C,C'-azodi(formamide)

Endpoint summary

Description of key information

Skin sensitization in human: Some evidence of transient skin sensitization but not sufficient for assessment on the sensitization potential of Azodicarbonamide.

Respiratory effects in human: respiratory health effects in case reports and health surveillance data after occupational exposure.

Additional information

Skin sensitization in human

Three case reports on skin sensitization have been published. In the most recently reported investigation, a male textile worker exposed to azodicarbonamide in foam ear-plugs was patch tested to discover the cause of a recurrent dermatitis of the ear (Nava et al., 1983; Bonsall, 1984; Yates & Dixon, 1988). No response was elicited with a number of standard (International Contact Dermatitis Research Group standardseries) allergens. However, the individual gave a strong positive reaction to the ear-plugs at 48 and 96 h and also to azodicarbonamide (a component of the ear-plugs) at a concentration of 1 and 5% in petrolatum but not at 0.1% in petrolatum. Ten control subjects patch tested with 1 and 5% azodicarbonamide in petrolatum did not respond, and the individual reported no further symptoms upon discarding the ear-plugs.

 

Respiratory sensitization in human

Case reports

A number of reports have been published of individual azodicarbonamide workers alleging asthma induced by exposure to azodicarbonamide.

The strongest evidence comes from a study of two individuals (one atopic and one non-atopic) who worked at the same plastics factory for about 4 years (Malo et al., 1985; Pineau et al., 1985). Both were intermittently exposed (1–2 weeks’ duration, 3–4 times per year) to azodicarbonamide at work. A few months after their first encounter with azodicarbonamide, both developed symptoms described as “eye/nose irritation” at work, followed a few hours later by nocturnal asthmatic symptoms. After a 1-month period free from exposure, both subjects underwent lung provocation studies. Baseline values for forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and the concentration of histamine required to produce a 20% drop in FEV1 (PC20H) were obtained by spirometry. Both subjects performed a control challenge using lactose and then a 50:50 mixture of lactose and azodicarbonamide for 15 s on the next day. On both days, lung function was monitored to follow the time course of any response. It was reported that the trial was not carried out blind.

 

No effects on lung function were observed following challenge with lactose alone. After the azodicarbonamide challenge, however, the atopic individual developed a late respiratory response starting 3 h after challenge and reaching a maximum 24% drop in FEV1 6 h after challenge. A drop in PC20H was also reported, demonstrating increased airway hyperreactivity, and this parameter did not return to the baseline value until 6 weeks after challenge. The non-atopic individual showed a dual response to azodicarbonamide. Peak reductions in FEV1 of greater than 20% were recorded 30 min and 5–6 h after exposure. No significant reduction in PC20H was reported for the second individual. A control atopic subject with underlying asthma who worked in the same industry but did not experience work-related respiratory effects was also tested. His baseline PC20H was similar to that of the atopic subject, but no change in lung function was observed following a 15-min exposure to azodicarbonamide under similar conditions (as this subject had less reactive airways, a much longer exposure duration was utilized). Owing to the insolubility of azodicarbonamide, skin prick tests were not performed.

 

Six other cases have been reported in the literature, but in each case the evidence that azodicarbonamide was the cause of the respiratory symptoms is less strong. In some cases, there had been previous exposure in industries associated with potential exposure to other asthmagenic substances; for others, the bronchial challenge test was either poorly conducted or not conducted at all (Valentino & Comai, 1985; Alt & Diller, 1988; Normand et al., 1989).

 

Epidemiological data

Workplace health surveys have also been carried out where azodicarbonamide was either manufactured or used to investigate the presence of respiratory symptoms in azodicarbonamide workers.

 

A prevalence study of occupational asthma was carried out among a group of 151 workers at a factory manufacturing azodicarbonamide (Slovak, 1981). Diagnosis of asthma was made on the basis of an administered questionnaire and a detailed occupational history taken by the author. The population was divided into three groups: those classified as potentially sensitized, on the basis of questionnaire results; those with daily exposure but without symptoms; and those with no exposure to azodicarbonamide or any other known sensitizer. On one day, pre- and post-shift spirometry was performed, and FEV1, FVC, and the FEV1/FVC ratio were determined. Skin prick tests were also attempted using both common allergens to determine atopic status and azodicarbonamide at concentrations of 0.1, 1, and 5% in dimethylsulfoxide. Concurrent personal sampling measurements were made to determine the levels of airborne azodicarbonamide to which individuals were exposed.

 

Personal sampling indicated that, at the time of the investigation, airborne concentrations of azodicarbonamide ranged between 2 and 5 mg/m3, as 8-h time-weighted averages. From the questionnaires and occupational histories, 28 individuals (18.5%) were diagnosed as having asthma apparently related to azodicarbonamide exposure. Twelve further cases of occupational asthma were identified from company records of past employees. Skin prick tests with azodicarbonamide could not be adequately performed owing to the insolubility of the substance.

 

Of the 28 current workers classified as sensitized, over half developed symptoms within 3 months of first exposure and 21/28 (75%) within 1 year. Symptoms and signs included shortness of breath, chest tightness, wheezing, cough, rhinitis, conjunctivitis, and rash. Reactions were of an immediate type for 6/28 (21%) individuals, late onset for 16/28 (57%), and dual onset for 6/28 workers. Of those showing a dual response, all but one had initially shown a late onset pattern. A total of 13/28 (46%) workers reported worsening of symptoms with continuing exposure to azodicarbonamide and a shortening of the time between returning to work and reappearance of symptoms. Eight out of 13 workers exposed to azodicarbonamide for more than 3 months after development of symptoms also developed sensitivity to previously well-tolerated irritants (e.g., sulfur dioxide and tobacco smoke), which persisted for over a month after removal from exposure to azodicarbonamide.

 

In five individuals, this airway hyperreactivity persisted for over 3 years. There were no changes in FEV1 or FVC over the work shift in any group. In view of the latency in development of effects, late or dual onset of symptoms in 12/28 (43%) symptomatic workers, increase in sensitivity with repeated exposure, and the persisting lung hyperreactivity in workers with prolonged exposure after developing symptoms, it seems likely that these individuals had become sensitized to azodicarbonamide.

 

 

Whitehead et al. (1987) conducted detailed investigations of the workforce at a plastics factory employing about 325 workers. Lung function tests and interviews to gather information on occupational history, smoking habits, past illnesses, and respiratory, nasal, eye, and skin irritation, including the time course of any symptoms, were carried out with a large percentage of the workforce. There were no clear differences in the results of lung function studies between those exposed to azodicarbonamide and non-exposed individuals. However, responses to the questionnaire revealed a significant association between symptoms of irritation, cough, wheezing, shortness of breath, and headache and present or previous employment as an injection mould operator. There was also a slight but not statistically significant increase in the reporting of skin rash among those with current or previous work in the injection moulding department. The prevalence of all the above symptoms was reduced among those whose employment in this department was limited to the period before azodicarbonamide was introduced or after a change in the process significantly reduced the use of azodicarbonamide at the plant. Personal sampling showed that concentrations of airborne azodicarbonamide ranged from below the limit of detection (0.001 mg/m3) to 0.32 mg/m3 (median 0.006 mg/m3; geometric mean 0.004 mg/m3) averaged over the full shift. The highest concentration of azodicarbonamide recorded (for an injection mould operator) was 0.01 mg/m3. Toluene, styrene, phenols, and triphenyl phosphate were also detected at concentrations at or below the odour threshold for each substance.

 

Other personal sampling data for a group of 17 individuals revealed levels of azodicarbonamide ranging from traces to 0.8 mg/m3 (median 0.03 mg/m3; geometric mean 0.02 mg/m3) averaged over the full shift. The second highest value recorded was 0.4 mg/m3, and the next highest, 0.06 mg/m3. A moderate although statistically significant reduction in FEV1 (mean reduction of 64 ml) and FVC (mean reduction of 77 ml) occurred following shifts in which workers were exposed to azodicarbonamide. Coughing at work, wheeze, and chest tightness were also reported, and symptoms were apparently worse during the week than on Sunday.

 

A detailed investigation of the workforce at a plant making floor coverings was conducted after nosebleeds, mucous membrane irritation, and skin rashes were reported in workers handling azodicarbonamide (Ahrenholz et al., 1985, cited in CICAD 16 document on Azodicarbonamide, 2005). Two surveys were carried out. The initial survey revealed, in decreasing order of prevalence, symptoms of eye irritation, nose irritation, cough, and nocturnal cough, shortness of breath, wheeze, and chest tightness. The more extensive follow-up survey was conducted 6 weeks later. Pre- and post-shift auscultation, lung function tests, and respiratory symptoms (recorded by questionnaire) were recorded. Blood samples were also taken for immunological investigations. Responses to the questionnaire revealed 15/30 regularly exposed workers experiencing occupationally related lower respiratory tract symptoms (cough, wheeze, and shortness of breath) compared with 1/16 never-exposed workers. No significant differences in pre- and post-shift FEV1 and FVC measurements were found. For those workers apparently not exposed to azodicarbonamide or exposed indirectly (working in the vicinity but not directly handling azodicarbonamide), levels (8-h time-weighted average) ranged from <0.001 to 0.1 mg/m3. However, during weighing and charging operations, peaks of between 0.15 and 12 mg/m3 (median 2.7 mg/m3) were measured for individuals directly involved. 

• The weight of evidence presented by the available case studies seems to suggest that ADCA may be involved in respiratory sensitisation, however following a review of the literature a number of deficiencies in study conduct were noted, as follows:
• Very few of the studies discuss the purity of ADCA. There may be impurities that causes additive, synergistic, or potentiation effects.
• Medical histories of workers would have a biased effect on the potential for respiratory sensitization due to an already compromised immune system. However, affected worker medical histories reported in the studies were incomplete in several studies (Anderson & Ahrenholz, 1983; Dunn et al., 1985; Ferris et al., 1977; Kwon et al., 2015). Summarized histories were provided in a majority of the human studies on respiratory sensitization (Kim et al., 2004; Malo et al., 1985; Normand et al., 1989; Pineau et al., 1985; Slovak, 1981; Whitehead et al., 1987); many of the affected workers had compromised immune systems due to allergies and/or eczema that were non-ADCA related, alcoholism, and smoking, either former or current. However, none of the studies evaluated any correlation between an already weakened immune system and the potential for ADCA respiratory sensitization.
• Only 30% (4/12) of the studies provided ADCA concentrations in the workplace (Anderson et al., 1985; Ferris et al., 1971; Slovak, 1981; Whitehead et al., 1987) and all but one (11/12) did not determine if there were other chemicals in the workplace atmosphere in addition to ADCA. If other chemicals were listed, none of them characterized the potential additive, synergistic or potentiation effects from the presence of other chemicals in the workplace such as ADCA pyrolysis products (ammonia, styrene, and triphenylphosphate)(Anderson & Ahrenholz, 1983), byproducts formed during molding (urazol, biurea, cyamelide, cyanuric acid, polyphenylene oxide) (Whitehead et al., 1987), or other substances (i.e., herbicides, nylon tertpolymers, aluminum oxide, sulfanilamide, amorphous silica, fiberglass, antimony, polyurethane resins, formaldehyde, melanmine formaldehyde) undergoing grinding within the same facility (Ferris et al., 1977; Normand et al., 1989).
• Studies did not discuss the potential for workers to be exposed to other respiratory sensitizers through activities at home (e.g., hobbies) or home environment (presence of mold, dampness).

The above-noted deficiencies in study or review conduct are considered to raise some issues regarding the reliability of the affected occupational monitoring and case study data. On this basis the available data cannot be considered to be a definitive indication of respiratory sensitisation caused by ADCA and it should be noted that significant uncertainty about these effects still remain.