Reaction mass of trientine and trientine, mono- and di-propoxylated

Endpoint summary

Description of key information

Reaction mass of trientine and trientine, mono- and di-propoxylated is a multiconstituent substance (cas# 26950-63-0) containing differing forms of triethlenetetramine (TETA).  Due to the use of triethlenetetramine (TETA) in pharmacology there is considered to be sufficient understanding of the toxicokinetics, metabolism and distribution of TETA and therefore additional testing is considered unnecessary.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

40

Absorption rate - dermal (%):

20

Absorption rate - inhalation (%):

80

Additional information

Reaction mass of trientine and trientine, mono- and di-propoxylated is a multiconstituent substance (cas# 26950-63-0) containing differing forms of triethlenetetramine (TETA).

TETA is a polyamine like substance that forms strong ionic interactions, its configurational versatility and a large capacity to form hydrogen bonds lead to several crystalline structures Henriet et al (2015). TETA has been used in pharmacology for decades in particular as a Cu²⁺-selective chelator commonly used as an alternative to D-penicillamine-copper chelate in the treatment of Wilsons disease Kodama et al (1993). The drug is approved by the FDA and may be taken orally in maximum adult daily doses of 30 mg/kg, taken in two to four divided portions Greenman et al (1996). Recently, it has been identified that TETA can be used in the treatment of cancer because it possesses telomerase inhibiting and anti-angiogenesis properties and in addition it was shown that TETA could ameliorate left ventricular hypertrophy in humans and rats with diabetes Lu (2010).

TETA is poorly absorbed with a bioavailability of 8 to 30% and due to the greater molecular size of the propoxylated and diproxylated forms it is anticipated that bioavailability will be further reduced. Following administration TETA is widely distributed in tissues with relatively high levels measured in liver, heart and kidney. It is mainly metabolised via acetylation, and two major acetylated metabolites exist in human serum and urine. It is mainly excreted in urine as the unchanged parent and two acetylated metabolites. TETA has a relatively short half-life of 2-4 hours in humans.

The most recent discoveries in TETA pharmacology show that major pharmacokinetic parameters are not associated with the acetylation phenotype of N-acetyltransferase 2 which is traditionally considered the drug acetylation enzyme. The TETA-metabolising enzyme is actually thought to be spermidine/spermine acetyltransferase.

Studies in rat and dog studies have identified that TETA has a relatively slow and incomplete intestinal absorption. The T_maxfor rats, dogs and rabbits after oral TETA administration is 0.5 to 2.0 hours. The intestinal absorption rate in normal male Wistar rats has been reported to be 42% in the jejunum and 22.5% in the ileum using an in-situ loop method Kobayashi et al (1990). The intitial uptake of TETA has a K_mvalue of 1.1 mmol/L which is larger than that observed for spermine and spermadine, both of which can inhibit the uptake rate of TETA in a dose dependent manner. In humans, the absorption rate of the gut following oral TETA administration is also relatively slow (T_maxbetween 0.8 to 4 hours) and there is some evidence to suggest that food intake inhibits absorption Le (2010) and Nakano et al (2002).

In rats and humans TETA is extensively metabolised mainly via urine or bile excretion (minimal),in-vitro experiments have identified that about 50% of TETA was eliminated from the S9 liver fraction system after 2 hours of incubation Iseki et al (1992). One in-vivo study in rats showed that only 3.1% of an orally administered dose of TETA was measured in a 24-hour urine collection as the unchanged parent compound and metabolites accounted for 32.6%. Two acetylated metabolites have been identified N₁-acetyltriethylenetetramine and N₁,N₁₀diacetyltriethylenetetramine. In humans, unchanged TETA and a number of metabolites have been found in urine, two major metabolites (MAT and DAT) are both acetylation products of the parent compound. As TETA is a structural analogue of spermidine/spermine acetyltransferase (SSAT) it is reasonable to assume that SSAT may be the enzyme responsible for the two TETA acetylation metabolites.

The renal clearance of TETA in rat is about 30% higher than creatine clearance, which indicates that TETA is actively excreted from the renal tubule into urine Kobayashi et al. (1997). It has been identified that the Na⁺/spermine antiporter in the rat renal tubule brush-border membrane is responsible for active secretion of spermine, TETA and any other straight-chain polyamine compounds with more than four amino groups Kobayashi et al. (1999) (i.e; propoxylated and dipropoxylated forms) . In general, dermal absorption will not be higher than oral absorption, no default factor is introduced for the oral to dermal extrapolation. The REACH Guidance on information requirements and chemical safety assessment (R.8.4.2) prescribes a default factor of 1 in case of oral to dermal extrapolation. Based on the log Kow of -2.42 and molecular weight of the substance (mean Mw 209), the skin permeability according to Fitzpatrick et al (2004) of the substance is considered to be marginally permeable to the skin. Therefore, a ratio of 0.5 for oral to dermal absorption is provisonally suggested for DNEL derivation. Details of the calculation are presented below;

Skin permeability according to Fitzpatrick et al. (2004)		Values
Chemical name		TETA PO
Molecular weight of chemical	Mw	209
Logarithm octanol/water partition coefficient	logKow	-2.42
Logarithm skin permeation coefficient	logKp	-6.40795
Interpretation:		marginally permeable
Interpretation
< -10	non-permeable
< -06 >= -10	marginally permeable
< -03 >= -06	slightly permeable
< -01 >= -03	moderately permeable
> = -01	permeable