Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.168 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12.5
Dose descriptor starting point:
NOAEL
Value:
1.2 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
2.1 mg/m³
Explanation for the modification of the dose descriptor starting point:
NOAEL (oral, rat) = 1.2 mg/kg/day. NOAEC = 1.2 x 1/0.38 x 6.7/10 = 2.1 mg/m3
AF for dose response relationship:
1
Justification:
This factor is applied because the dose-descriptor starting point is a NOAEC.
AF for differences in duration of exposure:
1
Justification:
DNEL is based on a chronic study (104 weeks).
AF for interspecies differences (allometric scaling):
1
Justification:
AF not used for inhalation.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 is applied for remaining difference.
AF for intraspecies differences:
5
Justification:
A factor of 5 is applied for worker DNELs.
AF for the quality of the whole database:
1
Justification:
The key study is considered as a reliable study with a klimisch score of 2
AF for remaining uncertainties:
1
Justification:
No other assessment factor is applied.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
101.8 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
37.5
Dose descriptor starting point:
LOAEC
Value:
2 060 mg/m³
Modified dose descriptor starting point:
LOAEC
Value:
3 516.5 mg/m³
Explanation for the modification of the dose descriptor starting point:
Modification of the starting point : LOAEC (4h) = 2060 mg/m3 -Time extrapolation: Time extrapolation to the reference period of 15 minutes for acute effects, using the modified Haber's law (Cnx t = k) with ancoefficient of 3 for extrapolation from a longer to a shorter exposure duration: LOAEC (15 minutes) = 5191 mg/m3 - Modification for respiratory volume. Respiratory volume of human is 0.2 L/min/kg, for 15 minutes we have a respiratory volume of 3 L/kg, corresponding to 0.21 m3/person (70kg). Respiratory volume light activity for worker (8h) is 10 m3/person. For 15 minutes we have a respiratory volume of 0.31 m3/person. LOAEC = 5191 x 0.21/0.31 = 3516.5 mg/m3
AF for dose response relationship:
3
Justification:
This factor is applied because the dose-descriptor starting point is a LOAEC.
AF for interspecies differences (allometric scaling):
1
Justification:
AF not used for inhalation.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 is applied for remaining difference.
AF for intraspecies differences:
5
Justification:
A factor of 5 is applied for worker DNELs.
AF for the quality of the whole database:
1
Justification:
The key study is considered as a reliable study.
AF for remaining uncertainties:
1
Justification:
No other assessment factor is applied.

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.024 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):
50
Dose descriptor starting point:
NOAEL
Value:
1.2 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1.2 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No data on dermal absorption is available on TMTD.
AF for dose response relationship:
1
Justification:
This factor is applied because the dose-descriptor starting point is a NOAEL.
AF for differences in duration of exposure:
1
Justification:
DNEL is based on a chronic study (104 weeks).
AF for interspecies differences (allometric scaling):
4
Justification:
An allometric scaling factor of 4 must be applied because the key study was performed on rats.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 is applied for remaining difference.
AF for intraspecies differences:
5
Justification:
A factor of 5 is applied for worker DNELs.
AF for the quality of the whole database:
1
Justification:
The key study is considered as a reliable study with a klimisch score of 2
AF for remaining uncertainties:
1
Justification:
No other assessment factor is applied.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

DNEL (long-term, systemic effects)

Note : If we use the NOAEL of 0.4 mg/kg bw/day found in the dog repeated study, we have the same DNELs for the systemic effects (long-term).

DNEL (dermal, workers) = 0.4 / (1.4 x 2.5 x 5) = 0.023 mg/kg/d

DNEL (inhalation, workers) = (0.4 x 1/0.13 x 6.7/10) / (2.5 x 5) = 0.168 mg/m3

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.042 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Dose descriptor starting point:
NOAEL
Value:
1.2 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
1.04 mg/m³
Explanation for the modification of the dose descriptor starting point:
NOAEL (oral) = 1.2 mg/kg. NOAEC = 1.2 x 1/1.15 = 1.04 mg/m3
AF for dose response relationship:
1
Justification:
This factor is applied because the dose-descriptor starting point is a NOAEC.
AF for differences in duration of exposure:
1
Justification:
DNEL is based on a chronic study (104 weeks).
AF for interspecies differences (allometric scaling):
1
Justification:
AF not used for inhalation.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 is applied for remaining difference.
AF for intraspecies differences:
10
Justification:
A factor of 10 is applied for the general population DNELs.
AF for the quality of the whole database:
1
Justification:
The key study is considered as a reliable study with a klimisch score of 2
AF for remaining uncertainties:
1
Justification:
No other assessment factor is applied.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
69.2 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
75
Dose descriptor starting point:
LOAEC
Value:
2 060 mg/m³
Modified dose descriptor starting point:
LOAEC
Value:
5 191 mg/m³
Explanation for the modification of the dose descriptor starting point:
LOAEC (4h) = 2.06 mg/l = 2060 mg/m3 Modification of the starting point: -Time extrapolation : Time extrapolation to the reference period of 15 minutes for acute effects, using the modified Haber's law (Cn x t = k) with a n coefficient of 3 for extrapolation from a longer to a shorter exposure duration: LOAEC (15 minutes) = 5191 mg/m3 - No Modification for respiratory volume for general population.
AF for dose response relationship:
3
Justification:
This factor is applied because the dose-descriptor starting point is a LOAEC.
AF for interspecies differences (allometric scaling):
1
Justification:
AF not used for inhalation.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 is applied for remaining difference.
AF for intraspecies differences:
10
Justification:
A factor of 10 is applied for the general population DNELs.
AF for the quality of the whole database:
1
Justification:
The key study is considered as a reliable study.
AF for remaining uncertainties:
1
Justification:
No other assessment factor is applied.

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.012 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
Dose descriptor starting point:
NOAEL
Value:
1.2 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1.2 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No data on dermal absorption is available on TMTD.
AF for dose response relationship:
1
Justification:
This factor is applied because the dose-descriptor starting point is a NOAEL.
AF for differences in duration of exposure:
1
Justification:
DNEL is based on a chronic study (104 weeks).
AF for interspecies differences (allometric scaling):
4
Justification:
An allometric scaling factor of 4 must be applied because the key study was performed on rats.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 is applied for remaining difference.
AF for intraspecies differences:
10
Justification:
A factor of 10 is applied for the general population DNELs.
AF for the quality of the whole database:
1
Justification:
The key study is considered as a reliable study with a klimisch score of 2
AF for remaining uncertainties:
1
Justification:
No other assessment factor is applied.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.012 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
Dose descriptor starting point:
NOAEL
Value:
1.2 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1.2 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Not required
AF for dose response relationship:
1
Justification:
This factor is applied because the dose-descriptor starting point is a NOAEL.
AF for differences in duration of exposure:
1
Justification:
DNEL is based on a chronic study (104 weeks).
AF for interspecies differences (allometric scaling):
4
Justification:
An allometric scaling factor of 4 must be applied because the key study was performed on rats.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 is applied for remaining difference.
AF for intraspecies differences:
10
Justification:
A factor of 10 is applied for the general population DNELs.
AF for the quality of the whole database:
1
Justification:
The key study is considered as a reliable study with a klimisch score of 2
AF for remaining uncertainties:
1
Justification:
No other assessment factor is applied.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Note : If we use the NOAEL of 0.4 mg/kg bw/day found in the dog repeated study, we have the same DNELs for the systemic effects (long-term).

DNEL (dermal, general population) = 0.4 / (1.4 x 2.5 x 10) = 0.011 mg/kg/d

DNEL (inhalation, general population) = (0.4 x 1/0.4) / (2.5 x 10) = 0.04 mg/m3