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EC number: 206-019-2 | CAS number: 288-32-4
- 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
Basic toxicokinetics
Administrative data
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1985
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Meets accepted scientific standards and is described in sufficient detail.
Data source
Reference
- Reference Type:
- publication
- Title:
- Pharmacokinetic profile of imidazole 2-hydroxybenzoate, a novel nonsteroidal antiinflammatory agent.
- Author:
- Kuemmerle H-P et al.
- Year:
- 1 987
- Bibliographic source:
- Int J Clin Pharm Ther Toxicol 24: 581-597
Materials and methods
- Objective of study:
- toxicokinetics
Test guideline
- Qualifier:
- no guideline required
- Principles of method if other than guideline:
- This was a crossover study with four different groups for tablets and drops (single and multiple dosing). Each group consisted of 18 healthy,male volunteers between 18-25 years of age having within 20 % of their ideal body weight. Informed written consent was given after the
purpose of the study and the nature of the compound was explained. - GLP compliance:
- no
Test material
- Reference substance name:
- Imidazole
- EC Number:
- 206-019-2
- EC Name:
- Imidazole
- Cas Number:
- 288-32-4
- Molecular formula:
- C3H4N2
- IUPAC Name:
- 1H-imidazole
- Details on test material:
- ITF 182 (antiinflammatory drug) containing equimolar
quantities of imidazole and 2-hydroxybenzoate
Drug formulation
Tablets: Imidazole 2-hydroxybenzoate tablets were used containing 750 mg of the active compound, lactose, microcrystalline cellulose, carboxy-methylstarch, PVP and Mg stearate. The tablets were swallowed with tap water.
Drops (40 % solution, 40 drops = 800 mg) consisted of imidazole 2-hydroxybenzoate (400 mg), Glycerol (180 mg), Lemon flavor (0.02 ml), Saccharin sodium (10 mg), Sodium chloride (10 mg), purified water (0.52 ml)
Constituent 1
- Radiolabelling:
- no
Test animals
- Species:
- human
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- 4 groups of healthy male volunteers attended the study. Age ranged between 18-25 years. Body weight was within 20% of their ideal body
weight.
Administration / exposure
- Route of administration:
- other: oral tablet and/or drops
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- Male probands received 1 tablet (containing 750 mg drug) or 40 drops (containing 400 mg drug) in the morning after fasting overnight in the single dose study. In the crossover multiple dosing study they received 3 times one tablet (or 3 times 40 drops) for 3 days and one dosing inthe morning of the 4th day.
- Duration and frequency of treatment / exposure:
- see "details on exposure"
Doses / concentrations
- Remarks:
- Doses / Concentrations:
750 mg of drug (containing 248 mg imidazole), or 3 times 750 mg drug/day for 3 -4 days (10 treatments)
- No. of animals per sex per dose / concentration:
- not applicable
- Control animals:
- other: not applicable
- Details on dosing and sampling:
- Medical, biochemical, and hematological examination was performed before and after the study.
Blood sampling - single dosing
0, 15, 30, 45, 60, 75, 90, 105, 120, 135, 150, 165, 180, 195, 210, 225, 240, 360, 480 min and 24 h after administration
Blood sampling - multiple dosing
15, 30, 45, 60, 90, 120, 180, 240 min and 5, 6, 7, 8, 9, 10, 12 h, and thereafter every 12 hours. After the last dose on day 4 blood samples were taken at 0, 30, 60, 90, 120, 180, 240, 300, 360, min and 8, 24, 36 hours.
Urine sampling periods were 0-2, 2-4, 4-6, 6-8, 8-24, 24-36 and 36-48 h after single dosing.
In the multiple dosing study periods were 0-12 and 12-24 h for days 1, 2 and 3; for day 4 periods were the same as after single dosing.
Clinical chemistry included bilirubin, transaminases, alcaline phosphatase, LDH, gamma-GT, triglycerides, cholesterol, creatinine, uric acid, glucose, total protein, albumine, globuline, sodium, potassium, chloride.
Hematology included red blood cell count, hemoglobin, hematocrit, leucocytes including differential count, and platelets.
Imidazole was analyzed with HPLC. - Statistics:
- Descriptive statistics included calculation of means, standard deviations, medians, minima and maxima. The means and the p-values
between the application of imidazole and salicylic acid were calculated according to a paired Wilcoxon-test.
Results and discussion
- Preliminary studies:
- In a pilot study imidazole 2 - hydroxybenzoate was applied as a 5% gel (82 mg Imidazole in 5 g gel) to the forearm skin
(area about 25 cm²) of four male volunteers to determine possible systemic influence. Neither imidazole 2 - hydroxybenzoate nor
imidazole, salicylic acid or salicyluric acid were found in urine up to 12 hours after application. Plasma samples were not examined.
No adverse effects were seen either locally or systemically
Toxicokinetic / pharmacokinetic studies
- Details on absorption:
- The parameters clearly show that peak plasma concentrations were rapidly attained following single or multiple administration of tablets or
drops, thus indicating fast absorption. - Details on distribution in tissues:
- not applicable
- Details on excretion:
- Renal elimination of imidazole was approx. 10 to 15 % of the dose.
Toxicokinetic parametersopen allclose all
- Test no.:
- #1
- Toxicokinetic parameters:
- Cmax: 3.445 (mean; single dose tablets + drops)
- Test no.:
- #1
- Toxicokinetic parameters:
- Tmax: 0.75 (mean; single dose tablets + drops)
- Test no.:
- #1
- Toxicokinetic parameters:
- AUC: 14.145 (mean; single dose tablets + drops)
- Test no.:
- #1
- Toxicokinetic parameters:
- half-life 2nd: 2.73 (mean; single dose tablets + drops)
- Test no.:
- #2
- Toxicokinetic parameters:
- Cmax: 2.705 (mean; multiple dose tablets + drops)
- Test no.:
- #2
- Toxicokinetic parameters:
- Tmax: 0.595 (mean; multiple dose tablets + drops)
- Test no.:
- #2
- Toxicokinetic parameters:
- AUC: 8.165 (mean; multiple dose tablets + drops)
- Test no.:
- #2
- Toxicokinetic parameters:
- half-life 2nd: 1.99 (mean; multiple dose tablets + drops)
Metabolite characterisation studies
- Metabolites identified:
- yes
- Details on metabolites:
- The metabolites hydantoin and hydantoic acid were present in plasma and urine, although below the limit of detection as
no radioactive label was used.
Any other information on results incl. tables
Pharmacokinetic parameters of imidazole following oral
dosing (tablet and drops combined, means):
single dose multiple dose
------------------------------
Cmax (mg/l) 3.445 (tablet+drops) 2.705(tablet+drops)
Tmax (h) 0.75 (tablet+drops) 0,595(tablet+drops)
t1/2ß (h) 2.73 1.99 protein (% of dose) 5 - 15%
binding
bioavailability 138% 113%
---------------------------------------------
Legend:
Cmax maximum concentration (mg/l)
t1/2ß elimination half-life (h) No statistically significant difference was noted between tablets and drops treatment, only one p-value was < 0.01. Tolerability was good, no adverse reactions were noted. Topical application (gel 5%) did not show any systemic effects or adverse reactions. Local tolerability was reported to be very good.
Applicant's summary and conclusion
- Executive summary:
Pharmacokinetic parameters for imidazole are presented from single and multiple oral dose studies. No differences were noted between administration as tablet or as drops. Pharmacokinetic parameters were very similar in both the single and multiple dose
study. Imidazole is rapidly absorbed and excreted. Bioavailability is high, protein binding is low.
It is concluded from these data that bioaccumulation is unlikely.
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