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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Similar to guideline study but no information is available on GLP. The study was published in a peer-reviewed journal.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1991

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
2-ethylhexane-1,3-diol
EC Number:
202-377-9
EC Name:
2-ethylhexane-1,3-diol
Cas Number:
94-96-2
Molecular formula:
C8H18O2
IUPAC Name:
2-ethylhexane-1,3-diol
Test material form:
other: liquid
Details on test material:
98% purity of radiolabeled substance. Nonlabeled substance had a purity of 99.7%.
Radiolabelling:
yes
Remarks:
14C

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals or test system and environmental conditions:
Male Fischer 344 strain rat, 10-12 weeks of age, weight 200-250 g.
Acclimated at least 7 days, housed in polypropylene cages in groups of 3-4.
Studies took place in Roth metabolism cages with a 2-day acclimation period prior to dosing using a jugular cannula surgically implanted.
Food was Purina Certified rodent Chow #5002, and water was from the municipal drinking water source.

Administration / exposure

Route of administration:
intravenous
Vehicle:
physiological saline
Details on exposure:
Doses were injected slowly over a 2-minute period via the indwelling jugular cannula. Blood was sampled via the cannula at 2.5, 5, 10, 20 and 40 minutes, and 1, 2, 4, 6, 12, 18, 24 and 48 hours after dosing. Urine was collected at 6 and 12 h post-dosing and thereafter in 12-h intervals. Feces were collected over two 24-h intervals. Room air was drawn through the Roth cages at a rate of approximately 500 ml/min and expired 14-CO2 was trapped over two 24-h intervals at room temperature. 48 h after dosing, rats were anesthetized with methoxyflurane. Carcasses were not assayed for radioactivity.
Duration and frequency of treatment / exposure:
One bolus dose, followed for 48 h monitoring.
Doses / concentrations
Remarks:
Doses / Concentrations:
150 mg/kg and 1.5 mg/kg body weight. The dose of 150 mg/kg was selected as the maximum tolerable level (MTD) for both sexes, and animals dosed at this concentration demonstrated a temporary narcosis which diminished within the first 5 minutes after administration. The 1.5 mg/kg dose was selected as 100-fold lower than the MTD.
No. of animals per sex per dose / concentration:
6 males/dose
Control animals:
no
Positive control reference chemical:
None
Details on dosing and sampling:
Body fluid and solid samples were assayed for radioactivity. Red blood cells were combusted for measurement of radioactivity. Urine samples were autoanalyzed chemically. Expired labeled 14C-CO2 was trapped using solutions of 2-methoxyethanol:ethanolamine (7:3) at room temperature and analyzed for radioactivity. Fecal samples were frozen until analysis using oxidation in distilled water (33%, w/v). Tissue oxidation was conducted in a Biological Materials Oxidizer (R.J. Harvey Instrument Corp, Hillsdale, NJ, USA) and by liquid scintillation spectrometry.
Statistics:
In groups of 4 rats per dose, a bioexponential equation for plasma concentration-time data was done using a nonlinear least squares data-fitting program (RSTRIP, Version 4.0, Micro-Math Inc., 1989, Salt Lake City, UT, USA) or by noncompartmental parameter estimation methods using the trapezoid rule approach described by Gibaldi and Perrier, 1982. Elimination and transfer processes were assumed to be first-oorder. Other values were calculated and plotted on semilog scales.

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
Time to Cmax = 0.0 min for both doses. Max plasma concentrations were 262.1 and 2.55 µg/g, for the 150 and 1.5 mg/kg doses, respectively.
Type:
distribution
Results:
The distribution half-life of 25.7 and 11.0 min, respectiively, for the 150 mg/kg and 1.5 mg/kg doses.
Type:
excretion
Results:
The elimination rate constant (min-1) was 0.0014 and 0.0013 for the for 150 mg/kg and 1.5 mg/kg doses, respectively. The combined half-life of elimination was 8.20 h and 8.67 h, respectively, for the two doses.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Delivered iv. Time to Cmax = 0.0 min for both doses. Max plasma concentrations were 262.1 and 2.55 µg/g, for 150 and 1.5 mg/kg, respectively.
Details on distribution in tissues:
Distribution from plasma was biphasic. An initial rapid rate constant (alpha) of 0.0270 and 0.0630 (min-1) was observed for 150 mg/kg and 1.5 mg/kg, respectively, with a half-life of of 25.7 and 11.0 min, respectiively. A slower terminal phase (beta) followed, with a half-life of 8.7 and 8.2 h, for the 150 mg/kg and 1.5 mg/kg dose groups, respectively. Doses were linear and independent; the distribution/elimination behaviour of the two doses were similar to each other. A slight increase in plasma concentration of the substance occurred between 4 and 6 h after administration, perhaps from reabsorption from the kidney or enterohepatic processes.
Details on excretion:
The majority of radioactivity (64.3 and72.4% at the high and low doses, respectively) was rapidly excreted in urine. Less than 10% was found in the feces (10.3% of the high dose and 4.99% of the low dose). Less than 1% of the administered dose was expired in the air as CO2. The elimination rate constant (min-1) was 0.0014 and 0.0013 for the two doses, respectively. The combined half-life of elimination was 8.20 h and 8.67 h, respectively, for 150 mg/kg and 1.5 mg/kg.
Toxicokinetic parametersopen allclose all
Toxicokinetic parameters:
half-life 1st: Distribution half-life: 25.7 min and 11.0 min, for 150 mg/kg and 1.5 mg/kg doses, respectively.
Toxicokinetic parameters:
half-life 2nd: Elimination half-life: 491.9 min and 520.2 min, for 150 mg/kg and 1.5 mg/kg doses, respectively.
Toxicokinetic parameters:
AUC: to infinite time: 18125 and 149.74, for 150 mg/kg and 1.5 mg/kg doses, respectively.
Toxicokinetic parameters:
Cmax: 262.1 and 2.550, for 150 mg/kg and 1.5 mg/kg doses, respectively.
Toxicokinetic parameters:
Tmax: 0.0 for both doses.

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
Unchanged substance was detected in plasma only within 18 h post-dosing. The AUC for unchanged substance was 16958 and 133.35 µg/g•min for the high and low doses at 48 hours, respectively, and 18125 and 149.74 when estimated through infinite time. The Vd, Cl and MRT indicated that the concentrations of the substance are cleared from the blood through first order body clearance processes.

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:
Accessible as administered intravenously.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
The pharmacokinetics of 2-ethyl-1,3-hexanediol, administered intravenously, were examined in rats at high and low doses. Values for pharmacokinetic parameters were obtained which indicate that the substance is rapid eliminated from the blood, primarily through the kidney (in urine), with some metabolism by the liver.