Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.19 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
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.95 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.32 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
5
Dose descriptor:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Most sensitive endpoint:
sensitisation (respiratory tract)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.2 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.2 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEL

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Additional information - workers

The inhalation DNEL for acute toxicity is derived based on the long-term inhalation DNEL (modified by multiplying with a factor of 5, considering the potency and the dose-response curve of the substance) because acute toxicity hazard (leading to C&L) has been identified and there is a potential for high peak exposures. For the dermal and oral exposure routes, ‘short-term’ exposures will be assessed using the long-term DNELs.

In relation to repeated dose toxicity (assuming the same bioavailability for experimental animals and humans), a NOAEL of 10 mg/kg bw/day was derived from a chronic oral study. NOAECs of 3.3 and 9.8 mg/m3for local and systemic effects respectively were derived from a subchronic inhalation study.

In line with Guidance on Information Requirements and Chemical Safety Assessment (2008), the overall AF for oral and dermal repeated dose toxicity is 50. This is established by taking into account an interspecies factor of 10 (4 for metabolic rate differences×2.5 for remaining differences) and an intraspecies factor of 5. The overall AFs for inhalation repeated dose toxicity which should be applied to the corrected NOAECs (3.3 mg/m3×6 h/d /8 h/d×6.7 m3/10 m3& 9.8 mg/m3×6 h/d /8 h/d×6.7 m3/10 m3) are 5 and 25. These are established by taking into account an interspecies factor of 2.5 (only for remaining differences of systemic effects), an intraspecies factor of 5, and a further factor of 2 to allow for subchronic to chronic extrapolation (only for exposure duration differences of systemic effects). A factor of 2.5 which would be normally used to take into account the remaining differences for local effects is not considered necessary here, as the adverse local effects in the repeated dose toxicity study (mainly eye/nasal irritation) are considered as effects via simple destruction of membranes. In addition, a factor to allow for subchronic to chronic extrapolation (usually a factor of 2) was not used for local effects here. It is not considered necessary, as relatively similar effects on the eye and nose, at doses of a comparable order of magnitude were observed in the 28-day study and so it is felt that exposure duration is not significant.

In relation to reproductive toxicity (assuming the same bioavailability for experimental animals and humans), a LOAEL of 20 mg/kg bw/day for effects on fertility and a NOAEL of 140 mg/kg bw/day for developmental toxicity were derived from a 2-generation study and a prenatal developmental toxicity study respectively.

In line with Guidance on Information Requirements and Chemical Safety Assessment (2008), the overall AFs for effects on fertility and developmental toxicity are 150 and 50. These are established by taking into account an interspecies factor of 10 (4 for metabolic rate differences×2.5 for remaining differences) and an intraspecies factor of 5, and a further factor of 3 to take into account the use of a LOAEL rather than a NOAEL.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.05 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.25
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEC

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.08 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
10
Dose descriptor:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Most sensitive endpoint:
sensitisation (respiratory tract)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.1 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.1 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
Overall assessment factor (AF):
10
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Most sensitive endpoint:
skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.06 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
DNEL related information
Overall assessment factor (AF):
300
Modified dose descriptor starting point:
LOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.1 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL

General Population - Hazard for the eyes

Additional information - General Population

The inhalation DNEL for acute toxicity is derived based on the long-term inhalation DNEL (modified by multiplying with a factor of 5, considering the potency and the dose-response curve of the substance) because acute toxicity hazard (leading to C&L) has been identified and there is a potential for high peak exposures. For the dermal and oral exposure routes, ‘short-term’ exposures will be assessed using the long-term DNELs.

In relation to repeated dose toxicity (assuming the same bioavailability for experimental animals and humans), a NOAEL of 10 mg/kg bw/day was derived from a chronic oral study. NOAECs of 3.3 and 9.8 mg/m3for local and systemic effects respectively were derived from a subchronic inhalation study.

In line with Guidance on Information Requirements and Chemical Safety Assessment (2008), the overall AF for oral and dermal repeated dose toxicity is 100. This is established by taking into account an interspecies factor of 10 (4 for metabolic rate differences×2.5 for remaining differences) and an intraspecies factor of 10. The overall AFs for inhalation repeated dose toxicity which should be applied to the corrected NOAECs (3.3 mg/m3×6 h/d /24 h/d& 9.8 mg/m3×6 h/d /24 h/d) are 10 and 50. These are established by taking into account an interspecies factor of 2.5 (only for remaining differences of systemic effects), an intraspecies factor of 10, and a further factor of 2 to allow for subchronic to chronic extrapolation (only for exposure duration differences of systemic effects). A factor of 2.5 which would be normally used to take into account the remaining differences for local effects is not considered necessary here, as the adverse local effects in the repeated dose toxicity study (mainly eye/nasal irritation) are considered as effects via simple destruction of membranes. In addition, a factor to allow for subchronic to chronic extrapolation (usually a factor of 2) was not used for local effects here. It is not considered necessary, as relatively similar effects on the eye and nose, at doses of a comparable order of magnitude were observed in the 28-day study and so it is felt that exposure duration is not significant.

In relation to reproductive toxicity (assuming the same bioavailability for experimental animals and humans), a LOAEL of 20 mg/kg bw/day for effects on fertility and a NOAEL of 140 mg/kg bw/day for developmental toxicity were derived from a 2-generation study and a prenatal developmental toxicity study respectively.

In line with Guidance on Information Requirements and Chemical Safety Assessment (2008), the overall AFs for effects on fertility and developmental toxicity are 300 and 100. These are established by taking into account an interspecies factor of 10 (4 for metabolic rate differences×2.5 for remaining differences) and an intraspecies factor of 10, and a further factor of 3 to take into account the use of a LOAEL rather than a NOAEL.