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EC number: 203-868-0
CAS number: 111-42-2
Correction for 8h exposure of workers compared to 6h used in the
According to the REACH “Guidance on information requirements and
chemical safety assessment”, a leading DN(M)EL needs to be derived for
every relevant human population and every relevant route, duration and
frequency of exposure, if feasible.
Kinetics (absorption figures for oral, dermal and inhalation route
DEA is well absorbed following oral administration in rats (57%)
and to a lower degree after dermal administration (3-16% in rats; 25 –
60% in mice). When applied dermally, DEA appears to facilitate its own
absorption, as higher doses were more completely absorbed than lower
doses. DEA (20 mg/cm²) applied to skin preparations in vitro showed
penetration rates of 6.68% (mouse) > 2.81 % (rabbit) >0.56% (rat) >
0.23% (human). Distribution to the tissues was similar via all routes
examined. DEA is cleared from the tissues with a half-life of
approximately 6 days. The highest concentrations are observed in liver
and kidney. Metabolism after oral administration revealed
non-metabolized DEA and smaller proportions of N-methyl-DEA (N-MDEA),
N,N-dimethyl-DEA (N’N-DMDEA) and DEA-phosphates co-eluting with
phosphatidyl ethanolamine and phosphatidyl choline. After digestion, 30%
of the phospholipids were identified as ceramides and the remaining 70%
as phosphog1ycerides. DEA is excreted primarily in urine as the parent
molecule (25-36%), with lesser amounts of O-phosphorylated and
N-methylated metabolites. Accumulation of DEA at high levels in liver
and kidney is assumed by a mechanism that normally conserves
ethanolamine, a normal constituent of phospholipids. DEA is incorporated
as the head group in phospholipids, presumably via the same enzymatic
pathways that normally utilize ethanolamine.
DEA is classified for acute oral toxicity (H302). However, oral
exposure is expressed as amount (per kg bw) per day. Therefore acute
oral exposure (peaks; in mg/kg bw) will not be higher than a calculated
total exposure per day (chronic; in mg/kg bw). Practically relevant peak
exposure therefore does not occur for DEA. Furthermore, DEA does not
have to be classified based on the acute inhalation and dermal toxicity
data. Therefore, no acute DNEL is needed.
DEA is a skin and severe eye irritant in rabbits (H318 + H315).The
available data do not allow a quantitative approach. According to the
REACH guidance on information requirements and chemical safety
assessment, Part E: Risk Characterisation, a qualitative risk
characterisation should be performed for this endpoint. In order to
guarantee ‘adequately control of risks’, it is necessary to stipulate
risk management measures that prevent skin and severe eye irritation.
DEA is not considered a skin sensitiser.
Repeated dose toxicity
Nose-only exposure of rats to DEA aerosols for 3 months resulted
in systemic effects:
- kidney effects (increased incidences of mild hematuria in both
sexes, some increase in renal tubular cells and granular casts in male
animals, slight increases in kidney weights, minimal or slight tubular
hyperplasia in some female animals and intratubular lithiasis slightly
more pronounced than in controls in some male animals);
- adaptive liver effects (mild increases of liver weights and
serum alkaline phosphatase serum levels without histopathological
- a mild normochromic microcytic anemia and some influence on the
male reproductive system consisting of diffuse testicular atrophy and
minimal to slight atrophy of the prostate was present at the high
Furthermore, local effects (respiratory tract irritation, squamous
metaplasia of the laryngeal epithelium, inflammatory response) were
observed. No functional or morphological evidence of neurotoxicity was
observed. The NOAEC for systemic effects was 15 mg/m³ and the NOAEC for
upper respiratory tract irritation was 3 mg/m³.
Repeated unoccluded dermal application of ethanolic DEA solutions
in subacute and subchronic studies with rats and mice led to mortality
at high dose levels (≥500
mg/kg bw in rats;≥1000
mg/kg bw in mice). In rats, systemic signs of toxicity consisted
predominantly of anaemia and nephropathy. In addition, liver weights
were increased without a histopathological correlate. In mice, systemic
effects occurred mainly in the form of liver and kidney damage. In both
species, local skin irritation was observed. A NOAEL for systemic
effects or local skin irritation could not be achieved (LOAEL 32 mg/kg
bw in rats; 80 mg/kg bw in mice).
In rats, subchronic oral treatment via the drinking water caused
mortality at the high dose in males (5000 ppm). Impaired body weight
gains were observed at concentrations equal to or higher than 320 ppm in
females and 630 ppm in males. Systemic effects consisted of anaemia,
nephrotoxicity, cortical vacuolization of adrenal glands and
demyelinization of brain/spinal cord without any neurofunctional
finding. In males, damage of reproductive organs in the form of
testicular degeneration and associated weight changes and impaired
spermatology was observed. Based on the observed anaemia and
nephropathy, a LOAEL of 25/14 mg/kg bw (equal to 320/160 ppm) was
achieved in males/females.
In the subchronic oral study in mice, mortality was observed in
ppm and in females at≥2500
ppm. Body weight gain was decreased in both species at concentrations of
1250 ppm (females) or 2500 ppm (males) and higher. Systemic effects
consisted of hepato- and nephrotoxicity and myocardial degeneration. The
most sensitive effect was necrotic liver damage at all concentrations. A
LOAEL of 104/142 mg/kg bw (equal to 630/630 ppm) was noted in
Mutagenicity and carcinogenicity
DEA is assessed as being non-mutagenic.
DEA formulated in ethanol showed no oncogenic potential in the rat
after unoccluded daily dermal exposure for 2 years. In the dermal mouse
carcinogenicity study using similar exposure techniques, there was an
increased incidence of liver neoplasms in males and females at all doses
tested and an increased incidence of renal tubule adenomas in males at
the high dose level only. The liver tumours in mice were considered to
be directly related to the observed increase in the cellular
proliferation rate, which is due to the observed enzyme induction, weak
peroxisome proliferation and choline depletion with subsequent
disturbance of its metabolism. While nitrosamine formation has been
highlighted as a matter of concern for DEA, and for this reason it has
been banned for use in cosmetics in the EU, nitrosamine formation was
ruled out under the conditions of this study. Benign kidney tumours
(adenomas) were only observed in male mice at the high dose level at a
low incidence, when using serial sections. Based on the increased
S-phase synthesis observed in this organ, it is conceivable that a
similar non-genotoxic mode of action involving choline deficiency is
responsible for the renal tubular adenomas.
In short term tests on carcinogenicity, DEA was not carcinogenic,
when tested in the Tg.Ac transgenic mouse model up to topical dose
levels exceeding the MTD. Cell transformation in Syrian hamster embryo
cells in vitro was observed predominantly in the range of cytotoxic
concentrations but supplementation of choline completely inhibited this
Various mechanistic in vitro and in vivo studies identified that
DEA induced choline depletion is the key event in the toxic mode of
action. DEA decreased gap junctional intracellular communication in
primary cultured mouse and rat hepatocytes, but all these events were
prevented with choline supplementation. DNA hypomethylation was observed
in mouse hepatocytes as a further epigenetic mechanism involved in liver
DEA decreased phosphatidylcholine synthesis by blocking the
cellular uptake of choline in vitro, but these events did not occur in
the presence of excess choline.
DEA increased S-phase DNA synthesis in mouse hepatocytes but had
no effect on apoptosis. No such effects were noted in human hepatocytes
in vitro. Apparent differences in the susceptibility of two different
mice strains (B6C3F1 > C57BL) were noted. B6C3F1 mice are extremely
sensitive to non-genotoxic effects and are known to possess a relatively
high incidence of spontaneous liver tumours. Moreover, chronic
stimulation and compensatory adaptive changes of hepatocyte hypertrophy
and proliferation are able to enhance the incidence of common
spontaneous liver tumours in the mouse by mechanisms not relevant to
humans. Analysis of gene expressions in animal studies showed an
increase in genes associated with cell proliferation, while a decrease
in genetic processes relevant for apoptotic mechanisms was observed.
In conclusion, based on the above evaluation, no separate risk
characterisation for mutagenicity and carcinogenicity is needed.
The 2 year studies with rats and mice also showed non-carcinogenic
effects. The overall dermal LOAEL based on the 13 weeks and 2 years
studies is concluded to be 8 mg/kg bw/day. Critical effects appear to be
kidney (nephropathy) and liver toxicity, anaemia and dermal
hyperkeratosis/acanthosis. Besides anaemia, nephropathy was observed at
the lowest tested dose in the 13 weeks dermal toxicity study (32 mg/kg
bw/day). After 13 weeks effects on the kidneys are not yet masked by
ageing and appear a treatment related adverse effect. Therefore, the
observation of nephropathy in females at the lowest tested dermal dose
of 8 mg/kg bw/day in the 2 years study, which was somewhat masked by
ageing, is also considered adverse. In males this effect was completely
masked by the ageing process after 2 years of exposure.
In the developmental toxicity studies with DEA, the substance
caused only developmental toxicity in the presence of clear maternal
toxicity. Furthermore, maternal toxicity was observed at levels
higher/comparable to general toxic effects in the repeated dose toxicity
For DEA CAS 111-42-2, an extended One-Generation Reproductive
Toxicity Study (EOGRTS) according to OECD TG 443 has been performed and
finalized on January 29th2018.
2,2’-iminodiethanol was administered to groups of 30 male and 30
female healthy young Wistar rats (F0 parental generation) as a solution
to the drinking water in different concentrations (0, 100, 300 and 1000
ppm). At least 16 days after the beginning of treatment, F0 animals were
mated to produce a litter (F1 generation). Mating pairs were from the
same dose group. Pups of the F1 litter were selected (F1 rearing
animals) and assigned to 5 different cohorts which were continued in
dose groups 10 - 13 in the same fashion as their parents and which were
subjected to specific post weaning examinations. The study terminated
with the terminal sacrifice of the male and female animals of cohort 1B.
Test drinking water containing 2,2’-iminodiethanol were offered
continuously throughout the study.
Intake of test substance: the overall mean dose of
2,2’-iminodiethanol throughout all study phase and across all cohorts
was approx. 12.75 mg/kg body weight/day (mg/kg bw/d) in the 100 ppm
group, approx. 37.68 mg/kg bw/d in the 300 ppm group and approx. 128.35
mg/kg bw/d in the 1000 ppm group.
Under the conditions of the present modified extended 1-generation
reproduction toxicity study the NOAEL (no observed adverse effect level)
for general toxicity is 100 ppm for the F0 parental animals, based on
evidence for distinct kidney toxicity and stomach irritation, as well as
corresponding effects on water consumption, food consumption, body
weights and clinical pathological parameters, which were observed at the
LOAEL (Lowest Observed Adverse Effect Level) of 300 ppm. Similar
toxicity was noted in the adolescent F1 animals, which had no stomach
irritation but liver toxicity in addition.
The NOAEL for fertility and reproductive performance for the F0
and F1 rats is 300 ppm, based on a lower number of implants,
prolonged/irregular estrous cycles as well as pathological changes in
sexual organs, pituitary and mammary glands of both genders at the LOAEL
(Lowest Observed Adverse Effect Level) of 1000 ppm. However,
eosinophilic cysts in the pituitary gland were present in the F1 animals
of cohort 1A down to the 100 ppm dose level, but no assessment on
adversity of this finding is possible at present. Therefore, no NOEL can
be established for this particular effect.
The NOAEL for developmental toxicity in the F1 progeny is 100 ppm,
based on impaired pup survival at 1000 ppm as well as reduced pup body
weights in the F1 offspring, which were observed at the LOAEL (Lowest
Observed Adverse Effect Level) of 300 ppm. As these weight reductions
were only observed in the presence of maternal toxicity, including lower
weight gain during pregnancy, they are not regarded as independent
effect of the treatment.
The NOAEL for developmental neurotoxicity for the F1 progeny is
300 ppm, based on adverse clinical observations, impaired auditory
startle response and corresponding neuropathological findings at the
LOAEL (Lowest Observed Adverse Effect Level) of 1000 ppm. In addition,
increased T4 values were noted in adult and adolescent males at 1000 ppm
as well as newborn and weanling females at 100 and 300 ppm.
The NOAEL for developmental immunotoxicity for the F1 progeny is
300 ppm, based on effects on the T-helper cells and cytotoxic T-cells in
the spleen in the F1 females at the LOAEL (Lowest Observed Adverse
Effect Level) of 1000 ppm. Lower mean and median anti-SRBC IgM antibody
titers of the positive control group (4.5 mg/kg bw/d cyclophosphamide,
oral) demonstrated that the test system worked properly.
In addition to the EOGRST / OECD 443 that is available for DEA,
there is a 3-month inhalation study in rats reporting an influence on
the male reproductive system at the high concentration. The NOAEC for
male fertility parameters was 0.15 mg/l. When DEA was orally
administered to rats via the drinking water for 13 weeks, decreases in
testis and epididymis weights, testicular degeneration, atrophy of the
seminal vesicles and prostate glands and associated effects on
spermatology were observed. The NOAEL for fertility effects in males was
48 mg/kg bw. In all of these studies no histopathological effects were
observed in female reproductive organs.
In conclusion, the long-term DNELs derived using the repeated dose
toxicity studies are also considered sufficient for reproduction
toxicity (effects on fertility and developmental toxicity).
Long-term – inhalation, local effects
For DEA a national “occupational exposure limit” OEL = MAK value
of 1 mg/m³ was established in Germany based on the critical NOAEC of 3
mg/m³ air (male/female) (BASF AG, 2002). At the next higher level,
respiratory tract irritation, squamous metaplasia of the laryngeal
epithelium and an inflammatory response in the respiratory tract were
In 2016, this national OEL has been re-evaluated by the German “Auschuss
für Gefahrstoffe” (AGS). The outcome is that the national OEL
(i.e. AGW) is now at 0.5 mg/m³ inconsistency with the most recent
delineation for related Ethanolamines (such as Monoethanolamine Cas No.
141-43-5 and Triethanolamine CAS No. 102-71-6). The scientific
documentation is currently only available in German language, the
justification of the selection of assessment factors within the
AGS-delineation hast been translated and can be found in the table given
Step 1) Relevant dose-descriptor
NOAEC (local effects) = 3 mg/m³
In a subchronic aerosol study according to OECD 413 DEA has been tested mainly as aerosol (MMAD 0.6 – 0.7 µm). The calculated saturated vapor pressure at RT is > 0.9 mg/m³. At 3 mg/m³ squamous-cell metaplasia was observed in males in the larynx level 1. The evaluation of the findings for humans is considered not adverse (Osimitz et la., 2007; Kaufmann et al., 2009), The concentration has therefore been considered the NOAEC with 8 mg/m³ being the LOAEC.
Step 2) Modification of starting point
No correction for 8h exposure of workers compared to 6h used in the animal experiment applicable as the effect on the respiratory tract underlies deposition of aerosol in the larynx. Therefore, no correction of the starting point has been applied.
Step 3) Assessment factors
No remaining differences are assumed as the effects are solely local effects and the rat is considered a sufficient conservative model.
Assessment factor for allometric scaling is not needed here as the local effects of aerosols rather depend on local deposition than on metabolism.
Assessment factor for the extrapolation from irritative effects on the respiratory tract according to Brüning, 2014 and Brüning et al., 2014.
Subchronic to chronic extrapolation standard factor REACH and AGS (2010)
Quality of the database
Actual guideline study and GLP-conform
3 / (1 x 3 x 2 x 1 x 1) = 0.5 mg/m³
Long-term – inhalation, systemic effects
Within the above described AGW delineation by the German AGS the
following two DNELs / AGW for long-term systemic effects (OPTIONs 1+2)
have been derived in comparison with the DNEL for long-term and local
effects as a plausibility check. OPTION 3 has been derived based on the
NOAELs obtained from the most recent OECD443 Extended-one-generation
reproductive toxicity study.
The following 3 possibilities have been taken into consideration
(please compare with the following 3 tables).
Overall, the DNELs long-term for systemic effects ranged from 0.74
to 0.81 mg/m³ and were above the DNEL for long-term local effects.
Therefore, the DNEL = AGW covering local effects on the respiratory
tract is thought to protect from systemic effects.
OPTION 1 - Long-term – inhalation, systemic effects
NOAEC (systemic effects) = 15mg/m³
NOAEC form 3-months inhalation study in Wistar rats. Effects were anemia, liver effects, kidney toxicity testis/prostate atrophy and erosion of the glandular stomach.
x 6h/d / 8h/d
x 6.7 m³ (8h) / 10 m³ (8h)
corrected NOAEC = 7.54 mg/m³
Correction for 8h exposure of workers compared to 6h used in the animal experiment
No remaining differences are assumed as the effects are solely local effects and the rat is a sufficient conservative model.
Assessment factor for allometric scaling is not needed here as the local and systemic effects of aerosols rather depend on local deposition than on metabolism.
Default assessment factor
Subchronic to chronic
Starting point was NOAEC
7.5 / (1 x 5 x 2 x 1 x 1) = 0.75 mg/m³
OPTION 2 - Long-term – inhalation, systemic effects
LOAEC (systemic effects effects) = 14 mg/kg BW/day
Systemic LOAEL from the 3-months drinking water study in rats. Effects were anemia, liver effects, kidney toxicity, degeneration of testis/seminiferous tubules and effects on sperm. No NOAEL could be identified.
0.29 m³/kg BW
6h/d / 8h/d
corrected NOAEC = 24.25 mg/m³
Respiratory volume rat (6h exposure)
Extrapolation from oral exposure to inhalation (NOAEL to NOAEC conversion)
No remaining differences are assumed here. The underlying mode-of-action has been well characterized (i.e. effects on choline-homeostasis).
Assessment factor for allometric scaling is not needed here as the extrapolation is already corrected form oral to inhalative exposure.
Default assessment factor worker
A factor of 3 is considered sufficient for extrapolation from a LOAEL to a NOAEL
24.25 / (1 x 5 x 2 x 3 x 1) = 0.81 mg/m³
OPTION 3 - Long-term – inhalation, systemic effects
LOAEC (systemic effects effects) = 12.75 mg/kg BW/day
The overall mean doses of DEA throughout all study sections and across all
cohorts were 12.75 mg/kg body weight/day (mg/kg bw/d) in the 100 ppm group. Under the conditions of the present modified extended 1-generation reproduction toxicity study
the NOAEL (no observed adverse effect level) for general toxicity is 100 ppm for the F0 parental animals, based on evidence for distinct kidney toxicity and stomach irritation, as well
as corresponding effects on water consumption, food consumption, body weights and clinicalpathological
parameters, which were observed at the LOAEL (Lowest Observed Adverse Effect Level) of 300 ppm. Similar toxicity was noted in the adolescent F1 animals, which had no
stomach irritation but liver toxicity in addition.
However, due to certain findings in all dose levels in the offspring (i.e. increase in t4 levels and eosinophilic cysts in the pituitary gland, a LOAEL = 100 ppm is assumed for this plausibility check.
corrected NOAEC = 22,1 mg/m³
A worst case approach is already used here as the adversity of the findings is not clear.
22,1 / (1 x 5 x 2 x 3 x 1) = 0.74 mg/m³
Long-term – dermal, systemic effects
LOAEC (local effects) = 8 mg/kgbw/day
The overall LOAEL based on the sub- and chronic dermal studies with rats and mice is 8 mg/kg bw/day. The critical systemic effects appear to be kidney and liver toxicity and anaemia. Besides anaemia, nephropathy was observed at the lowest tested dose in the 13 weeks dermal toxicity study (32 mg/kg bw/day in rats). After 13 weeks kidney effects are not yet masked by ageing. Therefore, the observation of nephropathy in female rats at the lowest tested dermal dose of 8 mg/kg bw/day in the 2-year study, which was somewhat masked by ageing, is also considered adverse.
Not applicable here
Assessment factor for allometric scaling.
Default assessment factor Worker.
The key study is a 2-year study.
A factor of 3 is considered sufficient for extrapolation from a LOAEL to a NAEL
8 / (4 x 5 x 1 x 3 x 1) = 0.13 mg/kgbw/day
Brüning T, Bartsch R, Bolt
HM, Desel H, Drexler H, Gundert-Remy U, Hartwig A, Jackh R, Leibold E,
Pallapies D, Rettenmeier AW, Schluter G, Stropp G, Sucker K, Triebig G,
Westphal G, van Thriel C (2014) „Sensory irritation as a basis for
setting occupational exposure limits, Arch.Toxicol.,
Brüning T (2014) Ableitung
von Grenzwerten für Stoffe mit sensorisch irritativer Wirkung,
Verfahrensvorschlag der ad hoc Arbeitsgruppe“ Grenzwertableitung bei
lokalen Effekten“, IPA Journal 03/2014, 12-17.
Kaufmann W, Bader R, Ernst
H, Harada T, Hardisty J, Kittel B, Kolling A, Pino M, Renne R,
Rittinghausen S , Schulte A, Woehrmann T, Rosenbruch M (2009) 1st
International ESTP Expert Workshop:‘‘Larynx squamous metaplasia’’.A
reconsideration of morphology and diagnostic capproaches in rodent
studies and its relevance for human risk assessment, Experiment.
Toxicologic Pathology, 61, 591–603.
Osimitz TG, Droegge W, Finch JM
(2007)Toxicologic significance of histologic change in the larynx of the
rat following inhalation exposure: A critical review, Toxicol. Appl.
Pharmacol., 225, 229–237.
Long-term – inhalation, local/systemic effects
Using the German AGW value of 0.5 mg/m3 as starting point, the
following DNEL is calculated:
0.5 mg/m3 * 10/20 (a) * 5/10 (b) = 0.125 mg/m3
(a) modification based on differences in exposure duration and
activity (10 m3 in 8 h for workers, 20 m3 in 24 h for the general
(b) correction for intraspecies differences: workers default
factor: 5, general population default factor: 10
inhalation, local/systemic effects
the German AGW value of 0.5 mg/m3 as starting point, the following DNEL
0.5 mg/m3 * 10/20 (a) * 5/10 (b) = 0.125 mg/m3
(a) modification based on differences in exposure duration and activity (10 m3 in 8 h for workers, 20 m3 in 24 h for the general population)
(b) correction for intraspecies differences: workers default factor: 5, general population default factor: 10
– dermal, systemic effects
LOAEL: 8 mg/kg bw/day
The overall LOAEL based on the sub- and chronic dermal studies with rats and mice is 8 mg/kg bw/day. The critical systemic effects appear to be kidney and liver toxicity and anaemia. Besides anaemia, nephropathy was observed at the lowest tested dose in the 13 weeks dermal toxicity study (32 mg/kg bw/day in rats). After 13 weeks kidney effects are not yet masked by ageing. Therefore, the observation of nephropathy in female rats at the lowest tested dermal dose of 8 mg/kg bw/day in the 2 year study, which was somewhat masked by ageing, is also considered adverse.
The key study is a 2 year study.
Quality of database
8 / (4 x 10 x 1 x 3 x 1) =0.07 mg/kg bw/day
– oral, systemic effects
LOAEL: 14 mg/kg bw/day
Based on anaemia, nephrotoxicity, increased kidney weight (rats)
Extrapolation to chronic exposure based on a sub-chronic toxicity study
Extrapolation from LOAEL to NAEL
14 / (4 x 10 x 2 x 3 x 1) =0.06 mg/kg bw/day
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