance. - Urinalysis findings:
- effects observed, treatment-related
- Description (incidence and severity):
- When compared with values recorded for male controls, slightly higher urinary volume and lower specific gravity and a higher incidence of haematuria were recorded after 104 weeks of treatment for male rats receiving 5000 ppm of the test substance. However, only the increased incidence of haematuria attained a level of statistical significance (p < 0.05, Fisher's exact probability test). Slightly inferior urinary concentrating ability was also recorded after 103 weeks of treatment for female rats receiving 1500 ppm of the test substance when compared with female controls (p < 0.05). However, the finding was unaccompanied by haematuria and was considered to be unrelated to the urinary effect observed at this time for males receiving 5000 ppm. There were no other changes in urinary composition that could be ascribed to the administration of the test substance.
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Higher absolute and bodyweight-relative kidney weights were recorded for male rats receiving 5000 ppm when compared with their respective controls (p < 0.05) for animals sacrificed after 105 weeks (mean absolute organ weight: 8.3 g vs. 6.8 g). Individual kidney weights were notably higher for 5 of 23 rats. For animals of the same group dying during the last 25 weeks of treatment no statistical significance was calculated (p > 0.05). The only microscopic change in these kidneys was geriatric nephropathy, a finding common in control rats of the same age.
Furthermore for the same group slightly increased weights for liver (29.8 vs. 27.6 g), spleen (1.5 vs. 1.21 g) and adrenal weights (91 mg vs. 81 mg) were also recorded, again no statistical significance were given. For females (5000 ppm) a significant difference in relative pituitary weight (4.5 vs. 3.3) was seen. But this is not considered to be of any importance. - Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no changes associated with treatment with the test substance for animals killed or dying prior to the end of the study and animals that were killed at the end of the study. There was a wide range of banal degenerative and inflammatory changes present, similar in type and incidence to those considered usual in CD rats at this Laboratory.
- Description (incidence and severity):
- There were no neoplasms associated with treatment of test substance in all animals
- animals killed or dying prior to end of the study
There was a wide range of neoplasms present, similar in type and incidence to those considered usual in CD rats at this Laboratory.
These included mammary gland benign fibro-epithelial tumours and carcinomas, pancreatic islet cell adenomas, pituitary adenomas and carcinomas, thyroid parafollicular cell adenomas, adrenal, benign phaeochromocytomas, testicular interstitial cell adenomas, skin and subcutis mesenchymal benign fibromas and lipomas and malignant lymphomas.
The number of malignant neoplasms was increased in the lowest and intermediate dosage groups (18 and 14 vs 5 in controls, p < 0.01 and p < 0.05) in female animals. However, this was not considered to be associated with treatment, but was due to a relatively low incidence in the control group.
There were no inter-group differences in the number of different neoplasms per animal.
-animals killed at termination of the study
Neoplastic findings were similar for animals killed at termination of the study. Nevertheless there were differences in the increase of the number of benign neoplasms and the total number of neoplasms in the highest male dose group (total number of neoplasms per animal: 45 vs. 24; p < 0.05, total number of benign neoplasms 44 vs. 21; p < 0.05). Due to the marginality of the effect and the lack of a dose-response relationship it was not considered to be associated with treatment.
-findings irrespective of death
The incidence of squamous papillomas among males receiving 5.000 ppm was significantly higher than the control incidence, (6 of 70, vs. 0 of 70 in controls, p < 0.05). However, the control incidence was lower than expected from background data.
-blood and bone smears
The quality of many of the smears was inadequate for useful examination. However, the limited material available did not suggest any disturbance of the haematopoietic system resulting from the prolonged administration of the test substance. - Dose descriptor:
- NOAEL
- Effect level:
- > 191.5 - < 241.3 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No cancerogenic effects associated with treatment of test substance
Reference
The test substance was tested on its toxicological and carcinogenic potential in a combined chronic toxicity study during prolonged dietary administration and was conducted on male and female CD rats over a period of 105 weeks with 70 animals per sex and group. The study was conducted similar to OECD guideline 453 (adopted in 1981-05-12).
Regards to gross pathology no treatment related effects with the test substance were seen.
In histopathology there were no changes associated with treatment with the test substance for animals killed or dying prior to the end of the study and animals that were killed at the end of the study.
Based on these results a NOAEL for cancer of 5000 ppm for female and male animals was derived. This is equivalent to a NOAEL of 191.5 mg/kg bw/d for males and a NOAEL of 241.3 mg/kg bw/d for females.
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 191.5 mg/kg bw/day
- Study duration:
- chronic
- Species:
- rat
Carcinogenicity: via inhalation route
Endpoint conclusion
- Endpoint conclusion:
- no study available
Carcinogenicity: via dermal route
Endpoint conclusion
- Endpoint conclusion:
- no study available
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 carcinogenicity under Regulation (EC) No. 1272/2008.
Additional information
In a 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, 500, 1500, 5000 ppm for duration of 105 weeks. 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 (males and females) doses. At the doses tested, there was no treatment related increase in tumor incidence when compared to controls. Neoplasms were detected that are typical in incidence and type for the strain of rats. For female rats dying or killed prior to study end in low and intermediate dosage groups a significant increase of malignant neoplasms was detected. This can be explained by the unexpectedly low tumor incidence rate of the control group. For male rats killed at the end of the study an increased number of benign neoplasms and increased total number of neoplasms was detected, showing statistical significance for the high-dose group (p < 0.05). This effect was marginal, and a dose-response relationship was missing. 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).
The finding of non-increased tumor incidence was confirmed by a further carcinogenicity study. The test substance was tested in a 2-year study in Wistar rats of both sexes. No current guideline was followed as the study was conducted between 1976 and 1979. The animals (20/sex) were treated continuously be receiving the test item in the diet; the dosage was 100 mg/kg diet. Mortalities were recorded and hematological examinations were conducted. At test ending, following sacrifice, the animals were subjected to detailed gross pathology and histopathology; particular attention was given to neoplastic changes. For control, a concurrent untreated group of 20 animals/sex was considered as well as a historical control group of 98 animals. All parameters considered revealed no treatment-related changes. The dose level referred to the amount of test item in the diet (100 mg/kg diet), however since no data on food consumption and body changes over the testing period were given, it was not possible to determine test item intake by the animals. Nevertheless, and despite of some deficiencies in study conduct and reporting, the pathological and histopathological findings reported give an indication about the carcinogenicity potential of the test item, which was in accordance with the results obtained from the key study.
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