Fatty acids, C18-(unsaturated) dimers and their monoesters and diesters with 2-ethylhexanol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

migrated 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:

other: acceptable, well documented publication meeting basic scientific principles, no information about GLP

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1994

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

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. The study was conducted by the state of scientific knowledge of that time.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Details on test material:

- Unlabelled 2-EH (Laboratory and Research Products, Eastman Chemical Co., Rochester, NY, USA) without impurities
- Radiolabelled [1- 14C-ethyl)2-EH (Wizard Laboratories, Davis, CA, USA), mass purity of >99%, and a radiochemical purity of 98.7%

Radiolabelling:

yes

Remarks:

[1-14C-ethyl]2-ethylhexanol

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

female

Details on test animals or test system and environmental conditions:

Test animals: female rat, Fischer 344 strain (CDF(F-344)/CrlBR)
Source: Charles River Laboratories, lnc., Kingston, NY, USA
Age: 9-11 weeks
Weight: 125-150 g
isolation for at least 5 days prior to use
Housing: suspended, stainless-steel mesh cages prior to study, transferred to the study room to allow acclimatization for at least 1 day prior to dosing
Diet: certified rodent diet (Agway® Prolab RMH 3000 or Agway® Prolab RMH 3200meal) ad libitum except for a 4-h period immediately after dosing
Water: Domestic tap water ad libitum

Administration / exposure

Route of administration:

other: oral (gavage), dermal, i.v.

Vehicle:

unchanged (no vehicle)

Duration and frequency of treatment / exposure:

- single oral gavage administration
- repeated oral gavage administration: 14 consecutive days
- dermal administration: 6 h exposure period
- single i.v. administration

Doses / concentrations

Remarks:

Doses / Concentrations:
- single oral gavage administration: 50 and 500 mg/kg
- repeated oral gavage administration: 50 mg/kg
- dermal administration: 1 g/kg bw
- i.v.: 1 mg/kg

No. of animals per sex per dose / concentration:

4

Control animals:

no

Details on study design:

- single oral gavage administration:
Neat [14C]2-EH was delivered using a metal bulb-ended catheter attached to a glass syringe at doses of 50 and 500 mg/kg (6-10 µCi/animal).

- repeated oral gavage administration:
Animals were dosed for 14 consecutive days with neat, unlabelled 2-EH at 50 mg/kg using a
metal bulb-ended catheter attached to a glass syringe. On day 15, the animals were dosed with 50 mg/kg [14C]2-EH (7-9 µCi/animal).

- dermal administration:
Neat [14C]2-EH was applied at a dose of 1 g/kg bw (14-17 µCi/animal). 24 h before the dermal administration, an area of hair (about 25 cm2) was clipped from the dorsal surface of the rat. The dose was applied inside Pyrex glass containment cells (17 mm i.d., exposure area 2.27 cm2) adhered to the clipped backs of the rats with cyanoacrylate adhesive (Permabond 910®, Permabond International Division, Englewood, NJ, USA). The cell was covered to prevent evaporation. 8 rats (two groups of four
animals each) were dosed dermally, four for ADME studies, and four for blood pharmacokinetic studies.
The dermal exposure period was 6 h, then the cells were opened, the dose remaining on the skin was recovered by aspiration, and the exposure site was washed repeatedly with a 40% v/v pH isoderm soap solution and dried. The total amount of test material recovered from the skin was determined by assaying the radioactivity in the aspirated solution and washings.

- i.v. administration:
Dose Ievel: 1 mg/kg [14C]2-EH in isotonic saline (about 0.5 mg/ml in the saline, 10 µCi/animal).
8 rats (two groups of four animals each) were dosed via the tail vein, four for ADME studies, and four for
blood pharmacokinetic studies.
All animals were transferred to glass metabolism cages immediately after dosing to permit the separate collection of urine, faeces, and expired air.

Details on dosing and sampling:

For the ADME studies, samples were collected from each rat for up to 96 h.
- Urine was collected at intervals from each rat into frozen containers, and aliquots were assayed for radioactivity by liquid scintillation spectrometry. The remaining urine from each animal was stored frozen for later use in metabolite identification.
- Faeces were collected at intervals from each rat into frozen containers and homogenized with water. Portions were combusted prior to assay for radioactivity by liquid scintillation spectrometry.
- The expired air from each rat was drawn through silica gel to adsorb volatile organic materials, followed by 2.5 M sodium hydroxide to collect expired CO2. The content of each bottle was replaced at intervals until the end of the study. The materials adsorbed to the silica gel were removed with methanol, and aliquots of each methanol and sodium hydroxide solution were assayed for radioactivity by liquid scintillation spectrometry.
- For the blood pharmacokinetic studies, heparinized blood samples (about 100 µl]) were obtained from the orbital sinus of each animal at intervals. Blood samples were prepared for assay by dissolution in a one-step digestant-scintillant (Fluorosol, National Diagnostics, Manville, NJ, USA) and then counted by liquid scintillation spectrometry.

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

oral: absorbed effectively by the gastrointestinal tract following by rapid elimination; dermal absorption rate: 0.57 mg/cm²/h

Main ADME results 2

Type:

metabolism

Results:

Urinary metabolites were predominately glucuronides of oxidized metabolites of 2-EH, including glucuronides of 2-ethyladipic acid, 2-ethylhexanoic acid, 5-hydroxy-2-ethylhexanoic acid and 6-hydroxy-2-ethylhexanoic acid.

Main ADME results 3

Type:

excretion

Results:

major portion was excreted within 24h, primarily in the urine, smaller amounts in the faeces

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Rapid absorption of the oral doses by the gastrointestinal tract was followed by rapid elimination.
A small portion of the dose (1 g/kg dermal application) was absorbed dermally. The 6-h exposure to [14C]2-EH resulted in a mean absorption of only 5.2% of the applied dose.

Details on distribution in tissues:

no data

Details on excretion:

The major portions of the oral doses were excreted within 24 h, primarily in the urine. Smaller amounts of the dose were excreted in the faeces primarily within 24 h. Urinary excretion of radioactivity accounted for means of about 70% of the dose in each oral study. Faecal excretion of radioactivity occurred primarily in the 8-24 h samples and was comparable for all three oral studies. Recovery of 14CO2 from the expired air may show a slight dose dependency, with about 8%-14% of the dose recovered as 14CO2.
The excretion balance data for the i.v. dose shows that a mean of 3% of the dose was recovered in the 8-24 h faecal collections.

Toxicokinetic parameters

Toxicokinetic parameters 1

Test no.:

#1

Toxicokinetic parameters:

AUC: (dermal) 87.2 µg-equivalent/g x h

Toxicokinetic parameters 2

Test no.:

#2

Toxicokinetic parameters:

AUC: (i.v.) 4.6 µg-equivalent/g x h

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

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-ethylhexanoic acid and 6-hydroxy-2-ethylhexanoic acid.

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

no data

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
This series of studies indicate that 2-EH is rapidly absorbed following oral administration, but is only slowly absorbed following dermal application. The absorbed doses underwent extensive oxidative metabolism and glucuronidation followed by rapid excretion, primarily in the urine. Some evidence of metabolic saturation was seen at the high oral dose Ievel, but repeated dosing with 2-EH at 50 mg/kg produced no evidence of metabolic induction.

Executive summary:

Excretion balance studies were conducted with 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 Ievel, 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.

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.

No evidence of metabolic induction was seen following the repeated low oral dosing.

All of the oral doses were eliminated rapidly, predominantly in the urine during the first 24 h following dosing.

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.

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-ethylhexanoic acid and 6-hydroxy-2-ethylhexanoic acid.