254 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS TABLE 6--REPEATED INSULT PATCH TEST WITH AN AGRICULTURAL INSECTICIDE 5•O AquEous EMULSION of 50 Subjects Tested: 44 Subjects--Negative, 6 Showed Allergic Reaction Subject Number 1 2 3 4 5 6 7 8 9 10 11 12 C 21 ........... 44-* 26 .......... 24- 34- * 37 ......... 14- 24-PM 34-* 38 ........... 44-* 41 ........... 44-* 46 ........... 44- *# * Delayed positive appeared 24 hours after removal of patch. PM Patch moved to different site. # Re-tested 2 mos. later--open patch test 3 drops: 24-. what constitutes a damaged skin? Is it mild redness such as a sunburn, sca•ification or mild and transitory redness (freezing) such as caused by ethyl chloride or more severe reaction such as produced by a vesicant? It is not exactly known what degree of damaged skin facilitates develop- ment of cutaneous allergy. If severe reaction is required on an appreciable number of subjects the method would not be practicable. Primary Irritant Reaction Closed Patch Test. This reaction elicited by closed patch to (a) a minimum concentration or to (b) use concentration indicates that the tested substance is inherently a cutaneous irritant. The latter action in actual use is to be expected from higher concentration in the case of category (a) or degree and duration of exposure in the case of category (b). An example of higher concentration is solution of dichromate. Some persons tested by closed patch with 1 per cent will show cutaneous reac- tion. However, in actual use its dermatitis potential (excluding sensitiza- tion) is at much higher concentration. Whereas, for example, in the case of category (b) solution of soap or of kerosene, dermatitis potential is in relation to degree and duration of exposure. In addition, other vari- ables the tolerance of the skin--high threshold of irritability ("tough skin"), low threshold of irritability ("sensitive skin") dry skin, winter or summer weather, more than usual exposure. Soap as ordinarily used (3) and kerosene (4) (or other solvents) in moderate contact with the skin (the hands of industrial workers) are not dermatitic but are if exposure is excessive and prolonged. Fatigue Reaction (Cumulative primary irritant action): The repetitive method (provided each application is made to the same site), detects substances that are not irritants on initial contact but are on repeated contact. This is manifested by positive reactions appearing early or late in the comse of consecutive applications and after prior negative reactions. This has been called fatigue reaction. It doubtless represents cumulative primary irritant action resulting from depression or exhaustion of the

INSULT PATCH TESTS IN STUDY OF CUTANEOUS REACTION 255 defensive mechanism of the skin to combat a cutaneous noxa. The term "fatigue" physiologically connotes no reaction used in the above sense it implies fatigue of the defensive mechanism and will be used with this meaning. This exhaustion, or fatigue reaction, is a replica of what is observed clinically and discussed in the aforegoing of dermatitis potential in relation to degree and duration of exposure. The phenomena as observed in the repetitive study is an interesting phase in study of primary cutaneous irri- tant action. The fatiguing action of a tested substance indicates that it is a sub- clinical primary irritant it exerts such action in relation to frequency and duration of cutaneous exposure. Its determination by the repetitive method is a severe test that may or may not be duplicated in actual use. In correlation of fatiguing action as determined by the repetitive method with actual use, considerations should be given to its incidence, its early or late appearance and the circumstances operative in actual use. For example, the antiperspirant studied in Table 4 showed high incidence and early appearance. Its actual use in the axilla would approach condi- tions of a closed patch test its contact with the skin would not be brief. In contrast the waterless cleanser (Table 2) showed low incidence and late appearance in actual use contact with the skin would be brief. The fatiguing action of many substances as demonstrated in the repet- itive method may not be operative in actual use. The repetitive method is therefore of more practical value in determining allergenicity than fatiguing action. Consideration should be given to fatiguing action in explanation of dermatitis allegedly caused by a cosmetic. Such dermatitis should be milder than an allergic one the patch test negative. Diagnosis of fatigue reaction would be presumptive and difficult to prove. If such reaction does occur, I think it would be more likely in the axilla for reasons already discussed. One occasionally sees (as shown in Fig. 1) an eczematous dermatitis confined to both axilla the history is prolonged use of the same antiperspirant, the patch test is negative. The eruption is not for example, seborrheic dermatitis that favors this region. An ob- stacle in diagnosis of fatigue reaction is the occurrence of a similar eruption in nonusers of antiperspirants that may be caused by chafing of two op- posing surfaces covered with perspiration. Fatigue rs../I//ergic Reaction: The former is distinct from the latter. The enhanced irritability, or reactability of the skin that gives rise to the fatigue reaction is reversible re-test after a short period is negative. This does not apply to an allergic reaction. In addition the latter is usually more pronounced (Fig. 2). In the repetitive method, fatigue reaction on the last of tke c• •secutive