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EC number: 429-750-0 | CAS number: 180898-37-7
- 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
Dermal absorption
Administrative data
- Endpoint:
- dermal absorption in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2002-08-15 to 2002-08-23
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: GLP study and although not following any guideline, the data are still scientifically acceptable and robust.
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 003
- Report date:
- 2003
Materials and methods
- Principles of method if other than guideline:
- The purpose of this study was to generate a kinetical profile of HR 02/N00002 Aq after single intravenous, oral and dermal (occlusive) administration of the test item to male Wistar rats. Additionally, the bioavailability of HR 02/N00002 Aq was calculated following oral and dermal application. Only data related to the kinetic behaviour following dermal treatment are presented in this section.
- GLP compliance:
- yes
Test material
- Reference substance name:
- -
- EC Number:
- 429-750-0
- EC Name:
- -
- Cas Number:
- 180898-37-7
- Molecular formula:
- C20H12N4O12S4.2Na
- IUPAC Name:
- disodium dihydrogen 2-[4-(5,7-disulfonato-1H-1,3-benzodiazol-2-yl)phenyl]-1H-1,3-benzodiazole-5,7-disulfonate
- Details on test material:
- - CAS name: 1H-Benzimidazole-4,6-disulfonic acid-2,2´-(1,4-diphenylene) bis, disodium salt
- Molecular formula: C20H12N4O12S4Na2
- Molecular weight: 674g/mol
- physical state: solid
Constituent 1
- Radiolabelling:
- no
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS - SPF Wistar rats
- Source: RCC Ltd, Laboratory Animal Services, CH-4414 Füllinsdorf, Switzerland
- Age at study initiation: approximately 9 weeks
- Weight and range at acclimatization/pretest: 186.5 - 267.8 grams (means 247.6 grams)
- Housing: individually in Makrolon type-3 cages with wire mesh topsand standardized softwood bedding ('Linocel' Schill AG, CH-4132 Muttenz/Switzerland, batch 02/0520701).
- Diet (ad libitum): pelleted standard Provimi Kliba 3433 (batch no. 34/02) rat maintenance diet (Provimi Kliba AG, CH-4303 Kaiseraugst / Switzerland)
- Water (ad libitum): community tap-water from Itingen
- Acclimation period: 6 days under test conditions after health examination. Only animals without any visible signs of illness will be used for the study
ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 3 °C
- Relative humidity: 30 - 70%
- Air changes: 10 - 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12/12 (music during the light period)
Administration / exposure
- Type of coverage:
- occlusive
- Vehicle:
- water
- Duration of exposure:
- 6 hours
- Doses:
- Nominal doses:
- 0 (group 1; intravenous administration),
- 100 mg/kg (group 5; dermal application), 400 mg/kg (group 6; dermal application), 800 mg/kg (group 7; dermal application)
- 8 mg/kg (group 8; intravenous administration)
Dose volumes:
- dermal: 7.51 mL/kg body weight
- intravenous: 1.5 mL/kg body weight
The dose volumes resulted by dividing the dose levels by the factor 1.065, which was supplied by the Sponsor as the density in g/mL of the 10% aqueous solution (stock solution).
Rationale for dose selection:
- information on dose levels were provided by the sponsor - No. of animals per group:
- Group 1: 10 males
Groups 5, 6 and 7: 10 males each
Group 8: 25 males - Control animals:
- yes
- Remarks:
- concurrent vehicle
- Details on study design:
- DOSE PREPARATION
The frequency of the preparation of dose formulation was once.
Preparation of the 10% aqueous solution (stock solution): the formulation consisted of approx. 79% bi-distilled water, approx. 11% NaOH (10% in water) and 10% of the test item. For a stock-solution with a total volume of 100 mL (as an example), about 6.5 mL NaOH-solution wre solved in 79 mL bi-distilled. Using a magnetic stirrer 10 g of the test item were added. The rest of the NaOH-solution (max. 3.5 mL) was added until the solution was clear. The final pH-value lied bewteen 7.0 and 8.0. If not all of the NaOH-solution was used, bi-distilled water, was added to a total volume of 100 mL.
Preparation of dilution 1, 2 and 3: dilution 1 was prepared by diluting one part of the stock-solution with the same amount of bi-distilled water. The preparation of dilution 2 was performed by diluting one part of dilution 1 (for example 10 mL) with 3 parts (for example 30 mL) of bi-distilled water. Dilution 3 was prepared by diluting one part of dilution 1 with 9 parts of bi-distilled water.
TEST SITE / SITE PROTECTION / USE OF RESTRAINERS FOR PREVENTING INGESTION / REMOVAL OF TEST SUBSTANCE
The rats were shaved on the back (approx. 3X3 cm) prior to application of the test item. After the treatment, the application site was covered with an occlusive membrane and fixed with an adhesive tape to guarantee occlusive conditions for the following 6 hours. After 6 hours, tape and the occlusive membrane were removed and the application site was cleaned with water using a sponge to avoid oral ingestion of remaining test item.
SAMPLE COLLECTION
- Collection of blood: blood samples (approx. 1 mL) were taken at different time points by retro-orbital bleeding into heparinized tubes under light isoflurane anesthesia. Control animals (group 1) were sampled at 24 hours after application. After terminal bleeding the animals were transferred to the histopathology group for necropsy. Plasma was prepared and stored at -17 to -23°C on dry ice for plasma level determination using a HPLC method.
- Necropsy: the animals were weighed and necropsied. The content of the stomach and the intestine was collected in all test item-treated animals. These samples were stored at -17 to -23°C on dry ice for possible further investigations.
ANALYSIS OF DOSE FORMULATIONS:
Concentration of the dose formulations was determined in samples taken directly after experimental start. The samples were stored deep frozen (-78 to -83°C) on dry ice. The analyses was perfromed using a HPLC method. - Details on in vitro test system (if applicable):
- not applicable
Results and discussion
- Signs and symptoms of toxicity:
- no effects
- Dermal irritation:
- not specified
- Absorption in different matrices:
- Single dermal administration:
- throughout all dermal groups (single administration at the dose levels 100, 400 and 800 mg/kg body weight) similar Tmax values (6 —8 hours), similar half-lives (13.8-16.4 hours) and a similar MRT (22.1 — 25.6 hours) were found.
- dose dependency: after single dermal administration at about 4 and 2 times higher dose levels (from 100 to 400 to 800 mg/kg), taking into account the high standard deviations and the extreme low levels at 100 mg/kg, AUC values increased similarly about 7 and 3 times; at about 8 and
2 fold higher Cmax values were found at similar half-lives (13.8-16.4 hours).
Single intravenous administration:
- the maximal observed average plasma concentration (Cmax) at 5 min (0.08 hours) post administration (Tmax) was 12965 ng/ml;
- after PK analyses, the Cmax intercept amounted to 17208 ng/ml;
- the AUC 04 value was 81691 ng*h/mI and the average level of HR 02/N00002 decreased to about 3.8 % of the observed Cmax at 24 hrs post dose.
Due to the different dose levels between the dermal groups against the i.v. group, values are compared alter dose normalisation. As compared to the normalized AUC value after i.v. administration (100 %) the percentage absorbed after dermal administration amounted to 0.1-0.3%.
Any other information on results incl. tables
Viability / mortality:
All animals survived until scheduled sacrifice.
Clinical signs (daily):
No clinical signs were evident during the blood, urine and feces sampling period of up to 48 hours.
Body weights:
The body weights were determined for the automatically calculated (TecTox Release 7.0) dose volumes.
Treatment (mean weight):
Group 1: 237 g
Group 5: 261 g
Group 6: 240 g
Group 7: 244 g
Group 8: 244 g
Applicant's summary and conclusion
- Conclusions:
- After single dermal administration of the test item at dose levels of 100 to 800 mg/kg to the skin of male Wistar rats, a linear dose dependency of plasma levels was found, taking into account the large standard deviations and the low values at 100 mg/kg.
Based on AUC comparison between i.v. administration (100% absorbed) and dermal applictaion, the percentage of absorbed test item amounted to about 0.1-0.3 % after dermal administration.
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