Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
20 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
12.5
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.6 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
180
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

Workers - Hazard for the eyes

Additional information - workers

The substance is of low acute toxicity. LD50 values were greater than 5000 mg/kg and 2000 mg/kg, following oral and dermal administration, respectively, while LC50 was greater than 1.2 mg/L, the maximal attainable concentration, following whole-body inhalation exposure. The substance is neither a skin nor an eye irritant and was found to not possess any skin sensitisation potential in a guinea pigs test performed according to the method of Buhler. On these bases no acute DNELs are required, either for systemic or local effects.

The genotoxic potential of the substance was evaluated in-vitro and in-vivo, with all endpoints resulting negative. On this basis the substance is considered to not possess genotoxic potential.

The carcinogenic potential of the substance was evaluated in fully compliant 2-year dietary studies in rats and mice, and no carcinogenic potential was demonstrated in either species.

Repeat-dose toxicity studies conducted in rats, mice and dogs indicate that the main target organ of toxicity is the kidney. The dog appears to be the most sensitive species, as sub-chronic (90 days) treatment at the limit dose of 1000 mg/kg/day was not tolerated in this species, whereas rodents did not show overt toxicity either when treated for a similar time period at dosages also greater than 1000 mg/kg/day. On this basis the lowest NOAEL of 100 mg/kg/day obtained in the chronic 1 year dog study has been chosen as the most appropriate end point for deriving the long-term inhalation DNEL. As the respiratory volume in dog is not well standardised as it is that for the rat, and rather different values can be found in other guidance documents and/or the public domain, the pathway indicated in the left side of example R. 8-2 Workers of the Chapter R.8 of the Guidance has been used to correct the starting point, using the AS factor of 1.4 indicated for the dog at page 30 of the same Chapter R.8.

As a dermal repeat-dose study in rabbits is also available, demonstrating that dermal exposure does not result in any systemic toxicity, this end point has been used to set the long-term dermal DNEL.

Fully compliant studies investigating reproductive and developmental toxicity demonstrated that the substance does not pose any risk, either for reproduction or for the offspring.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.8 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
360
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.8 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
35
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

The same end points used for workers have been used for calculating long-term DNELs for the general population. As already mentioned for workers, due to the lack of a definitive standard value for the respiratory volume of the dog, the left pathway of Example R. 8-1 General public has been used for correcting the starting point for the long-term inhalation DNEL calculation. The increased assessment factor for intraspecies sensitivity is considered to be adequately protective.