1,4-Diazabicyclo[2.2.2]octane-2-methanol

Endpoint summary

Description of key information

No studies are available. The molecular structure, molecular weight, physicochemical properties incl. water solubility and octanol-water partition coefficient of the substance do favour oral, inhalative and dermal absorption. However, the substance is only handled as aqueous solution and thus inhalation of the substance is considered negligible. Widely distribution within the water compartment of the body after systemic absorption and no accumulation in adipose tissues is expected. The substance might be metabolized and is expected to be excreted predominantly via the urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

In accordance with Annex VIII, Column 1, Item 8.8 of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2012), assessment of the toxicokinetic behaviour of the test substance was conducted to the extent that can be derived from the relevant available information on physicochemical and toxicological characteristics. There are no studies available evaluating the toxicokinetic properties of the substance.

The test substance is an off-white powder with lumps with a molecular weight of 142.2 g/mol. The substance has a low vapour pressure of <=1.6 Pa at 25 °C (van Doormalen-Schaap, 2014). The log Pow is <0.3 at 25 °C (Sato, 2013) and the water solubility is >1000 g/L at 20 °C (van Doormalen-Schaap, 2014).

 

Absorption

Absorption is a function of the potential of a substance to diffuse across biological membranes. The most useful parameters providing information on this potential are the molecular weight, the octanol/water partition coefficient (log Pow) value and the water solubility. The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2012).

Oral

Based on the physico-chemical properties of the test substance absorption is possible due to the low molecular weight of 142.2 g/mol. Generally the smaller the molecule the more easily it may be taken up. Molecular weights below 500 are favourable for absorption. In addition the very high water solubility, leading to a ready dissolution of the substance in the gastrointestinal fluids, favours oral absorption. Absorption of very hydrophilic substances by passive diffusion may be limited by the rate at which the substance partitions out of the gastrointestinal fluid. However, if the molecular weight is low (less than 200) the substance may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water.

Moreover, moderate lipophilicity (log Pow values between -1 and +4) is favourable for membrane penetration and thus absorption. Data from acute and repeated oral toxicity studies (Latour, 2014; Fujii, 2014) revealed no test substance related effects up to the limit doses. Therefore no conclusion can be drawn from these studies regarding toxicokinetic behaviour.

Nevertheless, absorption via the oral route is likely and is assumed to be almost complete.

Dermal

The relatively small size of the test substance favours dermal uptake. Moreover, the substance is sufficiently soluble in water to partition from the stratum corneum into the epidermis. However, since the water solubility is above 10 g/L and the log P value below 0 the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum.

The dermal permeability constant Kp of the substance was estimated to be 3.95E-04 cm/h using DermwinTM (v.2.01) and taking into account the log Pow and molecular weight. Further on the maximum flux Imax (Imax = Kp [cm/h] x water solubility [mg/cm³]) was calculated similar to the approach taken by Kroes et al. (2007) and yielded in a value of 400 µg/cm²/h. This flux value can be assigned to a high dermal absorption of 80% (Kroes at al., 2007).

Data from an acute dermal toxicity study revealed no effects of the test substance up to the limit dose of 2000 mg/kg bw (Latour, 2014b). Therefore no conclusion can be drawn from this study regarding toxicokinetic behaviour, as absence of effects could be due to chemical or toxicokinetic properties.

 

Inhalation

The test substance has a low vapour pressure of <= 1.6 Pa at 25 °C thus being of low volatility. Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapours, gases, or mists is not significant.

The MMAD of the test substance is 36.578 µm, D10 is 6.88 µm and D50 is 33.253 µm (Livingston, 2014). In humans, particles with aerodynamic diameters below 100 µm have the potential to be inhaled. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15 μm the alveolar region of the respiratory tract (ECHA, 2012). Based on the particle size the test substance may reach the respiratory tract upto the alveolar region. The moderate log P value (between -1 and +4) and the high water solubility may favour the absorption of deposited material. In the respiratory tract, the compound would readily diffuse into the mucous lining. However, very hydrophilic substances might be retained in the mucous in the upper respiratory tract and transported out by mucociliary activity. In general, the inhalative absorption of the test substance is considered to be not higher than through the intestinal epithelium. However it is to be mentioned that the substance will only be handled and used in water solution and therefore the exposure to particles and dust can be excluded.

 

Distribution

Distribution of a compound within the body depends on the physicochemical properties of the substance especially the molecular weight, the lipophilic character and the water solubility. In general, the smaller the molecule, the wider is the distribution. If the molecule is lipophilic, it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues (ECHA, 2012).

Based on its small size and its high water solubility the substance is supposed to be widely distributed within the water compartment of the body after systemic absorption and no accumulation in adipose tissues is expected.

 

Metabolism

No metabolism studies are available with the test substance itself. Prediction of compound metabolism based on physicochemical data is very difficult. Structure information gives some but no certain clue on reactions occurring in vivo.

Software supported QSAR of liver metabolism (OECD toolbox v3.0) revealed some oxidative metabolites of the test substance. Some suggested metabolites included oxidation of the hydroxyl group to an aldehyde or to an acid. Other calculated metabolites were the products of an dealkylation step (C2-unit), which can be further oxidized. There was no evidence for differences in genotoxic potencies due to metabolic changes in in vitro genotoxicity tests. The studies performed on genotoxicity (Ames test, gene mutation in mammalian cells in vitro, chromosome aberration assay in mammalian cells in vitro) were negative, with and without metabolic activation (Sarada, 2014; Verspeek-Rip, 2014; Saito, 2014).

 

Excretion

Only limited conclusions on excretion of a compound can be drawn based on physicochemical data. Due to metabolic changes, the finally excreted compound may have few or none of the physicochemical properties of the parent compound. In addition, conjugation of the substance may lead to very different molecular weights of the final product. The molecular weight (< 300 g/mol), a good water solubility and ionisation of the molecule at the pH of the urine are properties favouring urinary excretion. Thus the test substance is expected to be excreted predominantly via the urine.

References

ECHA (2012): Guidance on information requirements and chemical safety assessment – Chapter 7c: Endpoint specific guidance. European Chemicals Agency, Helsinki

Kroes et al. (2007): Application of the threshold of toxicological concern (TTC) to the safety evaluation of cosmetic ingredients. Food Chem Toxicol 45:2533-2562

Livingston, I. (2014). Particle Size Analysis on a Sample of [trade name]. Testing laboratory: Chilworth Technology Limited, Beta House, Southampton Science Park, Southampton, SO16 7NS, United Kingdom. Report no.: GLP111775R1V1/2014. Owner company: Tosoh Corporation, Yamaguchi, Japan. Report date: 2014-07-04.

Sato, T. (2013). Determination of the Partition Coefficient (n-octanol/water) of 1,4-product by HPLC Method.Testing laboratory: Institute of Ecotoxicology Co., Ltd., 2-28-1 Yoshino-cho, Kita-ku, Saitama City, 331-0811 Japan. Report no.: E4-13009-P6-TS. Owner company: Tosoh Corporation, Yamaguchi, Japan. Report date: 2013-04-30.