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Description of key information

Due to lack of quantitative data, absorption rates of 100% are indicated for all three routes. Available studies do not indicate a concern for bioaccumulation.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
100
Absorption rate - inhalation (%):
100

Additional information

No specific toxicokinetic, metabolism or distribution studies were identified for N-[2-(piperazin-1-yl)ethyl]C18-insaturated-alkylamide.(Tall oil reaction products with aminoethylpiperazine)

 

The manufacturing process basically involves the reaction under controlled conditions of a fatty acid with the primary amine of N- aminoethylpiperazine (AEP) leading to the formation of an amide. (see attached structure of the main componentN-[2-(piperazin-1-yl)ethyl]C18-insaturated-alkylamide)

 

1. Physical-chemical properties

Tall oil reaction products with AEP is described as a dark brown, viscous liquid which seemed to be heterogeneous (particles could be seen). No mp or bp were observed between -30 and 300 ºC; a low vapour pressure of <3 x 10-7 Pa 23°C.

The octanol-water partition coefficient (log Pow) is5.4.As the substance forms micelles in water the water solubility is expressed as the critical micelle concentration (CMC, a solubility limit) which is32 mg/L.

 

In physiological circumstances the nitrogen is positively charged (at pH 7.2 and below > 99% cationic), 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.

 

In the table below are molecular chemical profile and estimated properties listed. The experimentally determined and calculated properties are reasonably well comparable.

The alert forprotein binding indicates that the chemical is a strong sensitizer as a result of Amide aminolysis. Animal studies for skin sensitisation confirmed this concern.

The alert for DNA binding by OECD has not been confirmed by the various genotoxicity tests performed. This can possibly explained by low bioavailability due to the combination of low solubility and difficulty of surfactants to pass cell membranes.

 

2. Data from toxicity studies and irritation studies

Tall oil reaction products with AEPis severely corrosive to the skin.Acute toxicity datashows low acute oral toxicity hazardsand effects observed are attributable to its corrosive properties in the GI-tract. The two available studies indicate an acute oral toxicity of 1000 mg/kg based on the cut-off limit from an acuteAcute Toxic Class (OECD 423) studyand higher based on a classic (OECD 401) LD50- study. 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.

 

Data from animal studies for skin sensitisation indicate that the substanceshould beclassified as Skin sensitizer Category 1A. 

For corrosive substances, the use of protective gloves and other equipment, such as face shields, aprons and good work practices are mandatory. As a result, direct dermal contact is very unlikely.

Lack of exposures, also via inhalation, explains that although the substance can be considered a strong sensitiser based on the results from both studies, the producers are not aware of reported incidences of sensitisation among own employees or from customers.

 

For each endpoint, bacterial mutagenicity, mammalian mutagenicity and mammalian clastogenicity, a recent guideline and GLP compliant study is available which all indicate that there is no concern for genotoxicity.

 

Data from repeated dose toxicity studies also point at low systemic toxicity with a sub-chronic NOALE from a 90-day gavage study in rats of 50 mg/kg bw/day. The first effects occurring at higher levels are mediated by local responses in the GI-tract.

 

Available 28-day and 90-day sub-chronic studies further did not indicate specific effects on reproductive organs.There were specifically no indications of possible reproduction toxicity based on the additional parameters determined in the 90-day study: All females showed a normal (regular) estrous cycle of 4 days, and histopathological examination of the male and female reproductive organs did not show treatment-related lesions. An additionally performed Prenatal developmental toxicity has furthermore shown thatTall oil reaction products with AEPhad no impact on any of the fetal developmental parameters up to the highest dose level of 220 mg/kg bw/day, over 4 times the 90-day NOAEL. In view of the lack of effects in on reproductive parameters in these available studies, further testing of for fertility is of low priority.

 

3. Absorption, distribution, metabolism, excretion

Tall oil reaction products with AEP is mainly protonated under environmental conditions. The protonated fraction will behave as salt in water. It is surface active and has a low solubility in the form of CMC. Similarly to other cationic fatty nitrile derivatives, Tall oil reaction products with AEP is expected to sorb strongly to sorbents. As a consequence, absorption from gastro-intestinal system is likely to be slow. The Human Intestinal absorption (HIA) is estimated to be 91% (QSAR toolbox v. 3.1). An absorption of 100% is indicated as key value here.

 

At this stage no data are available on dermal absorption. Itis not expected to easily pass the skin in view of its ionised form at physiological conditions.Based on the severe corrosive properties, dermal absorption as a consequence of facilitated penetration through damaged skin can be anticipated. Dependent on the solvent and concentration, up to 60% dermal absorption might be suggested as a worst case for assessment purposes (value taken from the existing EU risk assessment on primary alkylamines). 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<3 x 10-7 Pa at 23°C, the potential for inhalation is limited. Relevant (in view of possible systemic absorption) 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.

Absorption via respiratory route is therefore also set at 100%.

 

 

Considering no increase of toxic effects following longer duration of dosing observed between a 28-day and 90-days dosing study, the potential for bioaccumulation of Tall oil reaction products with AEP is considered to be low.

 

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

 

 

Molecular chemical profile and estimated properties:

 

 

Tall oil reaction products with AEP – main component

Chemical name

N-[2-(piperazin-1-yl)ethyl]C18-insaturated-alkylamide

CAS

1228186-18-2

Physical state

viscous liquid

SMILES

CCCCCCCC\C=C\CCCCCCCC(=O)NCCN1CCNCC1

Molecular structure

(See attached)

Molecular formula

C24H47N3O

Molecular weight

393

Solubility:    avgLogS

                         (g/L)

-4.94

4.5 mg/L

Solubility (meas)

CMC 32 mg/L at 23°C, pH7

Density

0.964 ± 0.5 g/ cm3 @ 30°C

pKa:                        

                     neutral:

                           1+:

                           2+:

2 possible cationic amines: 3.99 resp. 9.23

> 99% at pH > 11.2

Max 99.52% at pH 6.6

10% at pH5 and >99% at pH ≤ 2

logPow(ALOGPS 2.1)

       (KOWWIN v1.68)

5,87 ±0,69

6.02

logPow (meas)

5.4 @ 25°C

logD (Chemaxon)

pH  logD

1,700 0,165

4,600 2,356

5,500 2,546

7,400 3,865

Mp (EPIWIN)

228.04 °C

bp (EPIWIN)

533.05 °C

Vp (EPIWIN)

3.49E-009 Pa 25°C

Mp (meas)

not in -30-300°C

bp (meas)

not in -30-300°C

Vp (meas)

<3 x 10-7 Pa at 23°C

Reactivity

DNA binding by OECD: Aliphatic tertiary amines

Protein binding OASIS v.1.2: Amide: Acylation: The chemical is a strong sensitizer as a result of Amide aminolysis.

Dermal penetration coefficient Kp (est)

0.0965 cm/hr

Human Intestinal absorption (HIA)

91%

Molecular formula, molecular weight, pKa and logD were all calculated using ChemAxon MarvinSketch (v.6.1.6).

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.3.2: profiling: DNA binding (OASIS v1.1; OECD); Protein binding (OASIS v1.1; OECD)

Absorption properties:

- dermal: EpiSuite v. 4.1; (water:0.0005 cm/hr): log Kp = -2.80 + 0.66 log Kow - 0.0056 MW

- intestinal: HIA: QSAR toolbox (version 3.2) (Human Intestinal Absorption)