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EC number: 203-079-1 | CAS number: 103-09-3
- 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
Endpoint summary
Administrative data
Link to relevant study record(s)
Description of key information
There are no hints on any bioaccumulation potential.
Key value for chemical safety assessment
- Bioaccumulation potential:
- no bioaccumulation potential
Additional information
Absorption
In acute oral toxicity studies, rats were administered 2-ethylhexyl acetate by gavage. The LD50 was reported to be 5140 mg/kg bw; partly, clinical signs of toxicity were observed; therefore bioavailability of 2-ethylhexyl acetate after oral administration is indicated (Schmidt & Bachmann 1969, see chapter 7.2.1 acute oral toxicity).
In acute dermal toxicity studies dose levels of up to 17400 mg/kg bw 2-ethylhexyl acetate were administered to rabbits (Smyth and Carpenter 1944, Moreno 1976). The LD50 level was not attained even with these very high doses, indicating primarily a very low dermal toxicity. Additionally, in a subacute study rats showed no signs of toxicity after repeated application of ca. 1070 mg/kg bw over 12 days (Schmidt 1969). QSAR based dermal permeability regarding molecular weight, logPow and water solubility, calculated a very low dermal absorption of 0.3 µg/cm2/h (DERMWIN v1.43, 2009). This value is considered as indicator for a dermal absorption of < 10%. Taken together the experimental very low acute dermal lethality/ toxicity and the calculated very low dermal absorption potential, dermal uptake of 2-ethylhexyl acetate is considered low.
2-Ethylhexyl acetate has a comparably low vapour pressure of 31 Pa at 25°C (HSDB 2006, see chapter 4.6 vapour pressure); subsequently, the calculated vapour saturation threshold is about 2.2 mg/L. In inhalation hazard tests with saturated vapour atmospheres, 0/20 rats and 0/5 guinea pigs died after 8 h exposure (Schmidt 1969). No clinical signs were observed and there were no necropsy findings, indicating a low potential of toxicity of the substance via the inhalative route. Nevertheless, absorption of the substance via the inhalative route can be assumed.
Metabolism
The rapid and complete hydrolysis of the acetate esters of simple primary alcohols have been demonstrated for methyl, ethyl, butyl, isobutyl, pentyl and isopentyl alkyl esters and has been demonstrated to occur for the acetate ester of 2-ethylhexanol as well. The hydrolysis reaction occurs in the gut, respiratory tissue, and skin thereby allowing the corresponding alcohol (in this case, 2-ethylhexanol (2-EH; CAS 104-76-7)) to be absorbed into the systemic circulation. Deisinger (2005) demonstrated the initial hydrolysis reaction in an in vitro experiment using rat blood. 2-EH was formed in vitro within blood in a concentration and time-dependent manner from the administered 2-ethylhexyl acetate. Further metabolism of 2-EH (derived from the orally administered 2-ethylhexyl acetate) to 2-ethylhexanoic acid was demonstrated in the in vivo portion of the experiment, demonstrating the same down-stream metabolites from 2-ethylhexyl acetate administration as has been reported from direct 2-EH administration. The half-life for metabolism of 2-ethylhexyl acetate to 2-EH within the blood in vitro was 2.3 minutes, demonstrating the rapid hydrolysis of the acetate ester to the corresponding alcohol. Since 2-ethylhexyl acetate is rapidly and completely hydrolysed to 2-EH within mammalian organisms, 2-EH toxicity data is an appropriate surrogate for identifying hazards associated with systemic exposures to 2-ethylhexyl acetate. The metabolism of the further hydrolysis product acetic acid in the organism corresponds to that of the acetate ion occurring in intermediary metabolism, which on the one hand is used to produce numerous endogenous substances, and on the other can be degraded, forming CO2. (OECD 2010)
Toxicokinetics of 2-ethylhexanol (2-EH; CAS 104-76-7; hydrolysis product (surrogate) of 2-ethylhexyl acetate)
The metabolism of 2 -EH following single (50 and 500 mg/kg bw) and repeated oral administration to rats (50 mg/kg bw) was examined by Deisinger et al. (1994). The high, low, and repeated low oral doses of 2-ethylhexanol showed similar absorption and excretion profiles, with some evidence of saturation at the 500 mg/kg dose level. No evidence of metabolic induction was seen following repeated dosing. The compound was rapidly excreted within the first 24 hr predominantly in urine. Glucuronides of oxidized metabolites prevailed. Trace amounts were detected of the unchanged compound. Recovery was high which indicates rapid metabolism and excretion and a low potential for bioaccumulation. Oral and dermal key study findings are summarized as follows:
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]2-EH, following repeated oral dosing with unlabelled 2-EH at the low level, following dermal exposure for 6 h 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. The 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-ethyladipoic acid, 2-ethylhexanoic acid, 5-hydroxy-2-ethylhexanoic acid and 6-hydroxy-2-ethylhexanoic acid.
In an earlier study, 2-EH was also efficiently absorbed following oral administration to rats. 14C associated with 2-ethyl[1-14C]-hexanol was rapidly excreted in respiratory CO2(6-7%), faeces (8-9%) and urine (80-82%), with essentially complete elimination by 28 h after administration. There was no difference between the low or high dose (9 µg/kg bw and 278 mg/kg bw, resp.). The major metabolite is 2-ethylhexanoic acid, which appears in urine; alternatively it may also be further metabolised by either beta-oxidation or omega and omega-1 oxidation. Only 3% of the 2-EH are excreted unchanged. Overall, 2-EH was rapidly absorbed, metabolised, and excreted mainly via urine within 28 hours following the oral administration to rats. Accumulation of 2-EH or its metabolites is unlikely to occur (Albro, 1975).
Barber et al. (1992) examined the dermal absorption of 2 -EH by rat and human skin in vitro. The absorption rate was 5.78 times higher with rat skin compared to human stratum corneum ( i.e 0.22 +/- 0.09 mg/cm²/hour with rat skin versus 0.038 +/- mg/cm²/hour using human skin. Therefore, using rat dermal absorption data may overestimate the degree of skin absorption in humans.
The presence of an ethyl or propyl substituent at the alpha position, such as in 2-ethyl-1-hexanol, inhibits beta-oxidation. Detoxification pathways of omega- and omega-1 oxidation compete with beta-oxidation of these sterically-hindered substances. In the principal detoxification pathway, the parent alcohol or corresponding carboxylic acid undergoes a combination of reactions including omega- or omega-1 oxidation and functional group oxidation leading to polar, acidic metabolites capable of being excreted in the urine (Deisinger et al., 1994). Bioaccumulation is unlikely due to virtually complete excretion (>95% within 96 hrs). When the principal pathway is saturated, the corresponding carboxylic acid conjugates with glucuronic acid and is excreted primarily in the urine (Albro, 1975; Deisinger et al., 1994). 2 -EH inhibits the mitochondrial beta-oxidation of fatty acidsin vitroandin vivo, which results in decreased levels of plasma ketones, and increased levels of hepatic total lipids and triglycerides. In contrast, the peroxisomal oxidation pathways are not inhibited by 2 -EH (Badr, 1990).
Justification and considerations for using data of bis(2 -ethylhexyl) terephthalate (DEHT, CAS 6422-86-2) for assessment of reproductive toxicity
There is no fertility study available for 2-ethylhexyl acetate. However, data of di (2 -ethylhexyl) terephthalate (DEHT) were used in a weight of evidence approach to predict the effect of 2-ethylhexyl acetate on fertility.
This weight of evidence approach was considered adequate because DEHT is metabolised immediately and entirely to 2-EH and terephthalic acid. The 2-EH moiety is thus available in the body after DEHT application. Stoichiometry of reaction at termination of metabolic hydrolysis using rat intestinal homogenate inin vitroconditions was indicating complete hydrolysis to terephthalic acid and 2-EH.
Information on toxicokinetic behaviour, metabolism and distribution of DEHT is provided in a study of Barber et al. (1994), which was divided into two parts (in vitro and in vivo; also summarised in the SIDS Initial Assessment Report by OECD (2004)).
From thein vitro study of metabolic hydrolysis using rat intestinal homogenate the following results can be taken into consideration
1) Half-life parent molecule (DEHT) was 53.3 minutes
2) Stoichiometry of reaction at termination was 1.97 moles 2-EH formed per mol DEHT, thus indicating complete hydrolysis to terephthalic acid
From the in vivo study where 100 mg/kg [Hexyl-2-14C]-DEHT was given to SD rats (oral gavage in corn oil, 10 adult males) the following results are considered relevant for further assessment:
1) Excretion occurs mainly via faeces (56.5 %) and urine (31.9 %), to a minor extend in expired air (3.1 %) and only 1.4% remain in the carcasse (total recovery approx. 93%)
2) Excretion is rapid (peak 10 h after administration >95 %; > 99 % by 48 h)
3) 90.7% of recovery of [14C] DEHT was found either in faeces (36.6%), urine (50.5%) or in expired air (3.6%). In faeces only unchanged DEHT was detected, whereas in urine and expired air only indicators of complete metabolism were found (unlabelled TPA and 14CO2, respectively). Thus amount of mono(2 -ethylhexyl)terephthalate is limited to maximum of 9.3% of oral administered dose (suggesting that hydrolysis in vivo might not be entirely complete as compared toin vitrosituation, but negligible for further considerations).
4) 73 % of the absorbed dose is excreted in the urine
Final conclusions used for further assessment:
a) “DEHT is not readily absorbed following oral administration and is capable of undergoing complete metabolic hydrolysis to TPA and 2-EH” (OECD, 2004)
b) Based on the data above approximately 65% of the 100 mg/kg of DEHT administered were absorbed by the rats (i.e. 36.6% of the dose recovered (corresponding to ca. 34 mg/kg) were excreted unchanged and thus rendered unabsorbed via the faeces. In reverse approximately 65% of the administered 100 mg/kg were absorbed). For further calculations 50% oral absorption of DEHT is assumed.
c) Complete hydrolysis of DEHT to 2 -EH and TPA (stochiometry 1 mole DEHT leads to 1.97 moles 2 -EH)
Justification and considerations for using data of 2-ethylhexanoic acid (CAS 149-57-5) for assessment of reproductive toxicity
The hydrolysis of 2-ethylhexyl acetate to 2-ethylhexan-1-ol is rapid. The subsequent metabolism of 2-ethylhexan-1-ol to 2-ethylhexaldehyde is presumed to occur with subsequent oxidation of the aldehyde intermediate to 2-ethylhexanoic acid. Metabolism and toxicokinetics studies with 2-ethylhexan-1-ol have demonstrated the presence of 2-ethylhexanoic acid in the plasma as well as glucuronide conjugates and oxidation products of 2-ethylhexanoic acid metabolism in the urine [Deisinger et al., 1994]. Since 2-ethylhexanoic acid is the major metabolite of 2-ethylhexan-1-ol, the result of the OECD 443 study with 2-ethylhexanoic acid is appropriate to assess the reproductive toxicity of 2-ethylhexyl acetate.
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