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EC number: 200-539-3 | CAS number: 62-53-3
- 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
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Meets generally accepted scientific standards, well documented and acceptable for assessment
Data source
Reference
- Reference Type:
- publication
- Title:
- Contribution of Aniline Metabolites to Aniline-lnduced Methemoglobinernia
- Author:
- Harrison JH Jr, Jollow DJ
- Year:
- 1 987
- Bibliographic source:
- Molecular Pharmacology, 21, 423 - 431
Materials and methods
- Objective of study:
- other: metabolism and MetHb formation
Test guideline
- Qualifier:
- no guideline required
- Principles of method if other than guideline:
- The relative contributions of aniline and aniline metabolites (phenylhydroxylamine, 2-aminophenol, and 4-aminophenol) to aniline-induced methemoglobinemia was evaluated in cultured rat erythrocytes and in male Sprague-Dawley rats after a single intraperitoneally injection. Furthermore, clearance of aniline and its metabolites from the blood after a single application of aniline was determined.
- GLP compliance:
- no
Test material
- Reference substance name:
- Aniline
- EC Number:
- 200-539-3
- EC Name:
- Aniline
- Cas Number:
- 62-53-3
- Molecular formula:
- C6H7N
- IUPAC Name:
- aniline
- Details on test material:
- Aniline was given as purified aniline HCl. No data on purity
Phenylhydroxylamine was synthesized and purified - no data on purity
Aminophenols (2- 3-, 4-) were pruchased from Aldrich Chemical Co., Milwaukee, WI, USA (reagent grade)
Constituent 1
- Radiolabelling:
- yes
- Remarks:
- Tritiated aniline
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- - Source: Camm Research Inc. Wayne, NJ, USA
- Weight at study initiation: 200 - 250 g
Administration / exposure
- Route of administration:
- intraperitoneal
- Vehicle:
- other: 0.9% saline
- Duration and frequency of treatment / exposure:
- single dose, intraperitoneally
Doses / concentrations
- Remarks:
- Doses / Concentrations:
Depending on the endpoint addressed 0.15, 0.375, 0.75, 1.5, and 2.25 mmol aniline HCl/kg (corresponding to 14, 35, 70, 140, and 209 mg [3H]aniline/kg, respectively) were administered
- No. of animals per sex per dose / concentration:
- 4 to 5
- Control animals:
- other: control values were obtained from test animals before administration of the test substance.
- Details on dosing and sampling:
- Aniline HCI, 2 -aminophenol, 4 -aminophenol (all in in 0.9% saline) and phenylhydroxylamine (0.9% saline containin 5% Tween-80) were injected intraperitoneally into rats in 1.0 ml of vehicle per kilogramm body weight. In some experiments, galactosamine, a noncompetitive inhibitor of hepatic glucuronidation of phenols was dissolved in 0.9% saline and injected intraperitoneally (200 mg/kg} 30 min before the test compounds.
Control blood samples were obtained from the orbital sinus in 75 µl heparinized capillary tubes immediately before injection of the test compounds. After injection, serial orbital sinus blood samples were collected until methemoglohin levels returned to baseline values.
Blood samples were analyzed for aniline, phenolic aniline metabolites, phenylhydroxylamine, and nitrosobenzene in plasma by HPLC with electrochemical detector.
Methemoglobin levels relative to total hemoglobin were measured spectrophotometrically based on the "cyanide method". - Statistics:
- Areas under the methemoglobin time course curves were estimated by fitting curves by eye to data from individual cell suspensions or animals plotted on graph paper, then counting the squares under the curves. Eslimates of relative potency were made by inspection of dose response
data plotted on logit paper. Statistical analyses used the Student's t test for pooled samples.
Results and discussion
Toxicokinetic / pharmacokinetic studies
- Details on excretion:
- At low doses (0.15 and 0.375 mmol/kg) aniline clearance from the blood approximated a first order kinetics with a half life of about 16 min at 0.15 mmol/kg (= 14 mg/kg). With increased dose the kinetics of aniline was marked by a capacity-limited phase. During this capacity-limited phase the "half-life" of aniline in the blood was about 3.5 hours which is comparable to the half-life of phenylhydroxylamine plus nitrosobenzene.
Metabolite characterisation studies
- Metabolites identified:
- yes
- Details on metabolites:
- The three aniline metabolites phenylhydroxylamine, 2 aminophenol, and 4-aminophenol but not aniline has been shown to induce MetHb in cultured rat erythrocyte suspensions with relative potencies of about 10:5:1, respectively. After a single intraperitoneal injection in rates relative potencies were reduced with respect to phenylhydroxylamine to 100:4:1, respectively.
Any other information on results incl. tables
The three aniline metabolites phenylhydroxylamine, 2 -aminophenol, and 4 -aminophenol but not aniline has been shown to induce MetHb in cultured rat erythrocyte suspensions. The relative potencies for MetHb production in vitro after phenylhydroxylamine, 2-aminophenol, and 4-aminophenol were about 10:5:1, at minimum concentrations of 20, 50, and 200 µM, respectively.
Compared with the in vitro data, the relative potencies of the aminophenols to induce methemoglobinemia in male rats after a single intraperitoneal injection were reduced with respect to phenylhydroxylamine to 100:4:1, respectively.
Phenylhydroxylamine produced the most rapid rise in MetHb levels: maximum levels were reached within 6 min after injection. In rats treated with 2-aminophenol or 4 -aminophenol maximum MetHb levels occurred 20 -30 min after aniline administration. Both 2 -aminophenol and phenylhydroxylamine were highly effective, producing MetHb levels of max. 70-80% of total hemoglobin however, higher dose levels of 2 -aminophenol (10 to 20 -fold) were required in vivo.
At low doses (0.15 and 0.375 mmol/kg) aniline clearance from the blood approximated a first order kinetics with a half life of about 16 min at 0.15 mmol/kg (= 14 mg/kg). With increased dose the kinetics of aniline elimination became more complex, and the plasma time course of aniline was marked by a capacity-limited phase, different from zero order kinetics, between 1 and 6 hours after anilline application. During this capacity-limited phase a "half-life" of aniline in the blood of about 3.5 hours has been observed, which is comparable to the half-life of first-order elimintation kinetics of phenylhydroxylamine plus nitosobenzene. After that (6 to 10 hours) a linear kinetics was observed with an apparent first-order elimination kinetics.
Maximum blood concentrations of the metabolites 4 -aminophenol, 4 -hydroxacetanillide, and phenylhydroxylamine plus nitosobenzene after a single i.p. injection of 1.5 mmol anilline HCl/kg (= 140 mg aniline/kg) were 5 µM, 30 µM, and ~55µM, respectively. No 2 -aminophenol could be detected in the blood (< 0.5 µM). Maximum concentration of 4 -aminophenol and 4 -hydroxyacetanillide were reached at >6 hours after anilline application. In contrast, maximum blood concentration of phenylhydroxylamine (plus nitrosobenzene) was observed within 10 min after dosing, which is in very good agreement with the observed time course of MetHb formation in rats in vivo.
Applicant's summary and conclusion
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