1H-1,2,4-triazole, sodium salt

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.65 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

25

Modified dose descriptor starting point:

LOAEC

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.16 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

LOAEL

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Additional information - workers

As 1,2,4-Triazole, sodium salt dissociates to form 1,2,4-Triazole, the toxicokinetics for 1,2,4-Triazole, sodium salt can be read-across from the supporting 1,2,4-Triazole.

WORKERS /DNELs Long-term exposure - systemic effects

Key study for DNELs calculation:

In the two-generation reproductive toxicity study reported in the US EPA dossier, rats (30/sex/dose) were exposed to 1,2,4-triazole continuously via the feed at nominal concentrations of 0, 250, 500 and 3000 ppm(US EPA HPV 2009, Pesticide fact sheet 2006)*.

In this two-generation study, there were no test substance-related effects on food consumption or clinical signs effects in either generation at any dietary level.

However, 1,2,4-triazole produced evidence of toxicity in P-generation animals at a dietary level of 3,000 ppm (188.6 and 217.9 mg/kg/day for males and females, respectively), including reduced fertility and neuropathology.

In F1-generation: the only evidence of toxicity at lower dietary levels of 250 and 500 ppm (16 and 32 mg/kg bw/d) was slightly reduced body weight in F1- males. This effect was observed at 500 ppm (37.5 mg/kg bw/d) in F1-females.

The combined (male and female) F2-pup body weights for the 250- and 500-ppm dietary groups were significantly decreased from control and are considered to be due to the incidental difference in the time of delivery and not exposure to the test substance.

Based on the slight decrease in body weight in the F1-males, the LOAEL is 16 mg/kg bw/d (it’s a smallest tested concentration). It’s the only observed effect.

Based on the marked reduction in fertility in P-generation animals, the reproductive (fertility) NOAEL is 34.4 mg/kg bw/day (500 ppm) and the LOAEL for this endpoint is 231.7 mg/kg bw/day (3000 ppm).

The critical effect was the decrease of body weight (-4.38% to –6.38% compared to control) in males F1 generation, therefore the LOAEL was 16.0 mg/kg bw/d (250 ppm).

In the Pesticide dossier(Pesticide fact sheet 2006), the same LOAEL (16.0 mg/kg bw/d) was used to calculate the Chronic Reference dose (cRfD).

1 Dermal DNEL

Step 1) Relevant dose-descriptor:LOAEL, rat = 16.0 mg/kg bw/d

Step 2) Modification of starting point:

* Correction for absorption difference between rat and human, and between dermal and oral absorption:No available data is reported for oral and dermal absorption, the oral and dermal absorption is therefore estimated to 100%.The correction factor is 1.

Step 3) Assessment factors:

* Interspecies : 4 x 2.5= 10

* Intraspecies : 5(factor for workers)

* Exposure duration : 2 (subchronic to chronic exposure)

* Quality of database : 1

* Dose response: 1 (LOAEL > NOAEL)

An additional safety factor of 1 (instead of 3) is proposed for LOAEL to NOAEL conversion. According to the Guidance on information requirements and chemical safety assessment (Chapter R.8): “The size of an assessment factor should take into account […] the extent and severity of the effect seen at the LOAEL” (p35).

- We have selected the Lowest Adverse Effect Level (LOAEL) of 16.0 mg/kg bw/d based on theslightdecrease in body weight in males (F1-generation) :decrease of 4.38 to 6.38% compared to control

-A decrease in body weight in F1-female was not observed at 18.9 and 37.5 mg/kg bw/d, therefore the NOAEL (F1-females) is equal to 37.5 mg/kg bw/d.

-Moreover, a NOAEL of 16 mg/kg bw/d was found in an other well conducted study (90-day oral study)(Pesticide dossier, 2006), based on a reduced TSH level in males at 33 mg/kg bw/d.

In conclusion, a safety factor of 1 instead of 3 can be considered as reasonable, sinceit’s a smalleffect.The value of 16 mg/kg bw/d can be considered as a NOAEL.

AF total = 10x5x2x1x1 = 100

Step 4) DNEL calculation:

DNEL value = 16.0 x 1 / 100 = 0.16 mg/kg bw

DNEL Long-term Dermal value based on LOAEL(oral) is 0.16 mg/kg bw

2 Inhalation DNEL

Step 1) Relevant dose-descriptor:LOAEL, rat = 16.0 mg/kg bw/d

Step 2) Modification of starting point:

* Correction for absorption difference between rat and human, and between inhalation and oral absorption:No available data is reported for oral and inhalation absorption, the oral and inhalation absorptions are therefore estimated to 100%.The correction factor is 1. 

* Correction of respiratory volume for relevant duration:For 8h of exposure, the respiratory volume of humans is 6.7m3/ person, and the respiratory volume light activity for worker (8h exposure) is 10 m3/person.The correction factor is 6.7/10.

* Correction or exposure duration in study (24h/d, 7d/wk) to default worker exposure (8h/d, 5d/wk):The correction factor is 24/8 x 7/5.

Step 3) Assessment factors:

* Interspecies: 2.5

* Intraspecies : 5(factor for workers)

* Exposure duration : 2 (subchronic to chronic exposure)

* Dose response: 1 (LOAEL > NOAEL)

* Quality of database: 1

AF total = 2.5x5x2x1x1 = 25

Step 4) DNEL calculation:

DNEL value = 16.0 x (6.7/10 x 24/8 x 7/5) / 25 = 0.65 mg/m3

DNEL Long-term Inhalation value based on LOAEL(oral) is 0.65 mg/m3

*Bibliographie :

-US EPA HPV Challenge program, 1H-1,2,4-triazole (TA) Cas number 288-88-0, July 2009

-1,2,4-Triazole, Triazole Alanine, Triazole Acetic Acid: Human Health Aggregate Risk Assessment in Support of Reregistration and Registration Actions for Triazole-derivative Fungicide Compounds. US EPA, office of prevention, pesticides and toxic substances, February 7, 2006

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

exposure based waiving

Acute/short term exposure

Hazard assessment conclusion:

exposure based waiving

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

exposure based waiving

Acute/short term exposure

Hazard assessment conclusion:

exposure based waiving

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

exposure based waiving

Acute/short term exposure

Hazard assessment conclusion:

exposure based waiving

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

exposure based waiving

Acute/short term exposure

Hazard assessment conclusion:

exposure based waiving

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

exposure based waiving

Acute/short term exposure

Hazard assessment conclusion:

exposure based waiving

DNEL related information