Sodium 2-hexyloxyethanolate

Dermal absorption

Administrative data

Endpoint:

dermal absorption in vivo

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: The study is comparable to OECD Guideline 427 with acceptable restrictions (partly limited documentation, only one dose level, only one termination timepoint).

Data source

Reference

Reference 1

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 2

Reference Type:

secondary source

Title:

Unnamed

Year:

2005

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 427 (Skin Absorption: In Vivo Method)

Deviations:

yes

Remarks:

only one dose level; only one termination timepoint

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Ethylene glycol monohexyl ether (EGHE)

IUPAC Name:

Ethylene glycol monohexyl ether (EGHE)

Constituent 2

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 the label: 1-hexyl and 1,2-ethanol positions

Radiolabelling:

yes

Remarks:

14C

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Sprague Dawley Inc. (Indianapolis, IN)
- Age at study initiation: 11-12 weeks
- Weight at study initiation: mean males: 204 g; mean females: 151 g
- Housing: plastic box cages
- Individual metabolism cages: yes, Roth-type metabolism cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 d in plastic box cages and 48 h before dosing in Roth-type metabolism cages

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

Administration / exposure

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Duration of exposure:

48 h

Doses:

- Nominal doses: 25 mg/kg bw
- Actual doses: 25 mg/kg bw
- Radioactive dose (mean +/- SD): males: 62.55 +/- 3.410 µCi/kg bw; females: 40.575 +/- 0.726 µCi/kg bw

No. of animals per group:

4 males and 4 females

Control animals:

no

Details on study design:

APPLICATION OF DOSE:
Each rat received a dose of 25 mg/kg bw to the clipped dorsal trunk skin, which was occluded with polyethylene sheeting for 48 h.

SAMPLE COLLECTION
- Collection of blood: 5, 15 and 30 min and 1, 2, 4, 6, 12, 18, 24, 36 and 48 h postdosing
- Collection of urine: in 6-12-h intervals
- Collection of feces: in 24-h intervals
- Collection of expired air: air passing through the metabolism cages was trapped for the collection of organic volatiles and 14CO2
- Terminal procedure: 48 h after dosing the rats were sacrificed and the dosed skin was removed
- Analysis of tissues and organs: radioactivity measurement of liver, kidney, brain, bone marrow, perirenal fat, heart, lung, muscle, gonads, uterus, skin remote from the dosing area, and carcass

SAMPLE PREPARATION AND ANALYSIS
- Blood samples, ca. 0.15 ml, were collected into heparinized capillary tubes, sealed with a clay sealer and centrifuged in a microhematocrit centrifuge. Spun tubes were broken at the plasma-packed cell interface, plasma was expressed into a tared scintillation vial and Aquasol counting scintillant (New England Nucler, Boston, MA) was added. These samples, and the Aquasol extracts of the charcoal and the 14CO2 traps, were analyzed for radioactivity by liquid scintillation spectrometry.
- Feces, carcass and tissues were homogenized in distilled water (33% w/v) and portions were analyzed for radioactivity by sample oxidation in a Biological Materials Oxidizer (R. J. Harvey Instrument Corp., Hillsdale, NJ)
- 14CO2 derived from combustion was quantitated by liquid scintillation spectrometry.
- EGHE was extracted from pooled plasma samples by a solid-phase extraction technique and analyzed using a capillary gas chromatograph coupled to a mass-selective detector. The amount of [14C]EGHE as a proportion of total labeled metabolites in urine samples was determined by HPLC separation and 14C quantitation with an in-line flow monitor.
- 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).

Results and discussion

Signs and symptoms of toxicity:

no effects

Dermal irritation:

not specified

Absorption in different matrices:

For details see table below.

Total recovery:

- Total recovery: 98,51 +/- 4.35% in males; 96,51 +/- 4.73% in females

Percutaneous absorption

Dose:

25 mg/kg bw

Parameter:

percentage

Absorption:

76.7 %

Remarks on result:

other: 48 h

Remarks:

calculated by the authors based on findings from i.v. study for males

Any other information on results incl. tables

Disposition of radiolabel in Fischer 344 rats following a 48 -h occluded epicutaneous application of [14C]EGHE at 25 mg/kg bw:

Fraction	Percentage recovered dose (mean ± SD)
	Time (h)	Males (n=4)	Females (n=4)
Urine	0-48	32.99 +/- 6.08	21.30 +/- 9.21
Feces	0-24	19.08 +/- 0.96	19.26 +/-7.40
	24-48	2.06 +/- 0.82	2.79 +/- 1.56
	0-48	21.13 +/- 5.00	22.06 +/- 7.12
Expired ^14CO2	0-24	2.34 +/- 0.43	2.36 +/- 0.37
	24-48	0.90 +/- 0.15	0.93 +/- 0.29
Volatiles	0-48	11.54 +/- 1.16	18.0 +/- 3.55
Cage wash		10.83 +/- 7.88	11.94 +/- 2.16
Tissues		0.39 +/- 0.062	0.46 +/- 0.09
Pelt and carcass		1.95 +/- 0.53	2.76 +/- 0.95
Dosing appliances		14.92 +/- 2.38	18.81 +/- 3.60
Skin rinses and dosed skin		1.52 +/- 0.32	1.19 +/- 0.44
Total % radioactivity recovered		98.51 +/- 4.35	96.51 +/- 4.73

 

Distribution of [14C]EGHE-derived radioactivity in tissues and organs of Fischer 344 rats following a 48 -h occluded epicutaneous application of [14C]EGHE at 25 mg/kg bw:

Tissue	Males (mean +/- SD; n= 4)		Females (mean +/- SD; n= 4)
	% of dose	µg Eq./g	% of dose	µg Eq./g
Liver	0.09 +/- 0.04	1.83 +/- 0.47	0.34 +/- 0.08	2.12 +/- 0.39
Kidney	0.43 +/- 0.01	1.31 +/- 0.34	0.05 +/- 0.01	1.41 +/- 0.22
Bone marrow	only partially sampled	3.35 +/- 1.00	only partially sampled	1.61 +/- 0.19
Spleen	0.02 +/- 0.01	1.03 +/- 0.27	0.03 +/- 0.01	1.24 +/- 0.19
Brain	0.003 +/- 0.01	0.12 +/- 0.23	0.003 +/- 0.01	0.09 +/- 0.17
Heart	0.01 +/- 0.001	0.43 +/- 0.08	0.01 +/- 0.01	0.54 +/- 0.17
Lung	0.02 +/- 0.01	0.94 +/- 0.25	0.02 +/- 0.003	1.06 +/- 0.12
Muscle	only partially sampled	0.24 +/- 0.34	only partially sampled	0.12 +/- 0.14
Fat	only partially sampled	0.14 +/- 0.21	only partially sampled	0.14 +/- 0.29
Ovaries	-	-	0.001 +/- 0.001	0.62 +/- 0.11
Uterus	-	-	0.003 +/- 0.001	0.68 +/- 0.16
Testes	0.01 +/- 0.01	0.26 +/- 0.30	-	-

The plasma 14C–time toxicokinetic profiles for both the males and females showed a rapid absorption phase, a transient distribution phase and a moderate elimination phase. The toxicokinetic parameters derived from the fitted curves are shown in the table below.

Toxicokinetic parameter estimates for a two-component open model of plasma total radioactivity for 48 -h occluded epicutaneous dosing of Fischer 344 rats with [14C]EGHE:

Parameter	Symbol	Estimated value
		2.5 mg/kg bw	25 mg/kg bw
Absorption rate constant (min^-1)	ka	0.01592	0.01240
Absorption half-life (min)	t1/2	43.54	55.91
Distribution rate constant (min^-1)	kd	0.01534	0.01190
Distribution half-life (min)	t1/2	45.23	58.25
Elimination rate constant (min^-1)	ke	0.000391	0.000394
Elimination half-life (min)	t1/2	1171.3	1760.2
Maximal plasma concentration (µg^-1)	Cmax	3.37	6.05
Time to Cmax (min)	tmax	97.70	113.09
AUC to 48 h (µg g^-1 min)	AUC48	4574	7298
AUC to infinite time (µg g^-1 min)	AUC∞	6712	10549

 

 

Applicant's summary and conclusion

Conclusions:

The toxicokinetic findings indicate a significant percutaneous absorption of the test substance across rat skin (calculated bioavailability for males: 76.7%), which is rapidly and extensively metabolized (metabolites not identified), with renal excretion being the principal route of elimination of metabolites. Very little of the recovered dose was in tissues and organs and there was no preferential accumulation in any organ or tissue.

Executive summary:

The study is comparable to OECD Guideline 427 with acceptable restrictions (partly limited documentation, only one dose level, only one termination timepoint).

Four male and four female Fischer 344 rats were administered a single dermal dose of 25 mg/kg bw [14C]EGHE under occlusive conditions for 48 h. Percutaneous absorption was rapid with > 95% of the radiochemical dose recovered, bioavailability was 76.7%, urinary excretion was 21 -33%, 14CO2 and volatiles accounted for 15 -18%. Extensive metabolism of the test substance took place.

Conclusion: The toxicokinetic findings indicate a significant percutaneous absorption of the test substance across rat skin (calculated bioavailability for males: 76.7%), which is rapidly and extensively metabolized (metabolites not identified), with renal excretion being the principal route of elimination of metabolites. Very little of the recovered dose was in tissues and organs and there was no preferential accumulation in any organ or tissue.