Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 201-877-4 | CAS number: 89-04-3
- 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:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Well conducted study in accordance with standards applicable at the time. For read-across justification see Section 13.
Data source
Reference
- Reference Type:
- secondary source
- Title:
- Absorption and metabolism of [Hexyl-2-14C] tri-(2-ethylhexyl)trimellitate in the rat
- Author:
- Enriquez PM, Giordano CJ and DiVincenzo GD
- Year:
- 1 984
- Bibliographic source:
- NTIS OTS0507501 Document ID 40-8465021
Materials and methods
- Objective of study:
- absorption
- metabolism
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 417 (Toxicokinetics)
- Deviations:
- yes
- Remarks:
- Only a single dose level investigated
- GLP compliance:
- yes
Test material
- Reference substance name:
- Tri-(2-ethylhexyl)trimellitate
- IUPAC Name:
- Tri-(2-ethylhexyl)trimellitate
- Details on test material:
- - Name of test material (as cited in study report): tri-(2-ethylhexyl)trimellitate
- Molecular formula (if other than submission substance): C33 H54 O6
- Molecular weight (if other than submission substance): 546.79
- Smiles notation (if other than submission substance): c1(c(ccc(c1)C(OC[C@@H](CCCC)CC)=O)C(OC[C@@H](CCCC)CC)=O)C(OC [C@@H](CCCC)CC)=O
- InChl (if other than submission substance): 1S/C33H54O6/c1-7-13-16-25(10-4)22-37-31(34)28-19-20-29(32(35)38-23-26 (11-5)17-14-8-2)30(21-28)33(36)39-24-27(12-6)18-15-9-3/h19-21,25-27H,7-18,22- 24H2,1-6H3
- Structural formula attached as image file (if other than submission substance): see 3319-31-1 structure.png
- Analytical purity: 91.7%
- Impurities (identity): di-(2-ethylhexyl)terephthalate
- Radiochemical purity (if radiolabelling): > 99%
- Specific activity (if radiolabelling): 4.82 mCi/mmole
- Locations of the label (if radiolabelling): [Hexyl 2-14C] tri(2-ethylhexyl)trimellitate
- Stability under test conditions: Stable
Constituent 1
- Radiolabelling:
- yes
- Remarks:
- [Hexyl 2-14C] tri(2-ethylhexyl)trimellitate
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Inc, Wilmington, MA
- Weight at study initiation: 200 - 300 g
- Fasting period before study: 16 hours
- Housing:
- Individual metabolism cages: yes
- Diet: Purina laboratory rodent chow Ref. 5001 available ad libitum immediately following dosing
- Water: ad libitum
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: Labelled substance mixed with non-labelled substance and dissolved/diluted in corn oil
VEHICLE
- Justification for use and choice of vehicle (if other than water): Commonly used vehicle for poorly water soluble substances
- Concentration in vehicle: Not reported
- Amount of vehicle (if gavage): Not reported
HOMOGENEITY AND STABILITY OF TEST MATERIAL: Not reported - Duration and frequency of treatment / exposure:
- Dosed once only
Doses / concentrations
- Remarks:
- Doses / Concentrations:
100 mg/kg body weight (16-18 microCi/animal)
- No. of animals per sex per dose / concentration:
- 4
- Control animals:
- yes
- Details on study design:
- Rats were dosed once only, by gavage, with 100 mg/kg TOTM. Following dosing animals were placed in separate glass metabolism chambers to permit separation of expired air, urine and faeces. Expired air was passed through two silica gel traps to remove volatile organic compounds and then through two NaOH traps to remove CO2. The silica gel traps were changed daily and the NaOH traps were changed at intervals up to 144 hours post dose. Urine and faeces were collected at 4, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours post dose an radioactivity measured. At each collection period the metabolism cages were rinsed with water. On termination following 144 hours cages were also washed with methanol followed by methylene chloride. Rats were killed 144 hours post dose and brain, heart, lungs, liver, spleen, kidneys, small and large intestines, testes and abdominal fat were removed.
Radioactivity Measurements - A Liquid Scintillation Spectrometer was used for measurement of radioactivity with efficiency corrections made by external standardisation. Most samples were counted in a naphthalene-dioxane based scintillator fluid.
Processing of Tissues and Excreta - Tissues were extracted twice with 95% aqueous acetone. Combined extracts were counted in scintillation fluid. Residues were dried, powdered, combusted and counted. Carcasses were shredded in a blender with acetone, the mixture refluxed overnight and then filtered. The residue was then refluxed with n-hexane and filtered. The acetone and n-hexane were then counted in scintillation fluid. Solid residues were powdered and counted for radioactivity. Faeces were homogenised in acetone. Solids were separated by centrifugation and residues extracted twice with acetone. Combined extracts were counted in scintillation fluid. Residues were then further extracted with methylene chloride and the extracts counted in scintillation fluid.
Analysis of TOTM and its metabolites in excreta - Radioactive components in faecal extracts were separated using HPLC utilising both spectrophotometric (uv/vis) and radiochemical detection. Standards used for metabolite characterisation were prepared from [Hexyl 2-14C] tri(2-ethylhexyl)trimellitate and from synthetic mixtures prepared by the incomplete esterification of trimellitic acid with 2-ethylhexanol. These mixtures were formed from 1:1 and 2:1 molar ratios of 2-ethyhexanol and trimellitic acid and were regarded as being mono- and di-esters, mono(2-ethylhexyl)trimellitate and di(2-ethylhexyl)trimellitate. Faecal extracts were analysed directly using HPLC. Urinary metabolites were analysed by GC/MS following solvent extraction in diethyl ether.
Analysis of Kinetic Data - Excretion half-lives were estimated from the rates of excretion of radioactivity in urine and in expired air. - Details on dosing and sampling:
- PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, expired air, cage washes, tissues (brain, heart, lungs, liver, kidneys, small & large intestines, testes and abdominal fat)
- Time and frequency of sampling: 4, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose - tissues at 144 hours only
METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine, faeces
- Time and frequency of sampling: 4, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose
- From how many animals: 4 animals. No details on pooling of samples
- Method type(s) for identification: GC-MS, HPLC-UV-vis
- Limits of detection and quantification: Not reported
: - Statistics:
- Students' t-test. Values of p < 0.05 regarded as significant
Results and discussion
Main ADME resultsopen allclose all
- Type:
- absorption
- Results:
- Half-life - 0.7 hours
- Type:
- excretion
- Results:
- Half-life - 42 hours
Toxicokinetic / pharmacokinetic studies
- Details on absorption:
- The excretion of radioactivity following administration of a single oral dose occurred mainly in the faeces, this accounting for approximately 75% of the administered dose with 16.3% found in the urine and 1.9% in expired air.
Two peaks in the plot of the rate of excretion of 14CO2 in expired air were observed for each rat in the study. The first was observed 2-3 hours post dose and the second 8-12 hours post dose, the authors suggesting this to be a result of metabolism of 2-ethylhexanol occurring from its release by hydrolysis from the tri-ester followed by a further hydrolysis step releasing 2-ethyl hexanol from the di-ester. The half-life for initial absorption was estimated to be approximately 0.7 hours. - Details on distribution in tissues:
- Residual radioactivity in the carcass 144 hours post dose was <0.6% of the administered dose. Tissues analysed for radioactivity revealed only liver (5x) and adipose tissue (3x) containing levels of radioactivity greater than the carcass average.
- Details on excretion:
- Radioactivity in the faecal extracts was identified as 86% TOTM, 7% di-(2-ethylhexyl)trimellitate and 1% mono-(2-ethylhexyl)trimellitate. Only one of the three possible mono-ester isomers was found.
Analysis of urine by GC/MS revealed the presence of 2-ethylhexanol, 2-ethylhexanoic acid, 2-heptanone and mono-(2-ethylhexyl)trimellitate. HPLC retention times indicated that the mono-ester was the same isomer found in faecal extracts. No isomers of di-(2-ethylhexyl)trimellitate were found. Urinary elimination of radioactivity was bi-phasic with half-lives of 3.1 and 42 hours
Metabolite characterisation studies
- Metabolites identified:
- yes
- Details on metabolites:
- Radioactivity in the faecal extracts was identified as 86% TOTM, 7% di-(2-ethylhexyl)trimellitate and 1% mono-(2-ethylhexyl)trimellitate. Only one of the three possible mono-ester isomers was found.
Analysis of urine by GC/MS revealed the presence of 2-ethylhexanol, 2-ethylhexanoic acid, 2-heptanone and mono-(2-ethylhexyl)trimellitate. HPLC retention times indicated that the mono-ester was the same isomer found in faecal extracts. No isomers of di-(2-ethylhexyl)trimellitate were found.
Any other information on results incl. tables
Disposition of Radioactivity -The excretion of radioactivity following administration of a single oral dose occurred mainly in the faeces, this accounting for approximately 75% of the administered dose with 16.3% found in the urine and 1.9% in expired air. Residual radioactivity in the carcass 144 hours post dose was <0.6% of the administered dose. Tissues analysed for radioactivity revealed only liver (5x) and adipose tissue (3x) containing levels of radioactivity greater than the carcass average. Recovery was 94.1% of the administered dose.
Characterisation of Faecal and Urinary metabolites -The radioactive components of faecal extracts were characterised by HPLC. Using the prepared standards it was possible to identify three monoesters and two diesters while evidence for a third diester was obtained by UV spectral analysis. Radioactivity in the faecal extracts was identified as 86% TOTM, 7% di-(2-ethylhexyl)trimellitate and 1% mono-(2-ethylhexyl)trimellitate. Only one of the three possible mono-ester isomers was found.
Analysis of urine by GC/MS revealed the presence of 2-ethylhexanol, 2-ethylhexanoic acid, 2-heptanone and mono-(2-ethylhexyl)trimellitate. HPLC retention times indicated that the mono-ester was the same isomer found in faecal extracts. No isomers of di-(2-ethylhexyl)trimellitate were found.
Kinetics -Two peaks in the plot of the rate of excretion of14CO2in expired air were observed for each rat in the study. The first was observed 2-3 hours post dose and the second 8-12 hours post dose, the authors suggesting this to be a result of metabolism of 2-ethylhexanol occurring from its release by hydrolysis from the tri-ester followed by a further hydrolysis step releasing 2-ethyl hexanol from the di-ester. The half-life for initial absorption was estimated to be approximately 0.7 hours. The die-away of14CO2was bi-phasic with half-lives of 4.3 and 31 hours. Urinary excretion of radioactivity was also bi-phasic with half-lives of 3.1 and 42 hours.
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results (migrated information): low bioaccumulation potential based on study results
TOTM is only partially hydrolysed in the gastro-intestinal tract to 2-ethylhexanol and the corresponding di-ester and, following further hydrolysis, the mono-ester. Only 2-ethylhexanol and a single isomer of mono-(2-ethylhexyl)trimellitate appear to be absorbed. Following absorption, 2-ethylhexanol was extensively metabolised with metabolites eliminated in the urine and as expired 14CO2.There was no evident metabolism of mono-(2-ethylhexyl)trimellitate, this being eliminated unchanged. - Executive summary:
The absorption, distribution, metabolism and elimination of a structural analogue of the substance (tris-(2 -ethylhexyl)trimellitate), in which the ester chains are C-8 branched rather than C-8 linear, has been investigated in the rat following oral administration of a single dose. Findings indicate that the substance is only partially hydrolysed in the gastro-intestinal tract to 2-ethylhexanol and the corresponding di-ester and, following further hydrolysis, the mono-ester. Only 2-ethylhexanol and a single isomer of mono-(2-ethylhexyl)trimellitate appear to be absorbed. Following absorption, 2-ethylhexanol was extensively metabolised with metabolites eliminated in the urine and as expired14CO2. There was no evident metabolism of mono-(2-ethylhexyl)trimellitate, this being eliminated unchanged.
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.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.