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Description of key information

Rapid absorption, metabolism and excretion of 2-EH as polar glucuronides predominantly in urine occurs following oral ingestion. Bioaccumulation is unlikely due to virtually complete excretion (>95% within 96 hrs).
Dermal absorption of 2-EH by rat skin is slow and bioavailability is low. Metabolism and excretion show no differences compared to the oral route.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - dermal (%):
6.6

Additional information

Toxicokinetics, metabolism and distribution

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 (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-Ethylhexanol 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-ethylhexanol 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).

According to the review of WHO in 1998 2 -ethylhexanol is a good substrate for mammalian alcohol dehydrogenase. 2 -EH is therefore metabolised to 2 -ethylhexanal and then to 2 -ethylhexanoic acid. 

The presence of an ethyl or propyl substituent at the alpha position, such as in 2-ethyl-1-hexanol, inhibits beta-oxidation (Deuel, 1957). Detoxication pathways of omega- and omega-1 oxidation compete with beta-oxidation of these sterically-hindered substances. In the principal detoxication 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 (Williams, 1959; Deisinger et al., 1994). When the principal pathway is saturated, the corresponding carboxylic acid conjugates with glucuronic acid and is excreted primarily in the urine (Williams, 1959; Albro, 1975; Deisinger et al., 1994).

 

Basic toxicokinetics

Rapid absorption, metabolism and excretion of 2-EH as polar glucuronides predominantly in urine was demonstrated in rats following oral ingestion. Bioaccumulation is unlikely due to virtually complete excretion (>95% within 96 hrs). 2 -EH is a good substrate for mammalian dehydrogenases which leads to 2-ethylhexanoic acid which can be conjugated or further metabolised via partial beta-oxidation, or omega- and omega-1 oxidation, followed by conjugation (Albro, 1975; Deisinger, 1994).

2 -EH inhibits the mitochondrial beta-oxidation of fatty acids in-vitro and in-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).

Dermal absorption

2-EH was only slowly absorbed following dermal application of 1g/kg bw in the rat as less than 7% of the dose was absorbed within 6 hours of skin contact. The absorbed dose underwent rapid oxidative metabolism and glucuronidation followed by rapid excretion, predominantly in the urine. The absorption rate was 0.57 mg/cm²/h, which is in the range that was determined for rat skin in vitro (0.22 mg/cm²/h; Barber et al., 1992). The metabolic pattern was similar in all experiments, i.e there were no differences that could be attributed to the oral or dermal route, the low or hig dose level, or to single or repeated treatment. One exception is the marginally delayed excretion at 8 hours after dosing in the group receiving the high oral dose which indicates some saturation of the metabolic capacity (Deisinger, 1994).

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.

Justification and considerations for read-across to bis(2 -ethylhexyl) terephthalate (DEHT):

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 (2003)).

I

In short:

* From the in vitro study of metabolic hydrolysis using rat intestinal homogenate the following results can be taken into consideration

o Half-life parent molecule was 53.3 minutes

o 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:

o 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%)

o Excretion is rapid (peak 10 h after administration >95 %; > 99 % by 48 h)

o 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 to in vitro situation, but negligible for further considerations).

o 73 % of the absorbed dose is excreted in the urine

* Final conclusions used for further assessment:

 “DEHT is not readily absorbed following oral administration and is capable of undergoing complete metabolic hydrolysis to TPA and 2 -EH” (OECD, 2003).

 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.

 Complete hydrolysis of DEHT to 2 -EH and TPA (stochiometry 1 mole DEHT leads to 1.97 moles 2 -EH).