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Basic toxicokinetics

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basic toxicokinetics in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Meets generally accepted scientific standards, well documented and acceptable for assessment

Data source

Reference Type:
Report date:

Materials and methods

Objective of study:
Principles of method if other than guideline:
Single high and low and repeated low dose oral administration of test substance, dermal application of test substance, i.v. application of test substance; analysis of excretion, metabolic induction and dermal absorption
GLP compliance:

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Details on test material:
- Name of test material (as cited in study report): 2-ethylhexanol
- Analytical purity: unlabelled: No impurities were detected; radiolabelled: >99%

Test animals

Fischer 344
Details on test animals or test system and environmental conditions:
- Source: Charles River Laboratories, Inc., Kingston, NY, USA
- Age at study initiation: 9-1 1 weeks
- Weight at study initiation: 125-150 g
- Housing: suspended, stainless-steel mesh cages prior to study, and were transferred to the study room
- Individual metabolism cages: yes/no
- Diet (e.g. ad libitum): certified rodent diet (Agway Prolab RMH 3000 or Agway Prolab RMH 3200 meal) adlibitum except for a 4-h period immediately after dosing
- Water (e.g. ad libitum): tap water was available ad libitum
- Acclimation period: at least 1 day prior to dosing

Administration / exposure

Route of administration:
other: oral, dermal and i.v.
unchanged (no vehicle)
Details on exposure:
Single high (500 mg/kg) and low (50 mg/kg) oral doses of radiolabelled [14C]2-EH: neat [14C]2-EH was delivered using a metal bulb-ended catheter attached to a glass syringe at doses of 50 and 500mg/kg (6-10 µCi/animal).

Repeated oral dosing: 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 exposure: [14C]2-EH was applied as the neat chemical at a dose level of 1 g/kg body weight 14-17 µCi/animal). Twenty-four hours 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. Eight 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, after which time 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) pHisoderm 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.: the dose level was 1 mg/kg [14C]2-EH in isotonic saline (about 0.5 mg/mL in the saline, 10 µCi/animal). Eight rats (two groups of four animals each) were dosed i.v. via the tail vein, four for ADME studies, and four for blood pharmocokinetic studies.

All animals were transferred to glass metabolism cages immediately after dosing to permit the separate collection of urine, faeces, and expired air.

Duration and frequency of treatment / exposure:
Oral: single doses and repeated doses for 14 days
Dermal: 6h
I.v.: single dose
Doses / concentrations
Doses / Concentrations:
Oral: single doses of 50 and 500 mg/kg bw, repeated dose of 50 mg/kg bw
Dermal: 1 g/kg bw
I.v.: 1 mg/kg bw
No. of animals per sex per dose / concentration:
Control animals:
Details on dosing and sampling:
For the ADME studies, samples were collected from each rat for up to 96 h as described below. 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 l00 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

Toxicokinetic / pharmacokinetic studies

Details on absorption:
The dose appears to have been absorbed effectively by the gastrointestinal tract followed by rapid elimination. The major portion of the dose was excreted within 24 h, primarily in the urine. Smaller amounts of the dose were excreted in the faeces primarily within 24 h. A mean of 11% of the dose was recovered from the sodium hydroxide breath traps as 14CO2, but only a fraction of a percent of the dose was recovered from the breath as [14C] volatile organics. The major portion of the applied dermal dose was recovered at 6 h from the glass containment cells, either as a liquid, in the cell
washings, or on the cell cover. The small portion of the dose that was absorbed dermally was eliminated primarily in the urine, with smaller amounts eliminated in the faeces, and as 14CO, in the breath. Urinary excretion was rapid following the i.v. dose, with 52% of the dose recovered from the urine within 8 h postdosing. A large portion of the dose was recovered from the sodium hydroxide breath traps, and a small amount of the dose was recovered in the faeces.
Details on excretion:
For all three of the oral dose studies, elimination of [14C]2-EH was rapid, occurring predominantly in the first 24 h following dosing, and recovery was essentially complete by the conclusion of the studies at 96 h, averaging 94-98% of the administered doses.

Metabolite characterisation studies

Metabolites identified:
Details on metabolites:
5-OH-EHA, 2-Ethyladipate + 5-OH-EHA, 6-OH-EHA, Lactones of 5-OH-EHA, 2-Ethyl-5-hexenoic acid, EHA, 2-Ethylhexanol

Any other information on results incl. tables

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 level, but repeated dosing with 2-EH at 50 mg/kg produced no evidence of metabolic induction.

Applicant's summary and conclusion