JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS The medico-biological approach of the problem which will not be dealt with has recently been referred to by Calnan 2, where methods of biological determination were discussed. Experimental evidence clearly shows the necessity for the low molecular sensitizing agent to form a high molecular compound with proteins, or protein derivatives of the organism, before sensitization takes place a. For the time being, however, this part of the mechanism of sensitization does not give much of a clue with regard to the structural condition with which the sensitizer must comply, for chemical reactions with proteins can be brought about by numerous organic compounds which have never been known to cause sensitization. There is no doubt that apart from the presence of specific reactive functional groups, other structural requirements will have to be met. An important part, for instance, will be played by such factors as steric hindrance and spacial structure, a part which, how- ever, can only be made understandable in its relation to the molecular structure of the proteins involved. For the time being too little is known about the changes in properties which a protein has to undergo before it can act as an antigene for contact sensitization. Only when this knowledge has been extended can conclusions be drawn with respect to the requirements for the structure of organic sensitizers a. It is true, though, that certain indications of a limited scope have been obtained about this aspect by the study of the phenomenon of cross- sensitization or group-reactions. Whilst sensitization reactions are in general brought about only by specific contact with the product with which the organism has been sensitized, this reaction can in certain cases also be brought about by contact with compounds which are chemically allied to the sensitizing agent. The structural problem can be approached by the study of this relationship which can easily be carried out experimentally, although it has already been clearly established that in human beings individual differences in reactions in cross-sensitization occur. In several recent investigations the relationship between the sensitizing action, and the chemical structure, by means of cross-sensitization has been the subject of a study by Fregert 4 on sensitization of a group of products allied with stilbestrol, and by Hjorth 5 concerning balsam of Peru, and constituents thereof. In tests carried out on persons who showed a distinct sensitization for these products, the reaction capacity in respect of products which showed a specific structural relationship, was investigated. In judging the results of this type of experiment, a clear distinction should be made between compounds which are converted into the original sensitizing agent either by means of a chemical reaction or as a result of enzymatic processes in the skin, and products which possess a structural analogy with the allergene 6.

CONTACT SENSITIZATION DUE TO PERFUMERY RAW MATERIALS 317 Investigations carried out by Schulz* have shown that cross-sensitization can cause over-sensitiveness to a specific product, e.g. ammonium thio- glycolate, in persons who have been in prolonged contact with this material, without spontaneous sensitization taking place. Under the influence of sensitization for the related thioglycolic hydrazide Voss 8 was able to prove these phenomena both on test persons and in guinea pigs for the same type of compounds. Inasmuch as the number of human test objects who are sensitized for a specific compound is nearly always limited, the more or less identical reaction in guinea pigs in cross-sensitization constitutes a very valuable addition to the test material. This is all the more true as cross- sensitization can be highly individual, and a group of test persons sensitized by a primary allergene can react very differently among themselves to a series of secondary allergenes, i.e. allergenes which produce cross-sensitization reactions. When a larger group of secondary allergenes is tested, one will observe distinctly individual reaction patterns. The occurrence of this individual pattern is explained by Sulzberger 9, who assumes that different functional groups of one sensitizing agent may give rise to different allergenes of which only homologous secondary allergenes may lead to cross-sensitiza- tion, whereas no reaction will occur in the absence of this related allergene. On the one hand there exists a group allergy whereby many facts can be concealed from experimental observation as a result of a very individual reaction pattern. On the other hand, there is the possibility of the forma- tion of over-sensitiveness for already known low, or non-sensitizing, products by primary sensitization due to new structurally related chemicals. This leaves the perfumery chemist with a problem which will continue to claim his attention in research, because structures from practically the entire field of organic chemistry play an important part in perfumery. With our limited, and frequently fragmentary, knowledge of the relationship between chemical structures and sensitizing capacity, it is almost impossible to draw correlations between them in prospective odoriferous chemicals. The biological experiment will therefore always have to supply the necessary data and such an experiment is greatly complicated by the phenomena discussed above. The formation of an allergene from a low-molecular organic chemical takes place by the reaction of the organism of the test object with a protein or a derivative thereof. As a result, this protein acquires specific properties which distinguishes it from the body protein and against which the organism builds up its anti-bodies. There are indications that the proteins from which the allergenes are formed, are in a removed position from the epidermic surface, so that the synthesis of the allergene must be preceded by a process of transport in or through the epidermis a. The extent in which this penetration, and this transport of the sensitizing