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Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Meets generally accepted scientific standards, well documented and acceptable for assessment
Objective of study:
toxicokinetics
Principles of method if other than guideline:
A series of aliphatic amines (C4-C10 and C13) labeled with carbon-11 (T 1/2 = 20.4 minutes) has been used as a model for studying some basic parameters affecting amine uptake and metabolism by the lung and other tissues in mice after iv injection.
GLP compliance:
no
Radiolabelling:
yes
Remarks:
carbon-11
Species:
mouse
Strain:
other: Swiss albino mice, BNL strain
Details on test animals and environmental conditions:
No details
Route of administration:
intravenous
Vehicle:
unchanged (no vehicle)
Remarks:
Doses / Concentrations:
0.5 to 5.0 X 10E-10 mol/mouse (0.1-1 mCi/mouse)
Metabolites identified:
not measured

The lung uptake (percentage of dose per organ) of aliphatic amines at 1 minute increased from 2.18 +/- 0.13% for butylamine to 13.33 +/- 0.84% for tridecylamine. Partition coefficients (between n-octanol and pH = 7 buffer) were measured for the C4 through C10 amines and for octanoic acid and octanenitrile. Within the amine series, the partition coefficient correlated with lung uptake. A comparison of a series of compounds all having a carbon chain length of eight but with different functional groups (--NH2, --C=N, --CO2H, --OH) showed that the amino group as well as the relatively lipophilic alkyl group were required for lung specificity. The 11C-aliphatic amines were rapidly metabolized via monoamine oxidase (ultimately to 11CO2). Non-amine metabolites in blood and lungs at 5 minutes postinjection were 95 and 50%, respectively. Pretreatment of mice with iproniazid and with pargyline decreased 11CO2 excretion, and iproniazid significantly increased the radioactivity retained by the brain, lungs and liver at 15 minutes.

Tridecylamine had the longest carbon chain of the tested series of amines. Liberation of carbon dioxide from injected Tridecylamine was relatively slow. It was only ca. 14% of the injected dose at 20 min post injection. At the same time point CO2-excretion of the alkyl amines C4 to C10 amounted to more than 40% of the dose, and exceeded 50% in the case of C6 and C7 alkylamines. Pretreatment with inhibitors of Monoamine Oxidases (MAO) significantly increased the radioactivity retained by the brain, lungs, and liver (after injection of 11C-n-octylamine). The rate of CO2-excretion depended on the carbon chain length in the order C4<C5<C6>C7>C8>C9>C10>C13.

Description of key information

Key value for chemical safety assessment

Additional information

Absorption

Tridecylamine, branched and linear (TDA) has a molecular weight of app. 200 g/mol, a low vapour pressure of 1 -20Pa, and is hardly soluble in water (23 -32mg/L). The latter matches the high logPoW value of app. 5.

The low molecular weight favors oral absorption and might even permit passage through aquaeous pores despite the low water solubility. Additionally, TDA might be taken up via micellular solubilisation due to a log PoW > 4. All in all, oral uptake is considered efficient. This is also supported by the systemic effects observed in the repeated dose toxicity study.

Absorption after inhalation is considered possible, though due to the low vapour pressure, exposure will be limited, if no aerosols are generated (sat. vapour concentration of app. 1.6mg/L). Because TDA is not readily soluble, it will enter the lower respiratory tract, where it can be absorbed vie micellular solubilisation.

Based on the physico-chemical properties it would be expected that the substance quickly enters the stratum corneum (logPoW > 4), from where it is absorbed at low to moderate speeds based on a water solubility between 1 and 100mg/L. It must however be considered that the substance is highly corrosive. Dermal uptake will be enhanced after the skin is damaged.

In summary, absorbtion can occur via the GI tract and inhalation, and after dermal exposure.

Metabolism and excretion

Fowler and coworkers (1976) showed that aliphatic amines including Tridecylamine injected into mice tended to concentrate in lung tissue. Lung uptake of Tridecylamine at 1 minute after injection was ca. 13.5% of the administered dose. The authors reported that the amino group and a relatively lipophilic alkyl group were required for lung specificity. It was also shown that the radiolabeled amines were rapidly metabolized. Tridecylamine had the longest carbon chain of the tested series of amines. Liberation of carbon dioxide from injected Tridecylamine was relatively slow. It was only ca. 14% of the injected dose at 20 min post injection. At the same time point CO2-excretion of the alkyl amines C4 to C10 amounted to more than 40% of the dose, and exceeded 50% in the case of C6 and C7 alkylamines. Pretreatment with inhibitors of Monoamine Oxidases (MAO) significantly increased the radioactivity retained by the brain, lungs, and liver. The rate of CO2-excretion depended on the carbon chain length.

It is assumed as a worst case from the limited analytical information in the study that the C13 chain was linear. The registered substance is an UVCB of C13 molecules with different degrees of branching. Aside from deamination and N-dealkylation, aliphatic chains can also be shortened in a step-wise process by C2 -units via mitochondrial beta-oxidation. This process is most efficient for linear molecules, but though side chains slow the reaction, they do not terminate it. Based on data on the isotridecanol used in the manufacturing process of the registered UVCB, metabolism is thought to occur and to eventually result in CO2 and urea, but it is thought to be slower than for a linear side chain.