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EC number: 619-682-1 | CAS number: 224049-04-1
- 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
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 29 Jul 2004 - 8 Jun 2006
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 006
- Report date:
- 2006
Materials and methods
- Objective of study:
- absorption
- distribution
- excretion
- metabolism
- toxicokinetics
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 417 (Toxicokinetics)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.7485 (Metabolism and Pharmacokinetics)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: Japan Ministry of Agriculture Forestry and Fisheries (JMAFF) guideline (12, Noshan number 8147)
- Deviations:
- no
- GLP compliance:
- yes
Test material
- Reference substance name:
- 3,4-dichloro-N-(2-cyanophenyl)-1,2-thiazole-5-carboxamide
- EC Number:
- 619-682-1
- Cas Number:
- 224049-04-1
- Molecular formula:
- C11H5Cl2N3OS
- IUPAC Name:
- 3,4-dichloro-N-(2-cyanophenyl)-1,2-thiazole-5-carboxamide
- Reference substance name:
- 3,4-dichloro-2'-cyano-1,2-thiazole-5-carboxanilide
- IUPAC Name:
- 3,4-dichloro-2'-cyano-1,2-thiazole-5-carboxanilide
Constituent 1
Constituent 2
- Radiolabelling:
- yes
- Remarks:
- Two different labelled forms: [Phenyl(U)-14C]-test substance with 14C on the phenyl ring and [lsothiazole-3-14C,Carboxamide-14C]-test substance with 14C on the 3 position of the isothiazole ring and the carboxamide
Test animals
- Species:
- rat
- Strain:
- other: Crl:Wl® (Han)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, lnc., Raleigh, NC
- Age at study initiation: 9-10 weeks
- Weight at study initiation: 198-363 g
- Housing: Individually metabolism cages
- Individual metabolism cages: Yes
- Diet (e.g. ad libitum): Lab Diet Feeds certified rodent diet No. 5002 ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25
- Humidity (%): 30-70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: 2% cremophor EL in HPLC grade water
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
VEHICLE
- Justification for use and choice of vehicle (if other than water): A solution of Cremophor EL 2% (v/v) in HPLC grade water was used as the vehicle for the test material since it provides homogeneous doses and is a standard vehicle used in toxicology studies.
- Amount of vehicle (if gavage): 10 mL/kg - Duration and frequency of treatment / exposure:
- Single dose, termination time up to and including 168 hours
Doses / concentrations
- Remarks:
- Doses / Concentrations:
4 and 200 mg/kg bw
- No. of animals per sex per dose / concentration:
- Pilot Pharmacokinetic Experiment: 1
Pilot Excretion Experiment: 2
Pharmacokinetic Experiment: 4
Single Dose Excretion and Distribution Experiments (maximum termination times): 4
Tissue Distribution Time Course Experiment (intermediate termination times): 3 - Control animals:
- yes, concurrent vehicle
- Details on dosing and sampling:
- PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: Expired air, urine, faeces, blood, plasma, serum or other tissues, cage washes, bile.
- Time and frequency of sampling: 6, 12 and 24h and in 24h interval until termination, blood collection at 0.25, 0.5, 1, 2, 6, 12, 24, 48, 72 and 120 h after dosing and at all termination time points.
- other: At termination, the following tissues were excised from the animals used in the Pilot Excretion Experiment, the Single Dose Excretion and Distribution Experiments and the Tissue Distribution Time-Course Experiment: adrenal glands, bone (femur), bone marrow (femur), brain, fat, heart, stomach, intestine, kidneys, liver, lungs, muscle, ovaries, pancreas, pituitary gland, prostate gland, spleen, testes, thymus, thyroid, uterus, skin with hair, mandibular gland, eye balls, spinal cord, sciatic nerve, whole blood, blood cells, and plasma.
METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: Urine, faeces, cage wash.
- Time and frequency of sampling: in 24h intervals.
- From how many animals: (samples pooled or not): Pooled.
- Sample preparation: Pooled excreta samples from selected time points were chosen for extraction and chromatographic analysis:
Urine: Hydrolysis with sulfatase enzyme (Type H-l from Helix pomatia) that has both sulfatase and glucuronidase activities;
Cage wash: Aliquots of the pooled cage wash samples from the lsothiazole label were concentrated under nitrogen and then analyzed by HPLC Method using a radiochemical detector equipped with a solid cell. Aliquots from the pooled cage wash samples containing the Phenyl label were analyzed (without concentration) by HPLC Method using a radiochemical detector equipped with a liquid cell.
Faeces: The pooled samples were extracted two times with acetonitrile, three times with 50% acetonitrile/warter containing 1% formic acid and one time with 50% methanol/water containing 1% formic acid. The ratio of the sample to solvent was 1:3 (wt:vol). After suspension in solvent, the samples were sonicated for 10 minutes, vortexed for l minute and then centrifuged at ~3000-5000 rpm for 10 minutes. The supernatant was transferred to a graduated cylinder, the volume was recorded and duplicate aliquots were taken for LSC. The supernatants from each extraction step were combined and concentrated by rotary evaporation. PES was analyzed by combustion for quantitation of unextractable residues.
Liver: Pooled liver samples were subjected to solvent extraction using the same method as used for the faeces samples. The extracts were taken to dryness by rotary evaporation and reconstituted in appropriate combination of acetonitrile/water. They were centrifuged and an aliquot was taken for LSC. An aliquot of the supernatant was taken for HPLC. If the total amount of radioactivity in the samples was low, chromatographic fractions of one-minute each were collected and analyzed by LSC to obtain radiohistograms. The postextraction solids (PES) were analyzed for radioactivity by LSC following combustion analysis of aliquots.
Kidney: Pooled kidney samples were subjected to solvent extraction rising the same method as used for the faeces samples. The extracts were taken to dryness by rotary evaporation and reconstituted in appropriate combination of acetonitrile/water. They were centrifuged and an aliquot was taken for LSC. Each supernatant was analyzed by HPLC. Total radioactivity in post»extraction solids (PES) quantitated combustion analysis followed by LSC.
Plasma: The pooled blood samples were separated into plasma and packed cells by centrifugation.
Aliquots (2 x l0 µL) of the pooled plasma samples were analyzed by LSC. Plasma samples from the 0.25 and 12-hour time points for the 4 mg/kg dose-group and the 0.5 and 24-hour 200 mg/kg dose dose-group (except for the samples with low levels of radioactivity) were analyzed by HPLC. The pooled plasma samples were prepared for analysis by solid phase extraction using Varian BondElut C18, 500 mg 3 mL columns (Varian Inc., Harbor City, CA).
- Method type(s) for identification: Liquid scintillation counting, Combustion analysis, HPLC-RAD, HPLC-LSC, LC-MS-MS, NMR. - Statistics:
- Pharmacokinetic: WinNonlin calculation
Results and discussion
Main ADME resultsopen allclose all
- Type:
- absorption
- Results:
- 30-36% (4 mg/kg bw), 10-14% (200 mg/kg bw) after 168 hours (calculated from the % of the dose recovered in urine, cage wash and tissues)
- Type:
- excretion
- Results:
- 91 - 96% after 48 hours
Toxicokinetic / pharmacokinetic studies
- Details on absorption:
- Total recovery for the isothiazole label was around 93% for the 4 mg/kg bw group and 98% for the 200 mg/kg bw group. For the phenyl label >92% for the 4 mg/kg bw and around 95% for 200 mg/kg bw group had been recovered.
The maximum plasma concentration (Cmax) of 0.2 - 0.36 µg test substance equivalents/g administered dose following the 4 mg/kg treatment was reached at 0.3 to 1.7 hours. Following the 200 mg/kg treatment the highest plasma concentration of 2.57 - 4.17 µg test substance equivalents/g administered dose was reached at 0.9-10.6 hours. Elimination half-lives (tm) were marginally longer at the 200 mg/kg close level (17.9-20.5 hours) than at the 4 mg/kg dose level (13.9-17.8 hours). There were slight differences in the genders at both dose levels. For the female rats values were greater than the corresponding values for male rats. The relative systemic exposure for the two dose levels, as determined by comparison of plasma Cmax and AUC values, was dose-dependent (nonlinear).
For the female rats values were greater than the corresponding values for male rats. The relative systemic exposure for the two dose levels, as determined by comparison of plasma Cmax and AUC values, was dose-dependent (nonlinear). - Details on distribution in tissues:
- After 168-h exposure period, total residues in tissues were below 0.2 % of the administered dose and total residues in the residual carcass were 0.12% of the administered dose or less. Within the 4 mg/kg dose group, the highest residue levels were found in liver (0.134 ppm) and kidney (0.068 ppm). Residue levels for all other tissues were less than 0.03 ppm or were not detectable for the 4 mg/kg dose level. No sex-related differences in tissue residue levels were observed.
Within the 200 mg/kg dose group, the highest residue levels in male rats were found in stomach (8.95 ppm), intestine (1.29 ppm), kidney (1.29 ppm), liver (4.92 ppm) and packed cells (0.98 ppm). Residue levels for all other tissues were less than 0.6 ppm or not detectable for the 200 mg/kg dose level. No sex-related differences in tissue residue levels were observed.
- Details on excretion:
- Isothiazole label:
4 mg/kg: male: 58% after 24 hours, 90 % after 48 hours and 93% after 168 hours, female: 79% after 24 hours, 91% after 48 hours and 93% after 168 hours.
200 mg/kg: male: 60% after 24 hours, 97% after 48 hours and 99% after 168 hours; female 59% after 24 hours, 96% after 48 hours and 98% after 168 hours.
Phenyl label:
4 mg/kg: male: 64% after 24 hours, 86 % after 48 hours and 93% after 168 hours, female: 82% after 24 hours, 104% after 48 hours and 106% after 168 hours.
200 mg/kg: male: 47% after 24 hours, 90% after 48 hours and 93% after 168 hours; female 65% after 24 hours, 95% after 48 hours and 97% after 168 hours.
Toxicokinetic parametersopen allclose all
- Test no.:
- #1
- Toxicokinetic parameters:
- half-life 1st: 4 mg/kg bw: 15.8 - 25.1 h
- Test no.:
- #2
- Toxicokinetic parameters:
- half-life 1st: 200 mg/kg bw: 13.6 - 40.2 h
- Test no.:
- #1
- Toxicokinetic parameters:
- AUC: 4 mg/kg bw: 3.87 - 4.84 µg x h/g
- Test no.:
- #2
- Toxicokinetic parameters:
- AUC: 200 mg/kg bw: 65.19 - 111.82 µg x h/g
- Test no.:
- #1
- Toxicokinetic parameters:
- Cmax: 4 mg/kg bw: 0.2 - 0.36 µg/g
- Test no.:
- #2
- Toxicokinetic parameters:
- Cmax: 200 mg/kg bw: 2.57 - 4.17 µg/g
- Test no.:
- #1
- Toxicokinetic parameters:
- Tmax: 4 mg/kg bw: 0.3 - 1.7 h
- Test no.:
- #2
- Toxicokinetic parameters:
- Tmax: 200 mg/kg bw: 0.9 - 10.6 h
Metabolite characterisation studies
- Metabolites identified:
- yes
- Details on metabolites:
- Isothiazole label:
Urine: 3,4-dichloro-5-isothiazolecarboxylic acid; glucuronide of 4’-OH- and 4’-OH-metabolites of test substance, respectively.
Faeces: Unmetabolised test substance (main 14C component), and to a minor degree 4’-OH- and 4’,5’-OH-metabolites of test substance, respectively.
Phenyl label:
Urine: 2-amino-5-hydroxybenzonitril; glucuronide of 4’-OH-, 4’-OH- and 4’,5’-OH-metabolites of test substance, respectively.
Faeces: Unmetabolised test substance (main 14C component), and to a minor degree 4’-OH- and 4’,5’-OH-metabolites of test substance, respectively.
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results (migrated information): no bioaccumulation potential based on study results
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