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Description of key information

Ethylene diamine has officially been classified as a skin and respiratory sensitiser.

Skin sensitisation:

WHO (1999)

EDA has been known for many years to be capable of inducing allergic skin reactions in humans. This has been observed both in the workplace and, most notably, in patients treated with aminophylline or with skin creams in which EDA was used as a stabilizer (Epstein & Maibach, 1968; Petrozzi & Shore, 1976; Booth et al., 1979; Wall, 1982; Hardy et al., 1983; Balato et al., 1984; Edman & Moller, 1986; Nielsen & Jorgensen, 1987; Terzian & Simon, 1992; Toal et al., 1992; Dias et al., 1995; Simon et al., 1995; Sasseville & Al—Khenaizan, 1997). The first reports of skin sensitizing effects in humans date back to the late 1950s, when cases were described of eczematous reactions in pharmacists who came into contact with EDA when using aminophylline (Baer et al., 1958; Tas & Weissberg, 1958).

Subsequent to these early reports, numerous studies and case reports have been published documenting the skin sensitizing properties of EDA both following clinical use and within the occupational setting, such that the substance has become incorporated into standard series for patch testing (Fregert, 1981; Shehade et al., 1991). An example from the clinical setting is that of the report on a series of 13 patients who had used skin cream containing EDA for, paradoxically, dennatitic conditions (Provost & Jillson, 1967). Use of the cream in 11 of these patients had resulted in the sudden appearance of a severe generalized patchy eczematous eruption following, in all but one of the cases, an initial improvement upon using the cream. Patch testing was conducted using a 1% aqueous solution of EDA, producing skin reactions in all patients ranging from erythema and oedema to erythema vesiculation and oedema vesiculation, which extended beyond the patch test site. Other substances tested also induced responses, but not in a consistent manner, with at most only four individuals responding in any one test.

As well as the original reports in pharmacists working with EDA, cases of skin sensitization to EDA have been reported in the occupational environment in a number of different settings, including use of floor polish remover (English & Rycroft, 1989), use of coolant oils (Crow et al., 1978), and in wire-drawing (Matthieu et al., 1993; Sasseville & Al—Khenaizan, 1997). Positive responses to patch testing with EDA have also been observed in other occupational settings, such as the offshore oil industry (Ormerod et al., 1989), but positive responses to other substances, including other polyamines, were also seen in such cases. Thus, it is unclear whether EDA had been responsible for inducing the sensitized state and/or cross-reacting following sensitization to another polyamine.

OECD-SIDS (2002):

Ethylenediamine has been positive in a number of human dermal sensitization studies (Eriksen, 1979; English and Rycroft, 1989). The first case reports on hypersensitivity appeared in the late fifties and concerned pharmacists handling aminophylline preparations (Baer et al., 1959). During a 20 year period, between 1967 and 1987, the International Contact Dermatitis Group (ICDRG) included ethylenediamine as part of its standard patch test series. The standard patch test series was conducted on different test populations consisting of 89-3216 individuals from several countries, including Poland, Canada, USA, Scotland, Sweden, Italy, Denmark and Germany. These individuals probably had some type of dermal irritation prior to visiting the physician’s office. The percentage positive for these various groups ranged from 0-17%. The higher incidence is probably due to individuals with ‘angry back syndrome’. In the seventies ethylenediamine had been nominated the second or the fifth most common contact allergen. In most cases sensitization was caused by topical preparations containing ethylenediamine as stabilizer (e.g. Mycolog in the US, Tri-Adcortyl in Great Britain, Kenacomb in Australia, Assocort and Halciderm Combi ointment in Italy). Mycolog is no longer produced in the US (PDR, 2000).

MAK (2003):

Occupationally—induced sensitization to ethylenediamine has been adequately demonstrated in numerous cases; usually local contact allergic reactions were observed after exposure to pharmaceuticals or epoxy resin hardeners containing ethylenediamine or after direct contact with ethylenediamine vapour. As early as 1958 the first cases of hypersensitivity to ethylenediamine were reported; eczematous skin reactions were observed in pharmacists who came into contact with ethylenediamine during the preparation of aminophylline formulations (Baer et al., 1959; Tas and Weissberg, 1958). Since these first publications, numerous other reports have been published which confirm the skin sensitizing potential ofethylenediamine as a component of topically applied medicines (Balato et al., 1984; Caraffini and Lisi, 1987; Edman and Moller, 1986; Freeman, 1986; Larsen, 1979; Nielsen and Iorgensen, 1987; Provost and Iillson, 1967). In addition, generalized reactions such as eczema or exfoliative erythroderma (Bernstein and Lorincz, 1979; Cusano et al., 1986; de Shazo and Stevenson, 1981; Elias and Levinson, 1981; Hardy et al., 1983; Mohsenifar et al., 1982; Petrozzi and Shore, 1976; Thompson et al., 1984;) and urticaria (Booth et al., 1979; de la Hoz et al., 1993; Kradjan and Lakshminarayan, 1981; Neumann, 1983; Saven and Lippmann, 1987; Urbani, 1994; Wong et al., 1971; Yoshizawa et al., 1999) were reported, which occurred after intravenous, intramuscular, subcutaneous, oral or rectal administration of preparations containing ethylenediamine, but which could not always be clearly attributed to ethylenediamine.

During the testing of differently sized collectives, which were not specified in any greater detail or characterized by different selection criteria, the frequency of positive results in patch tests with ethylenediamine or ethylenediamine dihydrochloride was found to vary greatly from between 0.1% and 15.7%. Unusual is the fact that the number of reactions to ethylenediamine in Germany seems to be much lower than that in studies from e.g. the United States or Canada. A reason for this may be the frequent use in these countries of fungicidal and antibacterial topical medicines (Pevny and Schafer, 1980) which contained ethylenediamine as stabilizer.

According to an incompletely documented report, in a patch test with 1% ethylenediamine dihydrochloride in a vehicle containing methyl cellulose a nurse with urticaria possibly induced by detergents containing ethylenediaminetetraacetate produced a papular-erythematous reaction in the test area after 15 minutes and pruritis and erythema on the palms ofthe hands and on the face (Baker et al., 1998). The simultaneous reactions to other polyamines, such as diethylenetriamine, triethylenetetramine or piperazine found in some studies (Balato et al., 1984; 1986; Burry, 1978; Eedy, 1993; Price and Hall-Smith, 1984; van Hecke, 1975; Wright and Harman, 1983), are possibly in some cases the result of polyvalent sensitization after dual exposure and do not (always) represent a cross-reaction. The same is probably true also for the only rarely described simultaneous reactions (Eriksen, 1975; Raymond and Gross, 1969) to ethylenediamine and ethylenediaminetetraacetate (EDTA), which otherwise is practically unknown as a contact allergen.

Patch test reactions to ethylenediamine, which according to 2 reports (Burry, 1986; Romaguera et al., 1986) were induced only by light or were amplified by it, are inadequately documented and an additive irritative effect cannot be excluded, so that photosensitizing effects cannot be deduced. In a modified Draize test, in 5 of 61 healthy volunteers who underwent induction treatment with 5% ethylenediamine dihydrochloride sensitization was detected on provocation with 1% ethylenediamine dihydrochloride (probably in petrolatum) (Marzulli and Maibach, 1976).


Respiratory sensitisation:

WHO (1999)

A large number of cases of occupational asthma reported to have been caused by exposure to EDA are available in the literature (Demehl, 1951; Gelfand, 1963; Popa et al., 1969; Valeyeva et al., 1975; Lam & Chan-Yeung, 1980; Chan-Yeung, 1982; Hagmar et al., 1982; Matsui et al., 1986; Aldrich et al., 1987; Nakazawa & Matsui, 1990; Lewinsohn & Ott, 1991; Ng et al., 1991; 1995). There are a few studies in which the potential for EDA to cause respiratory hypersensitivity has been examined using bronchial provocation testing and investigation of antibody formation. As EDA is corrosive, the vapour would be predicted to be a respiratory tract irritant, which is a complicating factor in interpreting the data available and in elucidating the underlying mechanism for any asthmatic responses seen.

Popa et al. (1969), in a well-conducted study, investigated 48 subjects with asthmatic symptoms caused by exposure to a number of low molecular weight chemicals, including EDA. None of the subjects had a history of respiratory disorder prior to occupational exposure, and the asthmatic response was associated only with occupational exposure in all cases. No information was given in the report on the workplace airborne concentrations of EDA to which these workers were exposed. A series of tests were performed in all subjects, including skin and inhalation tests with the test agent at sub-irritant concentrations; skin and inhalation tests to common allergens; skin tests (intraderrnal, scratch, and patch tests) using sub-irritant concentrations of the test substance; Prausnitz-Kustner transfer reaction (to test for the presence of immunoglobulin E antibodies); and determination of precipitating antibodies to EDA. For the inhalation test, the sub-irritant concentration was determined in control asthmatic subjects, and a 2- to 10- fold dilution of this was used for the bronchial challenge. No information was given on the airborne exposure concentrations generated under these test conditions. Control inhalation tests with the diluent, physiological saline, were also conducted. It is not stated in the report whether or not the inhalation challenge tests were conducted in a blind manner. Six subjects had an immediate, positive reaction to EDA in the workplace. Of these, four showed an immediate, positive response following inhalation testing with sub-irritant concentrations of EDA. These subjects developed marked bronchoconstriction following inhalation exposure to EDA, with a reduction in forced expiratory volume in 1 sec (FEV1) of 62% and an increase in respiratory resistance of 44%, compared with controls. Although not stated in the report, these values are presumed to be average changes. Intradermal skin tests with EDA were positive in these four subjects, whereas patch tests were negative. Inhalation challenges with common allergens were negative. The Prausnitz—Kustner test was positive in all subjects, and all had eosinophilia, determined in the sputum, although not, except in one case, in the blood. No precipitating antibodies were found. In the two other subjects, the inhalation challenge test was negative. No precipitating antibodies were found, and the Prausnitz-Kustner test was negative in both subjects. Eosinophilia was absent. Inhalation challenges with other common allergens were also negative. These data provide evidence that EDA may elicit an asthmatic response at sub-irritant concentrations and that the response is specific to EDA. Four out of six subjects responsive to EDA in the workplace also had a positive response to inhaled EDA at sub-irritant concentrations. This demonstrates that the reaction is not a generalized response to an irritant. The positive Prausnitz—Kustner reaction may be indicative of an immunological component, but the test is not specific, and no firm conclusions can be drawn from it. It provides supporting evidence in this case. The evidence suggests that the subjects were hypersensitive to inhaled EDA and that a state of respiratory hypersensitivity had been induced by the substance.

Although a number of other studies are available, the information is of poor quality. Lam & Chan-Yeung (1980) and Chan-Yeung (1982) describe the case of one worker in a photographic laboratory who developed asthma afler 2.5 years of exposure to a variety of chemicals, including EDA, but also other irritant substances. The worker developed symptoms of sneezing, nasal discharge, productive cough and nocturnal cough, wheezing, and dyspnoea. The symptoms coincided with the work shift and subsided at weekends. There was no previous history of asthma. No information was given in the report of the airborne concentrations of EDA (or other substances) to which the man was exposed at work. A series of controlled inhalation challenge exposures, designed to mimic work exposure conditions, were conducted with each of the chemicals to which the subject was exposed at work. The duration of exposure was determined by the patient’s tolerance, and exposure was terminated when eye irritation or cough was experienced. No information on the airborne exposure concentrations of EDA generated under these test conditions was given in the report. A methacholine inhalation test for bronchial hyperreactivity was also performed. Pulmonary function tests were conducted pre- and post-challenge, and blood samples were taken before, during, and after each challenge. The subject showed marked bronchial reactivity to methacholine. Exposure to an unknown concentration of vapour from a 1:25 solution of EDA was tolerated for 15 min. This exposure produced a marked bronchoconstriction. A late asthmatic response developed 4 h after the exposure, at which time FEV1 was reduced by 26% and continued to decrease over the next 3 h towards a 40% reduction. A 26% reduction was still apparent after 24 h, despite treatment with bronchodilator drugs. This pattern of response to EDA was reproducible. The patient did not respond similarly to any of the other chemicals tested: formaldehyde, sulfur dioxide, and two colour developing agents that were stated to be irritants. Exposure to formaldehyde (vapour from a 1:4 solution) produced an immediate small (<20%), transient reduction in FEV1, whereas exposure to sulfur dioxide caused coughing and chest tightness and an immediate transient reduction of 25% in FEV1. There was no increase in plasma histamine concentration during the period of bronchoconstriction, although EDA was shown to cause in vitro histamine release from whole blood taken from the patient and from two control subjects. A skin test using 1:100 EDA and a precipitin test for antibodies to EDA were both negative. The patient subsequently had to give up work because of respiratory symptoms and became asymptomatic after 2 weeks. Subsequent testing with methacholine, 2.4 months after ceasing work, showed that the subject had a reduction in the previous bronchial hyperreactivity. In conclusion, the subject showed an asthmatic response to EDA but not to formaldehyde or the colour developing agents. The pattern of response to sulfur dioxide was more immediate and suggestive of an irritation response. Overall, a clear pattern of asthmatic response that was specific to EDA was observed in this study. However, it is not possible to distinguish with certainty between an irritant response and a sensitization response, because it is possible that an irritant concentration was used for the bronchial challenge exposure, although little immediate response was observed. In addition, although exposure to irritant concentrations of the other workplace chemicals did not elicit the same pattern, magnitude, or severity of response as that seen with EDA, since accurate exposure levels were not given, it is not possible to determine whether or not the EDA concentration used had the greatest irritant potential. No evidence for any immunological involvement was found. In conclusion, this study provides only circumstantial evidence that EDA caused a state of respiratory hypersensitivity in this subject.

A number of other case reports are available of individuals who exhibited asthmatic signs and symptoms associated with exposure to EDA in the workplace (Gelfand, 1963; Valeyeva et al., 1975; Matsui et al., 1986; Nakazawa & Matsui, 1990; Ng et al., 1991). Although bronchial challenge testing with EDA produced asthmatic responses in these subjects, they had personal and/or family histories of allergic disease and/or they had worked with and responded on challenge to other substances. Retrospective studies using the medical records of populations of workers using EDA have indicated that about 10% of such populations developed signs and symptoms of occupational asthma (Aldrich et al., 1987; Lewinsohn & Ott, 1991). No challenge tests were carried out with these surveys. Thus, these case reports and population-based studies provide only supporting circumstantial evidence for the involvement of EDA in producing occupational asthma.

Although it is clear from these reports that EDA can provoke an asthma attack, in many cases there is insufficient information to indicate whether or not the hypersensitive state was induced specifically by EDA. However, from one well-conducted study, there is evidence that a hypersensitive state specific to EDA has been induced in workers and that an asthmatic response was provoked by sub-irritant concentrations of the substance. Overall, the results of this study, taken together with the supporting data from a substantial number of other reports of occupational asthma, indicate that EDA is capable of inducing a state of hypersensitivity in the airways, such that subsequent exposure may trigger asthma. The mechanism by which the hypersensitive state is induced is not proven. Given the skin sensitizing potential of EDA and the limited evidence of immunological involvement in workers with EDA-provoked occupational asthma, an immunological mechanism would seem plausible. Irrespective of the mechanism involved, the data available (specifically the lack of information on airborne exposure concentrations under both work and challenge test conditions) do not allow elucidation of a dose—response relationship or the identification of levels of EDA that are not capable of inducing a hypersensitive state or of provoking an asthmatic response.

OECD-SIDS (2002)

Cases of occupational sensitization in production facilities have only rarely been reported (Hagmar et al., 1982; Lewinsohn and Ott, 1991; Ng, 1991). Delayed-type asthma was observed in workers with rhinorrhea, sore throat and a hacking cough being observed first. Occasionally dual-type asthma has been observed. There have been no cases of immediate-type asthma reported. Humans sensitized to EDA have also been shown to be sensitive to diethylenetriamine, triethylenetetramine, tetraethylenepentamine and to a lesser extent, piperazine (Balato, 1986).  

MAK (2003)

There are numerous case reports available of occupational asthma after exposure to ethylenediamine, but most of them are incompletely documented. It must also be taken into account when evaluating the results that ethylenediamine vapour can lead to irritation of the respiratory passages. Ethylenediamine levels of 250 and 500 mg/m3 were given as the irritative concentration (Ruth 1986). In the most extensive study of the sensitizing effects of ethylenediamine, 6 patients with workplace-related bronchial asthma were described who were exposed to ethylenediamine in the plastics industry. None of the patients suffered from respiratory diseases before taking up the job. Bronchial provocation tests were carried out with test preparations of ethylenediamine in physiological saline, which did not trigger irritative reactions in 6 asthmatic control persons. In the provocation test with 0.1% ethylenediamine in physiological saline 4 of the 6 patients produced an immediate reaction. The spirometric investigation carried out in one of these 4 patients revealed a decrease in the forced expiratory volume in the first second (FEV1) of 62% and an increase in airway resistance of 44%. The 4 patients reacted also in the intracutaneous test to 0.01% ethylenediamine in physiological saline. Prausnitz-Kiistner tests also yielded positive results. The patch test with 10% ethylenediamine in physiological saline did not produce a reaction, and the precipitin reaction (test concentration 1%) and inhalation tests with ubiquitous allergens yielded negative results. There are no details of the control tests or the results of the provocation tests with other chemicals, and unspecific bronchial reactivity was not tested using histamine, methacholine or acetylcholine (Popa et al. 1969).

One employee, who had contact with formaldehyde, colour film developers and other substances, including ethylenediamine, during the production of colour photographs, developed after a latency period of 2.5 years rhinitis and asthmatic symptoms. Prick tests and intracutaneous tests with 1% ethylenediamine in physiological saline yielded negative results. Precipitins were not detected in the Ouchterlony test. In the inhalation test 4% ethylenediamine in physiological saline was applied to a piece of card in an exposure chamber for 15 minutes. About 4 hours after exposure, a delayed asthmatic reaction occurred with laboured breathing, coughing, wheezing and a FEV1 decrease of 26%. Within the next 3 hours a further FEV1 decrease was observed, and despite the administration of salbutamol and prednisolone the FEV1 was still decreased by 26% after 24 hours. The test results were reproducible after 2 weeks. After giving up the job, the patient became free of symptoms, and the unspecific bronchial hyperreactivity regressed with an increase in PC20 (the methacholine concentration which caused a decrease in the FEV1 of at least 20%) from 0.125 to 8 mg/ml. In inhalation tests with other substances found at the workplace (formaldehyde, sulfur dioxide and colour film developers) no delayed reactions occurred. The amount of histamine released into the blood after incubation with ethylenediamine did not differ between the controls and patient (Lam and Chan-Yeung 1980). In 2 employees of the chemical industry, after 4 and 7 months of occupational exposure to ethylenediamine, exposure-dependent coughing, wheezing and dyspnoea developed. Both patients were found to have unspecific bronchial hyperreactivity (PC20 methacholine: 19.5 and 78.1 ug/ml), and one patient additionally had allergic rhinitis; tests for ubiquitous allergens, however, yielded negative results, while the total IgE was increased. The documentation of the results of the skin tests and Prausnitz-Kiismer test contains discrepant information. Workplace-related re-exposure for 20 minutes led in one case to wheezing and shortness of breath 4 hours after exposure, with a decrease in the FEV1 of more than 20%, so that the test was terminated by the administration of a bronchospasmolytic preparation. In the second case, wheezing and shortness of breath developed 3 hours after exposure and a decrease in the peak expiratory flow (PEF) of 38% was found after 4 hours. After 5 hours an improvement was observed, but after 10 hours a renewed deterioration. In healthy control persons no reactions occurred; details of the test conditions were not given, however (Matsui et al., 1986; Nakazawa and Matsui, 1990).

An employee from a chemical company producing epoxy resin hardeners was exposed to numerous chemicals (amines, solvents), including ethylenediamine, in particular during the bottling of products containing 5—10% ethylenediamine. The ethylenediamine concentration in the workplace air was not determined. Three months after starting the job, symptoms such as coughing, Wheezing and shortness of breath developed in the patient (who previously had no respiratory problems) after exposure for several hours; the symptoms regressed if exposure was avoided. Workplace determination of the PEF revealed a deterioration over the course of the day and week. Bronchial provocation for 15 minutes under clinical conditions with an ethylenediamine concentration of 30 ml/m3 led after 3 hours to a decrease in the PEF of 23%, as well as to coughing and breathing difficulties, and 12 hours later to a further decrease in the PEF of 10%, so that medicinal treatment was necessary. Exposure for 15 minutes to an isopropanol concentration of 50 ml/m3 led after 3 hours to a similar decrease in the PEF, but without further deterioration. The patient was found to have marked unspecific bronchial hyperreactivity (histamine amount which caused a decrease in the FEV1 of at least 20% (PDZO): 0.065 umol) and reacted in the prick test to some ubiquitous allergens. Also other exposed persons complained of breathing difficulties. One worker changed department within the factory because of asthma; there are no details available, however (Ng et al. 1991). A further dozen employees of this factory were also exposed to ethylenediamine, mainly during the bottling of products containing ethylenediamine. In 2 workplace air samples ethylenediamine concentrations of 10.5 and 4.8 ml/m3 were determined. The reported symptoms were coughing in 7 of the 12 employees, exercise-induced dyspnoea in 3 employees and wheezing in 4 employees. In these 4 employees, who had no respiratory problems before taking up the job, the PEF decreased by at least 15% during the working day. Two of the 4 employees could not be examined further. In the other 2 employees also serial PEF determinations revealed workplace effects, and a provocation test with ethylenediamine (no details ofthe method) yielded positive results in one case. A dual reaction occurred; even after 12 hours the PEF value was decreased by about 40%, despite previous administration of a bronchospasmolytic preparation. A control test with denatured alcohol led after 30 minutes and after 18 hours to a decrease in the PEF of about 15%. The PEF was not determined, however, 6 to 17 hours after the control provocation. There are no data for unspecific bronchial reactivity (Ng et al., 1995).

According to a communication, in an employee from the detergent industry with occupationally induced asthma and contact with enzymes and ethylenediamine, in a 2-hour provocation test with ethylenediamine a 20% decrease in the FEV1 was observed after a delay of about 8 hours. Before provocation, unspecific bronchial reactivity to methacholine was negligible, but increased after provocation (Casas et al., 2002).

Employees with asthma who were exposed in the rubber industry (2 employees) or lacquer and shellac industries (7 employees in each case) to e.g. isocyanates, hexamethylenetetramine and ethylenediamine, produced immediate reactions in the intracutaneous test with 0.02 ml 1% ethylenediamine in coca solution (no reaction in control persons, no other details) and in the provocation test with ethylenediamine. Lung function tests were evidently not carried out. Some of the patients reacted in the provocation test also to other chemicals. Also for 13 of a further 14 persons exposed to cosmetics occupationally or in the private sphere, reactions to ethylenediamine were observed in the intracutaneous test. There are, however, no details of whether these persons had previous contact with ethylenediamine (Gelfand, 1963). As a result of the incomplete documentation, and as the criteria for a positive result in the provocation test were not given, it is not possible to evaluate these findings conclusively.

Other authors reported breathing difficulties in employees with exposure to ethylenediamine without giving details of the allergological test results, so that these investigations cannot be used to evaluate the sensitizing effects of ethylenediamine on the respiratory passages. In one study “respiratory allergy” to ethylenediamine was reported in 38 of 369 exposed persons; the substance was used as solvent for polymers and pigments for plastic coatings. In 2 years the ethylenediamine concentrations at the workplace were higher than 10 ml/m3 in 4 to 5% of the determinations, but did not exceed this value in 5 other years (Aldrich et al., 1987). In an evaluation of anamnestic, clinical and functional data for 197 employees in the production of ethylenediamine (93% of the workforce) and a control group of 186 employees (response 88%) not in ethylenediamine production, 72 employees from production and 3 employees from the control group reported symptoms resulting from exposure to ethylenediamine. Out of these 75 employees, sensitization of the respiratory passages was evident in 7 cases on the basis of the medical evaluation of the reported symptoms or as a result of the necessity to change workplace, and sensitization of the skin in 23 cases on the basis of existing test results and medical examinations (Lewinsohn and Ott, 1991). Also in two other communications bronchial asthma was reported, without details on allergological test results, in 3 employees of a chemical company (two dual reactions, one isolated delayed reaction) (Hagmar et al., 1982) and in 3 of 35 persons exposed to “ethyleneamines" during the production process; in 12 of these 35 employees dermatitis was also reported (Dernehl, 1951). To what extent this last group was also exposed to higher condensed amines such as diethylenetriamine or triethylenetetramine is not clear from the publication.

In addition, there are individual reports of reactions of the skin or respiratory passages which were observed in asthma patients after the use of theophylline preparations containing ethylenediamine. Due to the primary disease, and as the genesis of the reactions is unclear, a sensitizing effect of ethylenediamine on the respiratory passages cannot, however, be deduced from these reports. One of 3 asthmatic patients produced an urticaria  immediate reaction with generalized pruritus after oral administration of aminophylline. In a second patient an urticarial reaction and increased bronchospasm occurred after intravenous administration of aminophylline. The oral provocation with theophylline carried out in this patient did not, however, produce a reaction. Both patients produced immediate reactions in the intracutaneous test with 1% ethylenediamine (vehicle not stated). The third patient produced generalized erythrodermia 24 hours after intravenous administration of aminophylline and in the intracutaneous test with 1% ethylenediamine an erythematous-pruriginous reaction after 24 hours. Prick tests with 1% ethylenediamine yielded negative results in the 3 patients, as did intracutaneous tests with 1% ethylenediamine in 10 atopic and 10 non-atopic control persons (Lleonart et al., 1991).

In one man with atopic diathesis and existing asthma, marked shortness of breath, a decrease in blood pressure and cyanosis occurred after intravenous administration of aminophylline and dexamethasone. During construction work later, the asthmatic symptoms of the patient increased once more. The authors suspected the cause to be exposure to lacquers and shellac containing ethylenediamine. In the intracutaneous test the patient produced a bullous reaction to 0.01% ethylenediamine and erythematous reactions to 0.25% aminophylline and some corticoid preparations. Physiological saline was probably used as the vehicle. In control persons (no other details) no reactions were observed (Asakawa et al., 2000). After intravenous treatment with aminophylline for about 2 years, in a 3-year-old atopic boy an increase in respiratory symptoms and cyanosis were observed on several occasions around 5 minutes after the aminophylline infusion. Oral administration of theophylline did not produce such effects. In the prick test the patient produced an immediate reaction to 0.01% ethylenediamine and 0.01% aminophylline in physiological saline, while healthy and asthmatic control persons did not (no other details). Around 11 hours after a 1-hour tolerance test carried out by the infusion of aminophylline (5 mg/kg body weight per hour), an asthmatic reaction occurred that lasted for about one hour. When the test was repeated 3 days later, however, an immediate reaction occurred that lasted for about 20 minutes (whistling noises while breathing and dyspnoea). For this reason the infusion was terminated after 15 minutes and a bronchospasmolytic preparation was administered. In both tests the histamine level in plasma during and directly after the infusion was increased, but not during the delayed reaction in the first test. Control persons with asthma (no other details) did not produce respiratory reactions after a corresponding infusion (Motoyoshi et al., 1990).

According to an earlier study, pruriginous skin changes developed on the hands, arms and face of a pharmacist after contact for several weeks with aminophylline. Later, symptoms of the upper respiratory tract developed and finally marked asthmatic complaints. A patch test with 1% aminophylline (vehicle not specified) led to a bullous reaction; 100 control persons did not produce a reaction. The patient did not react to 1% theophylline (vehicle not specified) in the patch test. Exposure to sprays with graded, aqueous dilutions of aminophylline and theophylline (dilutions of 10E-12 to 0.1) and ethylenediamine (dilutions of 10E-12 to 10E-6) for about 5 minutes each did not lead to immediate reactions (determined on the basis of the vital capacity). Around 6 hours later exacerbation of the skin symptoms, which lasted for about 2 days, and a severe, 14-day asthmatic reaction with asthmatic crisis were observed. Other immunological investigations were not carried out (Tas and Weissberg, 1958).

Additional information

Ethylene diamine has officially been classified as a skin and respiratory sensitiser. However, although EDA has been positive in a number of human dermal sensitization studies, cases of occupational sensitization in production facilities have only rarely been reported. With regard to respiratory sensitisation, it appears that EDA can provoke an asthma attack, but in many cases there is insufficient information to indicate whether or not the hypersensitive state was induced specifically by EDA. Based on the available data, EDA seems capable of inducing a state of hypersensitivity in the airways, such that subsequent exposure may trigger asthma. The mechanism by which the hypersensitive state is induced is not proven. As liquid EDA is corrosive, the vapour would be predicted to be a respiratory tract irritant, which is a complicating factor in interpreting the data available and in elucidating the underlying mechanism for any asthmatic responses seen.

See also our review in section 7.10.4.