Amines, polyethylenepoly-, triethylenetetramine fraction

Endpoint summary

Description of key information

Amines, polyethylenepoly-, triethylenetetramine fraction (TETA) is considered to have an oral absorption of 20%, dermal absorption is possible, but maybe limited due to the fact that TETA is not sufficiently lipophilic to cross the stratum corneum and if inhaled at all inhalation absorption will take place. TETA will be metabolised mainly via acetylation after absorption and is considered to have a low bioaccumulation potential. Distribution in all tissues is was observed. Excretion of TETA and the metabolites is expected to be via urine.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

20

Additional information

There are no studies available in which the toxicokinetic behaviour of Amines, polyethylenepoly-, triethylenetetramine fraction (TETA, CAS 90640-67-8) has been investigated.

Therefore, in accordance with Annex VIII, Column 1, Section 8.8.1, of Regulation (EC) No 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017), assessment of the toxicokinetic behaviour of TETA (CAS 90640-67-8) is conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the available substance specific data on physico-chemical and toxicological properties according to Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017).

Furthermore, information from TETA salts TETA.2HCl (CAS 38260-01-4) and TETA.4HCl (CAS 4961-40-4) is also taken into account because TETA salts share the same main constituent with TETA but in form of an ammonium salt.

TETA is a liquid at room temperature with a molecular weight range of 146 - 172 g/mol and a water solubility of > 1000 g/L. The log Pow value ranges from -2.9 to -2.08 and the vapour pressure is 0.346 Pa at 20°C.

 

Absorption

Absorption is a function of the potential for 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, 2017).

 

Oral

In general, molecular weights below 500 and log Pow values between -1 and 4 are favourable for absorption via the gastrointestinal (GI) tract, provided that the substance is sufficiently water soluble (> 1 mg/L). One consideration that could influence the absorption of ionic substances (i.e. acids and bases) is the varying pH of the GI tract. It is generally thought that ionized substances do not readily diffuse across biological membranes. Therefore, when assessing the potential for an acid or base to be absorbed, knowledge of its pKa (pH at which 50% of the substance is in ionised and 50% in non-ionised form) is advantageous. Absorption of acids is favoured at pHs below their pKa whereas absorption of bases is favoured at pHs above their pKa (ECHA, 2017).

The high water solubility (>1000 g/L) and the low log Pow value of -2.9 to -2.08 of the compound indicate that absorption is likely by the ability to dissolve into GI fluids. Further, the pKa for TETA was measured to be 9.59 and 6.47. However, the experimental titration curves obtained in this study are consistent with a complex ionisation profile that would be expected for this type of molecule, indicating that protonation takes place over a wide pH range, starting at approximately pH 11 (unprotonated) and finishing at <pH2 (fully protonated). It is therefore not possible to identify specific dissociation constants. Thus, in consideration of the structure of the compound which includes ionisable groups (amines) absorption following oral administration is possible.

Studies on acute oral toxicity with TETA showed signs of systemic toxicity and mortality resulting in a LD50 value of 1716.2 mg/kg bw in rats (Pharmakon, 1992), indicating that some absorption has occurred.

A metabolism study with the TETA salt triethylenetetramine tetrahydrochloride (TETA.4 HCl, CAS 4961-40-4) is available which is used in the treatment of Wilson’s disease. Using 14-carbon labelled TETA.4HCl given to rats indicate that only some 20% of the drug is absorbed from the gut (Gibbs, 1986).

Further toxicokinetic studies with the TETA salt triethylenetetramine dihydrochloride (TETA.2HCl, CAS 38260-01-4) are available. The 8-hour TETA.2HCl excretion by 2 human volunteers was only 1.6 and 1.7%, respectively, of the administered dose. Further analysis of the urine suggest that orally administered TETA.2HCl in human is absorbed through the digestive tract, but that most of it is readily converted into a metabolite which loses its ability to chelate copper (Kodoma, 1993). TETA.2HCl itsself is a copper-chelating agent and is therefore a therapeutic drug for Wilson's disease. This was supported by Kobayashi (1990) showing that the bioavailability of TETA.2HCl in rat was below 10% and the plasma levels of TETA.2HCl in non-fasted rats were significantly lower than that observed in fasted rats. Similar results were observed in a further study, where bioavailability of 25.5% in rats in a fasting state and 14.0% in rats not in a fasting state was reported (Takeda, 1995). The main absorption route for TETA.2HCl might be permeation across the plasma membrane of intestinal epithelial cells, brush border membrane of rat small intestine (Kobayashi, 1990). The concentration of dosage solution and first pass metabolism in the intestinal wall may play an important role in the absorption of TETA.2HCl in humans as well as in rats (Takeda, 1995). Tanabe (1996a) showed that the predominant transport process of polyamines in rat intestinal brush-border membrane seemed to be passive diffusion which is dependent on the electrostatic binding to the acidic phospholipids such as phosphatidylserine. The uptake of TETA.2HCl by rat intestinal brush-border membrane vesicle shares with polyamine a common transport mechanism which includes a charge-interaction between the polycation and the negative charge of the inner membrane layer. This mechanism provides an explanation for the poor and variable absorption of TETA.2HCl.

Overall, taking into account the physico-chemical properties of TETA and the available toxicological data on TETA it can be concluded that some oral absorption takes place. Taking into account the data on the TETA salts TETA.2HCl and TETA.4HCl a similar low oral absorption of at most 20% can be assumed.

 

Dermal

There are no data available on dermal absorption of TETA. On the basis of the following considerations, the dermal absorption of TETA is considered to be low.

To partition from the stratum corneum into the epidermis, a substance must be sufficiently soluble in water. Thus, with a high water solubility between 100 and 10000 mg/L, dermal uptake of a substance is anticipated to be moderate to high. However, if water solubility is above 10,000 mg/l and the log P value below 0 the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum. Especially log Pow values <–1 suggest that a substance is not likely to be sufficiently lipophilic to cross the stratum corneum, therefore dermal absorption is likely to be low (ECHA, 2017). TETA has a high water solubility of > 1000 g/L, however a log Pow below -1 anticipating a low dermal absorption.

The dermal permeability coefficient (Kp) can be calculated from log Pow and molecular weight (MW) applying the following equation described in US EPA (2014):

log(Kp) = -2.80 + 0.66 log Pow – 0.0056 MW

The Kp was calculated for TETA. QSAR calculations revealed dermal flux rates ranging from 2.93 - 7.29 µg/cm²/h indicating a medium high dermal absorption potential for the compound.

A study with TETA (CAS 90640-67-8) and further ethylene amines, on carcinogenicity (Guzzie, 1982), states “Although no skin penetration studies were performed with these ethylene amines, such studies were performed in the rat with ethylene diamine (EDA). The results indicated that the rate of absorption was concentration dependent and relatively slow following topical application. The estimated absorption was 55 and 12% respectively, when 25 and 10% aqueous solutions were applied for 24 hr. Because of the higher weights and greater number of potentially positively charged amino groups of these ethylene amines compared to EDA, it is likely that there was very limited systemic circulation of the compounds in these studies. This would be consistent with the absence of systemic toxic effects”.

Overall, taking into account the physico-chemical properties of TETA and the QSAR calculations, the dermal absorption of the substance is possible, as TETA is also classified as corrosive. Therefore, damage to the skin surface may enhance penetration. This is observed in dermal acute toxicity studies. TETA resulted in necrosis of the skin at application sites and caused severe systemic effects e.g. mortality (Pharmakon, 1993). However, dermal absorption could also be limited due to the fact that substances with log Pow values <–1 are not likely to be sufficiently lipophilic to cross the stratum corneum.

 

Inhalation

Inhalation exposure of TETA is considered to be low since the test substance is a liquid with a low vapour pressure (0.346 Pa at 20°C) (ECHA, 2017). Generally, liquids, would readily diffuse/dissolve into the mucus lining of the respiratory tract. Very hydrophilic substances might be absorbed through aqueous pores (for substances with molecular weights below around 200 g/mol) or be retained in the mucus and transported out of the respiratory tract (ECHA 2017).

Based on the physical state and the physico-chemical properties of TETA, absorption via the lung is expected.

 

Distribution and accumulation potential

No data were found regarding the distribution of TETA. 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. Small water-soluble molecules and ions will diffuse through aqueous channels and pores. The rate at which very hydrophilic molecules diffuse across membranes could limit their distribution (ECHA, 2017).

Thus, due to the small molecular weight (146 - 172 g/mol) and the hydrophilic character distribution within the body is possible. As TETA has a low log Pow (-2.9 to -2.08) and thus its hydrophilic character a bioaccumulation potential is not expected.

Some data are available with the TETA salts TETA.4HCl and TETA.2HCl. TETA.4HCl was detected in all tissues analysed (plasma, liver, spleen, kidneys, muscle and gut wall), with a maximum concentration in the kidneys, after oral treatment of rats. (Gibbs, 1986). A later study using14C radio-labeled trientine showed that TETA.2HCl could be found in most rat tissues, including cerebrum, cerebellum, hypophysis, eyeball, harderian gland, thyroid, submaxillary gland, lymphatic gland, thymus, heart, lung, liver, kidney, adrenal, spleen, pancreas, fat, brown fat, muscle, skin, bone marrow, testis, epididymis, prostate gland, stomach, small intestine, and large intestine (Lu, 2010). However, concentrations in liver and kidney seemed to be much higher than those in plasma, and plasma concentrations were higher than those observed for other tissues. Apart from liver and kidney, other tissues did not accumulate significant amounts of TETA.2HCl after oral administration. In the analyses, it was observed that both the parent compound and metabolite(s) exist in all tissues (Lu, 2010). A later report confirmed such findings, showing that concentration ratios of liver/plasma and kidney/plasma were greater than 1, whereas brain, lung, spleen, and white fat have ratios lower than 1 (Lu, 2010). However, a study with beagle dogs showed that no significant accumulation of TETA.2HCl occurred during the dosing period (Maemura, 1998). It is proposed that TETA shares a common transport mechanism with polyamines in intestinal uptake. It is likely that TETA is also transported across biological membrane into mammalian cells by the same transporter for polyamines. The transporter of polyamines has been identified as glypican-1 (Lu, 2010). Inside cells, polyamines are further transported into mitochondria, where polyamine concentrations can reach millimolar level, electrophoretically by a specific polyamine uniporter (Lu, 2010). It is therefore not surprising that TETA is widely distributed in the body and can be accumulated in the tissues.

In conclusion, based on the physicochemical properties and information on TETA salts a distribution in all tissues and a possible accumulation potential for TETA is expected.

 

Metabolism

No data with TETA are available regarding metabolism. Prediction of compound metabolism based on physicochemical data is very difficult. Structure information gives some but no certain clue on reactions occurring in vivo. The potential metabolites following enzymatic metabolism were predicted using the QSAR OECD toolbox (v4.2, OECD, 2017). This QSAR tool predicts which metabolites may result from enzymatic activity in the liver and in the skin, and by intestinal bacteria in the gastrointestinal tract. Taking into account all constituents of this multi constituent substance 14 hepatic and 16 dermal metabolites were predicted for TETA, respectively. Up to 39 metabolites were predicted to result from all kinds of microbiological metabolism for the test substance. Thus, metabolisation of TETA will take place.

Some data are available with the TETA salts TETA.4HCl and TETA.2HCl. Gibbs (1986) found no evidence that the TETA.4HCl is broken down in the body, but rather biotransformation does occur, probably by acetylation and possibly other forms of conjugation. The conjugates can all be converted back to TETA by acid hydrolysis. The urinary excretion of unchanged TETA.2HCl during 24 h was only 3.5% of the orally administered dose in rats. However, the urinary excretion of total TETA.2HCl including metabolites, which have not been identified, was 35.7%. These results suggest that low bioavailability of TETA might be due to the rapid metabolism in the body after absorption from the gastrointestinal tract (Kobayashi, 1990). The amount of TETA.2HCl in the urine of two adults was only 1.6 and 1.7% of the dose administered. However, a large unidentified peak appeared in the urine after oral administration. This peak was not observed in a mixture of TETA.2HCl and control urine or in urine before TETA.2HCl administration. When the urine after TETA.2HCl administration was analyzed after hydrolysis with HCl, the unidentified peak disappeared, while the TETA.2HCl peak increased. These findings indicate that the substance which yielded the unidentified peak is a metabolite of TETA.2HCl, suggesting that most of the TETA.2HCl administered is metabolised and then excreted in the urine (Kodoma, 1993). To date, two acetylated metabolites, N1-acetyltriethylenetetramine (MAT) and N1,N10-diacetyltriethylenetetramine (DAT), have been identified in humans (Lu, 2010).

 

Excretion

The major routes of excretion for substances from the systemic circulation are the urine and/or the faeces (via bile and directly from the GI mucosa). Only limited conclusions on excretion of a compound can be drawn based on physicochemical data. Low molecular weight (below 300 g/mol in rat), good water solubility, and ionization of the molecule at the pH of urine are characteristics favourable for urinary excretion. Due to metabolic changes, the finally excreted compound may have few or none of the physicochemical properties of the parent compound. Thus, based on the available data it can be assumed that TETA and its metabolites are mainly excreted via urine.

Some data are available with the TETA salts TETA.4HCl and TETA.2HCl. TETA.4HCl is rapidly excreted in the urine and more slowly in the bile (Gibbs, 1986). Kobayashi (1990) observed that the urinary excretion of total TETA.2HCl including metabolites was 35.7%. The amount of TETA.2HCl in the urine of two adults was only 1.6 and 1.7% of the dose administered. However, a large unidentified peak appeared in the urine after oral administration as described above under “Metabolism”. These findings indicate that the substance which yielded the unidentified peak is a metabolite of TETA.2HCl, suggesting that most of the TETA.2HCl administered is metabolized and then excreted in the urine (Kodoma, 1993).

In conclusion, TETA and its metabolites are assumed to be excreted mainly via urine.

 

 

References

ECHA (2017): Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance. Version 3.0, June 2017

Lu (2010): Triethylenetetramine Pharmacology and Its Clinical Applications, Molecular Cancer Therapeutics 9 (9), September 2010, pp. 2458 - 2467.