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Toxicological information

Dermal absorption

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Administrative data

Endpoint:
dermal absorption in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: A well reported study that is considered scientifically robust. Ethyl acetate not tested as 100% pure but only as the vehicle for another substance.

Data source

Reference
Reference Type:
publication
Title:
Transdermal delivery of levonorgesterel. VIII. Effect of enhancers on rat skin, hairless mouse skin, hairless guinea pig skin and human skin.
Author:
Catz, P., Friend, D.R.
Year:
1990
Bibliographic source:
Int. J. Pharm. 58, 93 - 102

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Transdermal delivery systems were prepared and evaluated for their ability to co-deliver the contraceptive agent levonorgestrel and the penetration enhancer ethyl acetate across human, hairless guinea pig, hairless mouse, and rat skin. The study was designed to identify the best animal model for human dermal penetration by measuring the lag time and steady state flux of the vehicle solvents used in the study. Various combinations of ethanol and ethyl acetate were used but only the results for pure ethyl acetate are reported here (not all animals reported in the study were evaluated with pure ethyl acetate - only rat and human skin evaluated)
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Levonorgestrel excess suspension in ethyl acetate
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals and environmental conditions:
- Source: Simonsen Laboratories, Gilroy, CA
- Age at study initiation: 8-10 weeks
- Weight at study initiation: 180-220g

Administration / exposure

Details on in vitro test system (if applicable):
SKIN PREPARATION
- Source of skin: Donor rat and human
- Human skin: from autopsy (Stanford University Medical Centre). Excised by dermatome from two donor females, thigh area, within 24 hours of postmortem. Thickness 0.1-0.15mm. - Storage conditions: sealed in airless bags at -20C, used within 2 months.
- Type of rat skin: full thickness abdominal (shaved for rat prior to CO2 sacrifice)- subcutaneous fat removed, washed in physiological saline and used within 1 hour.

PRINCIPLES OF ASSAY
- Diffusion cell: Franz
- Receptor fluid: isotonic saline plus 0.05% sodium azide
- Solubility of test substance in receptor fluid: yes
- Flow-through system: yes
- Test temperature: 37C receptor, 32C donor side

Results and discussion

Any other information on results incl. tables

Transdermal steady state flux of ethyl acetate:

human cadavar skin: 0.5 mg/cm2/h, lag time: 24 h

rat skin: 12 mg/cm2/h, lag time: 8 h

Applicant's summary and conclusion

Conclusions:
The permeation of ethyl acetate through rat skin is 24x the rate through human skin. The lag time for permation through human skin is 3x that through rat skin.
Executive summary:

Catz and Friend (1990) reported the steady state transdermal flux rate for ethyl acetate through human, rat, mouse and guinea pig skin. The rate for human skin was 0.5 mg/cm2/hr with a lag time of 24 hours. Rat skin was shown to be much more permeable, with a steady state permeation rate of 12mg/cm2/hr and a lag time of 8 hours.