Allergic contact dermatitis from dicyclohexylmethane-4,4'-diisocyanate

From August 1999 to April 2001, there was an outbreak of severe eczema at a factory manufacturing medical equipment. A glue, mainly based on the isocyanate dicyclohexylmethane-4,4'-diisocyanate (DMDI), was suspected as being the cause of the problem. 16 workers with recent episodes of eczema were patch tested with a standard series, an isocyanate series and work material. The latter consisted of, among other things, the glue, DMDI, and an amine, dicyclohexylmethane-4,4'-diamine (DMDA), which is formed when DMDI reacts with water. 13 patients reacted to DMDI, 9 to 1,6-hexamethylenediisocyanate (HDI) and 4 to isophoronediisocyanate (IPDI), all of which are aliphatic isocyanates. None reacted to the aromatic isocyanates, diphenylmethane-4,4'-diisocyanate (MDI) or toluenediisocyanate (TDI). One explanation for this pattern could be that aromatic diisocyanates are more reactive than the aliphatic ones and that, therefore, they are inactivated before penetrating the skin. 5 patients reacted to DMDA and 5 to 4,4'-diaminodiphenylmethane (MDA). Concurrent reactions to DMDA and or MDA with DMDI could be due to cross-reactivity. The positive reactions to MDA could also be a marker of MDI exposure. Yet another patient, investigated in 1997 with suspected work-related contact dermatitis from the glue, is described. She, however, showed no positive reactions to any isocyanates.     

Contact sensitization to 4,4'-diaminodiphenylmethane and to isocyanates among general dermatology patients

Background:  Diisocyanates and 4,4'-diaminodiphenylmethane (MDA) are industrial sensitizers. Occupational asthma is a risk among workers exposed to diisocyanates. Exposure may also lead to contact sensitization and allergic contact dermatitis.
Objective:  The aim of this study was to determine the occurrence of contact sensitization to MDA and to diisocyanates among general dermatology patients.
Patients and methods:  Patch testing with MDA was carried out in 1595 patients. Diphenylmethane-4,4'-diisocyanate (MDI) and toluene-2,4-diisocyanate (TDI) were tested in 1023 patients and isophorone diisocyanate (IPDI) and 1,6-hexamethylene diisocyanate (HDI) in 433 patients. The clinical data and sources of exposure are analysed.
Results:  MDA reactions were seen in 17 (1.1%) patients and MDI reactions in 4 patients. Six MDA-positive patients reacted to p -phenylenediamine and two to epoxy chemicals. 5/10 of the TDI reactions were seen concurrently with reactions to MDI, MDA, HDI, or to IPDI. IPDI reactions were seen in eight patients and HDI reactions in two patients. Possible sources of exposure were traced in most patients, although the association with the current dermatitis was not apparent in all cases.
Conclusion:  (Di)isocyanates may induce contact sensitization with or without allergic contact dermatitis.     

The outcome of 9 years of consecutive patch testing with 4,4′‐diaminodiphenylmethane and 4,4′‐diphenylmethane diisocyanate

Background. Two outbreaks of allergic contact dermatitis caused by isocyanates at two companies in southern Sweden initiated a research project focusing on contact allergy to isocyanates. Within the project, there was an interest in determining how often contact allergy to the most common isocyanate, diphenylmethane‐4,4′‐diisocyanate (4,4′‐MDI), occurred. Objectives. To determine and compare the occurrence of contact allergy to 4,4′‐MDI, its corresponding amine 4,4′‐diaminodiphenylmethane (4,4′‐MDA), and polymeric diphenylmethane diisocyanate (PMDI) in a Swedish and a Belgian study population. Patients and method. The study population consisted of 6190 consecutively patch tested dermatitis patients: 5690 patients from Malmö, Sweden, and 500 patients from Leuven, Belgium. Patch test results were analysed and compared. Results. None of the Belgian patients reacted positively to 4,4′‐MDI, but 5 Swedish patients did. Contact allergy to 4,4′‐MDA was more common in the Belgian patients than in the Swedish patients: 3.6% and 0.9%, respectively. This could possibly be explained by the fact that the prevalence of p‐phenylenediamine allergy was higher in the Belgian population. Conclusions. The prevalence of contact allergy to 4,4′‐MDI, 4,4′‐MDA and PMDI is not high enough to justify their inclusion in any baseline series. Isocyanate allergic individuals should be detected by aimed testing with an isocyanate series and work materials.     

How to optimize patch testing with diphenylmethane diisocyanate

We have previously shown that patch test preparations of polymeric diphenylmethane diisocyanate (PMDI) are more stable than preparations of diphenylmethane-4,4'-diisocyanate (4,4'-MDI). This study was conducted to (i) investigate whether PMDIs yield as many positive reactions as 4,4'-MDI, (ii) study concurrent reactions to 4,4'-MDI and 4,4'-diaminodiphenylmethane (4,4'-MDA), and (iii) follow the course of positive reactions during 4 weeks. It was shown that PMDIs detect as many positive reactions as 4,4'-MDI. Thus, they are better patch test agents being more stable than preparations of 4,4'-MDI. We recommend that PMDIs with a monomer content of at least 35% is used in 2.0% petrolatum (pet.) (i.e. monomer patch test concentration approximately 0.7%). It was shown that reactions to 4,4'-MDI and PMDIs appear late and we recommend readings on both day (D) 3/4 and D7. 4,4'-MDA was shown to be a good marker for 4,4'-MDI and patch testing with 4,4'-MDA in 0.25% pet. can be used instead of PMDI. Concomitant reactions to 4,4'-MDI and 4,4'-MDA are probably not caused by conversion of 4,4'-MDI into 4,4'-MDA by reaction with water. Another explanation is a path of reactions leading to ureas and MDI conjugates with skin constituents, which are hydrolysed into 4,4'-MDA. This complex process depends upon several factors and might explain why positive MDI reactions appear after D7.     

Occupational contact allergy to monomeric isocyanates

Background. The monomeric isocyanates diphenylmethane diisocyanate (MDI), 2,4‐toluene diisocyanate (TDI), isophorone diisocyanate (IPDI) and 1,6‐hexamethylene diisocyanate (HDI) are used in polyurethane products and sometimes cause contact allergy. Objectives. To describe patients with isocyanate contact allergy in an occupational dermatology clinic. Methods. Test files were screened for allergic reactions to isocyanates and 4,4′‐diaminodiphenylmethane (MDA). Patients with allergic reactions to some of the allergens were analysed for occupation, exposure, concomitant reactions to other allergens, and diagnosis. Results. Over a period of almost 13 years, 54 patients reacted to isocyanates (9 to IPDI, 12 to MDI, 6 to TDI, and 1 to HDI) or MDA (44 patients). The motor vehicle, electronics and paint industries, and painting and construction work, were among the most significant occupational fields. An in‐house polymeric MDI (PMDI) test substance was superior to commercial MDI preparations. About half of the occupational cases related to MDI products were diagnosed by testing MDA. The most prominent cause of IPDI allergy comprised polyurethane paint hardeners. Some of the IPDI reactions could be explained by cross‐allergy to isophoronediamine in epoxy products. Specific exposure to MDA was difficult to trace. Conclusions. MDA and PMDI test substances were significant in the diagnosis of MDI contact allergy.     

Poor correlation between stated and found concentrations of diphenylmethane-4,4'-diisocyanate (4,4'-MDI) in petrolatum patch-test preparations

Diphenylmethane diisocyanate (MDI) is widely used in its polymeric form in the manufacturing of polyurethane products. Previous reports on MDI-related contact allergy have shown a pattern, where patients seem to react to their own MDI-based work material but not to commercial patch-test preparations, which contain 4,4'-MDI. Therefore, we performed chemical analyses of 14 commercial test preparations of 4,4'-MDI obtained from 8 European and 4 American dermatology departments as well as 2 preparations from 2 major European suppliers of patch-test allergens. A new method for monitoring 4,4'-MDI in petrolatum preparations was developed and the determination of 4,4'-MDI as the MDI-dibutylamine derivative using liquid chromatography-mass spectrometry was performed. None of the preparations obtained from the dermatology departments contained more than 12% of the concentration stated on the label. In most cases, 4,4'-MDI content was only a few percentages or less of the concentration stated. 7 of the 14 preparations were analysed before the expiry date. Yet, only 1 of them, a preparation directly obtained from the supplier, came close to the concentration stated on the label. Thus, using these preparations, patients will be tested with a lower concentration than intended, leading to possible false-negative reactions.     

Is it possible to improve the patch‐test diagnostics for isocyanates? A stability study of petrolatum preparations of diphenylmethane‐4,4′‐diisocyanate and polymeric diphenylmethane diisocyanate

We have previously shown that the concentration of diphenylmethane-4,4'-diisocyanate (4,4'-MDI) in commercial test preparations was so low that patch testing with the same was not reliable. The stability of 4,4'-MDI in petrolatum (pet.) was compared with pet. preparations of polymeric diphenylmethane diisocyanate (PMDI), which consists of a complex mixture of monomeric isomers and oligomers of MDI. Preparations of 4,4'-MDI and PMDI were stored under 3 different conditions, i.e. at room temperature, refrigerated and frozen. They were analysed continuously during 1 year with regard to the content of 4,4'-MDI, 3-ring oligomers and 4-ring oligomers using liquid chromatography-mass spectrometry. PMDI preparations kept frozen were stable for a year. All other preparations failed to fulfil the requirements of stability, i.e. +/-20% of the initial concentration. Storage in a freezer prolonged the lifetime for 4,4'-MDI. The decrease in concentration for preparations kept at room temperature and refrigerated was less rapid in PMDI preparations than in 4,4'-MDI preparations. PMDI preparations are better suited for patch testing patients exposed to MDI because they are more stable and homogeneous than 4,4'-MDI preparations. They better reflect possible allergens that workers are exposed to because products used in industry contain both monomers and oligomers.     

Occupational allergic contact dermatitis caused by isocyanates

Between 1978 and 2001, 22 patients were diagnosed with occupation-related allergic contact dermatitis from isocyanates and/or polyurethanes in our clinic. 13 had a positive reaction to the isocyanates, of whom 10 also reacted to diaminodiphenylmethane (MDA), which is used in the production or processing of isocyanates and polyurethanes; 9 reacted only to MDA. The object of the present study was to identify the trades and industries responsible for the development of contact allergy to these resins. Such patients must be patch tested with the isocyanates contacted at work, and account must be taken of positive reactions to MDA as a marker for isocyanate sensitivity.     

Dermal uptake study with 4,4'-diphenylmethane diisocyanate led to active sensitization

Background. To investigate the dermal uptake of 4,4′‐diphenylmethane diisocyanate (4,4′‐MDI), a study was performed in which 2 female volunteers were exposed to 10 and 25 mg, respectively, of 4,4′‐MDI by applying 2.0% 4,4′‐MDI in petrolatum over areas where the surface concentration corresponded to 800 µg/cm². Ten days later, they developed eczematous dermatitis at the area of application. Objectives. To investigate whether the dermal application caused active sensitization to 4,4′‐MDI. Methods. Chemical analysis of the 4,4′‐MDI preparation used in the application and the amount of 4,4′‐MDI not absorbed by the skin was performed with liquid chromatography–mass spectrometry. The volunteers were tested with serial dilutions of 4,4′‐MDI and the potentially cross‐reacting substances 4,4′‐diaminodiphenylmethane (4,4′‐MDA), p‐phenylenediamine (PPD), and dicyclohexylmethane‐4,4′‐diisocyanate (DMDI). Results. Patch test results suggested that the volunteers were actively sensitized to 4,4′‐MDI following the dermal uptake study, as they reacted positively to 4,4′‐MDA, a marker for 4,4′‐MDI allergy. No positive reactions were seen to PPD or DMDI. Chemical investigation confirmed that the correct concentration had been used for the dermal uptake study, and showed that about 70% of the applied 4,4′‐MDI was not absorbed. Conclusions. A dermal uptake study with 4,4′‐MDI in 2.0% pet. with an occlusion time of 8 hr induced active sensitization to 4,4′‐MDI and subsequently to 4,4′‐MDA.     

Triphenyl phosphite,a new allergen in polyvinylchloride gloves

Background. Contact allergy to polyvinylchloride (PVC) gloves has been reported relatively seldom. In spring 2011, 5 of our patients had patch test reactions to PVC gloves. We obtained a collection of PVC raw materials from industrial producers and suppliers of chemical compounds to be patch tested on patients with suspected PVC glove contact allergy. Objectives. To report the first results of these new test substances. Methods. The patients were patch tested with the newly obtained test substances, plastics and glues series, and isocyanates and isocyanate prepolymers. We analysed nine PVC glove samples for triphenyl phosphate and its derivatives. Results. Two patients reacted to a technical PVC antioxidant and one of its components, triphenyl phosphite (TPP). Contact allergy to TPP was very strong in 1 patient, and was the main cause of her hand dermatitis, whereas the other patient also had other contact allergies explaining her symptoms. Three patients reacted to their PVC gloves, but the specific allergen was not identified. Six PVC glove samples contained TPP at concentrations of 0.004–0.099%. TPP transforms into triphenyl phosphate during storage. Conclusions. TPP represents a new allergen in PVC gloves. It was detected in several PVC gloves in fairly high concentrations.     

Contact allergy to the active ingredients of Bioban P 1487

Bioban P 1487. consisting of the 2 active ingredients 4-[2-nitrobutylt]-morpholine (M) and 4.4'-(2-ethyl-2-nitro-1.3-propanediyl)-his morpholine (DM), is a preservative recommended for metal working fluids. The aims of this study were to assess the frequency of contact allergy so Bioban P 1487. when added 10 a standard patch lest series, as well us to test the individual active ingredients in patient- sensitized to Bioban P 1487. Of the patients consecutively tested, 1.5% reacted positively to Bioban P 1487. Positive test reactions were noted in only 4 of 12 Bioban P 1487-sensitized patients tested with the individual active ingredient. Both active ingredients are contact sensitizers. but in most patients with this contact allergy it remains difficult to identify the sensitizing hapten.     

Allergic contact dermatitis to DMDI in an office application

Contact dermatitis to isocyanates is a problem and is usually described within industrial settings. A patient who developed an acute allergic contact dermatitis using a dicyclohexylmethane-4,4'-diisocyanate (DMDI)-charged cartridge to create resin-coated '3D labels' within an office environment is described.     

Occupational allergic contact dermatitis from 2-N-octyl-4-isothiazolin-3-one

2-N-octyl-4-isothiazolin-3-one (OIT) is an antimicrobial agent that is mainly used in industrial settings. The objective of the study was to find the significance of OIT contact allergy at our clinic of occupational dermatology. We looked through our patient material from 1991 for allergic reactions to OIT and analysed the clinical records. We found 8 patients with ordinary allergic reactions to OIT and 1 late reaction. 2 workers in the manufacture of paints had occupational allergic contact dermatitis from OIT in biocides. 2 patients were machinists and 3 were female farmers: in these cases, however, we could not find any exposure. A sewing machine operator had patch test reactions to 2 of her mattress textiles, and chemical analysis of them showed 40-50 parts per million OIT. In conclusion, OIT is a rare sensitizer, and its contact allergies occur mainly in paint manufacturing. It is infrequently used in metal-working fluids and possibly sensitizes machinists. Although it is also used in some biocides recommended for use in the textile industry, there are no previous reports of contact allergy in this field. Our sewing machine operator with OIT contact allergy had probably been sensitized from mattress textiles.     

Contact allergy to air-exposed geraniol: clinical observations and report of 14 cases

Background. The fragrance terpene geraniol forms sensitizing compounds via autoxidation and skin metabolism. Geranial and neral, the two isomers of citral, are the major haptens formed in both of these activation pathways. Objectives. To investigate whether testing with oxidized geraniol detects more cases of contact allergy than testing with pure geraniol. Patients and methods. The pattern of reactions to pure and oxidized geraniol, and metabolites/autoxidation products, was studied to investigate the importance of autoxidation or cutaneous metabolism in contact allergy to geraniol. Pure and oxidized geraniol were tested at 2.0% petrolatum in 2227 and 2179 consecutive patients, respectively. In parallel, geranial, neral and citral were tested in 2152, 1626 and 1055 consecutive patients, respectively. Results. Pure and oxidized geraniol gave positive patch test reactions in 0.13% and 0.55% of the patients, respectively. Eight of 11 patients with positive patch test reactions to oxidized geraniol also reacted to citral or its components. Relevance for the positive patch test reactions in relation to the patients' dermatitis was found in 11 of 14 cases. Conclusions. Testing with oxidized geraniol could detect more cases of contact allergy to geraniol. The reaction pattern of the 14 cases presented indicates that both autoxidation and metabolism could be important in sensitization to geraniol.     

Contact allergy to 2,5-dimercapto-1,3,4-thiadiazole and phenyl-alpha-naphtylamine, allergens in industrial greases and lubricant oils--contact allergy to water-insoluble greases is uncommon but needs to be considered in some workers

Background:  Industrial lubricants are usually made of petroleum and contain no water. Industrial greases and neat oils (insoluble metalworking oils) cause contact allergy relatively seldom, and reported allergies to the components of engine oils, such as hydraulic oils, are extremely scarce.
Objective:  The aim was to describe patients with contact allergy to the components of industrial lubricants.
Results:  We describe 2 patients with allergic reactions to 2,5-dimercapto-1,3,4-thiadiazole. Their allergies derived from guide-way oil and grease. Guide-way oils are lubricants for metalworking machines. Machinists may have continuous skin contact to these oils, as the oils are leaked to the circulating metalworking fluid system and form the so-called 'tramp oil'. We also report a new case with allergy to phenyl-α-naphtylamine in grease.
Conclusion:  2,5-dimercapto-1,3,4-thiadiazole is an aromatic compound used in oils and greases. It has previously caused contact allergy to workers who have handled the pure chemical, but to our knowledge, there are no previous reports of contact allergy from products containing the chemical in a relatively low concentration. 1 of our 2 cases had been sensitized from grease and the other from a guide-way oil. The latter case shows that machinists may become sensitized to lubricants that leak to the metalworking fluid system.     

Occupational allergic contact dermatitis from 2,3-epoxypropyl trimethyl ammonium chloride (EPTMAC) and Kathon® LX in a starch modification factory

2.3-epoxypropyl trimethyl ammonium chloride (EPTMAO is used in the production of cationic starch (CS) for the paper industry. It has been shown to be a sensitizer in guinea pigs, but eases of human sensitization are few. 4 workers were previously sensitized to the substance in a Finnish plant. This report describes 3 process men from another plant examined because of recurring dermatitis. IS workers were involved in production, and had free access in ill work sites. 3 process men. whose work involved drying the CS, had dermatitis, although they had only occasional contact with the cationizing chemical. 2 were already verified to be allergic to EPTMAC' and had had variable dermatitis for 8–12 years. One had had dermatitis on his lace for 1 year. Patch testing with a dilution series (1%, 0.5%. 0.2%, 0.1% pet.) confirmed their allergy to the cationizing chemical containing EPTMAC, but tests with CS were negative. In addition, 2 had contact allergy to C1+ Me-isothiazolinone from contact with Kathon® LX used us a slimicide in the process. In longstanding (years) recurrent dermatitis, re-examination of patients with verified exposure history and skin tests is necessary. In line with our previous study, sampling the process materials, maintenance work and contamination of work sites and gloves caused sensitization. The results also confirm that EPTMAC is a strong human contact sensitizer. 0.2%–0.5% pure EPTMAC in pet. seem to be the optimal patch test concentration.     

FS12.6Sensitizing capacity and cross‐reactivity of phenyl glycidyl ether

Objectives:  Diphenylmethane‐4,4'‐diisocyanate (MDI) is a very common isocyanate which is used in the plastics industry in its' polymeric form in the production of polyurethane products such as rigid and flexible foams, elastomers (rubbers) and coatings. Previous reports on MDI‐related contact allergy have shown a pattern where patients seem to react to their own MDI‐based work material but not to the commercial patch test preparations of MDI. Therefore, we performed chemical analysis of 14 commercial patch test preparations of MDI.
Materials and Methods:  MDI preparations from 8 European and 4 American dermatology departments as well as preparations obtained from 2 major European suppliers of patch test allergens were analyzed with respect to MDI content using liquid chromatography mass spectrometry (LC‐MS).
Results:  None of the preparations obtained from dermatology departments contained more than 12% of the concentration stated on the label. In most cases the MDI content was only a few percentages or less of the concentration stated. In only 1 commercial preparation the MDI content came close to the declared concentration.
Conclusion:  7 of the 14 preparations were analyzed before the expiry date. Yet, only 1 of them contained a concentration that came close to that stated on the label. Thus, using these preparations patients will be tested with a much lower concentration than intended leading to a high risk of false‐negative reactions and thereby underdiagnosis of allergic contact dermatitis from MDI.     

Reactions causing reactions: Allergic contact dermatitis to an isocyanate metabolite but not to the parent compound

Industrial use of isocyanate resins rarely causes allergic contact dermatitis. We report a patient who developed allergic contact dermatitis to a transitory chemical breakdown product of the isocyanate 4,4'-diphenylmethane diisocyanate (MDI), diaminodiphenylmethane (DDM), although he was not sensitized to the suspected parent compound MDI.     

Concomitant sensitization to triglycidyl isocyanurate, diaminodiphenylmethane and 2-hydroxyethyl methacrylate from silk-screen printing coatings in the manufacture of circuit boards

A 48-year-old female silk-screen printer had worked in the manufacture of circuit boards for 12 years before she got the first symptoms of dermatitis on her wrists and lower arms. On the 1st patch test session, epoxy resin and the remainder of the standard series were negative, while a plastics and glues series gave an allergic reaction to 4,4'-diaminodiphenylmethane (DDM). The 2nd test session revealed allergic reactions to several acrylics, several epoxy compounds and 3 ink components. According to the material safety data sheets, 1 ink hardener contained DDM, but the causative agent in 1 ink and 1 ink hardener remained uncertain. The manufacturers of the 2 inks kindly provided us with their components for further patch tests. 2 of these components gave allergic reactions: triglycidyl isocyanurate (TGIC) and 2-hydroxyethyl methacrylate (2-HEMA). Our case report shows that the manufacture of circuit boards involves exposure to highly sensitizing chemicals. DDM, TGIC and 2-HEMA should be remembered as silk-screen printers' potential contact sensitizers in the manufacture of circuit boards.