Draize Rabbit Eye Test Compatibility with Eye Irritation Thresholds in Humans: A Quantitative Structure-Activity Relationship Analysis

Draize rabbit eye test scores, as modified maximum average

score (MMAS), for 68 pure bulk liquids were adjusted by the

liquid-saturated vapor pressure P°. These 68 adjusted scores, as

log (MMAS/P°), were shown to be completely equivalent to eye

irritation thresholds (EIT), expressed as log (1/EIT), for 23 compounds

in humans. Thus, for the first time the Draize eye test in

rabbits for pure bulk liquids is shown to be perfectly compatible

with eye irritation thresholds in humans. The total data set for 91

compounds was analyzed by the general solvation equation of

Abraham. Values of log (MMAS/P°) or log (1/EIT) could be fitted

to a five-parameter equation with R2 0.936, SD 0.433, AD

0.000, and AAD 0.340 over a range of 9.6 log units. When

divided into a training set of 45 compounds, the corresponding

equation could be used to predict the remaining 46 compounds in

a test set with AD –0.037 and AAD 0.345 log units. Thus, the

91-compound equation can now be used to predict further EIT

values to around 0.4 log units. It is suggested that the mechanism

of action in the Draize test and in the human EIT involves passive

transfer of the compound to a biophase that is quite polar, is a

strong hydrogen bond base, a moderate hydrogen bond acid, and

quite hydrophobic. The biophase does not resemble water or

plasma, but resembles an organic solvent such as N-methylformamide.