1,2-dihydro-3H-1,2,4-triazol-3-one

Endpoint summary

Description of key information

Triazolone - Toxicokinetic analysis:

There are no specific toxicokinetic or dermal absorption studies available for Triazolone (4H-1,2,3-Triazol-4-one). Therefore, following ECHA's Guidance on Information Requirements and Chemical Safety Assessment Chapter R.7c [1] the main toxicokinetic properties of Triazolone will be assessed based on its physico-chemical properties and with special regard to the results of the standard toxicity studies performed with Triazolone.

Triazolone is a white crystallised powder at room temperature with a molecular weight of 85.1g/mol. A log Pow of < 0was estimated from the single solubilities of the substance in n-octanol and water.

The vapour pressure was determined to be 0.003 Pa.

The test substance is a mono-constituent with a purity of 95 -100% (w/w).

Absorption

Oral route

Theoretically, based on its low molecular weight of 85.1 g/mol, Triazolone is likely to be quantitatively absorbed in the GI tract since small molecules with a molecular weight above <1000 g/mol favour absorption. This assumption is supported by the results of the repeated dose oral toxicity studies with Triazolone indicating signs of systemic toxicity after exposure to the test substance. Following repeated exposure up to the limit dose of 1000 mg/kg bw/day, thyroid toxicity was observed, lower body weighs and histopathological findings were recorded at up to 1000 mg/kg/day indicating that the test item was able to pass the intestinal wall in toxicologically relevant amounts.At 5 and 25 mg/kg/day, animals showed some signs of toxicity, such as piloerection, abnormal gait, hunched posture and/or pallor (mainly at 25 mg/kg/day), during the treatment period but these signs were occasional.

In conclusion, oral absorption is considered to have occurred.

 
Inhalation route

The vapour pressure of Triazolone was determined to be 0.003 Pa.

The particle size distribution of Triazolone was determined by conventional steel sieves to be 200 µm on average and no significant part smaller than 75 µm). As the particle size of the material is 200µm and 100% is greater than 75 µm, all the test substance, if inhaled, would be expected to be deposited in the upper respiratory tract and may be transported to the stomach via the mucociliary escalator. From here, it would be subjected to the same fate as any test substance that was dosed orally. Hazard identification and characterization for airborne exposures may, therefore, be extrapolated from data collected following oral administration. No experimental study was performed. In conclusion, absorption via the inhalation route is assumed to be negligible.

  

Dermal route

Based on the molecular weight of 85.1 g/mol, high solubility in water, physico-chemical properties, in silico assessment, and presence of skin irritating properties, skin permeability of Triazolone is expected to be very good. The in vitro Human Cell Line Activation Test (h-CLAT) (OECD 442E, 2017) considered triazolone positive for the third key event of the skin sensitisation Adverse Outcome Pathway (AOP).

In the local lymph node assay (OECD 429) studies with Triazolone, no potential for skin sensitisation was noted and there were no signs of systemic toxicity indicating that absorption through the skin could not be confirmed or ruled out. In an in vitro dermal penetration with a closely structurally related substance using human epidermal membranes, the dermal absorption was calculated to be 0.528% this is considered to be a worst case for Triazolone.

Distribution

As clinical signs were observed in a repeat dose oral toxicity studies with Triazolone, a distribution to potential target organs is considered to have occurred. Furthermore, there was indication of distribution to certain target organs ie thyroids and parathyroids, sternal bone marrow, adrenals, spleen, prostate, seminal vesicles and coagulating glands, epididymides, liver, thymus, heart and kidneys, mainly at 100, 300 and 1000 mg/kg/day, based on macroscopic and histopathology examinations following repeated oral exposure of Triazolone.

Due to the molecular weight of 85.1 g/mol, distribution through aqueous channels and pores is not restricted. An accumulative potential in adipose tissue can be excluded due to the estimated very low log Pow value of <0.

Metabolism

In the Ames test, in vitro cell gene mutation test, and chromosome aberration test with Triazolone no differences with regards to genotoxicity and cytotoxicity were seen in the presence or absence of metabolic activation systems. The results indicate that neither genotoxic nor more cytotoxic metabolites were formed in those test systems. Generally, metabolism will render a xenobiotic molecule more polar and harmless, leading to fast and quantitative excretion.

Excretion

Substance characteristics favourable for urinary excretion are low molecular weight (below 300 g/mol in the rat), good water solubility. Triazolone fulfils these characteristics and therefore the main route of excretion is expected to be via the urine. There is no pKa value available for Triazolone.

References

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

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - dermal (%):

0.528

Additional information

In an in vitro dermal absorption study ( U.S. Army Public Health Command, 2012) the penetration rate of  3-Nitro-1,2,4-triazol-5-one (NTO) was found to be 338.2 µg/cm2/hr for an administered dose of 100 mg. and considering penetration of skin area of 0.64 cm2, the penetration rate is 528.4375 µg/hr (338.2 µg/cm2/hr ÷ 0.64 cm2 = 528.4375 µg/hr). From this a dermal absorption rate (% total absorbed) is 0.528% (=528.4375 µg /100 mg) for NTO can be calculated.

Triazolone is the immediate precursor to NTO in the synthesis of NTO and, whilst their physicochemical properties are not identical, due to it's lower water solubility and higher Log Koc than Triazolone, NTO can be considered to represent a worst case value for Triazolone such that the dermal absorption of Triazolone is not considered to be greater than 0.528% but could be lower however the exact value is not known.