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Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study; hydrolysis product of 2-ethylhexyl acetate

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

Constituent 1
Chemical structure
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
Details on test material:
- Analytical purity: not speciifed
- Specific activity (if radiolabelling): not speciifed
- Locations of the label: 2-ethyl[1-14C]hexan-1-ol
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

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 cottonoil seed
High dose: 1µCi, 8.8 µg of labelled [14C]-2-EH dissolved in 0.4 mL cottonoil seed, 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
Remarks:
Doses / Concentrations:
Low dose: 29 µg/kg bw labeleld 2-EH
High dose: 278 mg/kg bw unlabelled 2-EH
No. of animals per sex per dose / concentration:
2 male rats per dose level
Control animals:
no

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on excretion:
1) there were no differences between the low dose (27 µg/kg bw) and the high dose ( 278 mg/kg bw) regarding absorption, metabolism, and excretion
2) excreta
CO2: radioactivity reached a peak in less than 2 hours, logarithmic decrease witzh t1/2= 3.5 hrs
Faeces: nearl ycomplete within 20 hrs; a total of 8.6% of the administered dose eliminated by this route.
Urine: 25% were 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:
Identiifed metabolites:
2- heptanone, 4-heptanone, CO2.
2-ethyl5-hydroxyhexanoic acid, 2-ethyl-5-keto-hexanoic acid, 2-ethyl-1,6-hexanedioic acid.
unchanged 2-ethylhexanol approx. 3%

Any other information on results incl. tables

(1) 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.
(2) 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.

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


(3) Other identified metabolites were 2-ethyl-5-hydroxyhexanoic
acid, 2-ethyl-5-ketohexanoic acid, and 2-ethyl-1,6-hexene-
dioic acid. Only about 3% of the ethylhexanol was excreted
unchanged.
(4) Ethylhexanol was a competitive inhibitor of yeast alcohol
dehydrogenase, but a good substrate for the mammalian horse alcohol
dehydrogenase.
(5) 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.

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).