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EC number: 925-259-5
CAS number: 140921-24-0
Based on physico-chemical characteristics, particularly water solubility and octanol-water partition coefficient absorption via oral and inhalation route is expected to be low. However, slow dermal absorption could not be excluded. Incozol EH is immediately hydrolysed into “fully hydrolysed Incozol EH” and 2-ethylhexanal. If absorbed, passive diffusion and active transport through aqueous pores is likely to be an entry routes to the systemic circulation. No metabolic activation of Incozol EH and its hydrolysis products is expected. Excretion via faeces is assumed to be the main excretion pathway of “fully hydrolysed Incozol EH” due to its molecular weight. Oxidation and conjugation products of 2-ethylhexanal were shown to be excreted via urine. Based on hydrolytical conversion of Incozol EH bioaccumulation is not likely to occur based on physico-chemical properties of the hydrolysis products.
profile of Incozol
oral toxicity study conducted with Incozol EH using rats revealed a LD50
value of greater the 2000 mg/kg bw (Bayer, 1991). Signs of intoxication
were rough coat, increased salivation and apathy, observed within 24
hours post-treatment. In a second study diuresis was observed when
Incozol EH was administered once orally to rats at 5000 mg/kg bw. No
animal died. No mortality and no systemic signs of toxicity occurred in
an acute dermal toxicity study with the test item (Bayer 1992). The LD50
value was therefore determined to be greater than 2000 mg/kg bw. No
dermal irritation symptoms were observed in all animals. No acute
inhalation toxicity study was performed with Incozol EH as inhalation
exposure is considered negligible due to its low vapour pressure.
In two in
vivo skin irritation studies conducted with Incozol EH on rabbits no
skin irritation was observed (Bayer 1978, Bayer 1991). Incozol EH did
not cause severe eye irritation in two in vivo eye irritation studies on
rabbits (Bayer 1978, Bayer 1991). A guinea pig maximisation test (GPMT)
revealed that Incozol EH has skin sensitising properties (Bayer, 1992).
did not induced reverse mutations in two bacterial reverse mutation
tests (Ames test) with four Salmonella typhimurium strains both in the
absence and presence of a metabolic activation system (Bayer, 1988,
1991). An in vivo micronucleus test on mice revealed no increase of
microncleated normochromatic erythrocytes. The test substance was
therefore judged to be not clastogenic in vivo (Bayer, 1992).
test item did not induce statistically significant increases in DNA
strand breaks at any of the tested dose levels in liver or stomach cells
in an in vivo Comet assay.
A 28 day
repeated dose toxicity study with Incozol EH was performed in male and
female Wistar rats. The chemical was administered orally (by gavage)
once a day for a total of 28 days at 0 (vehicle control), 40, 200 and
1000 mg/kg bw/day. No mortality was observed through this study. An
increased water consumption compared to control group was observed in
male and female animals of the high dose group. Food consumption was
only increased in female animals of the 1000 mg/kg bw/day dose group.In
hematological and histopathological analysis, no test item related
effects could be observed on blood parameters and hematopoietic organs
up to 200 mg test item/kg bw/day in male animals and up to 1000 mg/kg
bw/day in female animals. There was a significant decrease in hemoglobin
concentration and hematocrit value and a lower reticulocyte count
compared to control group in male animals of the high dose group.
Administration of 1000 mg/kg bw/day revealed an increased AST activity
in female animals and a reduced ALT activity in male animals compared to
control group. Albumin and total protein level were significantly
increased in both sexes of the 1000 mg/kg bw/day dose group. There was a
significant increase of liver weights in male and female animals of the
1000 mg/kg bw/day dose group. In the same dose group, an increased
adrenal gland and kidney weight was observed in male and female animals,
respectively. As there was no macroscopic or microscopic pathological
correlation a test item related kidney damage is not considered. In the
absence of any blood biochemical effect ormacroscopic
or microscopic organ and tissue alterations the respective NOAEL was set
to 200 mg/kg bw/day for male and female animals.
analysis of Incozol EH
is a pale yellowish liquid at room temperature with a molecular weight
of 598.8578 g/mol. The calculated water solubility of the substance is
1.68 mg/L at 20°C. The log Pow of Incozol EH was estimated to be 6.85.
Based on this log Pow, a BCF of 652.3 L/kg wet-wt was calculated. The
vapour pressure of Incozol EH is approximately 0.001 Pa at 25°C. In an
aqueous solution, Incozol EH is immediately degraded hydrolytically to2-ethylhexanal
and 1,6 hexanediyl-bis-carbamic acid bis(N-hydroxyethyl-2-aminoethyl)
ester (“fully hydrolysed Incozol EH”).Both
hydrolysis substances have a lower log Pow value than Incozol EH itself
hydrolysed Incozol EH”and 3.07 for 2-ethylhexanal).
Also the BCF values are lower as compared to Incozol EH (approximately
3.162 L/kg wet-wt for“fully
hydrolysed Incozol EH” and 49.27 L/kg wet-wt for 2-ethylhexanal).
Water solubility of both hydrolysis products is higher than of Incozol
EH itself (16 g/L for“fully
hydrolysed Incozol 4”and 450 mg/L for
2-ethylhexanal). The vapour pressure of 2-ethylhexanal is above the
value of Incozol EH (2.8 hPa).
was shown to immediately hydrolyse when getting in contact with water.
Therefore, bioavailability after oral exposure was assessed only for the
hydrolysis products 2-ethylhexanal and “fully hydrolysed Incozol EH”.
Based on physico-chemical properties especially water solubility and log
Pow value of “fully hydrolysed Incozol EH”, dissolution in the
gastro-intestinal fluids and contact with the mucosal surface might
occur and may allow direct uptake into the systemic circulation through
aqueous pores or via carriage of the molecules across the membrane with
the bulk passage of water. Passive diffusion might be a preferred entry
route of 2-ethylhexanal into systemic circulation as it has lipophilic
properties and a low water solubility. Clinical signs after a single
administration of 2000 mg Incozol EH/kg bw in 1,2-propanediol in an
acute oral toxicity study performed on rats were considered to be
treatment-related and not associated to bioavailability of the test
item. However, long-term administration of high doses of Incozol EH in a
28-day repeated dose toxicity study on rats indicated that the compound
or rather its hydrolysis products became bioavailable.
Based on the
vapour pressure of approximately 0.001 Pa at 20°C Incozol EH is not
expected to become airborne in its vapour form. However, if Incozol EH
is degraded hydrolytically, inhalation exposure of 2-ethylhexanal, one
of the hydrolysis products, could not be excluded due to its higher
vapour pressure in comparison to Incozol EH itself. If the substance
would reach the lungs, absorption directly across the respiratory tract
epithelium by passive diffusion is likely to occur due to its log Pow
value (3.07) and water solubility (450 mg/L).
Based on the
molecular weight and physico–chemical properties ofIncozol
EH dermal penetration ofthe substance might be slow. It is
general accepted that if a compound’s molecular weight is above 500
g/mol and water solubility falls between 1-100 mg/L, absorption can be
anticipated to be low to moderate. These assumptions based on the
physico-chemical properties are further supported by the results
achieved from a GPMT which revealed that Incozol EH has skin sensitising
properties and is thus absorbed dermally to a certain extent.
together, physico-chemical properties and experimental data indicate a
low bioavailability of Incozol EH via oral and dermal route.
Bioavailability after inhalation exposure is considered to be unlikely
due to the low vapour pressure of the non-hydrolysed compound.
that 2-ethylhexanal as one of the hydrolysis products is absorbed into
the body following oral intake, it may be distributed into the interior
part of the cells by passive diffusion due to its lipophilic properties
and in turn the intracellular concentration may be higher than
extracellular concentration particularly in adipose tissues. Direct
transport through aqueous pores is likely to be an entry route to the
systemic circulation of “fully hydrolysed Incozol EH” due to its higher
water solubility compared to 2-ethylhexanal.
Based on its
log Pow and BCF value Incozol EH might have a weak bioaccumulation
potential. However, as it immediately hydrolyses when getting in contact
with water bioaccumulation in the human body can be excluded. This
assumption is supported by the lower BCF values of the hydrolysis
products compared to Incozol EH.
Based on the
structure of the molecule, Incozol EH immediately degraded
hydrolytically after being in contact with an aqueous solution. The
first degradation product “fully hydrolysed Incozol EH” may be further
degraded hydrolytically to a certain extend to diethanolamine,
1,6-hexanediamine and carbon dioxide under basic conditions.
2-ethylhexanal is estimated to be oxidised to 2-ethylhexanoic acid which
was shown to be conjugated with glucuronic acid or further oxidised to2-ethyl-1,6-hexanedioic
acid,2-ethyl-6-hydroxyhexanoic acid and 2-ethylketohexanoic
acid (English et al, 1998).No
metabolic activation of Incozol EH and its hydrolysis products is
expected as indicated by the negative in vitro genotoxicity assays in
the presence of S9 mix.
above, Incozol EH will be hydrolysed after being in contact with an
aqueous solution and will probably not be excreted in its unhydrolysed
form. The degradation product“fully
hydrolysed Incozol EH” might be biliary excreted due to its molecular
weight(> 300 g/mol in rat). Renal
excretion might be a preferred excretion pathway of degradation products
of“fully hydrolysed Incozol EH”
described above. Oxidation and conjugation products of 2-ethylhexanal
were shown to be excreted via urine (English
et al, 1998).
physico-chemical characteristics, particularly water solubility and
octanol-water partition coefficient absorption via oral and inhalation
route is expected to be low. However, slow dermal absorption could not
be excluded. Incozol EH is immediately hydrolysed into“fully
hydrolysed Incozol EH” and 2-ethylhexanal.
If absorbed, passive diffusion and active transport throughaqueous
pores is likely to be an entry routes to the systemic circulation.No
metabolic activation of Incozol EH and its hydrolysis products is
expected. Excretion via faeces is assumed to be the main excretion
pathway of“fully hydrolysed
Incozol EH”due to its
molecular weight.Oxidation and
conjugation products of 2-ethylhexanal were shown to be excreted via
urine.Based on hydrolytical
conversion of Incozol EH bioaccumulation is not likely to occur based on
physico-chemical properties of the hydrolysis products.
(2008), Guidance on information requirements and chemical safety
assessment, Chapter R.7c: Endpoint specific guidance.
H., Schäfer S. (2004). Toxicology. Academic Press, San Diego, USA, 2nd
Deisinger PJ, Guest D. (1998) Metabolism of 2-ethylhexanoic acid
administered orally or dermally to the female Fischer 344 rat.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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