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EC number: 203-468-6
CAS number: 107-15-3
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.
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).
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%
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).
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.,
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.
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
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.
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