Sensitization to reactive diluents and hardeners in epoxy resin systems. IVDK data Part I: reaction frequencies

Transcription

1 Contact Dermatitis Original Article COD Contact Dermatitis Sensitization to reactive diluents and hardeners in epoxy resin systems. IVDK data Part I: reaction frequencies Johannes Geier 1, Holger Lessmann 1, Uwe Hillen 2, Christoph Skudlik 3 and Uta Jappe 4,5,6 1 Information Network of Departments of Dermatology, University of Göttingen, Göttingen, Germany, 2 Department of Dermatology, University of Essen, Essen, Germany, 3 Department of Dermatology, Environmental Medicine, and Health Theory, University of Osnabrück, Osnabrück, Germany, 4 Department of Dermatology, University of Heidelberg, Heidelberg, Germany, 5 Department of Dermatology, University of Lübeck, 23538, Lübeck, Germany, and 6 Division of Clinical and Molecular Allergology, Research Centre Borstel, Airway Research Centre North, Member of the German Centre for Lung Research, Borstel, Germany doi: /cod Summary Background. Epoxy resin systems (ERSs), consisting of resins, reactive diluents, and hardeners, are indispensable in many branches of industry. In order to develop less sensitizing ERS formulations, knowledge of the sensitizing properties of single components is mandatory. Objectives. To analyse the frequency of sensitization in the patients concerned, as one integral part of a research project on the sensitizing potency of epoxy resin compounds (FP-0324). Methods. A retrospective analysis of data from the Information Network of Departments of Dermatology (IVDK), , and a comparison of reaction frequencies with (surrogate) exposure data, were performed. Results. Almost half of the patients sensitized to epoxy resin were additionally sensitized to reactive diluents or hardeners. Among the reactive diluents, 1,6-hexanediol diglycidyl ether was the most frequent allergen, followed by 1,4-butanediol diglycidyl ether, phenyl glycidyl ether, and p-tert-butylphenyl glycidyl ether. Among the hardeners, m-xylylene diamine (MXDA) and isophorone diamine (IPDA) were the most frequent allergens. According to the calculated exposure-related frequency of sensitization, MXDA seems to be a far more important sensitizer than IPDA. Up to 60% of the patients sensitized to hardeners and 15 20% of those sensitized to reactive diluents do not react to epoxy resin. Conclusions. In cases of suspected contact allergy to an ERS, a complete epoxy resin series must be patch tested from the start. Key words: diluents. epoxy resin systems; hardeners; occupational contact allergy; reactive Epoxy resin systems (ERSs) are widely used in many industrial fields of application, and they constitute a well-known cause of occupational contact dermatitis Correspondence: Dr Johannes Geier, Information Network of Departments of Dermatology (IVDK), University of Göttingen, Von-Bar-Str. 2 4, Göttingen, Germany. Tel: +49 (0) ; Fax: +49 (0) jgeier@gwdg.de Conflicts of interest: The authors have no conflicts of interest to declare. Accepted for publication 21 September 2015 (1 6). The basic components of ERSs are resins, reactive diluents to adjust viscosity, and hardeners to cure the resin. All of these components may sensitize, with monomers and oligomers of diglycidyl ether of bisphenol A (DGEBA) being the most frequent and most important sensitizers (1 7). Numerous case reports and case series on allergic contact dermatitis caused by ERSs have been published in the last 20 years. Recently, Aalto-Korte et al., from the Finnish Institute of Occupational Health (FIOH), published two comprehensive retrospective analyses of their cases of occupational Contact Dermatitis, 74,

2 contact allergy to epoxy resin hardeners and reactive diluents (5, 6). In their study, m-xylylene diamine (MXDA), 2,4,6-tris-(dimethylaminomethyl)phenol (tris-dmp) and isophorone diamine (IPDA) were the most frequent sensitizers among the hardeners (5). Among the reactive diluents, phenyl glycidyl ether (PGE), 1,4-butanediol glycidyl ether (1,4-BDDGE) and p-tert-butylphenyl glycidyl ether (PTBPGE) were the most frequent sensitizers (6). Patients exposure to the allergens could be proven in most cases, but not in every case (5, 6). The German statutory accident insurance [Deutsche Gesetzliche Unfallversicherung (DGUV)], which also covers cases of occupational dermatitis, funded a research project Ranking of epoxy resin components according to their sensitizing potency (FP-0324), which was performed by the Forschungs- und Beratungsinstitut Gefahrstoffe (FoBiG) (Freiburg, Germany; and the Information Network of Departments of Dermatology (IVDK) ( and finished in December 2012 (8). Among other issues, IVDK data of the years on sensitization to the epoxy resin hardeners and reactive diluents listed in Table 1 were analysed as one part of this more comprehensive research project. Some of these IVDK data, and some additional analyses, are presented in two separate articles, focusing on (i) the frequency of reactions to hardeners and/or reactive diluents with or without concomitant reactions to epoxy resin, and (ii) concomitant reactivity among reactive diluents and hardeners. As information on the patients individual exposures is scarce in the IVDK, the two aspects covered by our analysis are of special interest against the background of the Finnish data mentioned above. This article covers the first of the two issues mentioned. Patients and Methods The IVDK is a network of, currently, 56 departments of dermatology in Germany, Switzerland and Austria dedicated to the epidemiological surveillance of contact allergy. Its routine operating procedure and quality control are described in detail elsewhere (9, 10). The medical history and clinical data, and all patch test results, of all patients patch tested in the departments of dermatology joining the IVDK are stored in local databases in a uniform structure. Twice yearly, anonymized data are transferred to the IVDK central office at the University of Göttingen. After a standardized quality control process, data are added to the IVDK central database and analysed according to published standards (9 11). All IVDK members are also members of the German Contact Dermatitis Research Group [Deutsche Kontaktallergie-Gruppe (DKG)]. Patch tests are performed and read according to DKG guidelines (12), which are based on internationally accepted guidelines. Patch test preparations (Table 1) were purchased from Almirall Hermal (Reinbek, Germany), except for MXDA and trimethylolpropane triglycidyl ether (TMPTGE), which were purchased from Chemotechnique (Vellinge, Sweden), and diethylene triamine (DETA), which was purchased from brial allergen (Greven, Germany) or SmartPractice Germany (Barsbüttel, Germany). Hardeners and reactive diluents were tested in varying frequencies, for the following reasons. Some test preparations, for example PGE and IPDA, were available for the total study period, whereas others, such as 1,6-hexanediol diglycidyl ether (1,6-HDDGE) and 1,4-BDDGE, were not commercially available before October Some other test preparations were included in the DKG resins/adhesives test series only from August 2008 onwards. Triethylene tetramine (TETA) was only tested as part of the DKG construction industry test series until August 2010 (Table 1). The patch test exposure time was 24 h in 18.3% of the patients, and 48 h in 81.7% of the patients. With a few (temporary) exceptions, Finn Chambers on Scanpor tape (inner diameter, 8 mm) were used as test chambers. For data analysis, patch test reactions at day (D)3 were selected. In a few exceptional cases, when a reading was performed at D4 instead of D3, this reading was chosen. Readings coded as +, ++ or +++, namely positive reactions with erythema, infiltration, papules and/or (coalescing) vesicles, according to scoring, were rated as positive in dichotomized analyses. Data management and analysis were performed with SAS 9.3 (SAS Institute,Cary, NC, USA). The frequency of sensitization to a certain compound does not necessarily depend solely on its sensitizing potency, but also on the number of exposed individuals and the route and extent of exposure. With regard to the latter, there are, unfortunately, no reliable data available. The manufacturers or product formulators, or their respective holding organizations, are not even able to specify the amount of single ERS components produced in recent years. Hence, we have no reliable denominator to which the number of sensitized patients can be related. As a surrogate, we chose the following. At the hazardous material information system of the statutory accident insurance of the construction industry [Gefahrstoff-Informationssystem der BG BAU (GISBAU); material safety data sheets (MSDSs) of epoxy resin products used in the construction industry are stored electronically. As most of these products consist of two components (with separate MSDSs), this information relates to 1850 products. We selected the number of MSDSs in which a certain ERS compound is 84 Contact Dermatitis, 74, 83 93

3 Table 1. Components of epoxy resin systems, with abbreviations, Chemical Abstract Service (CAS) numbers, and patch test concentrations, for which Information Network of Departments of DermatologyIVDK data were analysed Substance Abbreviation Structural formula CAS no. Patch test concentration (pet.) (%) Availability during study period Resin Based on diglycidyl ether of bisphenol A DGEBA resin All the time Reactive diluents 1,6-Hexanediol diglycidyl ether 1,6-HDDGE Since ,4-Butanediol diglycidyl ether 1,4-BDDGE Since 2006 Phenyl glycidyl ether PGE All the time p-tert-butylphenyl glycidyl ether PTBPGE Since 2008 Cresyl glycidyl ether CGE All the time Contact Dermatitis, 74,

4 Table 1. Continued Substance Abbreviation Structural formula CAS no. Patch test concentration (pet.) (%) Availability during study period Butyl glycidyl ether BGE All the time Trimethylolpropane triglycidyl ether TMPTGE Since 2008 Hardeners m-xylylene diamine MXDA Since 2008 Isophorone diamine IPDA All the time Trimethylhexane-1,6-diamine (mixture of isomers) TMHDA Since Contact Dermatitis, 74, 83 93

5 Table 1. Continued Availability during study period Patch test concentration (pet.) (%) Substance Abbreviation Structural formula CAS no. Diethylene triamine DETA All the time Triethylene tetramine TETA Until 2010 Test vehicle was petrolatum. mentioned as a surrogate marker for its usage, and hence for the number of workers exposed to it. We are aware of the problem that the number of products in which a certain compound is contained does not necessarily reflect the number of individuals exposed, because the products are produced and used in different amounts, and exposure conditions may vary. Another shortcoming of this approach is that information concerning sensitizers given in the MSDS is not always up to date and complete. Nevertheless, in the absence of more reliable data, we think that our approach is worthwhile. Results In the 10-year study period ( ), a total of patients had been patch tested in the IVDK. Of these, (90.8%) had been patch tested with the DKG baseline series. In the remainder, special test series or individually tailored tests were exclusively applied, mostly because of previous patch testing with the baseline series. DGEBA epoxy resin was patch tested in patients, representing 97.4% of all patients tested with the baseline series. Of these, 1453 patients (1.6%) reacted positively, with reactions, reactions, and reactions. Additionally, 438 (0.5%) erythematous (doubtful) and 91 (0.1%) irritant reactions occurred. Negative reactions were noted in patients. [General remark: owing to the selection of the 10-year period , test results of EPOX 2002 (13) (92 patients) are also included in the present data analysis.] At least one of the hardeners MXDA, IPDA, DETA, TETA or trimethylhexane-1,6-diamine (TMHDA) was tested in 605 of 1435 patients sensitized to DGEBA resin. Of these, 491 patients (81.2%) reacted to none of the hardeners, 82 (13.6%) reacted to one hardener, 27 (4.5%) reacted to two hardeners, 4 (0.7%) reacted to three hardeners, and 1 (0.2%) reacted to four hardeners. A corresponding analysis was performed with reactive diluents, except for PGE and cresyl glycidyl ether (CGE), which were excluded for the following three reasons. First, according to information from ERS product formulators, PGE and CGE are currently very rarely used in ERSs, if at all. Second, positive reactions to PGE are, in most cases, probably the result of immunological cross-reactions in patients primarily sensitized to DGEBA resin (14 16). Third, we learned from EPOX 2002 that positive reactions to CGE almost exclusively occur in patients reacting to PGE (13), and, owing to the high chemical similarities between PGE and CGE, immunological cross-reactivity can be assumed. Hence, positive reactions to PGE and/or CGE do not really contribute to answering the question of how often patients with sensitization to epoxy resin are also sensitized to reactive diluents. Contact Dermatitis, 74,

6 Table 2. Frequency of sensitization to at least one hardener (m-xylylene diamine, isophorone diamine, diethylene triamine, triethylene tetramine, or trimethylhexane-1,6-diamine) and/or at least one reactive diluent (1,6-hexanediol diglycidyl ether, 1,4-butanediol glycidyl ether, trimethylolpropane triglycidyl ether, butyl glycidyl ether, or p-tert-butylphenyl glycidyl ether) in 605 patients sensitized to diglycidyl ether of bisphenol A resin Hardeners Positive for at least one No positive reaction Total tested with at least one Reactive diluents Positive to at least one No positive reaction Total tested with at least one Table 3. Frequencies of patch tests and positive reactions to epoxy resin system components in patients sensitized to diglycidyl ether of bisphenol A (DGEBA) resin (n total = 1435), and in patients with negative patch test results for DGEBA resin (n total = ) DGEBA resin-positive patients Substance n tested n positive % positive (95%CI) DGEBA resin-negative patients Results of local lymph node assays: EC3 values (%) n tested n positive % positive (95%CI) Reactive diluents 1,6-HDDGE ( ) ( ) 1,4-BDDGE ( ) No data ( ) PGE ( ) ( ) PTBPGE ( ) ( ) CGE ( ) No data ( ) BGE ( ) ( ) TMPTGE ( ) ( ) Hardeners MXDA ( ) ( ) IPDA ( ) ( ) TMHDA ( ) ( ) DETA ( ) ( ) TETA ( ) No data ( ) 1,4-BDDGE, 1,4-butanediol glycidyl ether; BGE, butyl glycidyl ether; CGE, cresyl glycidyl ether; DETA, diethylene triamine; 1,6-HDDGE, 1,6-hexanediol diglycidyl ether; IPDA, isophorone diamine; MXDA, m-xylylene diamine; PGE, phenyl glycidyl ether; PTBPGE, p-tert-butylphenyl glycidyl ether; TETA, triethylene tetramine; TMHDA, trimethylhexane-1,6-diamine; TMPTGE, trimethylolpropane triglycidyl ether. Percentages are supplied with exact 95% confidence intervals (95%CIs). For comparison, EC3 values from local lymph node assays from the literature (17 20) are reported. In 576 of 1453 patients with contact sensitization to DGEBA resin, at least one of the reactive diluents 1,6-HDDGE, 1,4-BDDGE, TMPTGE, butyl glycidyl ether (BGE) or PTBPGE was patch tested. In 330 patients (57.3%), no positive reactions to any of the reactive diluents occurred. Seventy-nine patients (13.7%) reacted to one reactive diluent, 88 (15.3%) reacted to two reactive diluents, 56 (9.7%) reacted to three reactive diluents, 12 (2.1%) reacted to four reactive diluents, and 11 (1.9%) reacted to five reactive diluents. In all of the 576 patients tested with the reactive diluents mentioned above, the five respective hardeners were tested as well. Hence, the same group of 576 patients were tested with at least one member of both groups of ERS components, and at least one of the five hardeners was tested in an additional 29 patients. Table 2 shows how many of these 605 patients reacted to at least one hardener or reactive diluent. It is evident that reactions to reactive diluents were far more frequent than those to hardeners [246/605 (40.7%) versus 114/605 (18.8%)]. Sixty-seven patients reacted to at least one hardener and at least one reactive diluent, representing 58.8% of those reacting to hardeners, but only 27.2% of those reacting to diluents. The frequencies of patch tests and positive reactions to all of the ERS components listed in Table 1 are shown in Table 3. In addition, EC3 values from local lymph node assays from the literature, if available, are reported (17 20). Among DGEBA resin-positive patients, 1,6-HDDGE was the most frequent allergen among the 88 Contact Dermatitis, 74, 83 93

7 Table 4. Proportion of patients without sensitization to diglycidyl ether of bisphenol A (DGEBA) resin among patients sensitized to reactive diluents or hardeners Substance ntestedwith diluent/ hardener and DGEBA resin n diluent/ hardenerpositive, but DGEBA resin-negative % diluent/ hardenerpositive, but DGEBA resin-negative (95%CI) Reactive diluents 1,6-HDDGE ( ) 1,4-BDDGE ( ) PGE ( ) PTBPGE ( ) CGE ( ) BGE ( ) TMPTGE ( ) Hardeners MXDA ( ) IPDA ( ) TMHDA ( ) DETA ( ) TETA ( ) 1,4-BDDGE, 1,4-butanediol glycidyl ether; BGE, butyl glycidyl ether; CGE, cresyl glycidyl ether; DETA, diethylene triamine; 1,6-HDDGE, 1,6-hexanediol diglycidyl ether; IPDA, isophorone diamine; MXDA, m-xylylene diamine; PGE, phenyl glycidyl ether; PTBPGE, p-tert-butylphenyl glycidyl ether; TETA, triethylene tetramine; TMHDA, trimethylhexane-1,6-diamine; TMPTGE, trimethylolpropane triglycidyl ether. Percentages are supplied with exact 95% confidence intervals (95%CIs). reactive diluents, followed by 1,4-BDDGE, PGE, and PTBPGE, whereas sensitization to CGE, BGE and TMPTGE was less frequent. Of the hardeners, MXDA was the leading allergen among DGEBA resin-positive patients, followed by IPDA. Sensitization to TMPHA and DETA was noticed less frequently, and TETA was the least frequent allergen among the hardeners. Sensitization to reactive diluents and/or hardeners was much rarer among patients without sensitization to DGEBA resin. The frequencies of positive reactions ranged from 0.1 to 0.9%. However, a different perspective gives a different view of the results. Table 4 shows the number of patients patch tested with DGEBA resin and the respective diluent or hardener, and how many of them reacted positively to the diluent or hardener, but not to DGEBA resin. Although the absolute numbers of patients are comparably low, it is evident that a considerable proportion of patients were sensitized to hardeners or reactive diluents without being sensitized to the resin. This was particularly pronounced for hardeners such as TMHDA, DETA, and TETA, where % of the sensitized patients did not react to DGEBA resin. Of the patients sensitized to reactive diluents such as 1,6-HDDGE, 1,4-BDDGE, and BGE, % did not react to DGEBA resin. As explained in Patients and Methods, we calculated an exposure-related frequency of sensitization, taking the number of products containing the respective compound for which MSDSs are present at GISBAU as the denominator. Although there are limitations of this approach, it may provide an idea of the importance of the respective compounds as allergens in this occupational context. We restricted the comparison of sensitization frequencies with our surrogate marker of exposure to hardeners, because the very frequent concomitant reactions among the reactive diluents (which are probably mainly caused by immunological cross-reactivity; see Part 2 of this publication) would not allow a sensible interpretation of the results. ERSs containing products for which MSDSs are available at GISBAU are for use in construction materials. Hence, we did not use the general reaction frequencies as reported above for this comparison, but we selected reaction frequencies from among occupational dermatitis patients working in the construction industry (i.e. brick layers, tile setters, concrete workers, and construction workers). The results are shown in Table 5. It should be noted that the number of patients tested varied from 221 for TMHDA to 472 for IPDA. In order to take account of this fact, the 95% confidence intervals (95%CIs) are presented, which are larger in small samples than in large ones. This showed that the ranking of the exposure-related frequency of sensitization differs from the mere percentage of positive reactions, being MXDA > DETA > TMHDA > IPDA > TETA. Discussion Apart from the FIOH data (5, 6), this is the largest number of patch test results with ERS components reported up to now. From various scientific reports, it is well known that not only the resins, but also reactive diluents and hardeners, are relevant sensitizers in ERSs (1 7). However, the size of this problem has not yet been sufficiently investigated. In our data, of 1453 patients sensitized to DGEBA resin, only 605 (41.6%) had been patch tested with at least one hardener or reactive diluent. Of these, 293 (48.4%) reacted positively to at least one of these chemicals (Table 2). Considering that the reactive diluent PGE, which is known to cross-react with DGEBA resin (14, 15), and the chemically closely related CGE were excluded from this particular calculation, it is remarkable that almost half of those sensitized to the resin are also sensitized to additional components of ERSs. Hence, patch Contact Dermatitis, 74,

8 Table 5. Exposure-related frequency of sensitization to hardeners Column 1 Hardener Column 2 Column 3 Column 4 Number of MSDSs with the respective hardener % positive reactions among bricklayers etc. with OCD Exposure-related frequency of sensitization given as the ratio of the parameters in column 2 and column MXDA 16.5 ( ) ( ) IPDA 5.3 ( ) ( ) TMHDA 4.1 ( ) ( ) DETA 1.1 ( ) ( ) TETA 0.5 ( ) ( ) DETA, diethylene triamine; IPDA, isophorone diamine; MSDS, material safety data sheet; MXDA, m-xylylene diamine; OCD, occupational contact dermatitis; TETA, triethylene tetramine; TMHDA, trimethylhexane-1,6-diamine. Column 2 shows the percentage of positive reactions to each compound in a total of 804 bricklayers, tile setters, etc. with occupational dermatitis, independent of their reactivity to DGEBA resin. Column 3 shows the number of MSDSs present at GISBAU in which the compound is mentioned. The 95%CIs are given in parentheses. Column 4 shows the ratio of percentage of positive reactions among occupationally exposed patients (column 2) divided by the number of MSDSs with the respective hardener (column 3), multiplied by 1000 for better readability. testing with reactive diluents and hardeners should be obligatory in all patients with DGEBA resin sensitization. A proportion of only 41.6% tested patients, as we found in our study, is definitely too low. Although reaction frequencies as observed in the FIOH and in the IVDK cannot be compared directly, because of obviously differing indications for patch testing, there is concordance concerning the most frequent hardener allergens, namely MXDA and IPDA (5). However, Aalto-Korte et al. additionally found tris-dmp to be the second most frequent allergen among epoxy resin hardeners (5). According to MSDSs available at GISBAU, tris-dmp is frequently used in Germany, too. However, as no patch test preparation of this substance is commercially available, it was tested in single exceptional cases in the IVDK only (21, 22), so we have no data on its sensitization frequency within the IVDK. According to data from the FIOH, allergic reactions to hardeners without concomitant reactions to DGEBA resin seem to be quite rare (5, 7). Only 1 of 12 patients reacting to IPDA, and 2 of 9 patients reacting to DETA, were not sensitized to DGEBA resin (5), which is a considerably (although not statistically significantly) lower frequency than we observed (Table 4). However, with MXDA, the respective proportion observed at the FIOH was 11 of 24, that is, 46% (95%CI: 26 67%) (5), which is significantly higher than the 16% that we found. A note in the corresponding publication of Aalto-Korte et al. (5) seems to indicate that MXDA is more frequently used in Finnish ERSs than in German ones, which might explain the difference. In 2006, Chu et al. reported 9 workers with occupational allergic contact dermatitis caused by handling ERSs containing DGEBA and diglycidyl ether of bisphenol F resins, 1,6-HDDGE, TMPTGE, and MXDA (23). Only 1 of these patients was sensitized to DGEBA resin, but 5 were sensitized to MXDA, 4 were sensitized to 1,6-HDDGE, and 3 were sensitized to TMPTGE (23). This case series also shows that sensitization to hardeners and reactive diluents may occur independently of sensitization to the actual resin. This is confirmed by our findings. In our study, a relatively high proportion of patients were sensitized to reactive diluents or hardeners but not to DGEBA resin (Tables 3 and 4). A systematic investigation of such isolated sensitizations to reactive diluents or hardeners has not yet been performed. Approximately 15 20% of the patients sensitized to 1,6-HDDGE, 1,4-BDDGE or BGE did not react to DGEBA resin (for details, see Table 4), which is similar to the corresponding proportion seen at the FIOH (6). We are not aware of any common (occupational) exposure to these chemicals other than from ERSs, so we suppose that the patients concerned were exposed to ERSs (which is the reason why they were patch tested with ERS components) and, by this exposure, primarily sensitized to the reactive diluents. With hardeners, the situation was similar, or even worse, with 60% of patients being sensitized to TMHDA, DETA or TETA but not to DGEBA resin. Concerning MXDA and IPDA, allergen sources other than ERSs are theoretically possible. MXDA has been used in the production of polyurethane silk, where it caused occupational contact sensitization (24). However, this report is from 1990, and we are not sure whether this exposure still is relevant today. By analogy with 4,4 -diaminodiphenylmethane (MDA) sensitization, which may indicate sensitization to diphenylmethane-4,4 -diisocyanate (MDI) (5, 25), allergic reactions to IPDA may indicate sensitization to the corresponding isocyanate, which is isophorone diisocyanate (IPDI). In construction workers and other employees who are exposed to unhardened 90 Contact Dermatitis, 74, 83 93

9 plastic materials, exposure to IPDI may occur when two-component polyurethane systems are handled (26). Probably, IPDI is rapidly converted to IPDA on or in the skin, by analogy with the proven conversion of MDI to MDA (25). Hence, some of the allergic reactions to MXDA and IPDA could be attributable to exposures other than ERSs, but we assume that ERS is still the most widespread allergen source for these compounds. In summary, our data concerning isolated reactions to reactive diluents or hardeners also support the promotion of full patch testing with a complete set of ERS ingredients in patients with suspected epoxy resin contact allergy. Pontén et al. have shown that PGE is a potent contact sensitizer, and they also showed immunological cross-reactivity of DGEBA resin and PGE (16). Guinea-pigs sensitized to DGEBA resin also reacted to PGE (16). In a clinical study, they found that 7 of 23 DGEBA resin-positive patients reacted to PGE, which is a proportion of 30% (95%CI: 13 53%), and no positive reactions to PGE without sensitization to DGEBA resin (15). In our data, we found that 29% (95%CI: 25 33%) of the DGEBA resin-positive patients reacted to PGE, and 83% (95%CI: 78 88%) of the PGE-positive patients also reacted to DGEBA resin (Tables 3 and 4), although PGE is no longer used in ERSs (MSDSs at GISBAU; data not shown in detail). Hence, our data confirm the results of the clinical study of Pontén et al. It is remarkable that there is an inverse correlation between the EC3 values of hardeners and the frequency of sensitization as described in Table 3, giving, at least in part, an explanation for the observed ranking. However, concerning reactive diluents, we could not find such a correlation. Of course, the frequency of sensitization depends not only on the sensitizing potency (in this case expressed as an EC3 value, which itself possibly depends on the vehicle used), but also on the extent of usage of the allergen and exposure conditions. Concerning reactive diluents, interpretation of these data is additionally complicated by immunological cross-reactivity (see Part 2 of this publication). Beyond a mere description of reaction frequencies, we wanted to investigate a possible relationship between exposure to ERS components and sensitization. Two aspects hampered this: (i) a high degree of cross-reactivity among the glycidyl ethers (see Part 2 of this publication), and (ii) the lack of reliable data concerning the number of exposed workers. To overcome these problems, we (i) limited our calculation to the hardeners, among which immunological cross-reactivity has not yet been described, and (ii) took the number of MSDSs at GIS- BAU as a surrogate marker for their usage. As mentioned above, we are aware of the shortcomings of this approach, in particular of the fact that the number of MSDSs does not necessarily reflect the number of exposed individuals. However, in our opinion, with cautious interpretation, this model can provide information about the trend. From our calculations (Table 5), it can be deduced that IPDA is a frequent sensitizer in ERSs, not because it is a very potent allergen, but because its use is so very widespread. This is particularly true when considering that a certain proportion of sensitization to IPDA may be attributable to primary sensitization to the isocyanate IPDI. In contrast, MXDA seems to be a more potent allergen, sensitizing more exposed individuals, although it is not as frequently used as IPDA in ERSs. In this respect, TMHDA and DETA seem to have an intermediate position, whereas TETA could be rated similarly to IPDA. However, as TETA is far less frequently used, far fewer individuals are sensitized to TETA than to IPDA. Conclusions Approximately half of the patients sensitized to DGEBA resin are additionally sensitized to a reactive diluent or a hardener used in ERSs. Approximately 15 20% of the patients sensitized to a reactive diluent and up to 60% of the patients sensitized to an epoxy resin hardener do not react to DGEBA resin. Therefore, in cases of suspected contact allergy to ERS components, it is not sufficient to patch test with the baseline series, which contains DGEBA resin only; patch testing should also be performed with an epoxy resin series from the start. According to our model of exposure-related frequency of sensitization, MXDA might be a more potent allergen than IPDA or TETA, and TMHDA and DETA might have an intermediate position in this ranking. However, these results must be interpreted with caution. In order to compose safer, less sensitizing ERSs in the future, further investigations concerning sensitizing potency and exposure-related frequency of sensitization are needed. Acknowledgements Most of the data analyses presented in this article constitute part of the research project Ranking of epoxy resin components according to their sensitizing potency (FP-0324), which was supported and funded by the DGUV, and performed by the FoBiG ( and the IVDK. We are grateful to Dr Karin Heine and Dr Fritz Kalberlah (FoBiG) and Dr Reinhold Rühl and Dr Klaus Kersting [Statutory accident insurance of the building trade (BG BAU), Frankfurt, Germany] for excellent cooperation and fruitful discussion. Contact Dermatitis, 74,

10 We thank the colleagues from the clinical departments of the IVDK who contributed data to this analysis (in alphabetical order): Aachen (C. Schröder), Aarau (J. Grabbe), Augsburg (A. Ludwig), Basel (A. Bircher), Berlin Charité (T. Zuberbier and M. Worm), Bern (D. Simon), Bielefeld (I. Effendy), Bochum (H. Dickel), Bochum BGFA/IPA (M. Fartasch), Buxtehude (P. Große-Hüttmann and P. Hausenblas), Dessau (U. Lippert and A. Jung), Detmold (St. Nestoris), Dortmund (P. J. Frosch, B. Mydlach, C. Pirker, R. Herbst, and K. Kügler), Dresden (R. Aschoff, P. Spornraft-Ragaller, and A. Bauer), Dresden Friedrichstadt (A. Koch), Erlangen (V. Mahler), Essen (U. Hillen), Falkenstein (H. Schwantes), Freudenberg (Ch. Szliska), Gera (J. Meyer, H. Grunwald-Delitz, and M. Kaatz), Göttingen (Th. Fuchs and J. Geier), Graz (B. Kränke and W. Aberer), Greifswald (M. Jünger), Halle (G. Gaber, D. Lübbe, and B. Kreft), Hamburg (M. Kiehn, R. Weßbecher, and E. Coors), Hamburg BUK (K. Breuer, U. Seemann, and C. Schröder-Kraft), Hamburg Dermatologikum (V. Martin and K. Reich), Hannover (T. Schaefer and Th. Werfel), Heidelberg (M. Hartmann, U. Jappe, and K. Schäkel), Heidelberg AKS (H. Dickel, T. L. Diepgen, and E. Weisshaar), Heilbronn (H. Löffler), Homburg/Saar (P. Koch and C. Pföhler), Jena (A. Bauer, M. Kaatz, and S. Schliemann), Kiel (J. Brasch), Krefeld (A. Wallerand, M. Lilie, and S. Wassilew), Leipzig (R. Treudler), Lübeck (J. Grabbe, I. Shimanovich, and U. Jappe), Mainz (D. Becker), Mannheim (Ch. Bayerl, D. Booken, C.-D. Klemke, and W. Ludwig-Peitsch), Marburg (H. Löffler, M. Hertl, and W. Pfützner), Minden (R. Stadler), München LMU (T. Oppel, B. Przybilla, P. Thomas, T. Schuh, and R. Eben), München Schwabing (M. Agathos, K. Ramrath, M. Georgi, and G. Isbary), München TU (J. Rakoski and U. Darsow), Münster (B. Hellweg and R. Brehler), Nürnberg (I. Müller, D. Debus, and A. Bachtler), Oldenburg (M. Padeken), Osnabrück [H. J. Schwanitz ( ), N. Schürer, H. Dickel, Ch. Skudlik, and S. M. 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