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EC number: 222-357-3 | CAS number: 3444-17-5
- 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
Oral administration:
A study similar to OECD 408 guideline (Rhodes, 2005) was conducted on the source substance Chromium picolinate monohydrate with rats and mice. Subchronic exposure to the substance did not cause any toxic effects in rats and mice: all animals survived, no change of body weight, food consumption, hematology, clinical chemistry, pathology organ weight and histopathology were recorded compared to control animals.
After molecular weight's correction, the NOAELS were estimated to be:
rats = 4683 mg/Kg,
mice = 10089 mg/Kg.
Inhalation exposure:
A short-term repeated dose toxicity study does not need to be conducted because exposure of humans via inhalation in production and/or use is not likely based on physical form of the substance: the pure substance is a sticky paste.
Dermal exposure:
A subchronic or chronic dermal study is not available. The oral NOAEL can be extrapolated to the dermal route, since dermal absorption is expected to be in the same order of magnitude as oral absorption (very low absorption).
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:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Justification for type of information:
- 1. HYPOTHESIS FOR THE ANALOG APPROACH
The read across follows Scenario 2 - Different compounds have qualitatively similar properties: properties of the target substance predicted to be quantitatively equal to those of the source substance or prediction based on a worst-case approach (as described in the 2017 Read-Across Assessment Framework document).
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
TARGET: Chromium tris(2-ethylhexanoate) (EC 222-357-3, CAS 3444-17-5)
SOURCE: Chromium picolinate monohydrate (CAS n° 27882-76-4)
3. ANALOG APPROACH JUSTIFICATION
The target substance and the source substance are organic salts of Chromium (3+). The organic counter ion of the target and source substances are small (6-8 carbon) carboxylic acids of similar molecular weight and polarity. The biologically-reactive center of all the molecules would be predicted to be the Cr (3+).
4. DATA MATRIX
See Read Across document attached to CSR. - Reason / purpose for cross-reference:
- reference to other study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to other study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- yes
- Remarks:
- Examinations are limited compared to guideline requirements.
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- mouse
- Strain:
- B6C3F1
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- origin: Taconic Laboratory Animals ans Services, Germantown, NY, USA
age at initiation of the study: 6 weeks old
weight at initiation of the study: male = 19.4 - 19.6 g and female = 16.7 - 16.9 g
acclimatation period: 11-14 days
housing: 5 female per cage, male housed individually
temperature: 72+/- 3°F
relative humidity: 50 +/- 15%
12 hours light/dark cycle
feed and water available at libitum - Route of administration:
- oral: feed
- Details on route of administration:
- Dose formulations were prepared with irradiated NTP-2000 open formula diet (from Zeigle Brothers, Inc., Gardners, PA, USA).
- Vehicle:
- other: diet
- Details on oral exposure:
- Dose formulations were prepared 4 times thoughout the study.
Chromium picolinate monohydrate in feed was stable for at least 42 days when stored at room temperature, protected from light, and under simulated animal room conditions at a concentration of 82 ppm for 8 days at room temperature. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Dose formulations were analyzed 3 times during the study: all samples were within 10% of the target concentrations.
- Duration of treatment / exposure:
- 93 days
- Frequency of treatment:
- ad libitum
- Dose / conc.:
- 80 ppm
- Dose / conc.:
- 240 ppm
- Dose / conc.:
- 2 000 ppm
- Dose / conc.:
- 10 000 ppm
- Dose / conc.:
- 50 000 ppm
- No. of animals per sex per dose:
- 10 male and 10 female per dose for core study
+ additonal groups for special studies - Control animals:
- yes, plain diet
- Details on study design:
- Dose selection was based on the results of a 14-day palatability study with rat: 10 rats (5 male, 5 female) per group were administered the substance at concentrations of 1%, 3% and 5% of the diet. The chemical hd no effect on feed palatability an produced no sign of toxicity. The range of the doses for this sutdy were chosen based on the low adsorption of the substance by rats and the condition that the highest dose (50 000 ppm) did not exceed 5% of the diet, so as not to alter the nutritional value of the feed.
- Positive control:
- No
- Observations and examinations performed and frequency:
- - clinical findings recorded weekly for core study
- food consumption measured weekly by cage
- animals weight: day 1, weekly thoughout the study and at sacrifice
- hematology and clinical chemistry analyses: days 3, 21 (special study) and 93 (core study): rats were bled from the retroorbital sinus while under CO2/O2 anesthesia before sacrifice
- clinical chemistry parameters evaluated include sorbitol dehydrogenase, alkaline phosphatase, creatine kinase, creatinine, total protein,
albumin, blood urea nitrogen, total bile acids, and alanine aminotransferase
- hematology parameters evaluated include erythrocyte count, hemoglobin, packed cell volume (automated and spun hematocrit), mean orpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, reticulocyte count, nucleated red blood cell
count, total leukocyte count, differential leukocyte counts, red blood cell morphology, and platelet morphology
- complete necropsy performed on all core study animals: liver, right kidney, heart, lungs, thymus and right testis (males) were weighed, microscopy examinations were carried out.
- Sacrifice and pathology:
- - complete necropsy performed on all core study animals
- liver, right kidney, heart, lungs, thymus and right testis (males) were weighed
- microscopy examinations were carried out
- gross lesions examined - Other examinations:
- - sperm count and motility from male exposed to 0, 2000, 10000, 50000 ppm
- vaginal cytology evaluations performed the last 12 days of the study from female exposed to 0, 2000, 10000, 50000 ppm - Statistics:
- Organ and bodyweight data were analyzed with analysis of variance followed by the parametric multiple comparison procedures of Dunnett and Williams. Hematologyand clinical chemistry data were analyzed using Kruskal–Wallis analysis of variance by the nonparametric multiple omparison methods of Shirley and Dunn. Jonckheere's test was used to assess the significance of dose–response trends. Extreme values were identified by the outlier test of Dixon and Massey. The Cochran–Armitage and Fisher's exact tests were used to assess nonneoplastic lesion prevalence.
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- Administration of Chromium picolinate monohydrate produced no clinical signs of toxicity.
- Mortality:
- no mortality observed
- Description (incidence):
- All mice survived until the end of the study.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Final mean body weights of mice were similar to those of the controls.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Feed consumption by exposed mice was similar to that of controls.
- Food efficiency:
- not specified
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- No changes in hematology variables occurred in mice administered Chromium picolinate monohydrate.
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Organ weights and organ/bodyweight ratios of exposed animals were generally unaffected. Females displayed significantly decreased trends in right kidney and thymus weights. However, pair-wise comparisons did not reveal any significant differences between treated and control groups.
- Gross pathological findings:
- not specified
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Histopathological lesions were considered spontaneous or incidental and not related to substance's exposure.
- Histopathological findings: neoplastic:
- not specified
- Description (incidence and severity):
- Effects on reproduction:
Sperm motility, number of sperm per mg cauda, total number of sperm per cauda, number of spermatids permg testis, and total number of spermatids per testis of animals exposed to the substance were similar to those of control animals.
Evaluation of vaginal smears did not reveal anysignifi cant differences among the females in the amount of time spent in different estrous
stages, the number of cycles, or the numberof females with regular cycle.
Estrous cycle length increased by 31% in females exposed to 10000 ppm (5.1 ± 0.5 in exposed mice versus 3.9 ± 0.2 in controls), primarily due to 2 individual animals who had 8-day cycles. This was not considered to be indicative of reproductive toxicity because all other parameters were normal, the other animals
in the group had cycles of normal length, and no corresponding changes occurred in females exposed to 50000 ppm. - Dose descriptor:
- NOAEL
- Effect level:
- 50 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- clinical biochemistry
- clinical signs
- food consumption and compound intake
- haematology
- histopathology: non-neoplastic
- mortality
- organ weights and organ / body weight ratios
- Remarks on result:
- other: expressed as Chromium picolinate monohydrate
- Dose descriptor:
- NOAEL
- Effect level:
- 9 141 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- clinical biochemistry
- clinical signs
- food consumption and compound intake
- haematology
- histopathology: non-neoplastic
- mortality
- organ weights and organ / body weight ratios
- Remarks on result:
- other: expressed as Chromium picolinate monohydrate
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 10 089 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- clinical biochemistry
- clinical signs
- food consumption and compound intake
- haematology
- histopathology: non-neoplastic
- mortality
- organ weights and organ / body weight ratios
- Remarks on result:
- other: expressed as Chromium 2-ethylhexanoate
- Critical effects observed:
- not specified
- Conclusions:
- In the experimental conditions of a test equivalent to OECD 408 guideline, subchronic exposure to Chromium picolinate monohydrate did not cause any toxic effects in mice.
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Justification for type of information:
- 1. HYPOTHESIS FOR THE ANALOG APPROACH
The read across follows Scenario 2 - Different compounds have qualitatively similar properties: properties of the target substance predicted to be quantitatively equal to those of the source substance or prediction based on a worst-case approach (as described in the 2017 Read-Across Assessment Framework document).
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
TARGET: Chromium tris(2-ethylhexanoate) (EC 222-357-3, CAS 3444-17-5)
SOURCE: Chromium picolinate monohydrate (CAS n° 27882-76-4)
3. ANALOG APPROACH JUSTIFICATION
The target substance and the source substance are organic salts of Chromium (3+). The organic counter ion of the target and source substances are small (6-8 carbon) carboxylic acids of similar molecular weight and polarity. The biologically-reactive center of all the molecules would be predicted to be the Cr (3+).
4. DATA MATRIX
See Read Across document attached to CSR. - Reason / purpose for cross-reference:
- reference to other study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to other study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- yes
- Remarks:
- Examinations are limited compared to guideline requirements.
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- Fischer 344
- Remarks:
- F344/N
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- origin: Taconic Laboratory Animals and Services, Germantown, NY, USA
age at initiation of the study: 6 weeks old
weight at initiation of the study: male = 91 - 92 g and female = 93 - 94 g
acclimatation period: 11-14 days
housing: 5 animals per cage
temperature: 72+/- 3°F
relative humidity: 50 +/- 15%
12 hours light/dark cycle
feed and water available at libitum - Route of administration:
- oral: feed
- Details on route of administration:
- Dose formulations were prepared with irradiated NTP-2000 open formula diet (from Zeigle Brothers, Inc., Gardners, PA, USA).
- Vehicle:
- other: diet
- Details on oral exposure:
- Dose formulations were prepared 4 times thoughout the study.
Chromium picolinate monohydrate in feed was stable for at least 42 days when stored at room temperature, protected from light, and under simulated animal room conditions at a concentration of 82 ppm for 8 days at room temperature. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Dose formulations were analyzed 3 times during the study: all samples were within 10% of the target concentrations.
- Duration of treatment / exposure:
- 93 days
- Frequency of treatment:
- ad libitum
- Dose / conc.:
- 80 ppm
- Dose / conc.:
- 240 ppm
- Dose / conc.:
- 2 000 ppm
- Dose / conc.:
- 10 000 ppm
- Dose / conc.:
- 50 000 ppm
- No. of animals per sex per dose:
- 10 male and 10 female per dose for core study
+ additonal groups for special studies - Control animals:
- yes, plain diet
- Details on study design:
- Dose selection was based on the results of a 14-day palatability study with rat: 10 rats (5 male, 5 female) per group were administered the substance at concentrations of 1%, 3% and 5% of the diet. The chemical hd no effect on feed palatability an produced no sign of toxicity. The range of the doses for this sutdy were chosen based on the low adsorption of the substance by rats and the condition that the highest dose (50 000 ppm) did not exceed 5% of the diet, so as not to alter the nutritional value of the feed.
- Positive control:
- No
- Observations and examinations performed and frequency:
- - clinical findings recorded weekly for core study
- food consumption measured weekly by cage
- animals weight: day 1, weekly thoughout the study and at sacrifice
- hematology and clinical chemistry analyses: days 3, 21 (special study) and 93 (core study): rats were bled from the retroorbital sinus while under CO2/O2 anesthesia before sacrifice
- clinical chemistry parameters evaluated include sorbitol dehydrogenase, alkaline phosphatase, creatine kinase, creatinine, total protein,
albumin, blood urea nitrogen, total bile acids, and alanine aminotransferase
- hematology parameters evaluated include erythrocyte count, hemoglobin, packed cell volume (automated and spun hematocrit), mean orpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, reticulocyte count, nucleated red blood cell
count, total leukocyte count, differential leukocyte counts, red blood cell morphology, and platelet morphology
- complete necropsy performed on all core study animals: liver, right kidney, heart, lungs, thymus and right testis (males) were weighed, microscopy examinations were carried out.
- Sacrifice and pathology:
- - complete necropsy performed on all core study animals
- liver, right kidney, heart, lungs, thymus and right testis (males) were weighed
- microscopy examinations were carried out
- gross lesions examined - Other examinations:
- - sperm count and motility from male exposed to 0, 2000, 10000, 50000 ppm
- vaginal cytology evaluations performed the last 12 days of the study from female exposed to 0, 2000, 10000, 50000 ppm - Statistics:
- Organ and bodyweight data were analyzed with analysis of variance followed by the parametric multiple comparison procedures of Dunnett and Williams. Hematologyand clinical chemistry data were analyzed using Kruskal–Wallis analysis of variance by the nonparametric multiple omparison methods of Shirley and Dunn. Jonckheere's test was used to assess the significance of dose–response trends. Extreme values were identified by the outlier test of Dixon and Massey. The Cochran–Armitage and Fisher's exact tests were used to assess nonneoplastic lesion prevalence.
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- Administration of Chromium picolinate monohydrate produced no clinical signs of toxicity.
- Mortality:
- no mortality observed
- Description (incidence):
- All rats survived to the end of the study.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No significant compound-related effects on growth or final mean body weights of rats were observed.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Feed consumption by exposed rats was similar to that by the control group
- Food efficiency:
- not specified
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- There were no statistically significant hematological changes.
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- There were no statistically significant clinical chemistry changes.
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Organ weights showed slight alterations in exposed animals. Male heart and liver weights showed significant dose-related negative trends (6–8% less than controls). Female right kidneyweights displayed trends toward significant increases in exposed animals (7–13% greater than controls).
These effects were not considered to be compound-related due to the small magnitude of the changes in conjunction with the lack of any clear
dose–response. - Gross pathological findings:
- not specified
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Histopathological lesions were considered spontaneous or incidental and not related to substance's exposure.
- Histopathological findings: neoplastic:
- not specified
- Description (incidence and severity):
- Effects on reproduction:
Sperm motility, number of sperm per mg cauda, total number of sperm per cauda, number of spermatids permg testis, and total number of spermatids per testis of animals exposed to the substance were similar to those of control animals.
Evaluation of vaginal smears did not reveal anysignifi cant differences among the females in the amount of time spent in different estrous
stages, the cycle length, or the number of cycles.
There was an increase in the number of females with regular cycles in the group exposed to 50000 ppm of substance. - Dose descriptor:
- NOAEL
- Effect level:
- 50 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- clinical biochemistry
- clinical signs
- food consumption and compound intake
- haematology
- histopathology: non-neoplastic
- mortality
- organ weights and organ / body weight ratios
- Remarks on result:
- other: expressed as Chromium picolinate monohydrate
- Dose descriptor:
- NOAEL
- Effect level:
- 4 243 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- clinical biochemistry
- clinical signs
- food consumption and compound intake
- haematology
- histopathology: non-neoplastic
- mortality
- organ weights and organ / body weight ratios
- Remarks on result:
- other: expressed as Chromium picolinate monohydrate
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 4 683 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- clinical biochemistry
- clinical signs
- food consumption and compound intake
- haematology
- histopathology: non-neoplastic
- mortality
- organ weights and organ / body weight ratios
- Remarks on result:
- other: expressed as Chromium 2-ethylhexanoate
- Critical effects observed:
- not specified
- Conclusions:
- In the experimental conditions of a test equivalent to OECD 408 guideline, subchronic exposure to Chromium picolinate monohydrate did not cause any toxic effects in rats.
Referenceopen allclose all
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 4 683 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- Klimish score: 2 (comparable to guideline study with acceptable restrictions)
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
- Dose descriptor:
- NOAEL
- 4 683 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- Extrapolation from 90-day oral toxicity study
Klimish score: 2 (comparable to guideline study with acceptable restrictions)
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
Justification for classification or non-classification
No classification according to Regulation (EC) 1272/2008 is required for Chromium 2-ethylhexanoate.
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.