Registration Dossier

Administrative data

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:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
LOAEC
DNEL value:
16
Explanation for the modification of the dose descriptor starting point:
No inhalation repeated toxicity study available.
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
DNEL based on a 2 generation study.
AF for interspecies differences (allometric scaling):
1
Justification:
Extrapolation from oral to inhalation
AF for other interspecies differences:
2.5
AF for intraspecies differences:
5
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
insufficient hazard data available (further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
insufficient hazard data available (further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
insufficient hazard data available (further information necessary)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.86 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
LOAEL
DNEL value:
16 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No repeated dose toxicity study by dermal route is available. A

safety factor of 3 is used to derive the NOAEL from the LOAEL.

AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
Based on the 2-generation study.
AF for interspecies differences (allometric scaling):
4
AF for other interspecies differences:
2.5
AF for intraspecies differences:
5
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
insufficient hazard data available (further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

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.

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

Step 2) Modification of starting point:

* Correction for absorption difference between rat and human, and between dermal and oral absorption: The results of a recent in vitro dermal absorption study revealed an absorption of 2.73 % though human skin. As no available data is reported for oral absorption in rats, the oral aborption is considered to be  100 %

  

      • Corrected dermal NOAEL, route    = oral NOAEL x (ABSoral-rat/ABSderm-rat) x (ABSderm-rat/ ABSderm-human)
      • = oral NOAEL x (ABSoral-rat/ABSderm-human)
      •      Corrected dermal LOAEL = 16 x 100/2.73 =586 mg/kg/day

Step 3) Assessment factors:

*LOAEL to NOEL: 1 : 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 assessement (Chapter R8): The size of an assessment effect factor should take into account [...] the extent and severity of the effects seen at the LOAEL.

* 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)

AF total = 3x 10x5x2x1x1 = 100

Step 4) DNEL calculation:

DNEL value = 586 mg/kg/day/100= 5.86 mg/kg

DNEL Long-term Dermal value based on LOAEL(oral) is 5.86 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:
DNEL (Derived No Effect Level)
Value:
0.08 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
LOAEL
DNEL value:
16 mg/kg bw/day
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
subchronic to chronic
AF for interspecies differences (allometric scaling):
4
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

General population

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).

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

Step 2: Modification of the starting point: No

No difference absorption are expected between rats and humans.

 

Step 3: Assessment factors:

-LOAEL to NOAEL= 1 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 assessement (Chapter R8): The size of an assessment effect factor should take into account [...] the extent and severity of the effects seen at the LOAEL.

- Interspecies differences: an allometric scaling factor of 4(standard for rats) is applied because no route-to-route extrapolation is performed. A factor of 2.5to correct for differences other than differences in metabolic rate is also applied.

- Intraspecies differences: the default assessment factor of 10 is applied.

- Differences in exposure duration: as the exposure in rats was around 18 months (2 generation study) a factor of 2 for subacute-to-chronic extrapolation is applied.

- Dose-response relationship: a factor of 1 is applied due to the use of a NOAEL as dose descriptor and the low toxicity of the test substance.

- Quality of whole database: 1

- Global assessment factor: 1x4 x 2.5 x 10 x 2 x 1 x 1 =200

 

Step 4: DNEL derivation:

General population DNEL (long term, systemic effects) = 16/ 200 = 0.08 mg/kg bw/day