Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
Overall assessment factor (AF):
1
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
Overall assessment factor (AF):
1
Dose descriptor:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
101 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
9
Modified dose descriptor starting point:
LOAEL
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

Workers - Hazard for the eyes

Additional information - workers

DNELs for acute effects are not considered since long-term DNELs are sufficient to ensure that these effects do not occur.

DNEL long-term – systemic effects – dermal

Relevant dose-descriptor for the endpoint concerned: LOAEL of 1000 mg/kg bw in a 4 w oral Guideline study with rats (Degussa, 1989)

Correction of starting point:

Bioavailability in humans: assumed to be comparable with rats (no correction)

Exposure conditions: daily exposure over 4 weeks. Conversion factor for workplace exposure (5 d/w): 1.4

Conversion factor (PBS4 <--> PBS1): 0.65

Overall correction factor: 1.4 * 0.65 = 0.91

Corrected starting point: 1000 mg/kg bw * 0.91 = 910 mg/kg bw

Assessment factors:

Starting point: LOAEL; assessment factor of 3 (LOAEL → NOAEL)

Route to route extrapolation (oral → dermal): default assessment factor of 1

Duration extrapolation (subacute → chronic): default assessment factor of 6

Interspecies differences (rat → human): default assessment factor of 4

Interspecies differences (remaining differences): default assessment factor of 2.5

Intraspecies differences (workers): default assessment factor of 5

Quality of whole database: sufficient (no additional assessment factor)

Overall assessment factor: 3 * 1 * 6 * 4 * 2.5 * 5 = 900

DNEL long-term – systemic effects – dermal: 910 mg/kg bw ÷ 900 = 1.01 mg/kg bw/d

As for the dermal route 1 % absorption can be assumed, the external DNEL is about 101 mg/kg bw/d

DNEL long-term – local effects – inhalation

There are no studies with repeated exposure via inhalation available and also no extrapolation from a subacute oral study can be made for the local effects in the airways. In the EU RAR (ECB, 2007), several studies concerning workplace surveillance were described in detail and from these data a typical exposure concentration of 1 mg/m3 was derived, which gave no indication for adverse effects even after long-exposure. Therefore, no additional assessment factors have to be addressed. Assuming an amount of the respirable fraction in workplace air of about 30 – 50 % of the inhalable fraction (ECB, 2007), a DNEL of 2 mg/m3 can be derived.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.5 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
Overall assessment factor (AF):
4
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.5 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
Overall assessment factor (AF):
4
Dose descriptor:
NOAEC
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:
DNEL (Derived No Effect Level)
Value:
36 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
18
Modified dose descriptor starting point:
LOAEL
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.36 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
1 800
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

DNELs for acute effects are not considered since long-term DNELs are sufficient to ensure that these effects do not occur.

DNEL long-term – systemic effects – dermal

Relevant dose-descriptor for the endpoint concerned: LOAEL of 1000 mg/kg bw in a 4 w oral Guideline study with rats (Degussa, 1989)

Correction of starting point:

Bioavailability in humans: assumed to be comparable with rats (no correction)

Exposure conditions: daily exposure over 4 weeks (no correction)

Conversion factor (PBS4 <--> PBS1): 0.65

Overall correction factor: 0.65

Corrected starting point: 1000 mg/kg bw * 0.65 = 650 mg/kg bw

Assessment factors:

Starting point: LOAEL; assessment factor of 3 (LOAEL → NOAEL)

Route to route extrapolation: default assessment factor of 1 (oral → dermal)

Duration extrapolation: default assessment factor of 6 (subacute → chronic)

Interspecies differences: default assessment factor of 4 (rat → human)

Interspecies differences: default assessment factor of 2.5 (remaining differences)

Intraspecies differences: default assessment factor of 10 (general population)

Quality of whole database: sufficient (no additional assessment factor)

Overall assessment factor: 3 * 1 * 6 * 4 * 2.5 * 10 = 1800

DNEL long-term – systemic effects – dermal: 650 ÷ 1800 = 0.36 mg/kg bw/d

As for the dermal route 1 % absorption can be assumed, the external DNEL is about 36 mg/kg bw/d

DNEL long-term – systemic effects – inhalation

There are no studies with repeated exposure via inhalation available and also no extrapolation from a subacute oral study can be made for the local effects in the airways. For workers (see above) the DNEL is calculated with 2 mg/m3.

Correction of starting point:

Exposure conditions: breathing volume for general population 20 m3/d vs. 10 m3/d in workers: 2

Corrected starting point: 2 mg/m3 ÷ 2 = 1 mg/m3

Assessment factors:

Intraspecies differences: assessment factor of 2 (general population)

Overall assessment factor: 2

DNEL long-term – systemic effects – inhalation: 1 mg/m3 ÷ 2 = 0.5 mg/m3

DNEL long-term – systemic effects – oral

Relevant dose-descriptor for the endpoint concerned: LOAEL of 1000 mg/kg bw in a 4 w oral Guideline study with rats (Degussa, 1989)

Correction of starting point:

Bioavailability in humans: assumed to be comparable with rats (no correction)

Exposure conditions: daily exposure over 4 weeks (no correction)

Conversion factor (PBS4 <--> PBS1): 0.65

Overall correction factor: 0.65

Corrected starting point: 1000 mg/kg bw * 0.65 = 650 mg/kg bw

Assessment factors:

Starting point: LOAEL: default assessment factor of 3 (LOAEL → NOAEL)

Same route of exposure: no additional assessment factor

Duration extrapolation: default assessment factor of 6 (subacute → chronic)

Interspecies differences: default assessment factor of 4 (rat → human)

Interspecies differences: default assessment factor of 2.5 (remaining differences)

Intraspecies differences: default assessment factor of 10 (general population)

Quality of whole database: sufficient (no additional assessment factor)

Overall assessment factor: 3 * 6 * 4 * 2.5 * 10 = 1800

DNEL long-term – systemic effects – oral: 650 mg/kg bw ÷ 1800 = 0.36 mg/kg bw/d

DNEL long-term – local effects – inhalation

There are no studies with repeated exposure via inhalation available and also no extrapolation from a subacute oral study can be made for the local effects in the airways. For workers (see above) the DNEL is calculated with 2 mg/m3.

Correction of starting point:

Exposure conditions: breathing volume for general population 20 m3/d vs. 10 m3/d in workers: 2

Corrected starting point: 2 mg/m3 ÷ 2 = 1 mg/m3

Assessment factors:

Intraspecies differences: assessment factor of 2 (general population)

Overall assessment factor: 2

DNEL long-term – local effects – inhalation: 1 mg/m3 ÷ 2 = 0.5 mg/m3