Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
31.1 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):
112.5
Dose descriptor starting point:
LOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
3 500 mg/m³
AF for dose response relationship:
3
Justification:
starting point is a LOAEL
AF for differences in duration of exposure:
2
Justification:
subchronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Three different species support the LOAEL, interspecies differences due to allometric scaling do not have to be taken into account.
AF for other interspecies differences:
2.5
AF for intraspecies differences:
5
AF for the quality of the whole database:
1.5
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.89 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):
112.5
Dose descriptor starting point:
LOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
LOAEL
Value:
1 000 mg/kg bw/day
AF for dose response relationship:
3
Justification:
starting point LOAEL
AF for differences in duration of exposure:
2
Justification:
subchronic to chronic
AF for interspecies differences (allometric scaling):
1
AF for other interspecies differences:
2.5
AF for intraspecies differences:
5
AF for the quality of the whole database:
1.5
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
185.8 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
30
AF for dose response relationship:
1
Justification:
Default, based on different concentrations tested in LLNA-test.
AF for interspecies differences (allometric scaling):
1
Justification:
DNEL based on LLNA with d-limonene having the lowest threshold value, while the human study with orange oil (hRIPT) does not show sensitization.
AF for other interspecies differences:
1
AF for intraspecies differences:
5
AF for the quality of the whole database:
2
Justification:
Use of d-limonene data for orange oil.
AF for remaining uncertainties:
3
Justification:
Vehicle or matrix effect (assuming human are exposed in matrix with no penetration enhancers or irritants)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

There is no information on repeated dose toxicity for orange oil, however, several sub-chronic repeated dose toxicity studies are available for its major constituent limonene, in different species. Although the most sensitive NOAEL is from the 1-year dog study, it may not be the most appropriate NOAEL to base the DNEL on. In the 90-d mouse study (NTP, 1990), a NOAEL of 500 mg/kg bw/day was observed, while the LOAEL in this study was the same as in the dog study (1000 mg/kg bw/day). As the studies are performed in different species, the choice for the mouse NOAEL of 500 mg/kg bw/day is arbitrary. However, the shared LOAEL can be used as a starting point for the derivation of the DNEL. Furthermore, an additional dog study is available in which a LOAEL of 1000 mg/kg bw/day was observed (NOAEL 340 mg/kg bw/day), and a 90-day rat study which resulted in a LOAEL of 1200 mg/kg bw/day.

As three different species support the LOAEL, interspecies differences due to allometric scaling do not have to be taken into account. Consequently, route-to route extrapolation from oral to inhalation was performed by correcting for bodyweight and respiratory volume of humans only. In accordance with the Guidance Document on Information Requirements, Chapter R8., absorption of 100% was assumed via the inhalation route, with regard to an oral absorption of 50%. Additionally, the following assessment factors were applied:

  • interspecies effects – remaining differences 2.5
  • intraspecies effects – worker 5
  • duration – subchronic to chronic 2
  • dose response – use of LOAEL 3
  • quality of the database – 1.5, based on limitations of report (publications) or limitations in experimental set-up (NTP-studies)

The DNELs were derived in accordance with the Guidance on Information Requirements and Chemical Safety Assessment Chapter R8.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7.78 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):
225
Dose descriptor starting point:
LOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
1 750 mg/m³
AF for dose response relationship:
3
Justification:
starting point LOAEL
AF for differences in duration of exposure:
2
Justification:
Subchronic to chronic
AF for interspecies differences (allometric scaling):
1
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
AF for the quality of the whole database:
1.5
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.44 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):
225
Dose descriptor starting point:
LOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
LOAEL
Value:
1 000 mg/kg bw/day
AF for dose response relationship:
3
Justification:
Starting point LOAEL
AF for differences in duration of exposure:
2
Justification:
Subchronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
As three different species support the LOAEL, interspecies differences due to allometric scaling do not have to be taken into account.
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
AF for the quality of the whole database:
1.5
AF for remaining uncertainties:
11.5
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
92.9 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
60
AF for dose response relationship:
1
Justification:
default, based on different concentrations tested in LLNA-test
AF for interspecies differences (allometric scaling):
1
Justification:
DNEL based on LLNA with d-limonene having the lowest threshold value, while the human study with orange oil (hRIPT) does not show sensitization
AF for other interspecies differences:
1
AF for intraspecies differences:
10
AF for the quality of the whole database:
2
Justification:
Use of d-limonene data for orange oil.
AF for remaining uncertainties:
3
Justification:
Vehicle or matrix effect (assuming human are exposed in matrix with no penetration enhancers or irritants).

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.44 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):
225
Dose descriptor starting point:
LOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
LOAEL
Value:
1 000 mg/kg bw/day
AF for dose response relationship:
3
Justification:
Starting point LOAEL.
AF for differences in duration of exposure:
2
Justification:
Subchronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
As three different species support the LOAEL, interspecies differences due to allometric scaling do not have to be taken into account.
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
AF for the quality of the whole database:
1.5
AF for remaining uncertainties:
1
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

There is no information on repeated dose toxicity for orange oil, however, several sub-chronic repeated dose toxicity studies are available for its major constituent limonene, in different species. Although the most sensitive NOAEL is from the 1-year dog study, it may not be the most appropriate NOAEL to base the DNEL on. In the 90-d mouse study (NTP, 1990), a NOAEL of 500 mg/kg bw/day was observed, while the LOAEL in this study was the same as in the dog study (1000 mg/kg bw/day). As the studies are performed in different species, the choice for the mouse NOAEL of 500 mg/kg bw/day is arbitrary. However, the shared LOAEL can be used as a starting point for the derivation of the DNEL. Furthermore, an additional dog study is available in which a LOAEL of 1000 mg/kg bw/day was observed (NOAEL 340 mg/kg bw/day), and a 90-day rat study which resulted in a LOAEL of 1200 mg/kg bw/day.

As three different species support the LOAEL, interspecies differences due to allometric scaling do not have to be taken into account. Consequently, route-to route extrapolation from oral to inhalation was performed by correcting for bodyweight and respiratory volume of humans only. In accordance with the Guidance Document on Information Requirements, Chapter R8., absorption of 100% was assumed via the inhalation route, with regard to an oral absorption of 50%. Additionally, the following assessment factors were applied:

  • interspecies effects – remaining differences 2.5
  • intraspecies effects – general population 10
  • duration – subchronic to chronic 2
  • dose response – use of LOAEL 3
  • quality of the database – 1.5, based on limitations of report (publications) or limitations in experimental set-up (NTP-studies)

The DNELs were derived in accordance with the Guidance on Information Requirements and Chemical Safety Assessment Chapter R8.