Registration Dossier

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. This basically indicates that, although the absorption is probably low, it is considered that no significant difference in absorption occurs between oral, dermal and inhalation route. 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 N-C16-18-alkyl-(evennumbered, C18 unsaturated) trimethylpropane-1,3-diamine used in this dossier is Diamine methylated.

 

The substance Diamine methylated consists mainly of two tertiary amines separated by a propyl group with a large carbon chain length of C16, C18 or C18 unsaturated (Oleyl) linked to one of the amines. The other substitutions to the tertiary amines are methyl-groups.

The manufacturing process is a single-step process, where in a reductive methylation step, a diamine is reacted with formaldehyde under hydrogenation conditions.

 

1. Physical-chemical properties

Diamine methylated has a molecular weight between 341 (alkyl chain is C16) and 369 (alkyl is C18). The substance is a yellow-brown liquid at 20 °C with a melting point of -4.19 ºC, a boiling point above 300°C,and a vapour pressure of 4.5E-04 Pa at 25 °C. Actual measured boiling point (> 300°C) and vp (4.5E-04 Pa at 25°C) are well in line. The calculated mp is generally not applicable of surfactant UVCBs.

The octanol-water partition coefficient (log Pow) is 4.06 at 20 °C (based on ratio solubility octanol/CMC in water)which is lower than what is estimated by QSARs (8.4 fromKOWWIN v1.68)due to the protonation of the tertiary amine in physiological circumstances with Pka resp. 7.45 & 10.01. The LogD at pH 7.4 estimated by Chemaxon results to 4.14, which is close to the measured value.

Similarly, the solubility in water is dependent on pH. As the substance forms micelles in water the water solubility is expressed as the critical micelle concentration (CMC, a solubility limit) at 70 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 tail 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.

The attached document provides an overview of the molecular chemical profile and estimated properties of Diamine methylated (focused on C18:1 – Oleyl alkyl chain).

 

2. Data from toxicity studies and irritation studies

Acute toxicity was evaluated in Acute Toxic Class (OECD 423) and resulted to aLD50 cut-off of 200 mg/kg bw.

Diamine methylatedis 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, 100% dermal absorption is considered as worst case assumption in risk assessment.

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. There is no information regarding sensitising properties available from testing. Due to its corrosive properties, further acutein vivotesting via dermal and inhalation route is not justified.Profiling and QSARs indicate a low risk for sensitisation, and due to use in industrial and professional setting only, with the application of adequate PPE related to the severe corrosive properties of the etheramine, exposures are limited. There are no reports on incidents of sensitisation to diamine methylated available.

 

There are no concerns for genotoxicity following testing for bacterial mutagenicity,clastogenic or aneugenic effects in human lymphocytes and mutagenicity in the mouse lymphoma L5178Y test system. Also various available QSARs for genotoxicity endpoints do not indicate a concern.

 

Data from repeated dose toxicity studies:

Oral:

In a GLP-compliant guideline 90-day oral study with rats, combined with reproductive/developmental toxicity screening, the lowest tested level of 1 mg/kg bw/day was considered to be a LOAEL, based on the presence of granulomatous inflammation of the mesenteric lymph nodes with central necrosis at all dose levels with dose-related increase in severity.

The findings consist of

- accumulation of foamy macrophages in the mesenteric lymph nodes, resulting in a granulomatous inflammation with central necrosis at all dose levels which extended outside the lymph node (extranodal) in several animals at 5 and 15 mg/kg bw/day.

- infiltration of foamy macrophages in lamina propria intestines at 5 and 15 mg/kg bw/d

- Increased neutrophil counts at 5 and 15 mg/kg bw/d in males and females

- a lower bw gain in males at 15 mg/kg bw/d.

Otherwise no significant toxicological finding were seen up to the highest dose tested of 15 mg/kg. This result pattern does very well compare to effects seen for cationic surfactants in general.

A mode of action has not been established but it is possible to suspect the known corrosivity to be at least partially involved. It is indicative that the observed effects are local and they are by some interpreted as phospholipidosis, something commonly observed following treatment with cationic amphiphilic material, including marketed pharmaceuticals, and considered to be non-adverse. When taking into consideration the relatively strong corrosive effects of this substance, and the route of administration, it cannot be excluded that the overall toxicity reflects a point-of-first-contact effect.

Phospholipidosis is a plausible mechanism. In physiological circumstances, the diamines and Diamine methylated have 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. Noteworthy in this respect is that recent research shows that the log distribution coefficient for cationic surfactants between water and phospholipid are possibly several orders of magnitude higher than between water and oil. The complex of cationic surfactant and phospholipids are difficult to digest by the macrophages, and they accumulate with the lysosomes. Recent (unpublished) studies have shown that these cationic surfactants, are all lysosomotropic, and scored positive for phospholipidosis in in vitro studies with HepG2 cells.

 

Inhalation:

Diamine methylatedhas a low vp pressure (4.5E-04 Pa at 25 °C, experimental) andits use is limited to industrial settings that do not involve the forming of aerosols, particles or droplets of an inhalable size. So exposure to humans via the inhalation route will be unlikely to occur.

Furthermore, as the substance is classified as corrosive, local effects will be dose-limiting and preclude sufficient uptake for systemic effects to develop.

 

Dermal:

Diamine methylatedis corrosive to the skin and is not expected to easily pass the skinin view of its ionised form at physiological conditions. The skin is therefore not a preferred route when studying repeated dose systemic 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 toDiamine methylated. 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.

 

3. Absorption, distribution, metabolism, excretion

Diamine methylatedis mainly protonated under environmental conditions. The protonated fraction will behave as salt in water. Diamine methylated is surface active and has a low solubility in the form of CMC. Similarly to other cationic fatty nitrile derivatives, Diamine methylatedis expected to sorb strongly to sorbents. As a consequence, absorption from gastro-intestinal system is likely to be relatively slow. Profiling information suggest low oral absorption. (See profiling table below)

 

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. 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 of4.5E-04 Pa at 25 °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 that no increase of toxic effects following longer duration of dosing observed between a 14-day range finding and up to 104 days dosing in combined 90-day/OECD 422 study, the potential for bioaccumulation of Etheramine C10i is considered to be low.

 

Attached document provides an overview of the molecular chemical profile and estimated properties of Diamine methylated (focused on C18:1 – Oleyl alkyl chain).