Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7.7 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECETOC guidance (ECETOC, Technical Report No. 110, 2010)
Overall assessment factor (AF):
6
Dose descriptor starting point:
NOAEL
DNEL value:
37.5 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
46.3 mg/m³
Explanation for the modification of the dose descriptor starting point:

The substance fulfils the REACH Annex VII to Annex X information requirements in accordance with ECHA guidance R7.5-7.7 (2016) for assessing long-term systemic toxicity. Since no repeated dose inhalation study is available, route-to-route extrapolation from the oral exposure route is performed. The starting point is the NOAEL from the 90-day gavage study in rats; 37.5 mg/kg bw/day.

This oral rat NOAEL is converted to an inhalation NOAEC for rats by using a default respiratory volume for the rat corresponding to 8 hours (0.38 m3/kg bw/day). A factor for route-to-route extrapolation is included based on the default absorption values (R.7.12. June 2017). The resulting rat inhalation NOAEC is converted into inhalation worker NOAEC by correction for respiratory rate based on activity (6.7 m³ for normal light activity versus 10 m³ for worker activity) and by correction for 5 day exposure (7 days exposure per week in the study versus 5 days per week for workers): 37.5 * (1/0.38) * (50/100) * (6.7/10) * (7/5) = 46.3 mg/m3

AF for dose response relationship:
1
Justification:
In accordance with ECETOC guidance on derivation of assessment factors for human health risk assessment – No. 110, no assessment factor for dose response relationship is necessary since an appropriate NOAEL, derived from a study which is of good quality and without uncertainties, is available.
AF for differences in duration of exposure:
2
Justification:
In accordance with ECETOC guidance on derivation of assessment factors for human health risk assessment – No. 110, a default assessment factor of 2 is recommended for extrapolation from sub-chronic to chronic exposure.
AF for interspecies differences (allometric scaling):
1
Justification:
In accordance with ECETOC guidance on derivation of assessment factors for human health risk assessment – No. 110, no assessment factor for allometric scaling needs to be applied in case of oral to inhalation route-to-route extrapolation.
AF for other interspecies differences:
1
Justification:
In accordance with ECETOC guidance on derivation of assessment factors for human health risk assessment – No. 110, the application of allometric scaling is recommended for the interspecies extrapolation from animals to humans of systemic effects, with no need for a factor for any residual interspecies variability after scaling.
AF for intraspecies differences:
3
Justification:
In accordance with ECETOC guidance on derivation of assessment factors for human health risk assessment – No. 110, a default assessment factor of 3 is recommended for the worker population.
AF for the quality of the whole database:
1
Justification:
A sub-chronic study is available, that is a Klimisch 1 study (OECD Guideline and compliant to GLP). Therefore, the quality of the whole database is good and no assessment factor for this aspect is necessary.
AF for remaining uncertainties:
1
Justification:
There were no remaining uncertainties and therefore no assessment factor for this aspect is necessary.
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:
2.2 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECETOC guidance (ECETOC, Technical Report No. 110, 2010)
Overall assessment factor (AF):
24
Dose descriptor starting point:
NOAEL
DNEL value:
37.5 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
52.5 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The substance fulfils the REACH Annex VII to Annex X information requirements in accordance with ECHA guidance R7.5-7.7 (2016) for assessing long-term systemic toxicity. Since no repeated dose inhalation study is available, route-to-route extrapolation from the oral exposure route is performed. The starting point is the NOAEL from the 90-day gavage study in rats; 37.5 mg/kg bw/day.

No data for oral and dermal absorption is available, the default absorption factors are for both routes 50%, hence no factor for route-to-route extrapolation is included (R.7.12. June 2017). The resulting rat dermal NOAEL is corrected for 5-day exposure (7 days exposure per week in the study versus 5 days per week for workers): 37.5 * (7/5) = 52.5 mg kg bw/day.

AF for dose response relationship:
1
Justification:
In accordance with ECETOC guidance on derivation of assessment factors for human health risk assessment – No. 110, no assessment factor for dose response relationship is necessary since an appropriate NOAEL, derived from a study which is of good quality and without uncertainties, is available.
AF for differences in duration of exposure:
2
Justification:
In accordance with ECETOC guidance on derivation of assessment factors for human health risk assessment – No. 110, a default assessment factor of 2 is recommended for extrapolation from sub-chronic to chronic exposure.
AF for interspecies differences (allometric scaling):
4
Justification:
In accordance with ECETOC guidance on derivation of assessment factors for human health risk assessment – No. 110, the default assessment factor for allometric scaling from rat to human is 4.
AF for other interspecies differences:
1
Justification:
In accordance with ECETOC guidance on derivation of assessment factors for human health risk assessment – No. 110, the application of allometric scaling is recommended for the interspecies extrapolation from animals to humans of systemic effects, with no need for a factor for any residual interspecies variability after scaling.
AF for intraspecies differences:
3
Justification:
In accordance with ECETOC guidance on derivation of assessment factors for human health risk assessment – No. 110, a default assessment factor of 3 is recommended for the worker population.
AF for the quality of the whole database:
1
Justification:
A sub-chronic study is available, that is a Klimisch 1 study (OECD Guideline and compliant to GLP). Therefore, the quality of the whole database is good and no assessment factor for this aspect is necessary.
AF for remaining uncertainties:
1
Justification:
There were no remaining uncertainties and therefore no assessment factor for this aspect is necessary..
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)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.6 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECETOC guidance (ECETOC, Technical Report No. 110, 2010)
Overall assessment factor (AF):
10
Dose descriptor starting point:
NOAEL
DNEL value:
37.5 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
16.3 mg/m³
Explanation for the modification of the dose descriptor starting point:

The substance fulfils the REACH Annex VII to Annex X information requirements in accordance with ECHA guidance R7.5-7.7 (2016) for assessing long-term systemic toxicity. Since no repeated dose inhalation study is available, route-to-route extrapolation from the oral exposure route is performed. The starting point is the NOAEL from the 90-day gavage study in rats; 37.5 mg/kg bw/day.     

This oral rat NOAEL is converted to an inhalation NOAEC for rats by using a default respiratory volume for the rat corresponding to 24 hours (1.15 m3/kg bw/day). A factor for route-to-route extrapolation is included based on the default absorption values (R.7.12. June 2017): 37.5 * (1/1.15) * (50/100) = 16.3 mg/m3.

AF for dose response relationship:
1
Justification:
In accordance with ECETOC guidance on derivation of assessment factors for human health risk assessment – No. 110, no assessment factor for dose response relationship is necessary since an appropriate NOAEL, derived from a study which is of good quality and without uncertainties, is available.
AF for differences in duration of exposure:
2
Justification:
In accordance with ECETOC guidance on derivation of assessment factors for human health risk assessment – No. 110, a default assessment factor of 2 is recommended for extrapolation from sub-chronic to chronic exposure.
AF for interspecies differences (allometric scaling):
1
Justification:
In accordance with ECETOC guidance on derivation of assessment factors for human health risk assessment – No. 110, no assessment factor for allometric scaling needs to be applied in case of oral to inhalation route-to-route extrapolation.
AF for other interspecies differences:
1
Justification:
In accordance with ECETOC guidance on derivation of assessment factors for human health risk assessment – No. 110, the application of allometric scaling is recommended for the interspecies extrapolation from animals to humans of systemic effects, with no need for a factor for any residual interspecies variability after scaling.
AF for intraspecies differences:
5
Justification:
In accordance with ECETOC guidance on derivation of assessment factors for human health risk assessment – No. 110, a default assessment factor of 5 is recommended for the general population.
AF for the quality of the whole database:
1
Justification:
A sub-chronic study is available, that is a Klimisch 1 study (OECD Guideline and compliant to GLP). Therefore, the quality of the whole database is good and no assessment factor for this aspect is necessary.
AF for remaining uncertainties:
1
Justification:
There were no remaining uncertainties and therefore no assessment factor for this aspect is necessary.
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:
0.9 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECETOC guidance (ECETOC, Technical Report No. 110, 2010)
Overall assessment factor (AF):
40
Dose descriptor starting point:
NOAEL
DNEL value:
37.5 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The substance fulfils the REACH Annex VII to Annex X information requirements in accordance with ECHA guidance R7.5-7.7 (2016) for assessing long-term systemic toxicity. Since no repeated dose inhalation study is available, route-to-route extrapolation from the oral exposure route is performed. The starting point is the NOAEL from the 90-day gavage study in rats; 37.5 mg/kg bw/day.       

No data for oral and dermal absorption is available, the default absorption factors are for both routes 50%, hence no factor for route-to-route extrapolation is included (R.7.12. June 2017).

AF for dose response relationship:
1
Justification:
In accordance with ECETOC guidance on derivation of assessment factors for human health risk assessment – No. 110, no assessment factor for dose response relationship is necessary since an appropriate NOAEL, derived from a study which is of good quality and without uncertainties, is available.
AF for differences in duration of exposure:
2
Justification:
In accordance with ECETOC guidance on derivation of assessment factors for human health risk assessment – No. 110, a default assessment factor of 2 is recommended for extrapolation from sub-chronic to chronic exposure.
AF for interspecies differences (allometric scaling):
4
Justification:
In accordance with ECETOC guidance on derivation of assessment factors for human health risk assessment – No. 110, the default assessment factor for allometric scaling from rat to human is 4.
AF for other interspecies differences:
1
Justification:
In accordance with ECETOC guidance on derivation of assessment factors for human health risk assessment – No. 110, the application of allometric scaling is recommended for the interspecies extrapolation from animals to humans of systemic effects, with no need for a factor for any residual interspecies variability after scaling.
AF for intraspecies differences:
5
Justification:
In accordance with ECETOC guidance on derivation of assessment factors for human health risk assessment – No. 110, a default assessment factor of 5 is recommended for the worker population.
AF for the quality of the whole database:
1
Justification:
A sub-chronic study is available, that is a Klimisch 1 study (OECD Guideline and compliant to GLP). Therefore, the quality of the whole database is good and no assessment factor for this aspect is necessary.
AF for remaining uncertainties:
1
Justification:
There were no remaining uncertainties and therefore no assessment factor for this aspect is necessary.
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)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

General Population - Hazard via oral 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:
other: ECETOC guidance (ECETOC, Technical Report No. 110, 2010)
Overall assessment factor (AF):
40
Dose descriptor starting point:
NOAEL
DNEL value:
37.5 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The substance fulfils the REACH Annex VII to Annex X information requirements in accordance with ECHA guidance R7.5-7.7 (2016) for assessing long-term systemic toxicity. Since no repeated dose inhalation study is available, route-to-route extrapolation from the oral exposure route is performed. The starting point is the NOAEL from the 90-day gavage study in rats; 37.5 mg/kg bw/day.

AF for dose response relationship:
1
Justification:
In accordance with ECETOC guidance on derivation of assessment factors for human health risk assessment – No. 110, no assessment factor for dose response relationship is necessary since an appropriate NOAEL, derived from a study which is of good quality and without uncertainties, is available.
AF for differences in duration of exposure:
2
Justification:
In accordance with ECETOC guidance on derivation of assessment factors for human health risk assessment – No. 110, a default assessment factor of 2 is recommended for extrapolation from sub-chronic to chronic exposure.
AF for interspecies differences (allometric scaling):
4
Justification:
In accordance with ECETOC guidance on derivation of assessment factors for human health risk assessment – No. 110, the default assessment factor for allometric scaling from rat to human is 4.
AF for other interspecies differences:
1
Justification:
In accordance with ECETOC guidance on derivation of assessment factors for human health risk assessment – No. 110, the application of allometric scaling is recommended for the interspecies extrapolation from animals to humans of systemic effects, with no need for a factor for any residual interspecies variability after scaling.
AF for intraspecies differences:
5
Justification:
In accordance with ECETOC guidance on derivation of assessment factors for human health risk assessment – No. 110, a default assessment factor of 3 is recommended for the worker population.
AF for the quality of the whole database:
1
Justification:
A sub-chronic study is available, that is a Klimisch 1 study (OECD Guideline and compliant to GLP). Therefore, the quality of the whole database is good and no assessment factor for this aspect is necessary.
AF for remaining uncertainties:
1
Justification:
There were no remaining uncertainties and therefore no assessment factor for this aspect is necessary.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population