Registration Dossier

Administrative data

Endpoint:
dermal absorption in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1984
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study (publication) contains sufficient data to permit a meaningful evaluation of study results

Data source

Reference
Reference Type:
publication
Title:
Absorption of some Glycol Ethers through Human Skin in-vitro
Author:
Dugard P.H. et al
Year:
1984
Bibliographic source:
Env. Health Pers.; Vol. 57, 193-197

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
To assist evaluation of the hazards of skin contact with selected undiluted glycol ethers, their absorption across isolated human abdominal epidermis was measured in vitro.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Glycol Ethers
- Physical state: liquid
- Analytical purity: approximately 95% 1-methoxy-propan-2-ol
- Impurities (identity and concentrations): not specified in the publication
- Composition of test material, percentage of components: not specified in the publication
- Isomers composition: not specified in the publication
- Purity test date: not specified in the publication
- Lot/batch No.: not specified in the publication
- Expiration date of the lot/batch: not specified in the publication
- Stability under test conditions: not specified in the publication
- Storage condition of test material: not specified in the publication
Radiolabelling:
yes
Remarks:
Tritiated water (Radiochemical Centre)

Test animals

Species:
human
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
Human abdominal whole skin (dermis plus epidermis) was obtained post mortem. The subcutaneous fat was removed and the skin immersed in water at 60°C for 45 sec. The epidermis was then gently separated from the dermis and the epidermal sheet was then floated on water and picked up onto aluminum foil.

Administration / exposure

Type of coverage:
not specified
Vehicle:
unchanged (no vehicle)
Duration of exposure:
8 hours
Doses:
undiluted glycol ether (approximately 95% 1-methoxypropan-2-ol)
No. of animals per group:
not applicable
Details on study design:
For assessment of glycol ether absorption, the donor chamber of each diffusion cell (vertical membrane) was filled (circa 5 mL) with undiluted glycol ether or 1 mL placed in the donor of diffusion cells with horizontal membranes. Receptor chambers were filled with a known volume of distilled water. In each experiment a "control" diffusion cell was employed in which the donor chamber was left empty but distilled water placed in the receptor and sampled so that interfering compounds could be recognized. Samples were taken hourly from the receptors (0.25 mL, monoglycol series) or halfhourly (0.75 mL, diethylene glycol compounds) and glycol ether content assayed in duplicate 2 ,uL aliquots of the receptor samples as described below. Each receptor sample was replaced with an equal volume of fresh distilled water. All glycol ether experiments were run for 8 hr. The results of the assay of receptor solution glycol ether content were converted to total amount having penetrated (with correction for sample removal) and plotted against time. The slope of this plot gives the rate of absorption of glycol ether through 1.8 cm2 of epidermis, simple division yielding rate per 1 cm2. Permeability constants for the glycol ethers were calculated from the linear, steady-state, region of the above plots by dividing the rate per unit area by the applied concentration.
After 8 hr contact, the donor glycol ethers and receptor solutions were removed and replaced with distilled water overnight. The distilled water wash was removed and the second determination of membrane permeability to tritiated water made. The ratio of final tritiated water permeability constant to the initial value, the "damage ratio," provides an indication of irreversible alterations in epidermal diffusion barrier function occurring during the experiment.
Details on in vitro test system (if applicable):
Epidermal membrane discs, 3 cm in diameter, were cut with a punch, floated on water and drawn over the "receptor" chamber of diffusion cells of either of the types shown in Figure 1. The experimental conditions were identical whether diffusion cells having horizontal or vertical membrane orientation were used. The donor chambers of the diffusion cells were clamped in place to give 1.8 cm2 of epidermal surface available for absorption. All receptor solutions were stirred by a Teflon-coated stirring bar and experiments were conducted at 30°C.
The integrity of epidermal membranes was established before and after contact with the glycol ethers by measurement of their permeability to tritiated water. The donor chambers of diffusion cells were filled with tritiated water (5 µCi/mL), and the appearance of radiolabel in a measured volume of distilled water in receptor chamber was followed with time. Samples (25 µl) were taken hourly from the third to the sixth hour after addition of the donor tritiated water. Donor solutions were sampled at zero and 6 hr. A permeability constant for tritiated water was calculated from the slope of the (linear) plot of "sample counts versus times" . Epidermal membranes displaying tritiated water permeability constants greater than 1.5 x 10 cm/hr in the
initial determination were deemed to have been damaged in preparation and were rejected. Tritiated water was desorbed from acceptable membranes into distilled water in donor and receptor membranes overnight and both chambers were emptied prior to measurement of glycol ether absorption.

Results and discussion

Absorption in different matrices:
The absorption of all glycol ethers achieved maximum steady rates within the experimental period. The mean steady rates and the permeability constants derived from them are shown in Table 2. EM was the most readily absorbed glycol ether of the series tested. PM, EE, and EEAc were also readily absorbed, while EB was the most slowly absorbed monoglycol ether. EE and its acetate exhibited similar rates of absorption. For the three diethylene glycol ethers, DM, DE, and DB, rates of absorption were significantly slower than their monoethylene glycol equivalents, EM, EE and EB, respectively.
The lag time is determined by extrapolating the linear portion of these curves to zero absorption. This parameter is used to compare the early time course of absorption for different compounds (6) but tends to be difficult to determine with accuracy. However, the lag time displayed by DB of approximately 2 hr was clearly longer than for other glycol ethers (Table 2) with the exception of EM. The apparent lag time for EM varied between 1 and 3 hr, and this is discussed below. Control damage ratio values for water contact alone lie between 1.0 and 2.0. Thus slight irreversible effects on barrier function occurred for EM, EE, PM and DM.

Any other information on results incl. tables

Figure 1: Glass diffusion cells

Table 1: Skin absorption of glycol ethers

Applicant's summary and conclusion

Conclusions:
An absorption rate of 1.17 mg/cm2/hr was estimated for undiluted PGME.
Executive summary:

To assist evaluation of the hazards of skin contact with selected undiluted glycol ethers, their absorption across isolated human abdominal epidermis was measured in vitro. Epidermal membranes were set up in glass diffusion cells and, following an initial determination of permeability to tritiated water, excess undiluted glycol ether was applied to the outer surface for 8 hr. The appearance of glycol ether in an aqueous "receptor" phase bathing the underside of the epidermis was quantified by a gas chromatographic technique. A final determination of tritiated water permeability was compared with initial values to establish any irreversible alterations in epidermal barrier function induced by contact with the glycol ethers. 2-methoxyethanol (EM) was most readily absorbed (mean steady rate 2.82 mg/cm2/hr), and a relatively high absorption rate (1.17 mg/cm2/hr) was also apparent for 1-methoxypropan-2-ol (PM). There was a trend of reducing absorption rate with increasing molecular weight or reducing volatility for monoethylene glycol ethers (EM, 2.82 mg/cm2/hr; 2-ethoxyethanol, EE, 0.796 mg/cm2/hr; 2-butoxyethanol, EB, 0.198 mg/cm2/hr) and also within the diethylene glycol series: 2-(2-methoxyethoxy) ethanol (DM, 0.206 mg/cm2/hr); 2-(2-ethoxyethoxy) ethanol (DE, 0.125 mg/cm2/hr) and 2-(2-butoxyethoxy) ethanol (DB, 0.035 mg/cm2/hr). The rate of absorption of 2-ethoxyethyl acetate (EEAc) was similar to that of the parent alcohol, EE. Absorption rates of diethylene glycol ethers were slower than their corresponding monoethylene glycol equivalents. Combination of intrinsic toxicity and ability to pass across skin contribute to assessment of hazards of contact with undiluted glycol ethers.