1-(N,N-bis(2-ethylhexyl)aminomethyl)-1,2,4-triazole

Endpoint summary

Description of key information

Toxicokinetic assessment

The test substance is a colorless to yellow liquid with a vapor pressure of 0.0071 Pa at 25°C (Ciba-Geigy, 1986). It decomposes at temperatures higher than 220°C before it reaches the boiling point (Ciba-Geigy, 1986). It is soluble in organic solvents (>400g /100 g fat, Ciba-Geigy, 1985) with a low solubility in water (58 mg/l, Ciba-Geigy, 1985). The log Pow was calculated to be 5.3 (Ciba-Geigy, 1985).

 

In acute and repeated dose toxicity studies (Ciba-Geigy, 1985; CIT, 1986), the dominant effect observed was local irritation, due to the corrosive nature of the test substance. As a result, no conclusion on systemic availability can be derived. However, in a guinea pig maximization test (Ciba-Geigy 1985), the test substance has demonstrated strong skin sensitization potential; therefore absorption through skin followed by systemic availability is expected.

 

The results of the Hydrolysis study (Ciba, 2009) could show that the test item hydrolyzes rapidly in water. The proposed degradation products are bis(2-ethylhexyl)amine, 1H-1,2,4-triazole and formaldehyde. The study included two sets of experiments: In the first experiment, investigation by LC/MS showed one sharp peak which is identical with a degradation product of the test item. This proves that the test item hydrolysis almost instantly, when it comes into contact with the aqueous eluent of the HPLC. In the second experiment, investigation by H-NMR showed that solutions of the test item are stable in pure acetonitrile for at least 20 hours. Immediately after addition of water the degradation products of the test item occurred. These experiments demonstrated that hydrolysis of test item, even with small amounts of water, is very fast.

 

Therefore, rapid hydrolysis can be expected upon oral ingestion. After dermal exposure, minimal amounts of sweat will cause fast hydrolysis of the test substance as well, however the corrosive properties will still be the most dominant effects after dermal exposure. In regard to this fast hydrolysis, the resulting degradation products are discussed in the following paragraph.

 

Bis(2-ethylhexyl)amine is a liquid with similar chemical properties as the test substance (vapor pressure of 0.013 hPa, low solubility in water, log Pow of 6.75; GESTIS, BASF 1989). Bis(2-ethylhexyl)amine is also corrosive and the findings reported in acute toxicity studies are caused by the corrosive potential of the test item (BASF, 1967 and 1991). Due to the lipophilic nature of the compound, it may be taken up by micellular solubilisation (ECHA guidance document 7c, 2008). Because of the low vapor pressure bioavailability of Bis(2-ethylhexyl)amine after inhalative administration is of less importance. If not excreted unchanged, secondary amines like bis(2-ethylhexyl)amine could be N-dealkylated and also N-oxygenated with oxidative N-dealkylation as predominant process which lead to aldehydes as products (Mayer R.T., 2007; Seto J., 1993; Yamada H., 1997). Due to its molecular weight, as well as its vapor pressure, bis(2-ethylhexyl)amine is expected to be excreted predominantly via the urine (ECHA guidance document 7c, 2008).

 

1H-1,2,4-Triazole is a powder which is well soluble in water (1-10 g/L) and a Log Pow between – 0.5 and -1. In a 90 day toxicity effects on organs were observed, indicating systemic availability of the test substance. This was confirmed in a toxickokinetic study performed with rats. The applied radioactivity was evenly distributed by the circulation to all tissues. All tissue concentrations were similar and did not indicate any tissue preference. This pattern was stable and did not change until complete excretion. The analysis showed a nearly complete renal elimination of radioactivity in the rat. About 3-4% of the applied dose was excreted with the feces. The renal elimination occurred fast, the plasma half-life was about 12 hours and was independent of the dose applied. Experiments with animals surgically treated with a bile duct-duodenal fistula (cholangiostomy) showed that 15-20% of the applied dose was subjected to enterohepatic circulation. Based on these results1H-1,2,4-Triazole does not have bioaccumulation potential (data taken from ECHA homepage).

 

Formaldehyde is absorbed after inhalation and deposited in the upper respiratory tract, the site of first contact. The localization of uptake in each species is determined by nasal anatomy, mucus coating and clearance mechanisms. The overall uptake by the nasal passages at resting airflow rates has been predicted to be 90% in rats, 67% in monkeys, and 76% in humans (BfR, 2006; summary reviews). The physiological level of formaldehyde in the blood of humans and experimental animals is not increased after inhalation exposure due to its rapid oxidation to formic acid and reactivity at the site of first contact. After oral exposure formaldehyde is rapidly and nearly completely absorbed from the intestinal tract of rats and mice. After dermal application to rats and guinea pigs ca. 40% of the applied formaldehyde is absorbed via the skin and in monkeys about 15%.

Formaldehyde reacts spontaneously and non-enzymatically with glutathione to form S-hydroxymethylglutathione. In the presence of NAD+, S-hydroxymethylglutathione can be converted to formylglutathione catalysed by formaldehyde dehydrogenase (FAD). In the presence of water, formylglutathione can be cleaved by S-formylglutathione hydrolase to glutathione and formic acid. Formic acid can be excreted as its sodium salt via urine or oxidized to CO2 and exhaled. As formate an uptake into the carbon-1-metabolic pathway is also possible (BfR 2006, OECD 2004, summary reviews).

In inhalation studies in rats using 14C-labelled formaldehyde 40% of applied radioactivity was excreted within the following 70 hours via exhalation, 17% via urine and 5% via feces. Oral studies have shown that ca. 60% of the applied radioactivity was exhaled as CO2 within 12 h after gavage and minor amounts via urine and feces (IARC, 2006).

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential