Fatty acids, C16-18 (even numbered, C18 unsaturated), 2-ethylhexyl esters, epoxidized

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Remarks:

Performed with metabolic degradation product

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1975

Materials and methods

Objective of study:

other: ADME

Principles of method if other than guideline:

Oral rat ADME studies using [14]C-2-EH

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-ethylhexan-1-ol

EC Number:

203-234-3

EC Name:

2-ethylhexan-1-ol

Cas Number:

104-76-7

Molecular formula:

C8H18O

IUPAC Name:

2-ethylhexan-1-ol

Specific details on test material used for the study:

- Analytical purity: not speciifed
- Specific activity (if radiolabelling): not speciifed
- Locations of the label: 2-ethyl[1-14C]hexan-1-ol
- The test item 2-ethylhexan-1-ol is a metabolic degradation product of the substance to be registered.

Radiolabelling:

yes

Remarks:

[14]C

Test animals

Species:

rat

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 300 g
- Individual metabolism cages: not speciifed
- Diet: ad libitum
- Water: ad libitum
- Housing: The animals were held in metabolism cages

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: cottonseed oil, 0.4 mL

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Low dose: 1µCi, 8.8 µg of labelled [14C]-2-EH dissolved in 0.4 mL cottonseed oil
High dose: 1µCi, 8.8 µg of labelled [14C]-2-EH dissolved in 0.4 mL cottonseed oil, additionally 0.1 mL (83.3 mg) of unlabeled 2-EH.

VEHICLE
Amount of vehicle (if gavage): 0.4 mL

Duration and frequency of treatment / exposure:

Single dose

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

29 other: µg/kg bw

Remarks:

labelled 2-EH/ low dose group

Doses / concentrations 2

Dose / conc.:

278 mg/kg bw/day (actual dose received)

Remarks:

unlabelled 2-EH plus 29 µg/kg bw labelled 2-EH/ high dose group

No. of animals per sex per dose / concentration:

2 male rats per dose level

Control animals:

no

Details on dosing and sampling:

SAMPLING:
CO2 was collected in ethanolamine: cellososolve (1:8). Urine and faeces were collected at hourly intervals. The excreta, an ethanol wash of the cages, the rat hearts, brains, livers, kidneys and the carcass were examined for the radiolabel.

PROCESSING OF URINE:
2 mL of urine were passed through a Dowex 50-H column, 200-400 mesh and eluted with deionised water. Fractions were collected and monitored for radioactivity. Urine fractions from the high dose animals covering the first 18 hours after administration were pooled, made basic and extracted with diethyl ether, then adjusted to pH1 and extracted with diethyl ether. The two extracts were dried and used for characterisation of metabolites.

ANALYSES:
metabolites were separated by GC using FID. Mass spectrometry: chemical ionisation mass spectra and electron impact spectra were taken.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

2-Ethylhexanol was efficiently absorbed following oral administration to rats. There were no differences between the low dose (27 µg/kg bw) and the high dose ( 278 mg/kg bw) group.

Details on excretion:

- There were no differences between the low dose (27 µg/kg bw) and the high dose ( 278 mg/kg bw) group regarding excretion
- 14C associated with 2-ethyl[1-14C]-hexanol was rapidly excreted in respiratory CO2 (6-7%). The radioactivity reached a peak in less than 2 hours, logarithmic decrease witzh t1/2= 3.5 hrs
- Faeces: nearly complete within 20 hrs; a total of 8.6% of the administered dose eliminated by this route.
- Urine: 25% was excreted within 8 to 10 hrs, approx. 80% after 28 hrs
- Total: 96.1% were excreted after 28 hrs. Cage wash accounted for 2.7%. Only 1.4% was found in the carcasses.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

IDENTIFIED METABOLITES:
2- heptanone, 4-heptanone, CO2. 2-ethyl-5-hydroxyhexanoic acid, 2-ethyl-5-keto-hexanoic acid, 2-ethyl-1,6-hexanedioic acid. unchanged 2-ethylhexanol (approx. 3%)

ADDITIONAL INFORMATION ON METABOLISM
- The amount of label recovered in CO2 matched the amount of unlabelled 2-heptanone plus 4-heptanone recovered from urine, suggesting that both types of metabolites may have been derived from the major urinary metabolite, 2-ethylhexanoix acid, by decarboxylation following partial beta-oxidation. The 14CO2 appeared not to be derived from acetate or by reductive decarboxylation.
- There were no differences between the low dose (27 µg/kg bw) and the high dose ( 278 mg/kg bw) group regarding metabolism

OTHER INFORMATION ON METABOLIC PATHWAYS
- Ethylhexanol was a competitive inhibitor of yeast alcohol dehydrogenase, but a good substrate for the mammalian horse alcohol dehydrogenase.
- Metabolic pathways were suggested as follows:
(i) first step: oxidation of 2-ethyl-hexanol via alcohol dehydrogenase and aldehyde dehydrogenase to 2-ethyl-hexanoic acid (2-EHA)
(iia) omega-oxidation of 2-EHA, leading to the di-acid
(iib) omega-1 -oxidation of 2-EHA, leading to 5-hydroxy and 5-keto-2-ethylhexanoic acid
(iic) ß-oxidation, leading to the 2-keto- and 4-keto-pentanones and CO2.

Any other information on results incl. tables

Excretion of [14-C] within 28 hrs after oral administration to rats         (% of dose)
CO2	6-7
Urine	80-82
Faeces	8-9
Total excreted	96.1
Cage wash	2.7
Carcass	1.4

Applicant's summary and conclusion

Conclusions:

2-EH was rapidly absorbed, metabolised, and excreted mainly via urine within 28 hours after oral administartion to rats. Accumulation of 2-EH or its metabolites is unlikely to occur.

Executive summary:

2-Ethylhexanol was 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 ß-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).