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EC number: 209-544-5 | CAS number: 584-84-9
- 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
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: Comparable to OECD 417 guideline study (GLP), pure dried corn oil used as dosing vehicle may have resulted in degradation of TDI to unidentified producs.
Cross-reference
- Reason / purpose for cross-reference:
- reference to other study
Data source
Referenceopen allclose all
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 994
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 992
- Report date:
- 1992
Materials and methods
- Objective of study:
- absorption
- distribution
- excretion
- metabolism
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 417 (Toxicokinetics)
- GLP compliance:
- yes
Test material
- Reference substance name:
- 4-methyl-m-phenylene diisocyanate
- EC Number:
- 209-544-5
- EC Name:
- 4-methyl-m-phenylene diisocyanate
- Cas Number:
- 584-84-9
- Molecular formula:
- C9H6N2O2
- IUPAC Name:
- 2,4-diisocyanato-1-methylbenzene
- Details on test material:
- Unlabeled TDI:
- Name of test material (as cited in study report): 14C-labeled toluene 2,4 diisocyanate
- Analytical purity: 97.72%
- Isomers composition: 200:1 (2,4-TDI : 2,6-TDI)
- Lot. No.: 28F0167
- Supplier: Sigma Chemical Company (St. Louis, USA)
Radiolabeled TDI:
- Lot. No.: 089F9246
- Radiochemical purity (if radiolabeling): >95% (range throughout the study 94.6%-100%)
- Specific activity (if radiolabeling): 23.7 mCi/mmol
- Locations of the label (if radiolabeling): Uniformly ring labeled
- Supplier: Sigma Chemical Company (Milwaukee, USA)
Constituent 1
- Radiolabelling:
- yes
- Remarks:
- 14C-labeled
Test animals
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratory, Kingston, NY, USA
- Weight at study initiation: approximately 200 g
- Individual metabolism cages: yes
- Acclimation period: one week
ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12 h/ 12 h
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: pure dried corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
The radiotracer was diluted with non-radiolabeled 2,4-TDI to obtain a target radioactivity and concentration of 72.5 µCi and 21.7 mg/g of dosing solution, respectively. The dosing solution was prepared in a controlled atmosphere glove box under a dry N2 atmosphere. The dosing solution was analyzed for radioactivity via liquid scintillation counting. In addition, weighed aliquots (200 µl) of the dose solution were derivatized with 0.5 ml piperidine in 2 ml toluene (1 hr, room temperature). The resulting 14 C-2,4-TDI-dipiperdyl derivative was then isolated by evaporation of the excess reagents and solvent (N2 stream) and reconstituted in acetone:acetonitrile:water. The samples were then analyzed by HPLC. The 14C-2,4-TDI dose solution contained 111% and 98% of target radioactivity and concentration, respectively.
VOLUME OF ADMINISTRATION
3ml/kg bw.
VEHICLE
- Justification for use and choice of vehicle (if other than water): TDI readily reacts with water - Duration and frequency of treatment / exposure:
- Single exposure
Doses / concentrations
- Remarks:
- Doses / Concentrations:
60 mg/kg bw
- No. of animals per sex per dose / concentration:
- 7 (4 animals were sacrificed 2 h after exposure, 3 animals 48 h after exposure)
- Control animals:
- no
- Details on study design:
- Groups of male rats were administered 14C-2,4-TDI orally at a target dose of 60 mg/kg of body weight. Following oral administration of 14C-2,4-TDI, three rats were housed in glass Roth-type metabolism cages and urine, feces, expired 14 C-volatile organics
and 14C02 were trapped for up to 48 hr and analyzed for radioactivity. At 48 hr post-dosing the rats were sacrificed, and selected tissues were collected and analyzed for radioactivity. Pooled urine specimens were analyzed by high performance liquid chromatography (HPLC) and gas chromatography/mass spectrometry (GC/MS). An additional group of four rats were administered 14C-2,4-TDI orally and were sacrificed at approximately 2 hr post-dosing (peak14C blood concentration) and selected tissues were collected and analyzed. - Details on dosing and sampling:
- - Body fluids sampled: urine, faeces, cage washes
- Tissues sampled: blood, fat, gastrointestinal tract, gastrointestinal tract contents, fat, kidney, liver, lung, skin and the remaining carcass.
- Time and frequency of sampling: Urine 12 h intervals, feces 24 h intervals, expired air 24 h
- From how many animals: samples pooled from 3 animals
ANALYTICAL METHODS USED
Urine:
- Liquid Scintillation Counting (LSC): determination of the overall radioactivity
- High Performance Liquid Chromatography (HPLC): Separation of the urinary metabolites
- Gas-Chromatography/ Mass Spectrometry (GC/MS): structural identification of the monoacetyl-TDA metabolite
- Gas-Chromatograpy/ Mass-Spectrometry/Mass Spectrometry (GC/MS/MS): for determination of the acetylated metabolites Feces, Air, Tissues:
- Liquid scintillation counting (LSC): determination of the overall radioactivity
Results and discussion
Toxicokinetic / pharmacokinetic studies
- Details on absorption:
- - Orally administered 14C-2,4-TDI is not very well absorbed. The minimum estimate for absorption was 12%, which assumed that the radioactivity recovered in the feces ca. 81% represented unabsorbed material.
- Details on distribution in tissues:
- 2 h after application most of the radioactivity was found in the GI tract and GI content (GI tract: 10.1%, GI content: 65.8%) after 48 h most of the radioactivity was excreted from the system (table 1).
- Details on excretion:
- The rats eliminated approximately 8% of the radioactivity in the urine and cage wash while 4% was recovered in the tissues and carcass and roughly 81% in feces (table 2)
Toxicokinetic parameters
- Toxicokinetic parameters:
- half-life 1st: 7.5 h for urinary excretion
Metabolite characterisation studies
- Metabolites identified:
- yes
- Details on metabolites:
- Monoacetyl 2,4-TDA, Diacetyl 2,4-TDA and free 2,4-TDA was detected in urine (see table 3).
65% of quantitated urinary metabolites existed as acid labile conjugates.
Any other information on results incl. tables
Table 1: Total percentage of administered 14C-2,4 -TDI in tissues of male rats 2 h and 48 h after single dosing
Percentage of administered dose 2 h after application | Percentage of administered dose 48 h after application | |
Blood | not analysed | 0.046 ± 0.017 |
Carcass | 5.497 ± 3.615 | 0.774 ± 0.2 |
Fat | 0.002 ± 0.002 | 0.002 ± 0.001 |
Kidney | 0.077 ± 0.017 | 0.023 ± 0.002 |
liver | 0.499 ± 0.145 | 0.109 ± 0.004 |
Lung | 0.063 ± 0.1 | 0.003 ± 0.22 |
Skin | 1.122 ± 0.53 | 0.149 ± 0.22 |
GI tract | 10.103 ± 3.085 | 0.104 ± 0.54 |
GI content | 65.821 ± 8.346 | 2.560 ± 0.838 |
Total | 83.184 ± 7.185 | 3.770 ± 0.867 |
Table 2: Distribution of radioactivity 48 h after male fisher rats were given an oral dose of 60 mg 14C-2,4 -TDI/kg bw
Percentage of administered dose | |
Urine | 8.38 ± 0.41 |
Feces | 80.67 ± 5.3 |
Tissue&Caracass | 3.77± 0.87 |
CO2 | not quantifiable |
14C volatile organics | not quantifiable |
Cage wash | 0.99 ± 0.52 |
Recovery | 93.8 ± 4.32 |
Table 3: Concentration of Monoacetyl, Diacetyl and free 2,4 -TDA expressed as 2,4 -TDA equivalents in the 0 -12 h urine specimen following oral exposure to 14C-2,4 -TDI
µg equivalents 2,4-TDA/ g urine | |
Monoacetyl 2,4-TDA | 5.12 |
Diacetyl 2,4-TDA | 8.17 |
Free 2,4-TDA | 2.08 |
free + acetylated 2,4-TDA | 15.37 |
Applicant's summary and conclusion
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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