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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
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 26 May - 19 Jun 1997
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Remarks:
- Deviations from current guideline version (e.g. ano-genital distance was not determined). For details please refer to materials and methods section.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 998
- Report date:
- 1998
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- adopted 2018
- Deviations:
- yes
- Remarks:
- No blood sampling for analysis of T3, T4 and TSH, weight of thyroid gland not determined, no histopathology of thyroid gland. Anogenital distance of foetuses not determined. Temperature slightly out of range (18 to 26°C instead of 19 to 25°C).
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- adopted 1981
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OTS 798.4900 (Prenatal Developmental Toxicity Study)
- 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
- Remarks:
- Crl:CD R BR VAF/PlusR
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Portage, Michigan
- Age at study initiation: approx. 10 weeks
- Weight at study initiation: 201 - 231 g
- Housing: individually (except during cohabitation period)
- Diet: Certified Rodent Diet #5002 (PMI Feeds, St. Louis, Missouri), ad libitum
- Water: reverse osmosis water with chlorine added as a bacteriostat, ad libitum
- Acclimation period: six days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 26
- Humidity (%): 30 - 70
- Air changes (per hr): min. 10
- Photoperiod (hrs dark / hrs light): 12 / 12
IN-LIFE DATES: From: 26 May To: 19 Jun 1997
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: aqueous 0.5% methylcellulose
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Suspensions of test substance were prepared weekly at the given concentrations. The test substance was considered 100% pure for the purpose of dosage calculations.
VEHICLE
- Concentration in vehicle: 1, 4, or 12.5 mg/mL
- Amount of vehicle: 10 mL/kg bw
- Lot/batch no.: 56H0439 - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples were taken at the beginning and end of the dosing period for concentration analyses. No test item contamination of the vehicle was observed. All samples for the 1, 4, and 12.5 mg/mL concentrations (10, 40 and 125 mg/kg bw/day dosages, respectively) were within 10% range of target concentration, except for the 1 mg/mL concentration from the first preparation, which was 15% above target (range: 98.4 - 115 %). Homogeneity of the test item in the vehicle was demonstrated in samples from the top, middle and bottom of a sample formulation. The relative standard deviation was not greater than 3.3% and the test item therefore considered homogenously distributed in the samples. Stability of the test item in the vehicle was established for up to 14 days (-3% deviation from Day 0).
- Details on mating procedure:
- - Impregnation procedure: cohoused
- M/F ratio per cage: 1/1
- Length of cohabitation: 4 days
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy (DG 0) - Duration of treatment / exposure:
- From gestation day (DG) 6 until DG 19.
- Frequency of treatment:
- Daily
- Duration of test:
- From DG 0 until DG 20
Doses / concentrationsopen allclose all
- Dose / conc.:
- 10 mg/kg bw/day
- Dose / conc.:
- 40 mg/kg bw/day
- Dose / conc.:
- 125 mg/kg bw/day
- No. of animals per sex per dose:
- 25
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: dosages were selected on the basis of a dosage-range study
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Before and one hour after dosage (DGs 6-19) and on DG 20. Rats were also observed for viability at least twice daily.
- Cage side observations checked: clinical observation of effects of the test item, abortions, premature deliveries, and deaths
BODY WEIGHT: Yes
- Time schedule for examinations: on DG 0, daily during dosage period (DG 6-19) and on the day of Caesarean-section (DG 20).
FOOD CONSUMPTION: Yes
- Food consumption was determined on DGs 0, 6, 9, 12, 15, 18, and 20.
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Gross necropsy of the thoracic, abdominal and pelvic viscera was performed. To confirm pregnancy status, uteri from rats that appeared nonpregnant were stained with 10% ammonium sulfide. Tissues with gross lesions were preserved in neutral buffered 10% formalin for possible future evaluation. All other maternal tissues were discarded. - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: distribution of implantation sites, live and dead foetuses - Blood sampling:
- - Plasma: No
- Serum: No - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter (those used for soft tissue examination) - Statistics:
- Clinical observation and other proportion data were analyzed using the Variance Test for Homogeneity of the Binomial Distribution.
Continuous data (e.g., maternal body weights, body weight changes, feed consumption values and litter averages for percent male foetuses, percent resorbed conceptuses, foetal body weights, foetal anomaly data and foetal ossification site data) were analyzed using Bartlett's Test of Homogeneity of Variances and the Analysis of Variance, when appropriate [i.e., Bartlett's Test was not significant (p>=0.05)]|. If the Analysis of Variance was significant (p<=0.05), Dunnett's Test was used to identify the statistical significance of the individual groups. If the Analysis of Variance was not appropriate [i.e., Bartlett's Test was significant (p<=0.05)], the Kruskal-Wallis Test was used, when less than or equal to 75% ties were present. In cases where the Kruskal-Wallis Test was statistically significant (p<=0.05), Dunn's Method of Multiple Comparisons was used to identify the statistical significance of the individual groups. If there were greater than 75% ties, Fisher's Exact Test was used to analyze the data.
Count data obtained at Caesarean-sectioning of the dams were evaluated using the procedures described above for the Kruskal-Wallis Test.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Clinical observations included localized alopecia on the limbs, underside, back and/or neck, chromorhinorrhea and missing/broken incisors. All observations were considered non-treatment related, since the incidences were not dosage-dependent or the observations occurred in only 1 or 2 rats and/or are common events in the laboratory environment.
- Dermal irritation (if dermal study):
- not examined
- Description (incidence and severity):
- Not applicable
- Mortality:
- no mortality observed
- Description (incidence):
- Not applicable
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- No effect on body weight or body weight changes was observed at the 10 mg/kg bw/day dosage level. In the 40 mg/kg bw/day group, body weight gain was significantly decreased (p<=0.01) compared to control. In the 125 mg/kg bw/day group a significant weight loss (p<= 0.01) was observed on DGs 6 to 9 and a significantly reduced weight gain (p<=0.01) in the entire dosage period (DGs 6 to 20) as well as through the entire gestation period (DGs 0 to 20). Therefore, average body weights were significantly reduced (p<=0.05 or p<=0.01) on DGs 7 through 20. Please refer to attachment 01.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Feed consumption (absolute+relative) was lower (p<=0.05 or p<=0.01) in 40 mg/kg bw/day dosed rats compared to control on DGs 6 to 9. In the 125 mg/kg bw/day group, feed consumption was decreased (p<=0.05 or p<=0.01) throughout the complete exposure period (calculated as DGs 6 to 20) and entire gestation period (calculated as DGs 0 to 20). No effect on food consumption was noted in the 10 mg/kg bw/day group. Please refer to attachment 02.
- 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:
- not examined
- Description (incidence and severity):
- Not applicable
- Clinical biochemistry findings:
- not examined
- Description (incidence and severity):
- Not applicable
- 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, non-treatment-related
- Description (incidence and severity):
- Gravid uterine weights did not significantly differ among the four groups.
- Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Necropsy findings consisted of a portion of the intermediate lobe of the liver adhered to the diaphragm, which was thin at the point of adhesion, for one 10 mg/kg/day dosage group dam (16230); slight dilation of the pelvis of each kidney for one 40 mg/kg/day dosage group dam (16261) and a dark red area on the dorsal surface of the left apical lobe of the lung for one 125 mg/kg/day dosage group darn (16292). All necropsy findings were considered unrelated to the test substance because each occurred in only one rat. The pregnancies of these dams were unaffected by the presence of these gross lesions.
- Neuropathological findings:
- not examined
- Description (incidence and severity):
- Not applicable
- Histopathological findings: non-neoplastic:
- not examined
- Description (incidence and severity):
- Not applicable
- Histopathological findings: neoplastic:
- not examined
- Description (incidence and severity):
- Not applicable
- Other effects:
- not examined
- Description (incidence and severity):
- Not applicable
- Details on results:
- Not applicable
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Description (incidence and severity):
- No abortions occurred during the study.
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- Not applicable
- Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- Not applicable
- Early or late resorptions:
- no effects observed
- Description (incidence and severity):
- Not applicable
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- No dead fetuses were observed.
- Changes in pregnancy duration:
- not examined
- Description (incidence and severity):
- Not applicable
- Changes in number of pregnant:
- no effects observed
- Description (incidence and severity):
- 23/25, 22/25, 24/25, and 25/25 rats (92%, 88%, 96% and 100%, respectively) were pregnant in the control, 10, 40, and 125 mg/kg bw/day dose groups, respectively.
- Other effects:
- not examined
- Description (incidence and severity):
- Not applicable
Effect levels (maternal animals)
open allclose all
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- 40 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- other: food consumption
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 10 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: no adverse effect observed
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- not examined
- Description (incidence and severity):
- not applicable
- Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- not applicable
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- not applicable
- Changes in litter size and weights:
- no effects observed
- Description (incidence and severity):
- not applicable
- Anogenital distance of all rodent fetuses:
- not examined
- Description (incidence and severity):
- not applicable
- Changes in postnatal survival:
- not examined
- Description (incidence and severity):
- not applicable
- External malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Umbilical hernia occurred in one control group fetus. This foetus had no other soft tissue or skeletal alterations.
One control group foetus had an edematous body (anasarca). Skeletal examination of this foetus revealed a short fibula and tibia of each hindlimb and variations in thoracic vertebral ossification (bifid centra of the 9th, 11th and 12th thoracic vertebrae).
A depressed eye bulge occurred in one 10 mg/kg bw/day foetus and in one 40 mg/kg bw/day dosage group fetus. Skeletal examination of the 10 mg/kg bw/day dosage group fetus revealed a small right eye socket as the only alteration. Microphthalmia of the right eye was first identified at soft tissue examination of the 40 mg/kg bw/day dosage group foetus.
No other gross external fetal malformations or variations occurred in this study. - Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- In individual cases fused, waved or additional ribs, short fibula and tibia in the hindlimbs, bifid centrum in thoracic vertebra, and affected ossifications of sternum or pelvis were noted. These events were considered to be not treatment-related, since no dose-dependency was observed and the findings were within normal variations.
- Visceral malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- In individual cases umbilical artery that descended to the left of the bladder, absent innominate artery or aortic arch dorsal to the trachea and esophagus were found. No dose-dependency was observed for these events and hence they are not considered treatment-related.
- Other effects:
- not examined
- Description (incidence and severity):
- not applicable
- Details on embryotoxic / teratogenic effects:
- Combination of malformations and variations resulted in 10 (43.5%), 10 (45.4%), 10 (41.7%) and 11 (44.0%) litters in the four respective dosage groups with fetuses with any alterations observed. In these same respective dosage groups, totals of 14 (4.7%), 10 (3.4%), 13 (3.9%) and 17 (5.0%) fetuses had any alterations observed, and averages of 4.7%, 3.4%, 3.9% and 4.9% of the fetuses per litter had an alteration.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 125 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: absence of any developmental toxicity effect
Fetal abnormalities
- Key result
- Abnormalities:
- effects observed, non-treatment-related
- Localisation:
- external: eye
- skeletal: sternum
- skeletal: rib
- skeletal: hindlimb
- visceral/soft tissue: cardiovascular
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- The current study was performed under GLP conditions and conformed the US EPA OTS 798.4900 guideline. The study is also in accordance with OECD TG 414 (adopted 2018) with some restrictions, such as no examination of anogenital distance of fetuses, and no blood sampling for analysis of thyroid hormones T4, T3 and TSH. Nevertheless, the study is reliable and valid. The developmental toxicity NOAEL in Sprague-Dawley rats was determined to be greater than 125 mg/kg bw/day due to the absence of any developmental toxicity effect in this study. A NOAEL for maternal toxicity was determined to be 10 mg/kg bw/day due to decreased body weight gain and food consumption in the 40 mg/kg bw/day group.
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