Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.68 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):
75
Dose descriptor starting point:
LOAEL
Value:
29 mg/kg bw/day
Modified dose descriptor starting point:
LOAEC
Value:
51.1 mg/m³
Explanation for the modification of the dose descriptor starting point:

Due to lack of repeated dose toxicity data by the inhalation route, a route to route extrapolation was performed. The NOAEL (oral) is converted into a NOAEC (corrected) in accordance to guidance on information requirements and chemical safety assessment, Chapter R.8, ECHA, May 2008. The NOAEL (oral) has to be divided by a factor of 0.38 m³/kg body weight and corrected for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m³/10 m³). The corrected starting point is therefore:

LOAEC (corrected) = 29 mg/kg / 0.38 m³/kg x (6.7 m³/10m³) = 51.1 mg/m³.

AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
extrapolation from subchronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is part of the route to route extrapolation
AF for other interspecies differences:
2.5
Justification:
standard factor for remaining uncertainties
AF for intraspecies differences:
5
Justification:
standard factor for worker
AF for the quality of the whole database:
1
Justification:
the database is considered sufficient
AF for remaining uncertainties:
3
Justification:
additional factor for using a LOAEL.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no 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:
0.5 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):
300
Dose descriptor starting point:
LOAEL
Value:
29 mg/kg bw/day
Modified dose descriptor starting point:
LOAEL
Value:
145 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The dermal route is typically covered by oral route information in the absence of data for this administration route. No data on skin permeation is available. According to the formula published by Fitzpatrick et al (Chemosphere. 2004 Jun;55(10):1309-14), a skin permeation coefficient logKp of -6.01 and -4.14 can be calculated for the diester and monoester, respectively. Based on these values, the test substance is slightly permeable. Based on these values a skin absorption of 20% is assumed. The LOAEL is therefore modified by a factor of 5. Taking into account that the point of departure was chosen very conservatively and most studies indicate a higher systemic no-effect level, this adaption is considered appropriate and sufficient.

AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
extrapolation from subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
extrapolation from rat to human
AF for other interspecies differences:
2.5
Justification:
standard factor for remaining uncertainties
AF for intraspecies differences:
5
Justification:
standard factor for worker
AF for the quality of the whole database:
1
Justification:
the database is considered sufficient
AF for remaining uncertainties:
3
Justification:
additional uncertainty factor for unsing a LOAEL.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Identification of relevant dose descriptor

Following a worst-case approach, the LOAEL observed in the subchronic rat study with the structural analogue was used as point of departure for the DNEL derivation. This study showed the most sensitive effect level regarding the commonly observed impacts on body weight gain. In this study, no NOAEL was found. The LOAEL of 29 mg/kg body weight is therefore the starting point.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.17 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):
150
Dose descriptor starting point:
LOAEL
Value:
29 mg/kg bw/day
Modified dose descriptor starting point:
LOAEC
Value:
25.2 mg/m³
Explanation for the modification of the dose descriptor starting point:

Because no inhalation study is available, a route to route extrapolation was performed. The NOAEL (oral) has to be modified into a NOAEC (corrected) in accordance to guidance on information requirements and chemical safety assessment, Chapter R.8, ECHA, May 2008. Here, the NOAEL has to be divided by a factor of 1.15 m3/kg body weight. The corrected starting point is therefore: LOAEC (corrected) = 29 mg/kg / 1.15 m3/kg = 130 mg/m3

AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
extrapolation from subchronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is part of the route to route extrapolation
AF for other interspecies differences:
2.5
Justification:
standard factor for remaining uncertainties
AF for intraspecies differences:
10
Justification:
standard factor for consumer
AF for the quality of the whole database:
1
Justification:
the database is considered sufficient
AF for remaining uncertainties:
3
Justification:
additional factor for using a LOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.25 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):
600
Dose descriptor starting point:
LOAEL
Value:
29 mg/kg bw/day
Modified dose descriptor starting point:
LOAEL
Value:
145 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The dermal route is typically covered by oral route information in the absence of data for this administration route. No data on skin permeation is available. According to the formula published by Fitzpatrick et al (Chemosphere. 2004 Jun;55(10):1309-14), a skin permeation coefficient logKp of -6.01 and -4.14 can be calculated for the diester and monoester, respectively. Based on these values, the test substance is slightly permeable. Based on these values a skin absorption of 20% is assumed. The LOAEL is therefore modified by a factor of 5. Taking into account that the point of departure was chosen very conservatively and most studies indicate a higher systemic no-effect level, this adaption is considered appropriate and sufficient.

AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable
AF for differences in duration of exposure:
2
Justification:
The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
3
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
2.5
Justification:
Recommended AF for other interspecies differences.
AF for intraspecies differences:
10
Justification:
The default value for the more heterogenous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
the database is considered sufficient
AF for remaining uncertainties:
3
Justification:
additional factor for using a LOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information
Justification:
the database is considered sufficient

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.05 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):
600
Dose descriptor starting point:
LOAEL
Value:
29 mg/kg bw/day
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
2.5
Justification:
Recommended AF for other interspecies differences.
AF for intraspecies differences:
10
Justification:
The default value for the more heterogenous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
the data base is considered sufficient
AF for remaining uncertainties:
3
Justification:
remaining uncertainties for using a LOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Identification of relevant dose descriptor

The dose descriptor chosen is the same as for workers (see above). The LOAELL of 29 mg/kg observed in the oral 90-day repeated dose studies with a structural analogue was used as starting point to derive the DNELs.