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EC number: 433-460-1 | CAS number: 210880-92-5
- 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: dermal
Administrative data
- Endpoint:
- short-term repeated dose toxicity: dermal
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 13 Apr 1999 - 13 Oct 2000
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 000
- Report date:
- 2000
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
- Version / remarks:
- adopted 1981
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- -
- EC Number:
- 433-460-1
- EC Name:
- -
- Cas Number:
- 210880-92-5
- Molecular formula:
- C6H8ClN5O2S
- IUPAC Name:
- (E)-N'-[(2-chloro-1,3-thiazol-5-yl)methyl]-N-methyl-N''-nitroguanidine
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- The rat is a common species for toxicological testing and recommended by the guideline.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Inc., North Carolina, USA
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: approximately 8 weeks
- Weight at study initiation: 240 - 317 g (males), 171 - 213 g (females)
- Fasting period before study: not applicable
- Housing: individually in suspended, stainless steel cages
- Diet: Certified rodent diet (#8728C, Harlan Teklad), ad libitum
- Water: tap water, ad libitum
- Acclimation period: 16 days, collared for 18 h/day for 5 days before treatment
DETAILS OF FOOD AND WATER QUALITY: Diet and water was routinely checked, no signs of contaminants were found
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 26
- Humidity (%): 30 - 70
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 29 Apr To: 28 May 1999
Administration / exposure
- Type of coverage:
- occlusive
- Vehicle:
- water
- Details on exposure:
- TEST SITE
- Area of exposure: 5x5 cm
- % coverage: 10
- Type of wrap if used: gauze pad, fixed with surgical micropore tape and wrapped with Vetwrap®.
- Time intervals for shavings or clipplings: one week prior to initial treatment, one day prior to first treatment and whenever neccessary thereafter
REMOVAL OF TEST SUBSTANCE
- Washing (if done): sites were wiped with water-moistened paper tissues/towels
- Time after start of exposure: 6h (when exposure was terminated)
TEST MATERIAL
- Amount applied (volume or weight with unit): weight was based on the body weight of the test animal
- Constant volume or concentration used: no
- For solids, paste formed: no, but application site was moistenend with water
VEHICLE
- Justification for use: water
- Amount(s) applied (volume or weight with unit): 1 mL + water for moisturizing application site
USE OF RESTRAINERS FOR PREVENTING INGESTION: yes (flexible plastic collars) - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The stability of the test material was confirmed using HPLC. It was verified that TI-435 was stable for at least 53 weeks when stored in a refrigerator set to maintain 2 to 8 °C.
- Duration of treatment / exposure:
- 6 h/day for 29 days
- Frequency of treatment:
- 7 days/week
Doses / concentrationsopen allclose all
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Dose / conc.:
- 300 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: the low dose was chosen to cause no toxicity, the mid dose should cause an intermediate level of toxicity and in the high dose toxic effects should be observed but no severe skin effects or mortality meaningful evaluation
- Positive control:
- no
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- parameters checked: twice daily: mortality and moribundity, signs of poor health or abnormal behavior, once daily: indications of a toxic effect
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly
- parameters observed included changes in skin, fur, eyes, and mucous membranes; occurrences of secretions and excretions; and autonomic activity (e.g., lacrimation, piloerection, pupil size, unusual respiratory pattern). Changes in posture and reactivity to handling and the presence of clonic or tonic movements, stereotypies (e.g., excessive grooming, circling) or bizarre behavior (e.g., self-mutilation, walking backwards) and gait abnormalities.
DERMAL IRRITATION: Yes
- Time schedule for examinations: scored daily (modified Draize method)
BODY WEIGHT: Yes
- Time schedule for examinations: one day before treatment (-Day 1), on Day of first treatment (Day 1), and on Days 7, 14, 21, 28, and 30 (day of necropsy)
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes
WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: before initiation of treatment and during Week 4
- Dose groups that were examined: all
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Week 5 (at termination)
- Anaesthetic used for blood collection: Yes (sodium pentobarbital)
- Animals fasted: Yes, overnight
- How many animals: all animals
- Parameters checked: red blood cell (erythrocyte) count, hemoglobin, hematocrit, mean cell volume, mean cell hemoglobin, mean cell hemoglobin concentration, platelet count, white blood cell (leukocyte) count, differential blood cell count (segmented neutrophil count, lymphocyte count, monocyte count, eosinophil count, basophil count), blood cell morphology, reticulocyte count, activated partial thromboplastin time and prothrombin time
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Week 5 (at termination)
- Animals fasted: Yes, overnight
- How many animals: all animals
- Parameters checked:
glucose, urea nitrogen, creatinine, total protein, albumin, globulin, albumin/globulin ratio, total cholesterol, total bilirubin, alkaline phosphatase, alanine aminotransferase, gamma glutamyltransferase, aspartate aminotransferase, calcium, inorganic phosphorus, magnesium, sodium, potassium, chloride, creatine kinase and sorbitol dehydrogenase
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: once during Week 4 prior to dosing
- Dose groups that were examined: all
- Battery of functions tested: expanded clinical observation during handling and in an open field and for sensory activity, grip strength and motor activity.
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
All surviving animals were anesthetized with sodium pentobarbital after blood collection and sacrificed. Necropsy included a macroscopic examination of the external features of the carcass; external body orifices; the abdominal, thoracic, and cranial cavities; and organs/tissues.
Organ weights were recorded for adrenals, brain, epididymis, kidney, heart, liver, ovaries, spleen, testis, thymus and uterus.
HISTOPATHOLOGY: Yes
- Tissues were collected and preserved in 10% formalin with the following deviations:
* Fixed in Davidson's, ** preserved lobes were perfused with 10% neutral-buffered formalin, *** Fixed in Bouin's, subsequently rinsed with tap water, and transferred to 70% alcohol.
- Tissues collected: adrenal, aorta (thoracic), bone [femur (articular surface of the distal end) and sternum], bone marrow (femur and sternum), brain, cecum, colon, duodenum, epididymis, esophagus, eyes* (2, retina, optic nerve), gross lesions, heart, ileum, jejunum, kidneys, larynx, liver, lung**, mammary gland (female), lymph node (mesenteric), nasal turbinates***, ovaries, pancreas, pharynx***, pituitary, prostate, rectum, salivary gland (mandibular), sciatic nerve, seminal vesicle, skin (treated dorsal, untreated dorsal and untreated ventral inguinal), spinal cord (cervical, thoracic, and lumbar), spleen, stomach, testis***, thigh musculature thymus throidy (with parathyroid), trachea, urinary bladder and uterus
- embedding media: paraffin
- staining: hematoxylin and eosin
- animals: control and high-dose groups and from each animal that died or was sacrificed unscheduled, macroscopic lesions and skin (treated and untreated) were also examined microscopically from each animal in the low- and mid-dose groups. - Statistics:
- Homogenity of variance was checked with Levene's test. If heterogenity of of variance at p < 0.05, transformations were used to stabilize the variance. Comparison tests took variance of heterogeneity into consideration.
To analyze grip strength, motor activity, body weights, body weight changes, food consumption, food efficiency, continuous clinical pathology values, and organ weight data, an One-way analysis of variance, ANOVA, was used. If a significant difference was found, Dunnett's t-test was used for control versus treated group comparisons.
Significance was set at p ≤ 0.05
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- There was no difference observed between control and treatment animals. That also included the expanded clinical observations during neurobehavioral testing.
- Dermal irritation:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no test material-related dermal observations noted. A single incidence of very slight edema was noted at the application site in a female given 300 mg/kg bw/day. However, since it was a sporadic finding and no dose-response was found, the observation was considered incidental.
Summarized data can be found in Attachment 1 in the attached background material. - Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- One female receiving 100 mg/kg bw/day and one female receiving 1000 mg/kg bw/day died prematurely (Day 15). In both cases, cause of death was not determinable but no treatment-related signs were found and the deaths were therefore considered incidental.
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Only incidental differences in body weight and body weight gains were observed. The only finding was reduced body weight changes in males treated with 1000 mg/kg bw/day in the first week (-61%) but this was not seen in any other week. However, the lower body weight gain in the firt week resulted in overall lower body weight gain in males in this treatment group throughout the study (-20% for Day 1 to 28). Sice this was due to the finding in Week 1, it was also considered incidental. In females, no differences were found for body weight and body weight gain.
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- Sporadical differences in food consumptions were found for both sexes at the mid and high-dose treatment group. However, the differences ranged from -10.1 to +11% and no dose- or time-dependency could be established. they were therefore considered incidental.
- Food efficiency:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Corresponding to the reduced body weight gain seen in week 1 for males (1000 mg/kg bw/day), the food efficiency was also reduced. As for the finding in body weight change it was considered incidental. Additionally, food efficiency in the 300 mg/kg bw/day treatment group (males) was reduced in Week 2 but this was the only interval in which this was observed and it was therefore considered incidental.
- Water consumption and compound intake (if drinking water study):
- not examined
- Description (incidence and severity):
- not applicable
- Ophthalmological findings:
- no effects observed
- Description (incidence and severity):
- There were no differences between control and treatment groups.
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- There were no differences between control and treatment groups.
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- There were no differences between control and treatment groups.
- Endocrine findings:
- not examined
- Description (incidence and severity):
- not applicable
- Urinalysis findings:
- not examined
- Description (incidence and severity):
- not applicable
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- There were no differences between control and treatment groups.
- Immunological findings:
- not examined
- Description (incidence and severity):
- not applicable
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- There were no differences between control and treatment groups.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- There were no differences between control and treatment groups.
- Neuropathological findings:
- no effects observed
- Description (incidence and severity):
- There were no differences between control and treatment groups.
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- There were no differences between control and treatment groups.
- Histopathological findings: neoplastic:
- no effects observed
- Description (incidence and severity):
- There were no differences between control and treatment groups.
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- > 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No effects observed
Target system / organ toxicity
- Critical effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- The effect of repeated dermal application of the test substance was analyzed in a 28 day study in rats under OECD guideline 410 and GLP. Under the conditions of the test, no toxicity was observed after repeated dermal treatment with the test substance, so that the NOAEL was set at 1000 mg/kg bw, the highest concentration tested.
The study was done according to OECD guideline 410 and under GLP.
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