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EC number: 226-408-0 | CAS number: 5395-50-6
- 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
Skin sensitisation
Administrative data
- Endpoint:
- skin sensitisation: in vivo (non-LLNA)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- March 2002 until April 2002
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 002
- Report date:
- 2002
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 406 (Skin Sensitisation)
- Version / remarks:
- 1992
- GLP compliance:
- yes (incl. QA statement)
- Type of study:
- guinea pig maximisation test
- Justification for non-LLNA method:
- The Guinea Pig Maximization Test (GPMT) has been carried out as an animal test to predict human sensitization for over a decade and is recommended by international test guidelines such as OECD. When this study was performed, the LLNA had just been developed.
Test material
- Reference substance name:
- Tetrahydro-1,3,4,6-tetrakis(hydroxymethyl)imidazo[4,5-d]imidazole-2,5(1H,3H)-dione
- EC Number:
- 226-408-0
- EC Name:
- Tetrahydro-1,3,4,6-tetrakis(hydroxymethyl)imidazo[4,5-d]imidazole-2,5(1H,3H)-dione
- Cas Number:
- 5395-50-6
- Molecular formula:
- C8H14N4O6
- IUPAC Name:
- 1,3,4,6-tetrakis(hydroxymethyl)-octahydro-[1,3]diazolo[4,5-d]imidazole-2,5-dione
- Test material form:
- liquid
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Batch No.of test material: 0767
- Source: BASF AG
- Purity: aqueous formulation: active ingredient 49.5 g/100 g
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature
- Stability under test conditions: Was guaranteed for the study period.
- Stability of the test substance in the solvent: was not determined
- Homogeneity: The test substance was homogeneous by visual inspection but was not investigated by analysis as it was applied in solution.
- physical state: liquid
OTHER:
- Correctness of the concentration: was confirmed by analysis
In vivo test system
Test animals
- Species:
- guinea pig
- Strain:
- Dunkin-Hartley
- Remarks:
- Hsd Poc: DH (SPF)
- Sex:
- female
- Details on test animals and environmental conditions:
- TEST ANIMALS
- Source: Harlan Winkelmann GmbH, Borchen, FRG
- Females nulliparous and non-pregnant: not specified
- Microbiological status of animals, when known: SPF
- Age at study initiation: about 6 - 7 weeks
- Weight at study initiation: 340 g - 379 g
- Housing: fully air-conditioned rooms with five animals per cage
- Diet: Kliba Labordiät, Provimi Kliba SA, Kaiseraugst, Switzerland, ad libitum
- Water: tap water, ad libitum
- Acclimation period: Seven days before the first test substance application
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE: 19.03.2002 - 19.04.2002
Study design: in vivo (non-LLNA)
Inductionopen allclose all
- Route:
- intradermal
- Vehicle:
- other:
- Remarks:
- 0.9% aqueous NaCl-solution
- Concentration / amount:
- 5% test substance in 0.9% aqueous NaCl-solution or in (1:1) Freund's adjuvant/0.9% aqueous NaCl-solution
- Day(s)/duration:
- Day 0
- Adequacy of induction:
- highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically
- Route:
- epicutaneous, occlusive
- Vehicle:
- water
- Concentration / amount:
- 75% test substance preparation in doubly distilled water
- Day(s)/duration:
- Day 7
- Adequacy of induction:
- highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically
Challenge
- No.:
- #1
- Route:
- epicutaneous, occlusive
- Vehicle:
- water
- Concentration / amount:
- 75% test substance in doubly distilled water
- Day(s)/duration:
- Day 21 for 24 hours
- Adequacy of challenge:
- highest non-irritant concentration
- No. of animals per dose:
- Test group: 10
Control group: 5 - Details on study design:
- RANGE FINDING TESTS
INTRADERMAL PRETEST:
Six intradermal injections in groups of two per animal were applied to each animal
A) front row: Two injections each of 0.1 ml Freund's adjuvant (Supplier: DIFCO LABORATORIES, Detrolt/Michigan, USA) without test substance emulsified with 0.9% aqueous NaCl-solution in a ratio of 1:1
B) middle row: Two injections each of 0.1 ml of 5% test substance in 0.9% aqueous NaCl-solution
C) back row: Two injections each of 0.1 ml Freund's adjuvant/0.9% aqueous NaCl-solution (1:1) with 5% test substance.
- Site of application: neck region
- No. of animals: Two per test substance concentration
- Reading: 24 h after the beginning of application
EPICUTANEOUS PRETEST.
2 x 2 cm gauze patches (6 Iayers surgical gauze Ph. Eur. from Lohmann GmbH & Co. KG) Gontaining 0.5 ml of the undiluted test substance /75% of the test substance formulation were applied to the skin of the flanks under an occlusive dressing. The dressing consisted of rubberized linen patches (4 x 4 cm from Russka), patches of Idealbinde (5 x 5 cm from Pfälzische Verbandstoff-Fabrik) and Fixomull® Stretch (adhesive fleece) from Beiersdort AG.
- Duration of exposure: 24 h
- Site of application: flank
- Number of test animals: Three per test substance concentration
- Readings: 1 h, 24 h, and 48 h after removal of the patches
MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: Six intradermal injections in groups of two per animal were given
- Control group:
A) front row: Two injections each of 0.1 ml Freund's adjuvant (Supplier: DIFCO LABORATORIES, Detrolt/Michigan, USA) without test substance emulsified with 0.9% aqueous NaCl-solution in a ratio of 1:1
B) middle row: Two injections each of 0.1 ml of the undiluted vehicle
C) back row: Two injections each of 0.1 ml of a 50% formulation of the vehicle without test substance emulsified with Freund's adjuvant/0.9% aqueous NaCl-solution (1:1)
- Site of application: neck region
- Frequency of applications: once
- Reading: 24 h after the beginning of application
- Test groups:
Same as for intradermal pretest, see above.
- epicutaneous induction:
- was carried out one week after intradermal induction
2 x 4 cm gauze patches (6 Iayers surgical gauze Ph. Eur. from Lohmann GmbH & Co.KG) containing 75% of the test substance formulation were applied to the 5km of the flank region under an occlusive dressing. The dressing consisted of rubberized linen patches (4 x 6 cm from Russka) and Fixomull® Stretch (adhesive fleece) from Beiersdorf AG.
1 ml of the test substance formulation was applied to each animal.
The control animais were not treated since the distilled water used as formulating agent was not expected to influence the result of the study.
- Duration of exposure: 48 hours
- Site of application: neck region, same area as in the case of the previous intradermal application
- Readings: 48 hours after the beginning of application
B. CHALLENGE EXPOSURE
- Duration of exposure: 24 hours
- Exposure period: challenge was performed 14 days after the epicutaneous induction
- Test groups and control group: were treated with the test substance formulation (control group 2 remained untreated)
- Site of application: intact flank
- Concentrations: 0.5 ml of 75% of the test substance formulation was applied to each animal.
- Readings: 24 and 48 hours afte rthe removal of the patch
2 x 2 cm gauze patches (6 Iayers surgical gauze Ph. Eur. from Lohmann GmbH & Co. KG) containing the test substance formulation were applied to the skin of the flank under an occlusive dressing. The dressing consisted of rubberized linen patches (4 x 4 cm from Russka), patches of Idealbinde (5 x 5 cm from Pfälzische Verbandstoff-Fabrik) and Fixomull® Stretch (adhesive fleece) from Beiersdorf AG. - Challenge controls:
- no
- Positive control substance(s):
- yes
- Remarks:
- Seperate study conducted twice a year
Results and discussion
- Positive control results:
- A positive control (reliability check) with a known sensitizer is not included in this study. However, a separate study is performed twice a year in the Iaboratory. The positive controls with alpha-Hexyl cinnamic aldehyde techn. 85% showed that the test system was able to detect sensitizing compounds under the Iaboratory conditions chosen.
In vivo (non-LLNA)
Resultsopen allclose all
- Key result
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- test chemical
- Dose level:
- 75% test substance preparation in doubly distilled water
- No. with + reactions:
- 10
- Total no. in group:
- 10
- Clinical observations:
- Details on local reactions given below
- Remarks on result:
- positive indication of skin sensitisation
- Key result
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- test chemical
- Dose level:
- 75% test substance preparation in doubly distilled water
- No. with + reactions:
- 9
- Total no. in group:
- 10
- Clinical observations:
- Details on local reactions given below
- Remarks on result:
- positive indication of skin sensitisation
Any other information on results incl. tables
Table 1: Results of the Challenge Test in treated group
|
Right flank middle: Form of application: Test substance 75% in doubly distilled water |
|
Animal number |
Findings 24 hours after removal of the patch |
Findings 48 hours after removal of the patch |
831 |
2 S |
2 S |
832 |
2 |
1 |
833 |
2 S |
2 S |
834 |
3 S |
3+ |
835 |
2 |
1 |
836 |
1 |
0 |
837 |
2 |
2 S |
838 |
2 S |
2 S |
839 |
2 |
2 S |
840 |
3 |
2 SS |
Assessment of the skin reactions:
0 = no visible change
1 discrete or patchy erythema
2 = moderate and confluent erythema
3 = intense erythema and swelling
S =scaling
SS = severe scaling
+ = eczematoid skin change
Applicant's summary and conclusion
- Interpretation of results:
- Category 1 (skin sensitising) based on GHS criteria
- Conclusions:
- Based on the evaluation criteria cited under 3.6. the results of this study show that the test substance has a sensitizing effect on the skin of the guinea pig in the Maximization Test under the test conditions chosen.
- Executive summary:
The test substance was tested for its sensitizing effect on the skin of the guinea pig in the Maximization Test based on the method of Magnusson and Kligman.
The test substance concentrations for the main test were selected based on the results of the pretest. The intradermal induction was performed with a 5% test substance preparation in 0.9% aqueous NaCI-solution or a 5% test substance preparation in Freund's adjuvant 1 0.9% aqueous NaCI-solution (1: 1) and the epicutaneous induction with a 75% test substance preparation in doubly distilled water. For the challenge a 75% test substance preparation in doubly distilled water was chosen. The study was initiated with 2 control groups and 1 test group.
The intradermal induction was performed on day 0 and the epicutaneous induction on day7.
A challenge was carried out 14 days after the epicutaneous induction. The intradermal induction caused moderate and confluent erythema and swelling or intense erythema and swelling at the injection sites of the test substance preparation in all test group animals. After the epicutaneous induction incrustation, partially open (caused by the intradermal induction) could be observed in addition to moderate and confluent
erythema and swelling in all test group animais. After the challenge discrete or patchy to intense erythema and swelling were observed
in addition to eczematoid skin change, scaling and severe scaling in all animais of the test group. The number of animals with skin findings after the challenge is summarized in the following table:
Challenge
Test substance 75% in doubly distilled water
24 h
48 h
Total
Control group 1
0/5
0/5
0/5
Control group 2*
No application of test substance
Test group
10/10
9/10
10/10
x/y: number of positive reactions/number of animais tested (reading at 24 h andlor 48 h after the removal of the patch)
*: control group 2 that had been intended for a potential 2nd challenge was not treated with the test substance, since a 2nd challenge was not necessary on the basis of the unambiguous results of the 1st challenge.
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