Amitrole

Endpoint summary

Description of key information

Based on available data, the substance is expected to be bioavailable via the oral and the inhalation routes and barely bioavailable via the dermal route. The substance may cross cellular barriers or may be distributed into tissues with a rapid cell turnover. The substance is rapidly and mainly excreted in urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - dermal (%):

3.54

Additional information

In accordance with the section 8.1.1 of Annex VIII of Regulation (EC) No 1907/2006 (REACH), the toxicokinetic profile of the registered substance (i.e. absorption, distribution, metabolism and elimination) was derived from the relevant available information collated in the dossier. The physical chemical characteristics of aminotriazole, the results obtained from acute, repeated-dose, and reproductive toxicity studies, as well as information gained from genotoxicity assays were used to predict its toxicokinetic behaviour.

 

Physico chemical characteristics

 

Aminotriazole has a low molecular weight of 84.082 g/mol. The substance is considered as moderate soluble in phosphate buffer 0.5M (264 g/L) and low volatile according to its vapour pressure (3.3 x10^-5Pa at 20°C). Furthermore, aminotriazole has no potential for bioaccumulation since it is low hydrophobic based on the partition coefficient (log Kow = -0.77).

 

Absorption

 

The physical chemical characteristics described above suggest that aminotriazole is of adequate molecular size to participate in endogenous absorption mechanisms within the mammalian gastrointestinal tract. In vivo experiments using¹⁴C by oral route showed a rapid and almost complete absorption from the gastrointestinal tract followed by rapid excretion in the urine within 48 hours. Moreover, an acute oral gavage toxicity study identified neither systemic toxicity (including mortality), nor clinical or macroscopic effects (LD50 > 10000 mg/kg bw).

The sub-chronic repeated dose toxicity, the pre-natal developmental toxicity studies and the two-generation reproductive toxicity study using the oral route gave a NOAEL below 1.5 mg/kg bw/day (gavage), 4 mg/kg bw/day and 0.12 mg/kg bw/day (diet), respectively, based on effects on thyroid.

In a ten-week toxicity study, the absorption and elimination of the substance were also evaluated by HPLC in serum from satellite animals. Absorption of the test substance was observed at all time points in both sexes and comparable C_maxwere noted 2 hours after the administration of the test substance (394 and 341 µg/mL in males and females respectively). Extent of absorption, as measured by AUC_{0 -24h} was somewhat greater in the males than in the females (725 and 668 µ.g/h respectively).

The observation of those systemic effects indicates the oral bioavailability of aminotriazole and/or its metabolites.

However, exposure by oral route is not anticipated in human since only worker uses are identified for the substance.

 

Regarding the dermal absorption, being low hydrophobic, the rate of uptake of aminotriazole into the stratum corneum is expected to be low (<10%). Data on dermal absorption are available in animals and in human cells where a low dermal absorption is determined. Dermal absorption is determined in in vitro using human cells (3.54%). These results are consistent with the absence of systemic effects following a single dermal application of aminotriazole up to 2000 mg/kg bw. Moreover, enhanced skin penetration is not expected since aminotriazole is not a skin irritant or corrosive.

 

Both the partition coefficient and the moderate water solubility of aminotriazole, are favourable for absorption by inhalation.

A study in rats exposed by inhalation is available. Following a « whole body » or a « head-only » exposure, it is demonstrated that the substance was bioavailable. However, exposure by inhalation o vapour is negligeable based on the low volatility of aminotriazole (3.3 x10^-5Pa at 20°C). Moreover, considering that aminotriazole is not skin and eye irritant, no respiratory irritation is anticipated that could increase inhalation absorption.

 

Distribution

 

Distribution of aminotriazole was studied in several in vivo experiments. After an oral administration in mice and rats, there is a rapid distribution of the substance throughout the body, with a slight accumulation in tissues with a rapid cell turnover, and moderatly in the thyroid gland. After 3 days, a significant amount was found only in the liver. Moreover, aminotriazole was found mostly in the cytoplasm of the cells.

 

Regarding the dermal route of exposure in rabbits, the majority of the substance was still at the site 24 hours following application. For the amount of substance that penetrated, it was mesured in blood after 24 hours extremely rapidly, and then excreted. The remaining substance after 24 hours was found in urine, faeces, gall bladder, liver, bladder, gastrointestinal tract and other organs.

 

Based on available data, aminotriazole administered in rats by inhalation exposure was rapidly and mostly found in the urine.

 

Metabolism

 

The metabolism of aminotriazole has been studied in rats by a daily analysis of the urine. Aminotriazole and metabolites were detected which demonstrated that a few part of the substance is metabolised by the liver and conjugated with glutathion. The 2 identified metabolites were 3-amino-1,2,4-triazolyl-5-mercapturic acid and 3-amino-5-mercapto-1,2,4-triazole.

 

Excretion

 

Aminotriazole is bioavailable via oral route and inhalation route as aerosol. Limited systemic absorption via dermal route is anticipated.

 

The bioavailability of aminotriazole should be limited following exposure by dermal route.

 

Aminotriazole having a molecular weight lower than 300 g/mol, it is expected – and demonstrated in several studies – to be mainly excreted in urine. It is shown in experiments that aminotriazole is excreted unchanged or as metabolites (i.e. 3-amino-1,2,4-triazolyl-5-mercapturic acid and 3-amino-5-mercapto-1,2,4-triazole) following the metabolisation by the liver. Following oral ingestion, the low substance amount that may not be absorbed from the gastro-intestinal tract will be excreted in the faeces.

Moreover, following an oral exposure, traces of¹⁴C were detected in the expired air within 72 hours.

In the ten-week toxicity study, elimination, estimated by apparent t_maxwas not influenced by gender (2 hours for both sexes).

 

Following dermal exposure, the low amount of substance which has been absorbed will be excreted mostly in urine, faeces and gall bladder.

 

As for the oral and dermal route, following an inhalation exposure, the substance is rapidly and mostly absorbed and excreted via the urine.

 

 

Sources :

* Monograph, Aminotriazole – Volume 3 : B.5 Toxicology and metabolism: 

- Fang, S.C., Khanna, S., Rao, A.V. 1966. Further study on the metabolism of labelled 3-amino-1,2,4-triazole (ATA) and its plant metabolites in rats. J. Agric. Food Chem. 14, (3), 262-265

- Fang, S.C., George, M., Yu, T.C. 1964. Metabolism of 3-amino-1,2,4-triazole-5-14C by rats. J. Agric. Food Chem. 12 : 219-223

- Franco L., Municio, A.M. 1975. Comparative metabolism of 3-amino-1,2,4-triazole. Gen Pharmacol. 6 (2-3) : 163-9

- Grunow, W., Altmann, H.J., Boehme, C. 1975. On the metabolism of 3-amino-1,2,4-triazole. Arch. Toxicol. 34 (4) 315-24

- Mc Donald, C.M., Pullinger, D.H. 1976. A pharmacokinetic study to compare "head only" and "whole body" inhalation methods of 14C-amitrole exposure. Hazleton Labs Europe, UK. Report No.: 291/1. Unpublished report.

- Shah, P.V., Guthrie, F.E. 1977. Dermal Absorption, Distribution and the Fate of Six Pesticides in the Rabbit. Pesticide Management and Insecticide Resistance, Academic Press, 547-554.

- Tjälve, H. 1974. The distribution of labelled aminotriazole in mice. Toxicology 3 (1) 49-67

* Addendum to Amitrole Monograph, Vol. 3 ANNEX B, Summary, Scientific Evaluation and Assessment. France : Ministère de l'Agriculture, DGAL ; March 2000

- Marty, J.M. 1999. In vitro release and diffusion evaluation through human skin of Amitrole. Faculté de Pharmacie, France.