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Physicochemical Properties of 1,2,4-Triazole Relevant to Toxicokinetics

Molecular weight: 69.07 g/mol [1]

Water solubility: Appreciably soluble [2]

n-Octanol/water partition coefficient (Log Pow): -0.76 at 25°C (calculated) [3]

Vapour pressure: 2.15 x 10-4kPa at 20°C [4]

Dissociation constant (pKa):3 and 10 at 25°C (calculated) [3]

Toxicokinetic Assessment:

Considering the physicochemical properties of 1,2,4-triazole, [i.e.,low molecular weight (69.07 g/mol) and negative log Pow value (-0.76)], absorption of 1,2,4-triazole from various routes of exposure, such as oral, dermal or inhalation is expected. However, given the low vapour pressure of 2.15 x 10-4kPa at room temperature, exposureviainhalation of 1,2,4-triazole vapours is likely to be of low relevance. The absence of systemic effects in the acute inhalation studies in mice and rats [5] supports the conclusion that the substance is poorly absorbedviathe respiratory route.

The presence of systemic effects such as sedation, uncoordinated movements, and lateral and ventralrecumbencyfollowing acute oral or dermal exposures in rats or mice indicated that some absorptionviaoral and dermal routes must be occurring [6,7]. The nature of systemic effects observed in the aforementioned studies suggests that 1,2,4-triazolemay have transferred through the blood-brain barrier (BBB). Additionally, thetiming of the occurrence of these effects (within 1 hour following exposure) is also indicative of rapid absorptionviaeither route. Consistent with this assumption are the results of a toxicokinetic (TK) study in rats, which demonstrated a nearly complete renal elimination of radiolabeled 1,2,4-triazole administered orally (1 mg/kg), intravenously (i.v., 0.1 to 100 mg/kg), or intraduodenally (1 mg/kg) [8]. In a similar TK study in rats, more than 90% of the radiolabeled oral dose (10 mg/kg) was eliminated in the urine in the form of unchanged 1,2,4-triazole, within the first 8 hours after administration [9].


Taking into consideration the pKa values of 3 and 10.18 (at 25°C) for 1,2,4-triazole, it is expected that this compound becomes protonated in the low pH of the stomach, which hinders its absorption through this route. Conversely, in the high pH of the small intestine, the unionized form of the 1,2,4-triazole is expected to predominate, which is likely to favor its absorption through the intestinal portal.

In a prenatal developmental toxicity study, oral administration of 1,2,4-triazole to rats at dose levels of up to 30 mg/kg bw did not induce any treatment-related adverse effects in dams or foetuses. At 100 mg/kg bw effects in dams (decreased body weight gain) and foetuses (decreased body weight and greater number of runts) were observed. Thus, the embryotoxic NOAEL and maternal toxic NOAEL were both considered to be 30 mg/kg bw [10]. In a similar developmental toxicity study, conducted as a supplement to the previous study, oral administration of 1,2,4-triazole to rats at a dose of 200 mg/kg bw resulted in a decrease in body weight of the dams; this effect was not observed at a dose of 100 mg/kg bw. At doses of 100 and 200 mg/kg bw, mean foetal body weight was reduced, and the number of foetuses with slight bone changes increased. The embryotoxic LOAEL was considered to be 100 mg/kg bw, while maternal NOAEL was 100 mg/kg bw [11]. Considering the systemic effects noted in the foetal and newborn rats in these two studies, it is likely that following absorption in dams, 1,2,4-triazole passes the placental barrier exerting embryotoxic effects in the absence of maternal effects.


Following oral, iv, or intraduodenal administration in rats, 1,2,4-triazole was widely distributed with no tissue preference, except for some transient accumulation in the eye [8]. Analysis of the urine samples of rats treated orally with 10 mg/kg 1,2,4-triazole suggested limited metabolism; metabolites detected in the urine were larger in size than the parent compound, and therefore can be assumed to be conjugates [9].

Elimination of 1,2,4-triazole occurs predominatelyviathe urine (>90% of the administered dose is eliminated unchanged), with a small occurrence in the faeces (approximately 3%) [8]. Eliminationviabile was also reported for 1,2,4-triazole, as 15-20% of the applied dose was subjected to enterohepatic circulation [8], suggesting that part of the absorbed substance is excreted into the bile which passes through the intestines before it is excreted in the faeces.

Based upon the rapid absorption and elimination of the dose (C14 triazole) with concurrent low tissue retention in rats in vivo, it was concluded that there would be only a minimal risk of adverse effects to mammals administered triazole at levels up to 9,000 ppm in their diet.= (Lai and Simoneau, 1986).

In summary, absorption of 1,2,4-triazole is expected to mainly occur via oral and dermal routes, with limited or no potential for respiratory absorption. The site of oral absorption is likely to be small intestine, in which the non-ionized form of the compound is expected to predominate. Upon absorption,1,2,4-triazole is anticipated to be widely distributed with likelihood of transfer through the BBB and placental barrier. 1,2,4-Triazole is shown to undergo limited metabolism as approximately 90% of an oral dose is eliminated unchanged in the urine. Approximately 15 to 20% undergoes enterohepatic circulation and small amounts (3 to 4%) are eliminated in the faeces. Taking into consideration the low log Pow of 1,2,4-triazole, its considerable solubility in water, and the extent of renal elimination, 1,2,4-triazole is not expected to bioaccumulate.


[1] Merck index,John Wiley & Sons; 13th edition (October 15, 2001)

[2] CRC Handbook of Chemistry and Physics (89th Ed)

[3] STN Registry Predicted

[4] Bayer : 288-88-0 1,2,4-Triazol_PC_Dampfdruck_Bayer 1989

[5] Saltigo: 288-88-0 1,2,4-Triazol_TOX_REV_acut studies_5926_1976.pdf

[6] DSM: 2009_06_10_15_10_04.pdf

[7] Saltigo: 288-88-0 1,2,4-Triazol_TOX_REV_acut studies_5926_1976.pdf

[8] Saltigo: 288-88-0 1,2,4-Triazol_TOX_Kinetik_7920_1978.pdf

[9] Saltigo: 288-88-0 1,2,4-Triazol_TOX_metabol_PH9478_PF1471_1980.pdf. 

[10] Slatigo 288-88-0 1,2,4-Triazol_TOX_embryo_17401_T5019339_1988.pdf

[11] Saltigo: 288-88-0 1,2,4-Triazol_TOX_embryo amendment_17402_T5019339_1.pdf