N1,N2-dimethyl-N1-{2-[methyl(propan-2-yl)amino]ethyl}-N2-(propan-2-yl)ethane-1,2-diamine

Endpoint summary

Description of key information

Toxicokinetic, metabolism and distribution

There are no studies available in which N,N-bis[3-(dimethylamino)propyl]-N',N'-dimethylpropane-1,3-diamine, CAS 1042950-30-0 has been investigated. Therefore, in accordance with Annex VIII, Column 1, Item 8.8.1, of Regulation (EC) No 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2016c), assessment of the toxicokinetic behavior of the substances which N2-dimethyl-N1-{2-[methyl(propan-2-yl)amino]ethyl}-N2-(propan-2-yl)ethane-1,2-diamine is conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the available substance specific data on physico-chemical and toxicological properties according to Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2016c) and considering further available information on the target and source substances.

Oral and dermal absorption of tertiary amines is anticipated because they have low molecular weights. Generally, the smaller the molecule the more easily it may be taken up. Molecular weights below 500 are favorable for absorption; molecular weights above 1000 do not favor absorption (ECHA, 2016). N2-dimethyl-N1-{2-[methyl(propan-2-yl)amino]ethyl}-N2-(propan-2-yl)ethane-1,2-diamine has a molecular weight of 229.40 mg/mol. Furthermore, Lipinski rule of five for the substance of interest indicated the substances to be bioavailable (OECD QSAR toolbox 4.5 SP, 2022). In addition to molecular weight the most useful parameters providing information on the absorption potential are octanol/water partition coefficient (log P) value and the water solubility (ECHA, 2016).

Water-soluble substance will readily dissolve into gastrointestinal fluids. 

Regarding the oral toxicity data, an acute oral toxicity study performed with the N2-dimethyl-N1-{2-[methyl(propan-2-yl)amino]ethyl}-N2-(propan-2-yl)ethane-1,2-diamine the LD50 rat was identified to be 300-2000 mg/kg bw due the presence of mortality. Clinical signs were slight ataxia and dyspnea.

Dermal absorption is influenced by many factors, e.g., physic-chemical properties of the substance. With regard, to the dermal absorption liquids and substances in solution are taken up more readily than dry particulates. A tiered approach for the estimation of skin absorption has proposed within a risk assessment framework (EC, 2007). Initially, basic physico-chemical information, should be considered, i.e., molecular mass and lipophilicity (log P). Following, skin absorption is generally predicted unless molecular mass is above 500 and log P is outside the range [-1, 4], in which case a value of 10% skin absorption is chosen.  Furthermore, the substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Thus, if the water solubility is below 1 mg/L, dermal uptake is likely to be low. Between 1-100 mg/L absorption is anticipated to be low to moderate and between 100-10,000 mg/L moderate to high.  However, if the water solubility is above 10,000 mg/L and log P values below 0 the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum. Based on the above consideration, dermal uptake for these substances will be low.

Source and target substance are both completely soluble in water and have a log P value between -2.1 and 0.27 respectively. Thus, both target and source substances have the potential to be well absorbed via dermal route.

Based on these considerations we can predict that signs of systemic toxicity indicate that absorption has occurred for target and source substance.

Regarding the absorption inhalation-route the important parameters are vapor pressure, hydrolysis test, and log P. Vapor pressure is a parameter for a substance to be available for inhalation as a vapor. As a general guide, highly volatile substances are those with a vapor pressure greater than 25 KPa (or a boiling point below 50°C). Substances with low volatility have a vapor pressure of less than 0.5 KPa (or a boiling point above 150°C). Both target and source substances have a low volatility. Moderate log P values (between -1 and 4) are favorable for absorption directly across the respiratory tract epithelium by passive diffusion. This is the case for the target and source substances as well.

Hydrolysis data are not available for N2-dimethyl-N1-{2-[methyl(propan-2-yl)amino]ethyl}-N2-(propan-2-yl)ethane-1,2-diamine. However, tertiary alkylamine are well known to be hydrolytically stable. 

Based on the physicochemical properties of target and source substances and data on acute inhalation toxicity of the target and source substances, the absorption via the lung is expected.

Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2016c) states that if the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration. Target and source resulted to be corrosive to skin.

Taken all together, based on the above consideration we can predict the target and source substances to be absorbed via dermal route.

Overall, it can be concluded that, target and source substances are expected to be well absorbed in the respiratory and gastro-intestinal tracts, which may be a route of low-level chronic exposure.

Distribution within the body through the circulatory system depends on the molecular weight, the log P and water solubility. In general, the smaller the molecule, the wider is the distribution. Small water-soluble molecules and ions will diffuse through aqueous channels and pores. The water solubility of the target and source substances favors extensive and possibly systemic distribution via the circulatory system. If the molecule has a log P> 0 it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues.

As explained in Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2016c) lipophilic substances have the potential to accumulate within the body depending on the conditions of the exposure. If the dosing interval is shorter than 4 times the whole half-life of the substance, then there is the potential for the substance to accumulate. It is generally the case that the substances with high log P values have long biological half-lives. Based on these considerations, daily exposure to a substance with a log P value of around 4 or higher may results in a build-up of that substance within the body. Substances with a log P value of 3 or less would be unlikely to accumulate with the repeated intermittent exposure patters normally encountered in the workplace but may accumulate if exposures are continuous. Once exposure to the substance stops, the substance will be gradually eliminated at a rate dependent on the half-life of the substance.

Highly lipophilic substances (log P between 4 and 6) that come into contact with the skin can readily penetrate the lipid rich stratum corneum but are not well absorbed systematically. Although they may persist in the stratum corneum, they will eventually be cleared as the stratum corneum is sloughed off. Thus, since target and source substances have log Pow lower than 4 then a low bioaccumulation potential due to for both substances.  

Metabolism of the tertiary aliphatic amines is generally well understood and mediated primarily by cytochrome P-450 and MFAO, leading to alpha-C oxidation and N-oxidation, leading to rapid clearance (Rose & Castagnoli, 1983).

There is a commonality in the metabolism of the tertiary amines. N-oxide formation and excretion of both freebase and N-form, with some dealkylation, appears to be the major route of excretion for the lower molecular weight tertiary amines.

Skin metabolism simulator and rat S9 metabolism simulator of the OECD QSAR toolbox 4.5 SP 1 show for the subject substance the generation of metabolites such as aliphatic amine (secondary and tertiary amines), aldehydes, ammonia and formic acid and formats aliphatic acids among others.

The major routes of excretion for substances from the systemic circulation are the urine and/or the faeces. The excretion processes involved in the kidney are passive glomerular filtration through membranes pores and active tubular secretion via carrier process. Substances that are excreted in the urine are likely to be water-soluble and of low molecular weight (below 300 in rat, mostly anionic and cationic compounds) and generally, they are conjugated metabolites (e.g., glucuronides, sulphates, glycine conjugates) from Phase II biotransformation. Most of them will have been filtered out of the blood by the kidneys through a small amount may enter the urine directly by passive diffusion. In the rat, molecules that are excreted in the bile are amphipathic (containing both polar and non-polar regions), hydrophobic/strongly polar and have high molecular weight. In general, in rats for organic cations with a molecular wight below 300 it is unlikely that more than 5-10% will be excreted in the bile. Taking all these considerations together and considering that the target and source substances have a molecular weight below 300 and high-water solubility, we can conclude that both substances are excreted mainly via urine.

 

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100