Triisooctylamine

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Toxicokinetik analysis of Triisooctylamine (CAS 25549-16-0)

The test substance is an UVCB substance appearing as colorless clear liquid at room temperature with a molecular weight of 353.67 g/mol and a relative density of 0.816. The test substance has a melting point below -107 °C. A boiling point could not be determined due to limited stability. The substance is moderately soluble in water, as water solubility was determined to be 0.031 and 0.146 g/L at 20 °C with a loading rate of 1 g/L and 10 g/L, respectively. Partition coefficient (logPow) of the main constituent was estimated by QSAR calculation to be 10.13 and is thus too high for determination by experimental study. Vapor pressure of the substance was determined to be 0.000927 Pa at 20 °C. 

1.1 Absorption

Oral route

Bioavailability via oral route is strongly linked to physico-chemical properties of the substance (ECHA Guidance, 2008). Generally, oral absorption is favored for molecular weights below 500 g/mol and with a logPow in the range of -1 to 4. Thus, with an estimated logPow of 10 and a molecular weight of 353.67 g/mol, the substance is expected to be not readily absorbed. Furthermore, the substance is only moderately soluble in water. Based on its structure, the substance is not expected to undergo hydrolysis (please refer also to IUCLID Section 5.1.2.). Taken together, the physico-chemical properties of the substance indicate that intestinal absorption might not be favored but cannot be ruled out completely. Therefore, the test substance is expected to be absorbed to a small extend, even though not readily.

The above considerations are confirmed by findings of toxicity studies with the test substance. Experimental toxicity data indicate that the substance induces toxicity in rats when applied via the oral route, giving clear indication that the substance is absorbed in the GI tract. In an acute oral toxicity study with rats, mortality was observed at 2000 mg/kg bw. LD50 was determined to be > 300 and < 2000 mg/kg bw. A combined repeated dose toxicity study with the reproduction/developmental toxicity screening test together with an additional 28 days repeated dose toxicity study in male rats also revealed signs of toxicity resulting in a NOAEL of 10 mg/kg bw/d. These observations give clear indication that the substance has been absorbed in the GI tract despite its not favorable physico-chemical properties.

Dermal route

Regarding dermal application, physico-chemical properties of the test item indicate that it probably does not becomes readily bioavailable. According to ECHA guidance on toxicokinetics, there are no exclusion criteria for skin permeability (ECHA, 2017). However, a molecular weight of > 500 Da and a log Pow of > 4 are given as indicators for low absorption (10% or less). Considering the calculated log Pow of 10, the latter criteria is fulfilled by the test item. The molecular weight of 353.67 g/mol, however, could still support dermal absorption. The same applies for water solubility which favors a low to moderate dermal absorption being between ca. 30 and 150 mg/L.
Based on the findings of an acute dermal toxicity study no signs toxicity were observed when the limit dose of 2000 mg/kg bw was applied to rat skin. Even though local effects of skin irritation were observed (classified as skin irritant cat. 2), no signs of systemic toxicity were recorded as observed in the acute oral toxicity study at doses as low as 300 mg/kg. This supports the assumption that the substance becomes bioavailable to a less extent via the dermal route. However, the substance has been identified as skin sensitizer indicating that at least some dermal uptake takes place. This is probably accomplished by tissue damage due to irritating properties of the test item.

Inhalation route

Due to a very low vapor pressure of 0,000927 Pa it is very unlikely that the substance is available as a vapor. Boiling point of the substance could not be determined due to technical reasons of limited stability. Therefore, regarding inhalation, exposure is not relevant since the substance is a non-volatile liquid. However, in the case of inhalation the substance is expected to not easily pass biological membranes of the respiratory tract based on the same indications as outlined above.

1.3 Distribution

As mentioned before, only moderate bioavailability is expected for the test item. When absorbed, distribution is expected to occur rather via plasma protein binding based on moderate water solubility and high logPow of the substance. Furthermore, the substance is not expected to bioaccumulate as indicated by several QSAR calculations.

1.4 Metabolism

Considering the chemical structure of the test item, enzymatic transformation would be plausible. Non-enzymatic hydrolysis and/or oxidation are not expected.

Tertiary amines are metabolised primarily by cytochrome P450 enzymes to alpha-C oxidation or N-Oxidation (Rose & Castagnoli, 1983). N-oxides that may be formed are probably further inactivated by reducing enzymes and anti-oxidizing substrates such as glutathione (GSH). Further, N-Acetyltransferases (NATs) may accomplish acetylation of the primary amine function which will not necessarily increase hydrophilicity but masks the amine function. The branched or linear carbon chain may be oxidized by phase I metabolising enzymes. The resulting carbon acid chains may be further degraded by endogenous fatty acid beta-oxidation pathway.

In vitro test systems applying exogenous metabolic activation systems (S9 mix), such as the HPRT assay, revealed an increased cytotoxicity of the test item to mammalian cells when S9 was not added compared to the runs where S9 was applied. This indicates that a metabolic deactivation of the test item takes place in vitro and probably also in vivo.

Oxidative metabolism occurs most prominently in the liver which is in line with the adaptive liver weight increase observed in female rats at the highest dose tested in the respective repeated dose toxicity study.

1.5 Elimination

Based on its molecular weight, the test item is expected to be elimination predominantly via the kidney. Further, metabolic transformation should in general lead to an increased hydrophilicity and thus support excretion via urine. The hydrocarbon chains are integrated and transformed in the endogenous pathways of energy metabolism and eliminated, accordingly.

2. Summary

Based on its physicochemical properties, particularly moderate water solubility, high logPow and molecular weight, absorption via the gastrointestinal tract is not favored for the test item. However, toxicity studies in vivo give clear indication that the test item becomes bioavailable via the oral route. In contrast, uptake of relevant amounts following dermal exposure is considered to take place to very less extent. This is supported by the lack of findings in an acute dermal toxicity study. Based on its very low vapor pressure it is highly unlikely that the test item will be available via the inhalation route. The test item is probably distributed by plasma protein binding due to its low water solubility. Bioaccumulation is not expected. The test item is not considered to undergo relevant abiotic transformation. However, metabolic transformation and inactivation of the test item is indicated by findings of in vitro tests and therefore anticipated. Degradation products are probably recycled in the endogenous metabolic pathway and or eliminated via the urine.

 

References

ECHA Guidance on Information requirements and Chemical Safety Assessment, Chapter R 7c Endpoint specific guidance Version 3.0, 2017

Rose, J. and Castagnoli N, Jr. “The metabolism of tertiary amines”. Med. Res. Rev., 1983 Jan-Mar, 3 (1):73-88