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Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
other information
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study is comparable to OECD Guideline 427 with acceptable restrictions (partly limited documentation, e.g. no identification of metabolites).

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Percutaneous toxicokinetic and repeated cutaneous contact studies with ethylene glycol monohexyl ether
Author:
Ballantyne B et al.
Year:
2003
Bibliographic source:
J Appl Toxicol 23; 301-314
Reference Type:
secondary source
Title:
Unnamed
Year:
2005

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
no
GLP compliance:
no

Test material

Constituent 1
Reference substance name:
Hexylglycol (EGHE)
IUPAC Name:
Hexylglycol (EGHE)
Constituent 2
Chemical structure
Reference substance name:
2-hexyloxyethanol
EC Number:
203-951-1
EC Name:
2-hexyloxyethanol
Cas Number:
112-25-4
Molecular formula:
C8H18O2
IUPAC Name:
2-(hexyloxy)ethanol
Details on test material:
- Analytical purity: 97.31%
- Specific activity: 2.1 mCi/mmol
- Locations of label: 1-hexyl and 1,2-ethanol positions
Radiolabelling:
yes
Remarks:
14C

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hazelton-Dutchland (Denver, PA)
- Age at study initiation: 9-10 weeks
- Weight at study initiation: 2-3 kg
- Housing: open rack-type metabolism cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 d

ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
intravenous
Vehicle:
other: 0.9% saline
Details on exposure:
Rabbits were dosed through the marginal ear vein
Duration and frequency of treatment / exposure:
One intravenous injection
Doses / concentrations
Remarks:
Doses / Concentrations:
- Nominal dose: 1 and 10 mg/kg bw
- Actual dose: 0.972 and 10.08 mg/kg bw
- Radioactive dose (mean +/- SD): 8.6680 +/- 0.003 and 9.2561 +/- 0.0068 µCi/kg bw
No. of animals per sex per dose / concentration:
4 males per dose
Control animals:
no
Details on study design:
- Dose selection rationale: based on preliminary intravenous LD50 study
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Samples: urine, faeces, blood & plasma, cage wash, carcass
- Time and frequency of sampling:
Blood & plasma: 2.5, 15 and 30 min and 1, 2, 4, 6, 12, 18, 24, 36 and 48 h
Urine: over 0–6 h, 6–12 h and thereafter at 12-h intervals up to 36 h
Faeces: over 24-h intervals
Cage wash: no details
- Plasma 14C concentrations were analyzed using computer-fitted, model-dependent methods. A bi-exponential equation was fitted to calculate mean values for plasma concentration–time data from four animals per dose using a non-linear least-squares data fitting program (RSTRIP; Micro-Math, Inc., Salt Lake City, UT). Parameters estimated included the distribution rate constant (kd), absorption rate constant (ka), elimination rate constant (ke), half-life (t1/2) for distribution, absorption and elimination, maximum plasma concentration (Cmax), time to Cmax (tmax), area under the curve through 48 h (AUC48), AUC to infinite time (AUC∞), apparent volume of distribution (Vd) and systemic clearance (Cltot).

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: plasma, urine, faeces
- Time and frequency of sampling:
Plasma: 2.5, 15 and 30 min and 1, 2, 4, 6, 12, 18, 24, 36 and 48 h
Urine: over 0–6 h, 6–12 h and thereafter at 12-h intervals up to 36 h
Faeces: over 24-h intervals
- From how many animals: 4 per dose (plasma samples pooled)
- Method types for identification: liquid scintillation spectrometry, capillary gas chromatography coupled to a mass-selective detector (sensitivity 10 pg), HPLC separation and 14C quantitation with an in-line flow monitor

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
The plasma pharmacokinetic profiles at both i.v. doses are roughly superimposable, with a constant tenfold difference in plasma concentrations at a given time point. At both i.v. dosages there was a prolonged distribution phase and a moderate rate of elimination. Toxicokinetic parameters derived from fitted curves are given in Table 1 below. The distribution rate constants were relatively large. Elimination rate constants were small, with t1/2 32–40 h. The Cmax, AUC48 and AUC∞ valeus were dosage proportionate, suggesting first-order elimination processes for the dosage range studied. The Vd values were large, suggesting a broad tissue distribution. The systemic clearances were similar and close to the rabbit glomerular filtration rate of 10 ml/kg bw, further indicating that renal excretion is the major elimination route. Measurements of plasma EGHE concentrations by gas chromatography showed no detectable EGHE at 1 h or with subsequent samples up to 48 h.
Details on excretion:
A very high proportion of 14C was recovered in urine (78–83% over 48 h). The high recovery (93–102%) indicates low expired 14CO2. Rates were similar for the two dosages, and the majority was eliminated in the first 24 h postdosing.
For details see table 2 below.

Metabolite characterisation studies

Metabolites identified:
not measured
Details on metabolites:
Using urine HPLC chromatograms and a C8 column, free EGHE could not be detected and most of the 14C eluted as a single peak at the column void volume (ca. 1–2 min). Using an Aminex column it was possible to separate 3–4 major peaks (8.75, 9.5, 11.25 and 15.75 min) and 1–4 scattered minor peaks.

Any other information on results incl. tables

Table 1: Toxicokinetic parameter estimates for a two-compartment open model of plasma total radioactivity following intravenous dosing of New Zealand White rabbits with EGHE:

Parameter

Symbol

Estimated value

1 mg/kg bw

10 mg/kg bw

Distribution rate constant (min-1)

kd

0.04097

0.01723

Distribution half-life (min)

t1/2

19.92

40.23

Elimination rate constant (min-1)

ke

0.000293

0.00360

Elimination half-life (min)

t1/2

2368

1925

Maximal plasma concentration (µg g-1)

Cmax

5.10

42.49

Time to Cmax (min)

tmax

0.0

0.0

AUC to 48 h (µg g-1 min)

AUC48

288.7

3958.5

AUC to infinite time (µg g-1 min)

AUC

357.4

4241.3

Apparent distribution volume (ml)

Vd

43640

32610

Systemic clearance (ml min-1)

Cltot

12.78

11.78

Table 2: Disposition of radiolabel in male New Zealand White rabbits following intravenous dosing with [14C]EGHE:

Fraction

Time (h)

Percentage recovered dose (mean ± SD; n=4)

1 mg/kg bw

10 mg/kg bw

Urine

0-48

83.05 +/-6.96

78.38 +/-3.04

Feces

0-24

1.18 +/-0.76

1.06 +/-0.56

24-48

0.43 +/-0.46

0.23 +/-0.12

0-48

1.61 +/-0.44

1.28 +/-0.60

Cage wash

3.12 +/-1.54

6.07 +/-1.56

Carcass

4.93 +/-3.52

16.22 +/-3.24

Total % radioactivity recovered

93.10 +/-2.17

102.40 +/-2.59

Applicant's summary and conclusion

Conclusions:
The i.v. toxicokinetic studies in rabbits showed first-order toxicokinetics in the range 1 -10 mg/kg bw. EGHE is rapidly and extensively metabolized, with elimination occurring mainly by renal excretion.
Executive summary:

The study is comparable to OECD Guideline 427 with acceptable restrictions (partly limited documentation, e.g. no identification of metabolites).

The toxicokinetics of EGHE was investigated in New Zealand White rabbits by intravenous (i.v.) dosing. Given i.v. to male rabbits (1.0 and 10 mg/kg bw) [14C]EGHE demonstrated first-order kinetics. Carbon-14 was eliminated mainly in urine (78–83%) as metabolites, with no free EGHE. The plasma free EGHE concentration declined very rapidly post-dosing and was not detectable by 1 h.

Conclusion: The i.v. toxicokinetic studies in rabbits showed first-order toxicokinetics in the range 1 -10 mg/kg bw. EGHE is rapidly and extensively metabolized, with elimination occurring mainly by renal excretion.