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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.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: 304-059-6 | CAS number: 94233-27-9
- 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
Endpoint summary
Administrative data
Link to relevant study record(s)
- Endpoint:
- basic toxicokinetics in vitro / ex vivo
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- other:
- Justification for type of information:
- According to hydrolysis test results, this substance is hydrolytically unstable with hydrolysis rate estimated to be several minutes. The hydrolysis products have been identified to be 2-ethylhexanol, acetylacetone and titanium dioxide. The discussion of toxicokinetics is based on the hydrolysis/degradation products.
- Reason / purpose for cross-reference:
- data waiving: supporting information
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study
- Objective of study:
- other: ADME and kinetics
- Radiolabelling:
- yes
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- female
- Route of administration:
- oral: gavage
- Vehicle:
- unchanged (no vehicle)
- Duration and frequency of treatment / exposure:
- 1) single dose exposure
2) repeated dose exposure, 14 days - Dose / conc.:
- 50 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 500 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose / concentration:
- 4
- Control animals:
- no
- Details on absorption:
- 2-EH was rapidly absorbed after oral administration of 50 and 500 mg/kg bw; evidenced by the rapid excretion (approx. 50% of the dose within
8 hrs). 95-97% of the dose were excreted within 96 hrs. - Details on distribution in tissues:
- Distribution into tissues is of minor relevance, due to rapid excretion, mainly as polar conjugates in urine. Bioaccumulation is unlikely to occur, as excretion was virtually complete (>95%) within 96 hrs.
- Details on excretion:
- 2-EH was rapidly absorbed after oral administration of 50 and 500 mg/kg bw; evidenced by the rapid excretion (approx. 50% of the dose within 8 hrs). 95-97% of the dose were excreted within 96 hrs, mainly as polar conjugates in urine. Bioaccumulation is unlikely to occur, as excretion was virtually complete within 96 hrs.
- Metabolites identified:
- yes
- Details on metabolites:
- The majority of the oral and dermal doses were eliminated as glucuronides of oxidized metabolites of 2-ethylhexanol (2-EH). Major metabolites:
glucuronides of 2-ethyladipic acid, 2-ethylhexanoic acid, 5-hydroxy-2-ethylhexanoic acid, and 6-hydroxy-2-ethylhexanoic acid. Only trace amounts of the unchanged 2-ethylhexanol were detected in urine. - Conclusions:
- No bioaccumulation potential based on study results.
1. Excretion balance studies were conducted with 2-ethylhexanol (2-EH) in female Fischer 344 rats following single high (500 mg/kg) and low (50 mg/kg) oral doses of 14C labeled 2-EH, following repeated oral dosing with unlabelled 2-EH at the low level, following dermal exposure for 6h with a 1 g/kg applied dose of [14C]2-EH, and following a 1 mg/kg i.v. dose of [14C]2-EH.
2. The high, low and repeated low oral dose studies with 2-EH showed similar excretion balance profiles of [14C], with some evidence of metabolic saturation at the high dose.
3. No evidence of metabolic induction was seen following the repeated low oral dosing.
4. All of the oral doses were eliminated rapidly, predominantly in the urine during the first 24 h following dosing.
5. T h e dermal dosing resulted in only about 5% absorption of the 1 g/kg dose, with the major portion of the dose recovered unabsorbed from the dermal exposure cell at 6 h.
6 . Urinary metabolites eliminated following the oral and dermal doses were predominately glucuronides of oxidized metabolites of 2-EH, including glucuronides of 2-ethyladipic acid, 2-ethylhexanoic acid, 5-hydroxy-2-ethylhexanoicacid and 6-hydroxy-2-ethylhexanoic acid. - Executive summary:
As the target substance hydrolyses rapidly (half-life < 30 minutes) the intrinsic properties are related to hydrolysis products of the target substance. This information is used as a supporting evidence on the toxicity of the target substance in CSA.
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other:
- Principles of method if other than guideline:
- Intravenous study: The substance was given to four adult male Fischer 344 rats per dose by single intra-venous injection. Target radioactivity was 2 – 5 mCi. Blood was collected at appropriate intervals from a lateral tail vein until 30 hr post dosing. At 48 hr a cardiac puncture was performed for a final blood sam-ple with all groups. Urine and feces were. For airborne collections, room air was drawn through the me-tabolism cages at approximately 500 ml/min. Expired 14CO2 was trapped.
Inhalation study: A total of fifty animals were exposed 6 hours nose-only to a target concentration and serial groups of 3 animals were removed at the blood sampling intervals during the absorption phase. Included was a group of 4 rats which were monitored by plethysmography during exposure to ensure that there was no excessive peripheral sensory irritation with consequent changes in minute volume. Respira-tory rate was measured. After exposure the animals were transferred to metabolism cages. - GLP compliance:
- yes
- Radiolabelling:
- yes
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male
- Route of administration:
- other: inhalation: dust; intravenous
- Vehicle:
- other: physiol. saline for intravenous, unchanged for inhalation
- Duration and frequency of treatment / exposure:
- IV: single exposure
Inhalation: single 6h exposure - Dose / conc.:
- 400 ppm
- Remarks:
- Inhalation
- Dose / conc.:
- 4.3 mg/kg bw/day (nominal)
- Remarks:
- I.V
- Dose / conc.:
- 43 mg/kg bw/day (nominal)
- Remarks:
- I.V.
- Dose / conc.:
- 430 mg/kg bw/day (nominal)
- Remarks:
- I.V
- Dose / conc.:
- 148.5 mg/kg bw/day (nominal)
- Remarks:
- I.V.
- No. of animals per sex per dose / concentration:
- I.V.: 4
Inhalation: 50 - Conclusions:
- Low bioaccumulation potential based on study results.
2,4-PD is readily absorbed during a 6 hr exposure to 400 ppm, and biexponentially eliminated from plasma postexposure. However, even at 48 hr postexposure, radioactivity derived from 14C-2,4-PD is still present. The majority of the dose is eliminated as CO2 and in urine, with at least 7 metabolites being detected in urine. Although there is no preferential tissue accumulation of 14C-2,4-PD-derived radioactivity, the plasma elimination profiles and the detection of some radioactivity in many tissues at 48 hr postexposure, indicates a potential for cumulative effects. The only definitive repeated exposure known toxicity, and with a latency to expression, is central neurotoxicity and 14C could still be detected in the brain 48 hr after a single exposure. The urinary elimination profiles suggest that biological monitoring might best be undertaken using a metabolite as marker. (from Frantz 1998). - Executive summary:
As the target substance hydrolyses rapidly (half-life < 30 minutes) the intrinsic properties are related to hydrolysis products of the target substance. This information is used as a supporting evidence on the toxicity of the target substance in CSA.
Referenceopen allclose all
Description of key information
Key value for chemical safety assessment
- Bioaccumulation potential:
- no bioaccumulation potential
Additional information
No studies were conducted on the target substance,Reaction product of Titanium tetrakis(2-ethylhexan-1-olato) and pentane-2,4-dione. As the target substance hydrolyses rapidly (half-life < 30 minutes) the intrinsic properties are related to hydrolysis products of the target substance. The hydrolysis products include 2-ethylhexanol, pentane-2,4-dione, and non-hazardous titanium dioxide. This information is used as a supporting evidence on the toxicity of the target substance in CSA.
Toxicokinetics of 2-ethylhexanol
Human data
No
studies on toxicokinetics in humans in vivo are available. In a
diffusion experiment by
Barber et al. (1992), the absorption rate of human skin in vitro was 38
µg per cm2 and hour.
Animal data
No quantitative data on the absorption by inhalation exposure are available. The occurrence of systemic toxic effects after inhalation exposure shows the efficient absorption by this route.
Absorption
The toxicokinetics of EH in female rats were studied by Deisinger et al. (1994). After oral gavage of 50 or 500 mg/kg the absorption rate was about 80%, independent of the administered dose. No differences in absorption were likewise observed following repeated exposures. The dermal absorption rate after exposure to 1000 mg/kg was reported to be about 5% in this study. In a diffusion experiment by Barber et al. (1992), the absorption rate of rat skin in vitro was 215 µg per cm2 and hour, i.e. about five times higher than in human skin.
Metabolism
In the study by Deisinger et al. (1994), the metabolism of EH was similar after oral and dermal exposure. The main metabolites in urine of orally treated rats were 2-ethylhexanoic acid, 5-hydroxy-2-ethylhexanoic acid, 6-hydroxy-2-ethylhexanoic acid and 2-ethyl-1,6-hexane diacid. Together, they represented 37 - 45% of the administered dose. Minor metabolites were 5-hydroxy-2-ethylhexanoic acid as well as lactones of 5-hydroxy-2- ethylhexanoic acid and 2-ethyl-5-hexanoneacid. They represented 3 - 5% of the administered dose. About 1% of the administered dose was recovered as 2-ethylhexanol. All these compounds were predominantly excreted as glucuronides (Deisinger et al., 1994). Albro (1975) reported the formation of about 50% 2-ethylhexanoic acid following a single oral exposure of rats to 275 mg/kg.
Excretion
After gavage to rats, 95% of EH was eliminated within 96 h (mostly within 24 h). About 70% of the administered dose was excreted in urine, 13% in faeces and 11% in expired air. A similar elimination pattern was found after dermal exposure, with lower absolute amounts due to lower absorption following dermal exposure. Older studies in mice and rats support the results of the most detailed study by Deisinger et al. (1994). (Cited and modified from SCOEL/SUM/158 ).
Toxicokinetics of pentane-2,4-dione (2,4-PD)
No studies are available concerning the mode of action of the substance. It is known, however, that 1,3-diketones unfold metal chelating properties in vivo which may lead to inhibition of enzymatic activity of metal containing enzymes such as peroxidases or cytochrome P450 without concomitantly lowering protein contents. In an inhalation study conducted in male Fischer 344 rats it could be shown that 14C-labeled-2,4-PD was readily absorbed by the inhalation route. Nose-only exposure to 400 ppm 14Clabeled-2,4-PD resulted in a rapid increase in plasma radioactivity during the first 3 hours of exposure, with a tendency to plateau toward the end of the 6 hour exposure period. Plasma unmetabolized 14C-labeled-2,4-PD was present throughout the whole of the exposure phase, but was significantly less than total 14C. Immediately postexposure, radioacivity was present in all tissues examined, but on a concentration basis (µg equivalents/g) there was no preferential accumulation of 14C in any tissue or organ. On a total organ basis, highest contents were in liver and kidneys. Post-exposure, plasma unmetabolized 14C-labeled-2,4-PD declined rapidly to undetectable concentrations by 12 hours. Elimination of 14C from plasma followed a biphasic pattern with a terminal half-life (beta t½) of 30.72 hours. Excretion over 48 hours of 14C was approximately equivalent between urine (37.6 %, mainly not identified metabolites) and expired 14 CO2 (36.3 %), which the most part of the radioactivity was eliminated in the first 12 hours. Expired volatiles, feces, tissues and carcass accounted for 2.29, 2.78, 1.66 and 17.15 % of the total administered radioactivity dose 48 hours postdosing, respectively (Frantz et al. 1998). (Cited from OECD SIDS, pentane-2,4-dione)
Toxicokinetics of Titanium dioxide
Titanium dioxide is insoluble in water and most ingested titanium is eliminated unabsorbed. In rats, about 95% ingested dose of titanium dioxide is recovered from faeces indicating that the most ingested titanium is not absorbed from gastrointestinal tract by blood (Patty, F. 1965). However, in humans detectable amounts of titanium can be found in the blood, brain and parenchymatous organs (Friberg, L. et al.1986). Based on average titanium concentrations found in human urine of about 10 µg/liter, it can be calculated that the absorption is about 3% (WHO, 1982).
Titanium dioxide released from target substance exists as hydrated form and thus human exposure via inhalation is not relevant.
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.