N-butyl-2,2,6,6-tetramethylpiperidin-4-amine

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

95

Additional information

The following remarks on the toxicokinetics of N-Butyl-2,2,6,6-tetramethylpiperidin-4-amine (N-Butyl-TAD) are based on physicochemical properties, in silico predictions as well as on data obtained in a basic dataset. There are no experimental toxicokinetic studies available and generation of new data is not required as the assessment of the toxicokinetic behaviour of the substance should be performed to the extent that can be derived from the relevant available information (REACh Annex VIII, 8.8.1).

N-Butyl-TAD has a molecular weight of 212.38 g/mol. It is a liquid at room temperature with a density of 0.864 g/cm3 (2012-0162-DGP). The vapour pressure of N-Butyl-TAD is determined to be 3 Pa at 20 °C (2011-0360-DKP). The estimated octanol/water partition coefficient Log Pow is 2.88 at 25 °C (2002-0058-DKB) and its water solubility determined using QSAR is 797 g/L at 20 °C (ACD Labs QSAR calculation).

Absorption

The observation of systemic toxicity following exposure by any route is an indication for substance absorption; however, this will not provide any quantitative information.

In an acute oral toxicity study (2002-0232-DGT), in which the doses of 2000 mg/kg bw and 300 mg/kg bw were administered to rats. Mortality and clinical signs including hunched posture, piloerection, salivation and lethargy were reported for the high dose group during the first day after administration. These observations indicate that absorption of the compound via the gastrointestinal tract (at least to some extent) has evidently occurred.

The gastrointestinal absorption is reported as 95% for a dose of 1 or 1000 mg (Danish EPA Database, 2016).
The molecular weight of 212.38 g/mol is in the range favourable for absorption in the GI tract (<500 g/mol). Based on its high water solubility, dissolving into the gastrointestinal fluids will occur. The log Pow of 2.88 is in the range favourable for absorption in the GI tract (between -1 and 4).

With regard to respiratory absorption the low vapour pressure of 0.003 kPa indicates that the substance may not be available for inhalation as a vapour (less than 0.5 kPa). The good water solubility may cause retention of the substance within the mucus. However, the moderate log Pow of 2.88 is in the range favourable for absorption directly across the respiratory tract epithelium by passive diffusion (between -1 and 4).

Based on the physical-chemical parameters dermal absorption will be possible based on the molecular weight of 212.38 g/mol (maximal dermal uptake with MW <100 g/mol; above 500 g/mol the molecule may be to large) and the liquid physical state. Log P values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal) particularly if water solubility is high. The water solubility of 797 g/L of N-Butyl-TAD is high and log Pow is in the optimal range, thus dermal absorption is expected to be high. Furthermore, the substance is a strong skin irritant, so damage to the skin may enhance dermal penetration. Also signs of toxicity observed in an acute dermal toxicity study performed with N-Butyl-TAD indicate that absorption has occured to a certain extent.

Distribution

Some information or indication on the distribution of the compound in the body might be derived from the available physico-chemical and toxicological data. Once a substance has entered the systemic circulation, its distribution pattern is likely to be similar for all administration routes. However, first pass effects after oral exposure influence the distribution pattern and distribution of metabolites is presumably different to that of the parent compound.

The smaller a molecule, the wider is its distribution throughout the body. Membrane-crossing substances with a moderate log Pow and molecular weight will be able to cross the blood-brain and blood-testes barrier and reach the central nervous system (CNS) or testes, respectively.The log brain/blood partition coefficient is estimated with 0.3994, which is categorized as medium (Danish EPA Database, 2016).
Thus, distribution of N-Butyl-TAD throughout the body – at least to some extent – can be presumed.

There are no data from toxicological studies with repeated exposure available and therefore, no possible target organ could be determined.

Bioaccumulation

Taking into account the high water solubility of 797 g/L and the log Pow of 2.88 which is below the trigger value of 4 it can be concluded that for N-Butyl-TAD the accumulative potential is rather low. Thus, accumulation in adipose tissue during 8 h-workday scenarios can be excluded.

Metabolism

Prediction of compound metabolism based on physico-chemical data is very difficult. Structure information gives some but no certain clue on reactions occurring in vivo. An important role plays the liver where many metabolites may arise.
11 possible liver metabolites were predicted using the rat liver S9 metabolism simulator in the OECD Toolbox 3.3. No data was found for any of the predicted metabolites:
CCCCNC1CC(C)(C)NC(C)(CO)C1
CC1(C)CC(NCCCCO)CC(C)(C)N1
CC(O)CCNC1CC(C)(C)NC(C)(C)C1
CCCCNC1(O)CC(C)(C)NC(C)(C)C1
CCCCNC1CC(C)(C)NC(C)(C=O)C1
CC1(C)CC(NCCCC=O)CC(C)(C)N1
CC(O)CCNC1CC(C)(C)NC(C)(CO)C1
CC(=O)CCNC1CC(C)(C)NC(C)(C)C1
CC(O)CCNC1(O)CC(C)(C)NC(C)(C)C1
CCCCNC1CC(C)(C)NC(C)(C(O)=O)C1
CC1(C)CC(NCCCC(O)=O)CC(C)(C)N1.
Metabolism prediction with regard to CYP2C9 and CYP2D6 gives negative results (Danish EPA Database, 2016).

Excretion

Only limited conclusions on excretion of a compound can be drawn based on physico-chemical data. Due to metabolic changes, the finally excreted compound may have few or none of the physico-chemical properties of the parent compound. In addition, conjugation of the substance may lead to very different molecular weights of the final product. N-Butyl-TAD and its potential metabolites (OECD Toolbox 3.3) have a molecular weight lower than 500 g/mol, thus, excretion via faeces/urine is likely.

 

References:

Danish EPA Database, 2016: http://qsar.food.dtu.dk/

OECD Toolbox, Version 3.3