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EC number: 248-363-6
CAS number: 27247-96-7
Short description of key information on absorption rate:
- in vitro (rat and human) and in vivo (rat) data on dermal absorption for the analog substance 2-ethyl hexanol (synthesis precursor of the registered substance),
- conservative corrections to account for any limitation of corresponding studies,
- a read-across matrix,
It is concluded that the following data can be used in human exposure assessment for the registered substance:
- dermal absorption rate: 0.42 mg/cm2/h;
- permeability constant Kp = 5.04 .10-4 cm/h
- absorption percent is not a relevant parameter because the in vivo study was possibly done at a saturating dose, and percent absorption is a dose- and time-dependent exposure parameter.
See attached documents.
Only the conclusions are presented here:
No measured data were available for any of the
assessed properties, except dermal penetration (see specific study
summaries, for the analogue substance 2EH). Discussion was therefore
based on results from toxicity studies, and in a second instance on
Here are the conclusions that could be drawn about
the toxicokinetic behaviour of 2EHN:
Oral: Absorption demonstrated by
existence of systemic effects after ingestion; extent/speed unknown.
Dermal: No evidence of
absorption based on effects in animals exposed dermally; dermal
absorption should be low and slow due to high lipophilicity; the
differences in toxic levels by the various routes tested enable to
conclude that, as a worst-case, dermal absorption is at least 3-fold
lower than oral absorption and 10-fold lower than inhalative absorption –
this will be used in DNEL setting, “route-to-route extrapolation” step.
Experimental data from the analog substance 2EH, synthesis precursor,
enabled to conclude after a thorough read-across, that maximal dermal penetration
rate = 0.42 mg/cm2/h and permeability constant Kp = 5.04 .10-4cm/h.
demonstrated by existence of systemic effects in animals and workers
after inhalation; extent/speed unknown.
Possibly to the liver,
based on loss of liver cell basophilia in an inhalation assay. Distribution
of parent or metabolites to blood vessels, based on reporting of
dizziness/headache in workers.
Probably not for the toxicologically relevant
item (parent or metabolite), based
on observation of rats after various durations of treatment in otherwise
similar conditions. Does not enable to exclude completely any
Suspected metabolism by liver enzymes due
to inactivation of cytotoxic effects by addition of S9 mix. Various acid-base
and oxido-reductive reactions of the terminal nitrate group are
possible, as well as a release the nitric oxide (NO) group, as
known for other organic nitrates
Mainly urinary for
the parent, based on high log Kow value, effects in liver and
suspected metabolism by liver.
Discussion on absorption rate:
The dermal absorption of the analog substance
2-ethylhexanol (2-EH, synthesis precursor of the registered substance)
has been investigated as:
Based on this :
1) The following equation on percutaneous absorption will
be used: In vivo human = In vivo rat x [In vitro
human/In vitro rat], but applied to absorption rates and not
absorption percent (unknown in vitro and possibly underestimated in
2) A lag phase of up to 2h needs to be taken into account
to revise rat in vivo absorption rate, leading to a worst-case:
revised rate = indicative rate corrected for actual time
of linear absorption = 0.63 to 1.61 mg/cm2/h / (4 h actual linear phase
/ 6h linear phase initially assumed) = 0.95 to 2.42 mg/cm2/h in
3) The in vivo dermal absorption rate in humans is
therefore estimated as, using equation under 1):
0.16-0.42 mg/cm2/h in vivo human; as a
worst-case the higher limit will be retained. 4) If needed in exposure
models, the permeability constant Kp can be calculated from the
concentration of the tested 2-EH, which is actually the density of the
neat product that was tested: Kp (cm/h) = rate (mg/cm2/h) /
concentration i.e. density of 2-EH (mg/cm3) = 0.42 mg/cm2/h / 834 mg/cm3
so Kp = 5.04 .10-4 cm/h; this is 11-fold higher than the
Kp determined in vitro in human stratum corneum,
confirming that above calculations, taking into account various
corrections due to the study limitations, lead to a clear worst-case.
All these above data on 2-EH can be extrapolated to
2-ethylhexyl nitrate, based on the structural closeness of both
substances (identical carbon chain structure with different functional
group in C1 position) and the fact that the dermal absorption is not
expected to be influenced by the functional group per se, but
rather by the possible differences in physico-chemical properties. This
extrapolation is supported by the following table summarizing
differential features of both substances and their impact on dermal
Determinants of dermal penetration: differential
analysis between 2-ethylhexanol and 2-ethylhexyl nitrate (based on
ECHA's Guidance on information requirements and chemical safety
assessment, Table R.7.12-3, 2008)
2EH: 2-ethylhexanol as tested in dermal penetration
studies under 7.1.2 i.e. undiluted liquid
2EHN: 2-ethylhexyl nitrate as in actual use i.e. liquid
*: metal ions, acrylates, quaternary ammonium ions,
heterocyclic ammonium ions, sulphonium salts, quinines, dialkyl
sulphides, acid chlorides, halotriazines, dinitro or trinitro benzenes
**: measured data from HSDB, EPI Suite and IUCLID
databases for 2EH
***: measured data from IUCLID database on 2EH
Based on the above table, the dermal penetration of
2-ethylhexyl nitrate and 2-ethylhexanol is essentially similar and
limited (liquid, low MW, no structural alert for skin binding, moderate
to high log Kow, important volatility, no surface active properties,
inconstant skin irritation potential). Furthermore, 2-ethylhexyl
nitrate is expected to penetrate less than 2-ethylhexanol due to
some key differential features (in bold: slightly higher MW, much lower
water solubility, around 2 orders higher log Kow, non irritant to skin).
Therefore data on 2EH dermal penetration will be used as a worst-case
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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