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EC number: 202-196-5 | CAS number: 92-84-2
- 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:
- 2002
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Article published in peer-reviewed journal. Study not according to GLP or OECD guidelines. However, materials and methods as well as results and discussion are sufficiently described.
Data source
Reference
- Reference Type:
- publication
- Title:
- Fate of the anthelmintic, phenothiazine, in man
- Author:
- Mitchell, S.C. et al.
- Year:
- 2 002
- Bibliographic source:
- Xenobiotica (2002), Vol. 32, No. 9, 771-782
Materials and methods
- Objective of study:
- excretion
- metabolism
Test guideline
- Qualifier:
- no guideline available
- Principles of method if other than guideline:
- - Radio labelled Phenothiazine has been administered orally to two healthy adult male volunteers
- Faeces and urine were collected
- Study lasted 5 days - GLP compliance:
- not specified
Test material
- Reference substance name:
- Phenothiazine
- EC Number:
- 202-196-5
- EC Name:
- Phenothiazine
- Cas Number:
- 92-84-2
- Molecular formula:
- C12H9NS
- IUPAC Name:
- 10H-phenothiazine
- Details on test material:
- Phenothiazine
- Phenothiazine (Sigma-Aldrich Ltd (Dorset, UK) was purified by recrystallisation from diethyl ether then aqueous ethanol to give light tan crystals
- Melting Point: 181 - 183 °C
- UV absorption: peaks at 254 and 317nm
- Mass spectrum: m/z 199
Radiolabelled Phenothiazine
- Radiolabelled Phenothiazine was synthesised by refluxing elementary [35 S]-sulphur (Nycomed-Amersham, UK) with diphenylamine in a molar ratio of 2:1.3 for 1hr at 180°C in 1,2-dichlorobenzene under an atmosphere of nitrogen; 1% (w/w) iodine was added as catalyst
- Radioactive Phenothiazine also was purified by recrystallisation to give yellow crystals
- Specific activity: 189.4mCi/mol
- Radiochemical purity: >98% (TLC)
- Mixed melting point: 181 - 183 °C
Constituent 1
- Radiolabelling:
- yes
- Remarks:
- [35 S]-phenothiazine
Test animals
- Species:
- human
- Strain:
- not specified
- Sex:
- male
Administration / exposure
- Route of administration:
- oral: capsule
- Vehicle:
- other: gelatin capsule was given with water
- Duration and frequency of treatment / exposure:
- - Administration 2hrs after light breakfast single exposure
- Study period: 5 days
Doses / concentrations
- Remarks:
- Doses / Concentrations:
Single dose of 6mg/kg body weight
- No. of animals per sex per dose / concentration:
- 2 male volunteers
- Control animals:
- no
Results and discussion
Main ADME resultsopen allclose all
- Type:
- excretion
- Results:
- see below
- Type:
- metabolism
- Results:
- see below
Toxicokinetic / pharmacokinetic studies
- Details on excretion:
- - Similar results for both volunteers
- 1/3 of the administered radioactivity was recovered from the urine, with the majority being voided during the first day
- 2/3 of the radioactive dose was recovered from faeces over 3-4 days with excretion tabering off towards the end of the study
- Overall, excellent recoveries of 98.4% and 100.4% were achieved
Metabolite characterisation studies
- Metabolites identified:
- yes
- Details on metabolites:
- - Conjugates (phenothiazine N-glucorinide and leucophenothiazone sulphate)
- Thionol
- Phenothazine sulphoxide
- Phenothiazone
Any other information on results incl. tables
Urine
- More than 90% of recovered radioactivity was associated to the conjugates phenothiazine-N-glucuronide and leucophenothiazone sulphate, while less than 10% were accounted for the metabolites. The most abundant metabolite was phenothiazine sulphoxide
Faeces
- Only radioactive component found in extracts of faeces was assigned to the parent compound phenothiazine
- Methanolic extraction proved to be efficient in removing [35S]-phenothiazine added to control faeces with recovery rates of about 80%; vice versa this means that a certain amount of radioactivity could not be accounted for
- It is assumed that the portions that could not be extracted were bound to cellulose and other polyphenolic components of the faeces
- Incubation of metabolites of phenothiazine with faeces resulted in no chemical alterations except for the nearly quantitative reduction of phenothiazine sulphoxide to phenothiazine
Half life
- Graphical plotting of the present 0 -24h urinary data was suggesting a biphasic excretion pattern with an initial half-life of around 6h (0 -12h) and a latter half-life of 16h (12 -24h period)
- Given half life is only to be considered as a rough estimate (was not focus of this study), because there are only few data points during this first day and there are only two volunteers.
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results (migrated information): no bioaccumulation potential based on study results
- Executive summary:
Radio labeled [35S]-phenothiazine has been administered orally to two healthy adult male volunteers. The administered dose was 6mg/kg body weight. About two thirds of the radioactivity were found to be excreted via faeces, the remainder via urine. Half-life (biphasic) was estimated to be 6 -16hrs. Radioactivity was completely recovered in the the course of the five day study.
Based on urine data is was shown that metabolism occurred via ring carbon oxidation to form phenothiazone and thionol and via ring sulphur oxidation to form phenothiazine sulphoxide. The vast majority of urinary material was present in the form of conjugates of phenothiazine and phenothiazone. Only unchanged phenothiazine was detected in faeces. Phenothiazine sulphoxide was reduced to phenothiazine during incubation with faecal homogenates.
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