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Administrative data

Link to relevant study record(s)

Description of key information

Due to lack of quantitative data, absorption rates of 100% are indicated for all three routes. Very likely this means an overestimation of the dermal absorption compared to oral route.Available studies do not indicate a concern for bioaccumulation.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
100
Absorption rate - inhalation (%):
100

Additional information

The common name for the substance 3-((C9-11-iso,C10-rich)alkyloxy)propan-1-amine, acetate used in this dossier is Etheramine C10i-acetate.

 

The substance Etheramine C10i consists mainly of the ether amine with the carbon chain length of C9-11-iso, C10 rich. The manufacturing process is a two-step process, where in the first step fatty alcohol is reacted with acrylonitrile at elevated temperature. In the second step the ethernitrile hydrogenated to the corresponding primary amine. The substance Etheramine C10i-Acetate is finally produced by neutralising Etheramine C10i with acetic acid.

Etheramine C10i is a strong base with a pKa of about 9.9. When Etheramine C10i-Acetate dissolves in water or physiological media, the solid structure of the salt is broken up again by water molecules surrounding the charged particles namely, the positive Etheramine C10i and negative acetate ions. Asthe acetate is not considered to contribute significantly to the possible toxicological potential, the information available on the Etheramine itself can be used for the evaluation. For justification for cross-reading to C10i-etheramine, see IUCLID chapter 13 'Support Cross-reading - EA acetate 20150304.pdf'.

 

1. Physical-chemical properties

Etheramine C10i has a molecular weight of 215 (between 200 and 230), and that of etheramine C10i-acetate 275 (between 260 and 290) of which about 78% represents Etheramine C10i. The substance is an amber liquid, with a melting point below -30ºC,a measured boiling point of34°Cat 1013 hPa. Thevapour pressure of etheramine C10i is 0.72 Pa at 20°C. The vapour pressure of its acetate salt is expected to be much lower.

The octanol-water partition coefficient (log Pow) of etheramine C10i is-0.34 which is lower than what is estimated by QSARs due to the protonation of the primary amine in physiological circumstances.As the substance forms micelles in water the water solubility is expressed as the critical micelle concentration (CMC, a solubility limit) at 149 mg/L.

In physiological circumstances the nitrogen is positively charged, resulting to a cationic surfactant structure which leads to high adsorptive properties to negatively charged surfaces as cellular membranes. The apolar tails easily dissolve in the membranes, whereas the polar head causes disruption and leakage of the membranes leading to cell damage or lysis of the cell content. As a consequence, the whole molecule will not easily pass membrane structures. Cytotoxicity at the local site of contact through disruption of cell membrane is considered the most prominent mechanism of action for toxic effects.This is a mechanism that is not pH dependent. This is supported with the observation that at repeated dose studies local irritating effects in the stomach at relatively low dose levels where the acidic environment is supposed to have a neutralizing effect.

 

2. Data from toxicity studies and irritation studies

Acute toxicity data of Etheramines with comparable alkyl chain lengths were evaluated in Acute Toxic Class (OECD 423) and comparable studies and resulted to a LD50 in the range of 300 - 2000 mg/kg bw, with a LD50 cut-off of 500 mg/kg bw.

Etheramine C10i is severely corrosive to the skin and is not expected to easily pass the skin in view of its ionised form at physiological conditions. However, as this is not quantitatively evaluated, dermal absorption is considered as worst case assumption in risk assessment to be the same as oral absorption, and both are therefore considered to be 100%.

 

Etheramines are severe corrosive substances (see under endpoint irritation/corrosion). In in vivo studies effects of corrosion occur following exposure of only 3 minutes. However, contrary in cases where such effects would quickly appear in case they were pH dependant, the corrosive effects developed within the course of a week. So, although the change of the pH by adding acetate will possibly have a mitigating effect on the severe corrosive properties of etheramines, it can still be expected to be a severe irritant, even likely corrosive.

 

As the substance is corrosive, symptoms of local respiratory irritation are expected, which is expected to limit the systemic uptake of amounts needed for systemic toxicity. Also for acute dermal toxicity, effects will be characterised by local tissue damage. Systemic uptake via skin is likely to be very limited, in view of the use of protective measure related to the handling of corrosive material.

Due to its corrosive properties, further acute in vivo testing via dermal and inhalation route is not justified. This is also applicable for testing for sensitization. There is no information regarding sensitising properties available from testing. Cross reading with primary alkylamines indicates that the substance would probably not be sensitising to skin.

There are no concerns for genotoxicity following testing for bacterial mutagenicity, and Etheramine C10i has been shown to be not clastogenic or aneugenic in human lymphocytes and not mutagenic in the mouse lymphoma L5178Y test system. Also various available QSARs for genotoxicity endpoints do not indicate a concern.

No adverse effects on reproductive organs were identified in the 90 day study in rats on Etheramine C10i, The available reproduction (OECD 422 reproduction screening) and developmental toxicity studies (OECD 414 and ZEDTA) do not indicate a concern, nor is this expected based on general molecular profiling and mode of action considerations. Additionally, QSARs also do not show alerts for reproduction/developmental toxicity.

 

Data from repeated dose toxicity studies:

Oral:

Testing of Etheramine C10i in a Combined repeated dose toxicity study with the reproduction/ developmental toxicity screening test (OECD 422) with dosing for up to 46 days (in females) resulted to limited local effects in the stomach following treatment of a corrosive substance, which fully recovered during a 14-day recovery period. A parental NOAEL of 50 mg/kg/day was derived for systemic toxicity. The study also did not indicate any effect on reproductive parameters and foetal development. This was confirmed in a subsequent 90-day oral gavage study in rats which also concluded to a NOAEL of 50 mg/kg. Higher doses were not tested since it was expected that a dose level higher than 50 mg/kg was not tolerated (based on previous results).

Additional information on the local effects in the stomach comes from adevelopmental toxicity study (OECD 414) in rats with Etheramine C10i. In this studythehighest dose level of 75 mg/kg bw used resulted to ulceration, diffuse forestomach hyperplasia and/or increased incidence and/or severity of hyperkeratosis of the limiting ridge.

 

Inhalation:

Exposure of humans to Etheramine C10i via inhalation is not likely taking into account the low vapour pressure and high boiling point of the substance as well as low possibility of exposure to aerosols or droplets of an inhalable size. Furthermore, as the substance is classified as corrosive, local effects will be dose-limiting and preclude sufficient uptake for systemic effects to develop.

 

Dermal:

There is no data from repeated dose studies via dermal route: Etheramine C10i(-acetate) is corrosive to the skin and is not expected to easily pass the skin in view of its ionised form at physiological conditions. The dermal route is therefore not a preferred route for dosing when evaluating repeated dose toxicity. Effects will be characterized by local corrosive effects that are related to duration, quantity and concentration, rather than by systemic toxicity due to dermal uptake. There is no consumer exposure to Etheramine C10i(-acetate). Further, manufacture and use are highly controlled. Its use is limited to industrial users where following its severe corrosive properties the applied protection measures will provide for sufficient protection to prevent exposure.

 

As the addition of acetate is not expected to have an effect on the intrinsic toxicological profile for repeated toxicity via oral dosing of Etheramine C10i, the results from Etheramine C10i are therefore considered to fully represent the hazard properties for the Etheramine C10i content (approx. 78%) in Etheramine C10i-acetate.

 

3. Absorption, distribution, metabolism, excretion

Etheramine C10i is mainly protonated under environmental conditions. The protonated fraction will behave as salt in water. Etheramine C10i is surface active and has a low solubility in the form of CMC. Similarly to other cationic fatty nitrile derivatives, Etheramine C10i is expected to sorb strongly to sorbents. As a consequence, absorption from gastro-intestinal system is likely to be relatively slow. Profiling information suggest a high oral absorption. The Human Intestinal absorption (HIA) is estimated to be 90.2% (QSAR toolbox v. 3.1). An absorption of 100% is indicated as key value here.

There is one limited publication available describing the kinetics of Etheramine C12 afteri.v.application of 5 mg/kg (5 ml volume) in 4 rabbits, reporting a biphasic course: first a rapid distribution from the peripheral blood (t½=2.2 min) linked to the lipophilicity of the active ingredient, followed by an also rapid elimination phase (t½=29.2 min). Excretion route is mainly into the urine. Removal becomes much slower after the first hour. In one of the four rabbits it was not possible to identify the lauryloxypropylamine in the urine. The rapid blood clearance and low amounts of lauryloxypropylamine found in the urine suggest that this active ingredient is processed or metabolized quickly.

 

At this stage no data are available on dermal absorption. Based on the severe corrosive properties, dermal absorption as a consequence of facilitated penetration through damaged skin can be anticipated. Although experience from other corrosive cationic surfactants do not give indication of facilitated uptake. Dependent on the solvent and concentration, up to 60% dermal absorption may be taken as a worst case for assessment purposes (value taken from the existing EU risk assessment on primary alkylamines).QSARs for dermal absorption indicate low levels.

Due to the lack of quantitative absorption data, 100% absorption is taken as a conservative approach.

 

Also for inhalationno data are available on absorption, and100% is proposed as worst case. With a vapour pressure of <1 Pa at 20 °C, the potential for inhalation is limited. Relevant exposures are only possible as aerosol. If any inhalation does occur, this can only be in the form of larger droplets, as the use does not include fine spraying. Droplets will deposit mainly on upper airways, and will be subsequently swallowed following mucociliary transportation to pharynx. This results to no principal difference in absorption compared oral route.

 

Considering the low octanol/water partitioning coefficient, and no increase of toxic effects following longer duration of dosing observed between a 14-day range finding and up to 46 days dosing in final OECD 422 study and 90-days in an OECD 408 study, the potential for bioaccumulation of Etheramine C10i is considered to be low.

 

The mode of action of Etheramine follows from its structure, consisting of an apolar fatty acid chain and a polar end of a primary amine from the ether part with primary amine. The structure can disrupt the cytoplasmic membrane, leading to lyses of the cell content and consequently the death of the cell. Etheramine C10i is corrosive to skin, and toxicity following dermal exposure is characterised by local tissue damage, rather than the result of percutaneously absorbed material.

 

Below are molecular chemical profile and estimated properties of Etheramine C10i compared to those of Etheramine C13i in order to estimate the possible impact of a slight change in the length of the alkyl chain in Etheramine.

 

Molecular chemical profile and estimated properties:

 

Etheramine C10i

Etheramine C13i

CAS

30113-45-2

50977-10-1

Physical state

Liquid

Liquid

SMILES

NCCCOCCCCCCCC(C)C

NCCCOCCCCCCCCCCC(C)C

Molecular formula

C13H29NO

C16H35NO

Molecular weight

215.3755

257.4552

Solubility:    avgLogS

                         (g/L)

-3.90

(27 mg/L)

-4.88

(3.4 mg/L)

Solubility (meas)

CMC 149 mg/L

CMC: 210 mg/L

Density

0.852

0.855

Viscosity (mPa s)

< 4

7.6

pKa:                        

                           1+:

10.14

≥99.9% at pH≤7.2

10.14

≥99.9% at pH≤7.2

logPow(ALOGPS 2.1)

       (KOWWIN v1.68)

3.75 (±0.58)

3.9246

5.00 (±0.74)

5.4714

logPow (meas)

-0.34 at pH 5-6

(no data)

logD (Chemaxon)

pH      logD

1,700   0,188

4,600   0,190

5,500   0,199

7,400   0,661

pH      logD

1,700   1,522

4,600   1,523

5,500   1,533

7,400   1,995

Mp (EPIWIN)

51.27°C

90.75°C

bp (EPIWIN)

278.48°C

330.10°C

Vp (EPIWIN)

0.464 Pa

0.0121 Pa

Mp (meas)

<-30°C

<-30°C

bp (meas)

276°C

228-292°C

Vp (meas)

0.72 Pa at 20°C

0.425 Pa at 20 °C

Reactivity

No alerts

No alerts

HOMO

LUMO

(difference)

-9.7(-9.81;-9.59) eV

2.87(2.71;3.09) eV

(12.57)

-9.71(-9.81;-9.39) eV

2.87(2.76;3.07) eV

(12.58)

Dermal penetration coefficient Kp (est)

0.0000576 cm/h
(based on Pow = -0.34)

0.00026 cm/h
(based on Pow = 1)

Max. dermal absorption

0.0000224 mg/cm²/hr
(based on Pow =0.199 )

0.000129 mg/cm²/hr
(based on Pow =1.533 )

Human Intestinal absorption (HIA)

90.2%

91.1%

Molecular formula, molecular weight, pKa and logD were all calculated using ChemAxon MarvinSketch (v.5.4.0.1).

Melting point, boiling point, vapour pressure and logPow were estimated by EPI Suite (v4.1).

Solubility and logPow are estimated using ALOGPS 2.1 (VCCLAB, Virtual Computational Chemistry Laboratory,http://www.vcclab.org, 2005)

Reactivity: QSAR Toolbox v.3.0: profiling: DNA binding (OASIS v1.1; OECD); Protein binding (OASIS v1.1; OECD)

HOMO/LUMO Energy, [eV], quantum-chemical descriptor (the energy of the highest occupied resp. lowest unoccupied molecular orbital), calculated in OASIS software, based on MOPAC 7.

(a large difference between HOMO and LUMO energies implies high stability and thus low reactivity)

Absorption properties:

- dermal: EpiSuite v. 4.1; intestinal (water:0.0005 cm/hr):

- HIA: QSAR toolbox (version 3.1) (Human Intestinal Absorption)

Max. dermal absorption: IH Skin Perm v1.03 from AIHA