IRRITANCY TO THE RABBIT EYE MUCOSA OF CREAM SHAMPOOS 673 comforting to realise that man finds the shampoos much safer than the rabbit finds them. MR. N.J. VAN ABsg.: It is extremely valuable to have this comparison of com- mercial products, but I do feel that it is quite possible to draw the wrong conclusions from it, and I would suggest that rather different conclusions can be drawn than are drawn in the paper. The fact that no complaints have been received by us on cream shampoos in the eye cannot be taken to mean that neat shampoo never gets in the eye. For instance, I feel that with the use of plastic tubes which occasionally splatter, some sufferers of neat shampoo in the eye must have appeared in the course of the years. If the reactions that they have suffered bore any resemblance whatever to the reactions in the rabbit, I feel quite certain that we would have known about it because we do know of things much less severe. Maybe the actual numbers of com- plaints do not represent the true figure in the whole population, but I cannot believe that anything resembling the severity produced in the rabbit occurring in a human would go unreported to the manufacturer. No such reports have appeared, and to my mind this means that the results obtained in the eye test are in some measure purely specific to the rabbit. I think that this is not unreasonable because I believe I am right in saying that lacrimation in the rabbit does not resemble lacrimation in the human eye. What I would be inclined to say is that the 10% test in the eye is a reasonable approximation to safety-in-use. This is the most likely occurrence during normal usage of a shampoo, whether cream or liquid. The neat applied test followed by washing, as in the original Draize procedure, seems to me to represent what hap- pens when a human subject accidentally gets neat cream shampoo in the eye- either it is washed out by tear secretion or by tap water within seconds. The response is essentially what you have reported in the Draize test with washing, which in fact is as mild, if not milder, than the effect from the 10% dilutions. I cannot help feeling that we are going beyond the bounds of reason if we regard the neat, unwashed application as being the ultimate toxicity. It would be if we were selling shampoos to rabbits, but I do not think it is so in selling them to humans. MR. F. RIDGWAY: I cannot agree with Mr. Van Abb• that this test should be carried out only on the diluted shampoo. If you consider the case of a child who might accidentally receive the concentrated shampoo or cream in its eye and develop an intense reaction, the eyes may be closed, the reaction may not become apparent, and the eyes would not be washed. Again, a perhaps not very intelligent mother, might neglect to wash the child's eye, and it could be some time before hospital treatment was given. I therefore think that the test should be carried out with a concentrated shampoo because there are conceivably conditions in use where washing may not be carried out within a short time of its getting into the eye. MR. R. E. DxvI•.S: There seems to be little doubt that consumer complaints do not indicate a hazard-in-use with cream shampoos. There have been two statements from the floor to support this. We would also agree that the rabbit eye test using undiluted shampoo does appear to indicate greater irritation than is seen in man. The dilution test may well be a more realistic assessment of safety-in-use, but my own feeling is that at the present time there is little scientific data either to confirm this or to indicate the correct dilution for any given class of products, such as the arbi- trarily chosen 10% dilution for • shampoos. I think it is unnecessary for me to stress the implications of "false negative" test results.

674 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS We should not overlook the fact that certain shampoo formulations have caused trouble in the past, and in this context I am thinking of the quaternary ammonium shampoos that were the subject of the famous FDA seizure in 1938. We are also aware of at least one example quoted by Rieger and Battista (6) of a product used as a neutraliser that was found to be innoxious in the rabbit test using the undiluted product, but which eventually proved to be an irritant to man. With regard to the predictive value of the results obtained with exaggerated exposures, we would emphasise that the effects recorded in our study resulted from the instillation of 1/l 0 ml of the shampoos as sold. This can hardly be described as an unrealistic exposure. I do not think that as a general premise we would accept Mr. Van Abb•'s comments, because as toxicologists it is almost axiomatic that we should establish what damage the material, at worst, is capable of causing. As far as human reaction is concerned, there are occasions when this procedure provides misleading information. A good example of this is probably provided by DMSO which, when given at high dosage to animals, causes characteristic changes in the lens of the eye and yet apparently has no effect upon the human eye, even when given for more prolonged periods of time. However, I am sure we all agree that current test methods involving animals are useful in the assessment of the safety of topical agents, provided the data is placed in its correct perspective. I think that these tests can yield valuable information relating new substances to others for which the hazards have been defined by both time and experience. Their use for predicting human responses in an absolute sense is tenuous at this present time. Many of us must feel that there is the greatest need for fundamental understanding of the mechanisms of injury and its causative factors. We may then be in a position to design more definitive and rational test procedures which, in turn, may increase their predictive value. MR. IX[. j. VAN ABBI•: I would say that the reactions obtained in the rabbit eye with neat shampoo are not tenuous in relation to human experience but totally wrong, and that either we are using the wrong test animal or using it in the wrong way. I agree that the dose is not an unreasonable one and I would imagine that it must have happened that humans have received considerably larger doses in their eyes. I just do not think they react in the same way. In reply to Mr. Ridgway, I would say that this is most likely due to the fact that the tear secretion dilutes out the shampoo rapidly so that the response is nothing like that which is seen in the rabbit. Consequently I am saying, not that you should not test on rabbits, but that you should adopt the Draize procedure rather than leaving the neat shampoo in the eye. MR. R. E. DAVIES: We do, in fact, add some support to this, although I would still stress th• p3int that p•rt of the value of the rabbit test is to relate the reactions seen with our new product to those observed with old or well-established products. On a comparative basis, it does have some value. The subject of species variation is a very thorny one in that we do not know enough about the basic morphology and physiology of different species of animals. We can compare different animal species and find staggeringly different results to standard test procedures. There have been a number of publications during the past few years (6) Rieger, M. M. ancl Batfists, G. W. J. So•. ½osm•tiv Chemists i5 161 (1964).