Tripropylamine

Endpoint summary

Description of key information

Tripropylamine is expected to be absorbed well after oral exposure, based on its low molecular weight, its water solubility and its LogPow of 0.9. Concerning the absorption after exposure via inhalation, as the chemical has high vapour pressure, it is clear, that the substance is well available for inhalation. Given its lipophilicity (LogPow 0.9) - if absorbed - it is expected to be absorbed directly across the respiratory tract epithelium or through aqueous pores and/or be metabolized by the alveolar and bronchial tissue. Tripropylamine is expected to be also absorbed following dermal exposure into the stratum corneum and into the epidermis, due to its molecular weight and its LogPow. Corrosive properties of tripropylamine due to its charged form (free base) can, however, affect the absorption, slowing the passage through biological membranes. Concerning distribution in the body, tripropylamine is expected to be distributed into the cells and into the intravascular compartment. The substance does not indicate a significant potential for accumulation. Tripropylamine is expected to be metabolised mainly via Cytochrome P450s by oxidases and oxygenases leading to N-oxide and/or hydroxylated derivatives with subsequent dealkylation products involved into intermediary metabolism. Tripropylamine and its metabolites will be eliminated mainly via urine. 

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

General

The toxicokinetic profile of tripropylamine (TnPA) was not determined by actual absorption, distribution, metabolism or excretion measurements. Rather, the physico-chemical properties of this substance were integrated with the available toxicological data on the read-across substances trimethylamine (TMA), triethylamine (TEA) and tributylamine (TBA) to create a prediction of the toxicokinetic behaviour of TnPA. The read-across tertiary amines show very similar physico-chemical properties (high water solubility, similar LogPow, no hydrolysis in water) and are thus believed to behave very similar in aqueous solutions.

Toxicological profile of Tripropylamine

 

Tripropylamine is acutely toxic via all exposure routes. An oral LD50 of 72.5 mg/kg bw, dermal LD50 of 430 mg/kg bw and an inhalation LC50 of 4500 mg/m³ (1-hour) were established in animal studies with rats (Smyth et al., 1969; Biosearch, 1975). The substance is corrosive to skin and highly irritating to eyes and respiratory tract (Smyth et al., 1969; Gagnaire et al., 1989). Since the nearest analogues TEA and TBA are not sensitisers, no skin sensitisation is expected for tripropylamine. TnPA was not mutagenic in any of the bacterial strains (Ames Test), and in mammalian cells (Mouse Lymphoma Assay conducted with cell line L5178Y) (Lawlor, 1996; Lloyd, 2012). No chromosome aberrations were detected in human lymphocytes (Watters, 2012). Corrosion/irritation is a primary effect of tripropylamine and, in analogy to other alkylamines, the effects by prolonged exposures are expected to be confined to local effects and no systemic toxicity could be reached. TMA and TBA were not toxic to reproduction in animal studies (Takashima et al., 2003; Mitterer, 1991).

 

Toxicokinetic data on structurally similar analogues TEA and TBA

TEA:

Akesson and co-workers investigated the fate of TEA in humans (Akesson et al., 1988). Triethylamine, is readily absorbed when inhaled (about 80%, as a result of dead space 20% are not absorbed). The plasma concentration increased during 4 to 8 hours following the intake of TEA, indicating that no saturation took place during the inhalation of 10 and 20 mg/m³. One hour after the end of exposure the plasma TEA concentration decreased in all experiments. The major part is excreted unchanged via the urine. In part TEA is metabolized (24 %) to triethylamine-N-oxide, which could be detected in the plasma and is then also excreted via the urine. The amount of TEA and TEAO excreted via urine corresponds to an average of 97%. During exposure the urinary TEA-level continuously increased in all experiments. After the end of exposure the elimination rapidly took place (half life 3.2 hours). The amount of urinary TEA and TEAO corresponds to an average of 97%. So elimination is mainly conducted via the urine and only a minor excretion occurred via exhalation. Moreover, the detection limit was not reached in the urine samples within the time period monitored, so elimination clearly occurred slowly. Additionally visual disturbances occurred in one subject exposed to an air level of TEA of 53 mg/m³ for four hours, in two subjects exposed to an air level of 35 mg/m³, and in four of five subjects exposed to 20 mg/m³ for eight hours.
The urinary determination is a possibility for biological monitoring concerning TEA exposure. But considering the extreme water solubility of the compound, it is probable that the absorption is proportional to ventilation. At moderately heavy work (ventilation 10 cm³/8h), an Air-TEA of 40 mg/ m³ would then correspond to a U-TEA of 320 mmol/ mol creatinine. Data on visual disturbances presented in this article and in previous publications (cited in Akkesson et al., 1988), however, indicate that 40 mg/m³ is too high a TLV; 10 mg/m³ would be more reasonable. This would correspond to an average U-TEA of about 40 mmol/mol creatinine in a resting worker and 80 mmol/mol creatinine in moderately heavy industrial work.

 

Another study was carried out in a polyurethane foam-producing plant, where 20 workers were exposed to TEA (Akesson et al., 1989a). The workers inhaled an average of approximately 500 µmol triethylamine per day; approximately 53% of the dose was excreted in urine as unchanged triethylamine and approximately 27% was excreted as TEAO during a 24 -hour period. There the above mentioned results were reproduced, and moreover the information was obtained that the excretion was not complete even next morning, so there seems to exist a slight tendency of accumulation during the work week. However, over the weekend, the body should be completely cleared of the agent. Additionally, they found no statistically significant differences between man and women concerning the half-life of TEA (means 3.0 vs. 2.7) and they noted an increasing fractional excretion of TEAO with rising age. They investigated also the metabolic fate of TEA and proved that TEA is not metabolized in vivo to DEA (less than 0.3 %) (Akesson et al., 1989a).

 

The same working group (Akesson et al., 1989b) investigated the fate of TEA after intravenous and oral administration and could reproduce many of the abovementioned results. After iv. administration at least 90 - 97 % could be found in the urine, also after oral administration the bioavailability was almost complete. The distribution of TEA was rapid in both cases and the apparent volume of distribution (Vz) after oral administration was about 3 to 4 times the body water content. The mean maximal plasma concentration was 1.17µmol/L and was reached 45 min – 1 hour after exposure. Triethylamine-N-Oxide was also identified in the plasma (Cmax =0.75 µmol/L) for a short period of distribution, then plasma concentrations and urinary excretion decreased to a constant rate. The apparent volume of distribution (Vz) during the terminal elimination phase (V) calculated for TEA after the i.v. dose was 192 L, and after oral doses, 196 L (range 180-208 L, assuming 100% bioavailability). No significant first pass metabolism occurred. The high renal clearance values for both TEA and TEAO indicate that they are excreted into the urine not only by glomerular filtration but also by tubular secretion. Renal clearance, A/AUC, for TEA averaged 27.9 L/hour and for TEA0 22.5 L/hour. Additionally they could show that TEA was excreted into the gastric juice (about 30 times the level in plasma). As TEA was absorbed efficiently from the GI tract after ingestion, there was probably an almost total reabsorption of TEA, and thus a gastroenteric circulation.

 

In summary, TEA has a bioavailability of nearly 100 % and is widely distributed throughout the body. In humans, following exposure to triethylamine via inhalation, ingestion, or i.v. injection, triethylamine was excreted in urine largely unchanged, to a lesser extent as triethylamine-oxide (TEAO) (about 27%) and, in trace amounts, as diethylamine.DEA is suspected to be nitrosated endogenously into N-nitrosodiethylamine (NNDE), which is carcinogenic (IARC, 1978; cited in Akesson et al., 1989a). The average plasma and urine half-life for triethylamine was 3 to 4 hours. There were indications of considerable interindividual variation in the metabolism of TEA. Neither first pass effect nor a significant excretion via exhalation was found.

 

TBA:

Two studies are available on the toxicokinetics and the metabolism of tributylamine.In a study, Wistar rats were given a single oral dose of 50 mg radiolabeled tributylamine hydrochloride/kg body weight (Jantz et al., 1990a). The oral absorption was complete. Maximum blood levels were determined in males within 4-8 h post application, in females within 4-6 hours after dosing. The elimination of the blood was biphasic with half lives of 5.0 and 65.4 hours in females and 6.6 and 69.8 hours in males, respectively. 27.8% of the administered dose was found in the expired air within 48 hours, 69.4 % in the urine and 3.7 % in the faeces within 7 days (only male animals tested). The excretion was biphasic with half lives of 4.6 and 42.3 in urine and 6.4 h and 48.9 hours in faeces, respectively. The highest concentrations of radioactivity were found in urinary bladder (0.73 µg equivalents/g), followed by retroperitoneal fat (0.61 µg equivalents/g), liver (0.48 µg equivalents/g), subcutaneous fat (0.46 µg equivalents/g), bones (0.43 µg equivalents/g) and lung (0.40 µg equivalents/g). The kidneys, brain, pancreas, gonads, and heart contained 0.4 -0.2 µg equivalents/g, stomach, skeletal muscle and smooth muscle few below 0.2 µg equivalents/g and the other tissues were at or below detection limit. 0.51 % was retained in the examined organs 1 week post application, the highest amount (0.2 %) was observed in the skeletal muscle. According to the authors these slight differences between the contents of organs indicate the metabolism of the test substance to endogenous substances, which are incorporated into the organism. The recovery of excreted material and radioactivity in the organs was complete.

In summary, Wistar rats received orally 50 mg TBA-HCl/kg bw. The substance contained a radiolabel: [14]C: Butyl*-N-(butyl) 2. The substance was rapidly absorbed, metabolised, and excreted. Excretion was complete, and only a small percentage of the administered dose remained in the carcass.

In a second study (Jantz et al., 1990b) the urinary metabolites from the above experiment were characterised. The unchanged test substance and the identified urinary metabolites accounted for approx. 86 % of the total radioactivity in urine. The unchanged test substance accounted for 10%; chain hydroxylation for 60%; and deamination to Di-n-butylamine derivatives for approx. 33% of the administered dose. 14% were unidentified.

It is concluded that deamination is not the sole metabolic pathway, but the secondary amine is formed to approx. 33% from the tertiary amine which justifies a vertical read across between the tertiary amine and the respective secondary amine. Further, C-hydroxylation is a major pathway fur tri-n-butylamine. This is also expected to hold true for more lipophilic substituents with larger chain length.

Tributylamine is caustic and no information is available on dermal absorption

 

Toxicokinetic analysis of Tripropylamine

Tripropylamine is a colourless liquid with ammonia-like smell (MW 143.27 g/mol) at 20°C. The substance is soluble in water (444 mg/L at 20°C) and has a LogPow of 0.9. It has a high vapour pressure of 430 Pa and melts at -93°C under atmospheric conditions. Tripropylamine is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyse under environmental conditions.

Absorption

Oral absorption is favoured for small water-soluble molecules with MW up to 200 which can pass through aqueous pores or can be carried with the bulk passage of water (TGD, Part I, Appendix IV, 2003). Based on the molecular weight of 143.27, the high water solubility and the moderate logPow value, TPA is expected to be readily absorbed via the gastrointestinal (GI) tract by passive diffusion. This thesis is supported by the fact that the acute toxicity via oral route is quite high (Cat 3, toxic if swallowed; Smyth et al., 1969). Moreover, the read-across analogues substances TEA and TBA given orally were absorbed rapidly in humans and in animals (Akesson, 1989a; Jantz et al., 1990a). 100% oral absorption is considered appropriate based on absorption data of analogous tertiary amines and the physico-chemical properties which are in the range suggestive of absorption from the gastro-intestinal tract.

Based on the high vapour pressure of tripropylamine, exposure by inhalation is relevant for this substance. It is very likely, that considerable amounts of the substance reach the lung and when this occurs, the substance is expected to be absorbed directly across the respiratory tract epithelium or through aqueous pores due to the logPow of 0.9. This was confirmed in the human study, where absorption of respirable TEA from the alveolar region was rapid and complete (80%) (Akesson et al., 1988). Besides this, tripropylamine is irritating to the mucous membranes of eyes, nose, and throat; this can intensify the absorption. Based on these data, 100% absorption is considered for inhalation (worst case (due to read-across); according to the ECETOC Report No 110).

Similarly, based on the physico-chemical properties of tripropylamine, the substance is likely to penetrate the skin to a certain extent as the substance is sufficiently lipophilic to cross the stratum corneum (logPow of 0.9) and sufficiently soluble in water to partition from the stratum corneum into the epidermis (water solubility of 444 mg/L). Absorption through the skin is anticipated to be moderate to high if water solubility lies between 100-10,000 mg/L. In addition, the molecular weight of 143.27 g/mol indicates a moderate potential to penetrate the skin as well. This is supported by the findings of the acute dermal toxicity study where LD50 of 430 mg/kg bw for both sexes was established (Smyth et al., 1969). However, due to the fact that the corrosive property of the substance is primary effect, the established LD50 is probably based on local effects and a systemic effect cannot be reached. Thus, it is very likely that absorption of unchanged chemical through the skin will be hindered due to its charged form. Due to the absence of substance specific information on absorption rates through the skin, according to TGD, Part I (2003), 100% of dermal absorption is considered for tripropylamine.

 

Distribution and accumulative potential

Due to high absorption rates via all exposure routes, a significant amount of tripropylamine is expected to be available for distribution. As the cell membranes require a substance to be soluble in both water and lipids to be taken up, TnPA is expected to reach the inner cell compartment due to its optimal molecular weight of 143.27, its LogPow of 0.9 and a sufficiently high solubility in water (444 mg/L). The substance is also expected to distributed into the intravascular compartment As it is known that “substances with LogPow values of 3 or less would be unlikely to accumulate with the repeated intermittent exposure patterns normally encountered in the workplace” (TGD, Part 1), no enhanced risk for accumulation will be associated with the substance. The analogues substances TEA and TBA have a wide distribution throughout the body. However, due to their short half-lives (about 3 hours) in the body no bioaccumulation potential was considered.

 

Metabolism

In analogy to TEA, tripropylamine is expected to be oxidized by cytochrome P450 enzymes to the corresponding N-oxide (TPAO). Tripropylamine can also undergo oxygenation at the C atom by oxygenases (oxidative dealkylation) forming a hydroxylated metabolic products, like the mono-, dihydroxy- and monohydroxydesbutyl derivatives in case of TBA. Aldehydes originated from dealkylation can be involved into intermediary metabolism (β-oxidation). Dealkylated tripropylamine in the gastrointestinal tract can potentially re-enter the system and undergo subsequent oxidation or hydroxylation reactions.

 

Excretion

As tripropylamine is a stable compound and sufficiently soluble in water, it can be filtered by the kidneys and undergo primarily urinary excretion. While TEA was excreted mainly unchanged via the urine, the excretion of unchanged TBA was only 10% due to its lipophilicity. Therefore, the percentage of unchanged TPA is expected to be between those of TEA and TBA. Excretion via the urine is also a major pathway for the oxidised and/or hydroxylated derivatives of tripropylamine. Metabolites which re-enter the system are expected to occur in a lesser extent.