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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.27 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:
36 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
31.7 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). In addition, a default factor of 2 is applied to account for differences in oral and inhalative absorption properties. The corrected starting point is therefore: NOAEC (corrected) = 36 mg/kg / 0.38 m³/kg x 0.5 x (6.7 m³/10 m³) = 31.7 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:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
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:
1.8 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:
36 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
180 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.

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:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
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

The most sensititive findings observed in several studies with repeated exposure are effects on the body weight and body weight gain of treated animals. In a 90d study with rats, effects on body weight were observed in females of all treatment groups, resulting in a LOEL of 29 mg/kg body weight, no NOEL was reported for females. However, in this study inflammation was observed in all animals in the study, including controls. In their final decision (Decision number: CCH-D-2114384240-56-01/F) ECHA considered "that the inflammation may have compromised the reliability of the study", therefore the DNEL derivation is based on the NOAEL of 36 mg/kg observed in the extended one-generation reproduction toxicity study (OECD 443) with a structural analogue. In this guideline-compliant study, body weight and body weight gain was also affected in male and female rats, however a clear NOAEL was described for this effect for both female and male rats. Therefore, this study is considered more relevant for risk assessment and the NOAEL of 36 mg/kg body weight us used as starting point for DNEL derivation. The derived DNELs are are also protective from the observed slight reprotoxic effects, since these effects ocurred only at higher dose levels with a higher NOAEL, reuslting in higher DNELs if chosen as starting points.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.31 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):
50
Dose descriptor starting point:
NOAEL
Value:
36 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
15.7 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. In addition, a default factor of 2 is applied to account for differences in oral and inhalative absorption properties. The corrected starting point is therefore: NOAEC (corrected) = 36 mg/kg / 1.15 m³/kg x 0.5 = 15.7 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:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
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:
0.9 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):
200
Dose descriptor starting point:
NOAEL
Value:
36 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
180 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:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
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:
0.18 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):
200
Dose descriptor starting point:
NOAEL
Value:
36 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:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
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 NOAEL of 36 mg/kg observed in the extended one-generation reproduction toxicity study (OECD 443) with a structural analogue was used as starting point to derive the DNELs.

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