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EC number: 449-410-5 | CAS number: 18084-64-5
- 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
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 2003
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP Guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 004
- Report date:
- 2004
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- -
- EC Number:
- 449-410-5
- EC Name:
- -
- Cas Number:
- 18084-64-5
- Molecular formula:
- C36H44N4
- IUPAC Name:
- 1,4,7,10-Tetrabenzyl-1,4,7,10-tetraazacyclododecane
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Sulzfeld, Germany
- Weight at study initiation: males 169-212 g, females 144-176 g
- Acclimatization time: 14 days
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: 9 mg physiological saline + 0.85 mg Myrj 53 (polyoxyl-50-stearate) ad 1 ml aqua p.i.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Recovery of test substance in formulations varied between 79.5 and 99.4% of the nominal (analytically verified). This is deemed an acceptable level for the toxicological evaluation considering that ZK 118759 is an intermediate in a production process.
- Duration of treatment / exposure:
- 4 weeks
- Frequency of treatment:
- once daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 8, 50, and 200 mg/kg bw; from day 8 onwards the high dose was reduced to 100 mg/kg bw due to severe intolerance in all animals
Basis:
actual ingested
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily
BODY WEIGHT: Yes
- Time schedule for examinations: once daily
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean weekly diet consumption: Yes
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: in week 1 and 4 of the study in 5 males/females per group
HAEMATOLOGY: Yes
CLINICAL CHEMISTRY: Yes
URINALYSIS: Yes
NEUROBEHAVIOURAL EXAMINATION: Yes
OTHER:
- bone marrow examination on days 29 to 32 - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes - Statistics:
- DUNNETT test
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- 200/100 mg/kg bw: 4 male and 4 female animals died or were killed in moribund condition between days 8 and 15. Clinical findings manly observed in agonizing animals consisted of e.g. apathy, irregular respiration, gait anomalies, ruffled fur, diarrhea
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- 200/100 mg/kg bw: 4 male and 4 female animals died or were killed in moribund condition between days 8 and 15. Clinical findings manly observed in agonizing animals consisted of e.g. apathy, irregular respiration, gait anomalies, ruffled fur, diarrhea
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- 200/100 mg/kg bw: body weight loss between days 1 and 8 after administration of 200 mg/kg bw; after reduction to 100 mg/kg bw animals gained weight during weeks 2 and 3; during week 4 body weight again decreased in males
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- 200/100 mg/kg bw: reduced
- Water consumption and compound intake (if drinking water study):
- effects observed, treatment-related
- Description (incidence and severity):
- 200/100 mg/kg bw: reduced
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- 200/100 mg/kg bw: increase in neutrophil counts in males on day 28; slight increase in platelet count (n.s.) in males and females on day 28
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- 200/100 mg/kg bw: increase in AST in males (mainly due to animal no. 65), and decrease in total protein in males and females and gamma globuline in females on day 28
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- effects observed, treatment-related
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- 200/100 mg/kg bw: reduced thymus (males) and spleen (males and females) weights
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- 200/100 mg/kg bw: erosions and hyperkeratosis in the forestomach of one male; atrophy in prostate, seminal vesicles, thymus as well as lymphoid depletion in spleen and hypocellularity in the bone marrow was observed in single animals
- Details on results:
- 200/100 mg/kg bw: it is likely that the effects in the forestomach are due to local irritation; with exeption of the effects in the gastro-intestinal tract all other clinical, macroscopic and microscopic observations noted were considered to be secondary to emaciation, moribundity and stress:
Effect levels
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 8 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Dose descriptor:
- LOAEL
- Effect level:
- 50 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: see 'Remark'
- Dose descriptor:
- dose level:
- Effect level:
- >= 100 - <= 200 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: The daily dose of 200 mg/kg bw, reduced on day 8 to 100 mg/kg bw, led to severe organ damage and deaths in males and females.
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
- Executive summary:
In a 4 week oral toxicity study on 10 male and 10 female rats per group the daily oral administration of the test substance in doses of 8 and 50 mg/kg bw was well tolerated. The findings (increased sialorrhea; increased incidences of porphyrin deposits in the Harderian gland of male and female animals) in the 50 mg/kg bw dose group were judged as of minor toxicological relevance.
Signs of severe intolerance including deaths were found after 7 days of treatment with 200 mg/kg bw, whereafter the dose was reduced to 100 mg/kg bw. The signs of intolerance were reduced after reduction of dose, however, the animals still showed signs of toxicity such as reduced body weight, changes in blood parameters, atrophy of male sexual organs and changes in the lymphatic system. Microscopic lesions were noted in the stomach, thymus, spleen, lymph nodes and bone marrow of both sexes and in the male sexual organs. Severe forestomach lesions were observed in some animals which died or were sacrificed during administration of the high dose which may be caused by local irritation. It is suggested by the author of the study that the other substance related effects are secondary to these lesions and the subsequently degenerating status of the animals.
The NOAEL was established in this study with 8 mg/kg bw/day, while the findings at 50 mg/kg bw (LOAEL) were considered as of minor toxicological relevance. The daily dose of 200 mg/kg bw, reduced on day 8 to 100 mg/kg bw, led to severe organ damage and deaths in males and females.
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