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EC number: 601-147-9 | CAS number: 111988-49-9
- 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:
- 19 Sep - 2 Nov 1995
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 997
- Report date:
- 1997
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:
- 3-(2-chlor-5-pyridyl-methyl)-cyanimino-1,3-thiazolidin
- EC Number:
- 601-147-9
- Cas Number:
- 111988-49-9
- Molecular formula:
- C10H9ClN4S
- IUPAC Name:
- 3-(2-chlor-5-pyridyl-methyl)-cyanimino-1,3-thiazolidin
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on species / strain selection:
- Commonly used specied for toxicological studies and recommended by the guideline.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Harlan Winkelmann GmbH, Borchen, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 7 - 8 weeks (males), 14 weeks or older (females)
- Weight at study initiation: 222 - 256 g (males), 208 - 235 g (females)
- Fasting period before study: not applicable
- Housing: individually in polycarbonate cages type IIA with low-dust wood shavings, during acclimation in groups of 3 or 5 in polycarbonate cages type III
- Diet: Altromin 1324 Diet for Rats and Mice (Altromin GmbH and Co. KG in Lage, Germany), ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 7 days
DETAILS OF FOOD AND WATER QUALITY: feed and water were regularly analyzed for contaminations
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2.0
- Humidity (%): approx. 55 ± 5
- Air changes (per hr): 15 - 20
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Type of coverage:
- semiocclusive
- Vehicle:
- unchanged (no vehicle)
- Remarks:
- only moistened by tap water
- Details on exposure:
- TEST SITE
- Area of exposure: 5.5 x 5.5 cm = 30.25 cm²
- % coverage: over 10%
- Type of wrap if used: gauze layer ("Hansapor steril" patch), secured in place using ,,Peha-Haft" cohesive stretch tape (8 x 23 cm), at weekends, a ,"Fermoflex®" dressing was used additionally
- Time intervals for shavings or clippings: one day before first day of treatment and twice weekly afterwards
REMOVAL OF TEST SUBSTANCE
- Washing: with soap and water
- Time after start of exposure: 6 h
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): the amount was weighed out onto the gauze layer ("Hansapor steril" patch)
- Constant volume or concentration used: no
- For solids, paste formed: no, the powder was only moistened with tap water
USE OF RESTRAINERS FOR PREVENTING INGESTION: yes (mobility of the rats was impaired by a ,,Lomir Biomedical Inc." rat jacket) - Analytical verification of doses or concentrations:
- no
- Details on analytical verification of doses or concentrations:
- Analytical verification was not performed because the substance was applied undiluted and only moistened with water immediately before application.
- Duration of treatment / exposure:
- 4 weeks treatment, 2 weeks recovery
- Frequency of treatment:
- First three weeks: 5 days/week, 4th week: 7 days/week
Doses / concentrationsopen allclose all
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Remarks:
- nominal dose applied to males and females of the main group, corresponding to 4.4-6.0 mg/cm²
- Dose / conc.:
- 300 mg/kg bw/day (nominal)
- Remarks:
- nominal dose applied to males and females of the main group, corresponding to 4.1-5.5 mg/cm²
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Remarks:
- nominal dose applied to males and females of the main group, corresponding to 6.7-9.5 mg/cm²
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Remarks:
- nominal dose applied to males and females of the recovery group, corresponding to 7.0-9.4 mg/cm²
- No. of animals per sex per dose:
- 5 (main and recovery groups)
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The doses were based on a previously conducted two-week dose range-finding study in male and female rats. At 1000 mg/kg bw/day, slightly lower feed consumption in Week 1 (males and females), decreased lymphocyte counts and increased counts of segmented neutrophils (females), increased cholesterol (males) and decreased triglyceride levels (females), increased liver weight (males) and lower thymus weights (males and females), and spleens of dark-red color (females) were observed. On the application area neither erythema nor edema of the skin were observed.
- Rationale for selecting satellite groups: reversibility of the observations should be assessed
- Post-exposure recovery period in satellite groups: 2 weeks - Positive control:
- no
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily, (once daily at weekends and on public holidays)
- Cage side observations: Mortality, moribund state, body surfaces and orifices, posture, general behavior, breathing and excretory products, including irritation at the dose site
DETAILED CLINICAL OBSERVATIONS: No data
DERMAL IRRITATION: Yes (scoring according to Draize, including swelling)
- Time schedule for examinations: daily before treatment
BODY WEIGHT: Yes
- Time schedule for examinations: weekly, starting on Day 0 before before the first application
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: No
WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Day 23/24 (main groups) and 41/42 (recovery groups) for glucose, on day of necropsy (Day 28 for main groups, Day 43 and 44 for recovery groups) for all other parameters
- Anesthetic used for blood collection: Yes (diethyl ether anesthesia, for all parameters except glucose) / No (glucose)
- Animals fasted: Yes (for glucose determination, blood taken from the distal vessels of the tail prior to necropsy) /No (everything else, blood taken by heart puncture at necropsy)
- How many animals: all animals
- Parameters checked: Erythrocyte count, hemoglobin, hematocrit, hepato quick, leucocyte count, mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume erythrocytes (MCV), thrombocytes (THROMBO) and differential blood count (eosinophils, lymphocytes, monocytes, normal RBC, segmented neutrophils).
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: see above
- Animals fasted: No
- How many animals: all animals
- Parameters checked: alanine aminotransferase (ALAT), albumin, alkaline phosphatase (APh), aspartate aminotransferase (ASAT), bilirubin total, cholesterol, creatinine, calcium, chloride, gamma-glutamyltransferase (GGT), glutamate dehydrogenase (GLDH), potassium, sodium, inorganic phosphorus, protein, triglycerides, urea and glucose.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- Surviving animals were sacrificed by exsanguination under deep ether anesthesia.
GROSS PATHOLOGY: Yes
The following organs were weighed: adrenal glands, brain, heart, kidneys, liver, lung, spleen, testes and thymus.
HISTOPATHOLOGY: Yes
The following organs were immersion-fixed in Davidson's solution: Adrenal glands, brain (cerebrum, cerebellum, pons/medulla), heart, kidneys, liver, lung, skin (treated and untreated), spleen, testes, thymus, thyroid gland with parathyroid gland, physical identifier (tattooed ears), and all organs or tissues with macroscopic findings.
One liver lobe and lungs (fixed by instillation of 4% aqueous formaldehyde solution) of all rats were immersion-fixed in 4% aqueous formaldehyde solution.
- embedding media: paraplast
- Thickness: 5 µm
- Staining: hematoxylin and eosin (H&E), cryo-cuts obtained from the formalin-fixed liver lobe were stained with Oil-Red-O (ORO)
Histopathological examination was limited to the following organs/groups:
Liver (HE), thyroid gland and necropsy findings: all animal groups (including the recovery group)
Skin treated and untreated, liver (ORO): main groups (0, 100, 300, 1000 ppm, no recovery groups)
Adrenal glands, brain, heart, kidneys, lungs, spleen, testes, thymus: control and high dose group (main group only) - Statistics:
- The quantitative results for individual animals were used to calculate arithmetic group means and standard deviations. The results for the groups that received the test substance were compared with those for the control group and significant differences indicated by "+" for p < 0.05 and "++" for p < 0.01. In case of numbers of values too low to calculate test statistics this is indicated by "0".
The Dunnett test was used for body weight, body weight gain, feed consumption and organ
weight data (relative organ weights subsequent to logarithmic transformation).
If possible, an ANOVA was used followed by a Dunnett's test for parametric measurements. For non-parametric data, a Kruskal-Wallis test followed by adjusted U test was performed.
Macro- and micropathological data were processed with the PATHDATA program, version 3.6. B.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No significant difference between control and treatment group was observed.
- Dermal irritation:
- no effects observed
- Description (incidence and severity):
- The skin redness and skin thickness were comparable between control and treated animals.
- Mortality:
- no mortality observed
- Description (incidence):
- not applicable
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No significant difference between control and treated animals was observed.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- - 1000 ppm: transient decrease of feed intake in females in the first week compared to controls
This significant transient decrease could also be a sign of stress caused by the treatment rather than the test substance so this finding is ambiguous. As the effect is transient, it is not considered toxicologically relevant. The statistically significantly increased values for feed consumption in g/kg body weight and day that was recorded for males of the recovery group are considered incidental and a result of the slightly lower body weights of these animals, as the mean feed intakes per animal and day show no abnormalities.
Summarized data can be found in Attachment 1 in the attached background material. - Food efficiency:
- not examined
- Description (incidence and severity):
- not applicable
- Water consumption and compound intake (if drinking water study):
- not examined
- Description (incidence and severity):
- not applicable
- Ophthalmological findings:
- not examined
- Description (incidence and severity):
- not applicable
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- There were no significant differences between control and treatment groups.
- Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Statistically significant differences were observed in males of the main groups regarding cholesterol (100 and 300 mg/kg bw/day, -18.1 and -16.7%, respectively), creatinine (-13% for 100 mg/kg bw/day and -14.8% for 300 mg/kg bw/day), protein (-4.5% for 100 mg/kg bw/day and -6.3% for 300 mg/kg bw/day), albumin (-8.5% for 300 mg/kg bw/day) and glucose (-7.9% for 300 mg/kg bw/day) compared to controls. They are considered as incidental as they are not dose related and were observed only in one sex. At the end of the recovery period no toxicologically significant changes compared to controls were observed, the only statistically significant observations was slightly decreased creatine in males, considered incidental.
- Endocrine findings:
- not examined
- Description (incidence and severity):
- not applicable
- Urinalysis findings:
- not examined
- Description (incidence and severity):
- not applicable
- Behaviour (functional findings):
- not examined
- Description (incidence and severity):
- not applicable
- Immunological findings:
- not examined
- Description (incidence and severity):
- not applicable
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- - 1000 mg/kg bw/day: increased absolute (+12.7%/+13.5%) and relative (+17.2%/+11.9%) liver weights (males/females) in the main group. This finding was reversible in the recovery group, so that this observation can therefore be seen as part of an adaptive process rather than a toxicologically relevant effect.
Summarized data can be found in Attachment 2 of the attached background material. - Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No significant differences between control and treatment groups were observed.
- Neuropathological findings:
- not examined
- Description (incidence and severity):
- not applicable
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- - 300 mg/kg bw/day: liver hypertrophy of centrilobular hepatocytes associated with a more homogeneously structured cytoplasm (3/5 males) in the main group compared to controls. At the end of recovery period these changes were still observed in males that received 1000 mg/kg bw/day (2/5).
- 1000 mg/kg bw/day: liver hypertrophy of centrilobular hepatocytes associated with a more homogeneously structured cytoplasm (5/5 males, 3/5 females) compared to controls. At the end of the recovery period, this was still observed in males (2/5) but not in females. In the main group, hypertrophy of the follicular epithelium in thyroids (3/5 males, 2/5 females, all compared to controls) was observed. These findings were reversible for females but only partially in males, since hypertrophy of the follicular epithelium in thyroids occurred in 1/5 males of the recovery group.
The changes are considered to be toxicologically relevant.
Summarized results can be found in Attachment 3 in the attached background material. - Histopathological findings: neoplastic:
- not examined
- Description (incidence and severity):
- not applicable
- Other effects:
- not examined
- Description (incidence and severity):
- not applicable
Effect levels
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- systemic
- Effect level:
- 100 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: No adverse effects occurred at this dose level.
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- systemic
- Effect level:
- 300 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: No adverse effects occurred at this dose level.
- Key result
- Dose descriptor:
- LOAEL
- Remarks:
- systemic
- Effect level:
- 300 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- histopathology: non-neoplastic
- Key result
- Dose descriptor:
- LOAEL
- Remarks:
- systemic
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- histopathology: non-neoplastic
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- dermal, local
- Effect level:
- >= 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effects observed up to this dose level.
- Remarks on result:
- other: Highest dose tested
Target system / organ toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 100 mg/kg bw/day (nominal)
- System:
- hepatobiliary
- Organ:
- liver
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- no
Applicant's summary and conclusion
- Conclusions:
- The study was conducted according to OECD guideline 410 and under GLP. Under the conditions of the test, the test substance caused liver and thyroid changes when applied dermally for four weeks in males and females. The changes in liver and thyroid were fully reversible for females but only partly reversible in males within the two-week recovery period. No dermal irritation was seen. Thus, 1000 mg/kg bw/day is regarded as the NOAEL for local skin effects and the NOAEL for systemic effects is 100 and 300 mg/kg bw for males and females, respectively.
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