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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

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Diss Factsheets

Administrative data

Link to relevant study record(s)

Description of key information

Short description of key information on absorption rate:

Based on:

- 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.

Key value for chemical safety assessment

Additional information

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 physico-chemistry data.

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.

Inhalation:     Absorption 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 bioaccumulation.


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:

  • In vivo, in rats treated at 1 g/kg with adequate occlusion and limitation of evaporation: dermal absorption of 5.7 to 14.6% of applied dose over 6h (likely underestimated due to saturation: 8-fold higher applied dose vs. guideline recommendation) and indicative dermal absorption rate (assuming a constant rate over exposure period) of 0.63 to 1.61 mg/cm2/h, both ranges depending whether non-recovered radioactivity and cage wash were considered as absorbed or not (conclusions as revised by RSS/CSR author).
  • In vitro, dermal absorption rates of 0.22 and 0.038 mg/cm2/h in full thickness rat skin and human stratum corneum, resp., due to important skin damage in rat but not human samples. The lag phase was 1-2 hours.

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 vivo)

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 vivo rat

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 absorption:

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)

Determinant of dermal penetration Influence on penetration:
favors (+) or limits (-)
Differential influence: 2EHN when compared with 2EH:
higher (+), lower (-) or similar (=) penetration
Physical state: liquid + (quicker than solid particles) = (both are liquids)
Molecular weight - (slows down) - to = (2EHN: 175, 2EH: 130)
Structural alerts for skin binding* - (bound = non absorbable) = (neither 2EHN nor 2EH present such alerts)
Water solubility + above 0.1 g/L - (2EHN: 0.013 g/L, 2EH: 0.88-1 g/L at 20-25°C**)
Log Kow (estimated by EPI Suite's WsKow)  + in range 1-4, - above 4 (limited transfer from stratum corneum) - (2EHN: 4.12, 2EH: 2.73)
Log Kow (measured) - (2EHN: 5.24, 2EH: 3.1***)
Vapour pressure - above 100 Pa (volatilizes) = (2EHN: 27 Pa at 20°C, 2EH: 14.4-40 Pa at 20°C***)
Surface active properties + below 10 mN/m = (neither 2EHN nor 2EH are expected surfactants)
Skin irritation potential + (damages skin) -(2EHN: non irritant in standard assay; 2EH***: irritant to skin)

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 for 2EHN.