Ethylenediamine

Endpoint summary

Description of key information

In a GPMT test 9 out of 20 guinea pigs were positive (45%). EDA was also studied in the Local Lymph Node Assay (LLNA). Groups of young adult Balb/c mice were administered EDA at concentrations of 1, 2.5, 5 and 10% (w/v). EDA produced a positive response at 5 and 10%.

Cytokine production was also studied. Mice were administered 50 μl EDA at a concentration of 10% (w/v) on each shaved flank at days 1 and 6. At days 11, 12, and 13, daily doses of 25 μl were applied to the ears. The cytokine production was measured 13 days after initiation of treatment. Cytokine production (IFN-γ) was demonstrated, supporting that EDA possess contact allergenic potential in mice. In the same study, EDA failed to provoke production of IL-4 and IL-10, which are normally thought of as markers of respiratory tract allergens.

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

Although in studies with exposed workers EDA has been shown to cause occupational asthma, as indicated above, cytokine production (IFN-γ) was demonstrated, supporting that EDA possess contact allergenic potential in mice. However, in the same study, EDA failed to provoke production of IL-4 and IL-10, which are normally thought of as markers of respiratory tract allergens. It could therefore be questioned whether EDA should be considered a respiratory allergen (causing asthma by an immunological mechanism); instead it could be considered an asthmagen (causing asthma by non-immunological mechanism).

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

See also section 7.10.

In 1999 the World Health Organization mentioned several cases of signs of respiratory senitisation apparently due to exposure to ethylene diamine but the incidence was not specified other than in one report when it was quoted to be 10%. This was a retrospective study so no challenge tests were done. Aldrich et al. published in 1987 'Smoking and ethylenediamine sensitization in an industrial population', J. Occup. Med. 1987 Apr; 29(4) 311 -314.; from the abstract the incidence of respiratory symptoms reported was 38 out of 337 workers (ca. 11%). In a paper by Hagmar et.al., 'Piperazine induced Occupational Asthma', J. Occ. Med. Vol 24 No 3. March 1982, three cases of respiratory symptoms were mentioned in a population of 130 workers; they had been exposed to ethylenediamine which was used until the previous year (ca. 3% incidence).

In a large review paper Chan-Yeung and Malo, 'Aetiological agents in occupational asthma', Eur Resp J 1994, 7, 346 -371, they reviewed about 200 agents implicated in occupational asthma; they only included some case reports of respiratory symptoms for ethylene diamine (they did give percentage incidence values for some known strong respiratory sensitisers such as the diisocyanates, including TDI and HDI and some acid anhydrides; for these substances the incidences were in the order of 28 -35%). 

According to 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). Although the evaluation of the effects on the respiratory passages is hampered by the irritative properties of the substance, according to MAK (2003) EDA should be designated with an “Sa” (meaning sensitization via inhalation).

It should however be noted that:

- The findings in humans do not conclusively point at respiratory sensitization as irritant-induced asthma and/or work-aggravated asthma cannot be excluded. EDA may act as an asthmagen, in which case adverse effects are caused by non-immunological mechanisms (Kimber et al., 2001).

- On a mechanistic basis there is significant evidence that respiratory sensitizers bind preferentially to lysine moieties whereas skin sensitizers bind both to cysteine and lysine (Sullivan et al., 2017). The absence of peptide depletion (only 0.7%) using lysine with 18.6% peptide depletion using cysteine (Bauch et al., 2012) would support EDA not being a true respiratory sensitizer but a skin sensitizer only.

- It has been suggested that EDA does not undergo direct reaction with protein residues but rather is metabolized to the electrophilic glyoxal aldehyde (oxidative deamination) to form a Schiff base that can then undergo substitution to for, a haptein-protein complex of sufficient size to be antigenic. However, although there are no data available regarding the metabolism of EDA it is concluded that if oxidative deamination would occur, the monoaldehyde (2 -amino-acetaldehyde) is formed. These low molecular weight aldehydes are known to be rapidly metabolized to the corresponding carboxylic acids. In the case of 2-aminoacetaldehyde this would lead to the formation of glycine (2-aminoacetic acid), a non-essential amino acid. This metabolic pathway is also supported by the corresponding log Pow values: glyoxal tends to be more lipophilic than EDA (log Pow: - 1.15 vs. -1.6), whereas the log Pow value of glycine is clearly lower (-3.21), i.e. formation of glycine would lead to a metabolite with increased hydrophilic properties, which is in favor of a physiological metabolism pathway. Thus, the formation of glyoxal as a highly reactive and electrophilic metabolite of EDA is not likely and highly speculative. It would even contradict EDA being a respiratory sensitizer since glyoxal is not classified for respiratory sensitization according to the harmonized classification.

- There are no more recent cases reported in literature and in view of the workforce exposed, it can be concluded that the current OEL of 10 ppm did not result in a substantial number of new cases during more than 2 decades, if at all, since the most recent study dates from 1995. This strongly indicates that current occupational hygiene standards and practices are sufficiently protective.

Overall, It is expected that substances such as diisocyanates are to be classified as cat. 1A for respiratory sensitization; if indeed EDA would need to be considered a respiratory sensitizer, the incidence of ca. 3 -11% seen in the case of EDA in a limited number of studies is therefore to be viewed in the low to moderate frequency range and thus supporting a classification of cat. 1B.

Justification for classification or non-classification

Although EDA has been positive in a number of human and animal 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 to be 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 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 allergic asthmatic responses seen.

See also our review in section 7.10.4.

According to the harmonized CLP classification, EDA should be classified as skin sensitizer cat. 1 (H317) and respiratory sensitizer cat. 1 (H334). In view of its potency, viz. ≥ 30% was responding at > 1 % intradermal induction dose,

and an EC3 value of 2.9% in the LLNA, and the failure of EDA at a test level of 10% to provoke production of IL-4 and IL-10, which are normally thought of as markers of respiratory tract allergens, it can be concluded that in these animal tests, EDA is of low potency which would warrant classification as cat. 1B for both skin and respiratory sensitization.