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Undertake Research on the Most Predictive Parameters for a QSAR Predicting Skin Permeation Rate

Background

In evaluating the risks presented by dermal exposure to chemicals, it is essential that producers, processors and consumers know the permeation rate through the skin and the bioavailability in the body in comparison in order this can be compared with the more general exposure route via inhalation.
In the present Technical Guidance Documents for risk assessments for new and existing substances, it is assumed that the experience gained from studying the skin permeation of pesticides can be directly used in assessing the risk of industrial chemicals. This can lead to serious over-estimations of industrial dermal exposure in the risk assessment by the authorities. For industrial chemicals, only limited data are available on experimental skin permeation rates. The lack of data is further compounded by the fact that where it is available, then it mostly derives from substances with a high permeation rate e.g. phenols, aromatic amines, nitro-aromatics, glycol ethers.
Little effort has been undertaken to explore the physical, chemical and biological properties of a substance in relation to the skin permeation rate and the bioavailability in the body. In order to make an efficient use of the available resources, it is recommended that the skin permeation rates are investigated according to a chemicals physico-chemical properties. The next step would then be to evaluate existing experimental studies and to establish new ones where appropriate. This would enable a quantitative analysis to be made of the influence of mode of application and of physico-chemical and biological properties upon permeation rate.

Objectives

Proposals
Proposals submitted for consideration should follow the format of the application from'Application for a CEFIC-LRI Grant' and should address the following areas under individual subheadings:
The title of the research proposal.
The name and affiliation of the principal investigator and the laboratory or laboratories in which the research will be conducted.
Evidence of the principal investigator's knowledge of, and contribution to, current understandings of the role skin permeation of industrial chemicals and prediction by means of QSAR.
A clear definition of the research objectives, including a description of the mechanistic basis for the proposed research.
A clear plan of investigation, including a clearly defined milestone plan that identifies all critical decision points in the research programme.
A detailed breakdown of costs.
Monitoring
The successful applicant(s) will be required to submit a progress report every 6 months during the course of the programme. At the end of the project, a detailed review of the project and the achievements made will be provided by the principal investigator. The successful applicant(s) will also be required to prepare for publication a manuscript describing the work undertaken and the results achieved.

Scope

Sponsor a project for studying improved parameters for predicting measured human skin permeation rates in vitro, already reported in the scientific literature. The improved parameters are log[K-DMPC]1 rather than log[Kow], and Molecular Volume instead of Molecular Weight.
Explore the goodness of fit of a QSAR for human skin permeation rate in vitro using log[K-DPMC] (membrane (L-alpha-dimyristoyl phosphatidyl-choline [DMPC])-water partition coefficients) rather than log[Kow] (n-octanol-water partition coefficient) as the independent parameter.
Explore the goodness of fit of a QSAR for human skin permeation rate in vitro, using molecular volume instead of molecular weight as the independent parameter.

Cost: Estimated costs of $25,000 for one-year maximum, to commence Q2/2000.

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