Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Guidance on Assessment Factors to Derive a DNEL
Overall assessment factor (AF):
45
Modified dose descriptor starting point:
NOAEC
DNEL value:
88.16 mg/m³
Explanation for the modification of the dose descriptor starting point:

Repeated toxicity studies are available only for the oral route. Effects observed in the acute toxicity studies by oral and inhalation routes are similar, and therefore a route-to-route extrapolation in considered appropriate.

AF for dose response relationship:
1
Justification:
The starting point for the DNEL calculation was a NOAEL, therefore the default assessment factor, as a standard procedure, is 1.
AF for differences in duration of exposure:
6
Justification:
An assessment factor of 6 has been applied in order to consider the differences in the duration of the exposure between the oral reproductive/developmental toxicity study and a chronic exposure.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling does not apply in case of oral-inhalation route to route extrapolation.
AF for other interspecies differences:
2.5
Justification:
As no allometric factor has been used, an assessment factor for other interspecies differences has been chosen
AF for intraspecies differences:
3
Justification:
Intraspecies AF for workers population, according to ECETOC guidelines
AF for the quality of the whole database:
1
Justification:
The available data are sufficient to correctly derive the inhalation DNEL
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are foreseen.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Guidance on Assessment Factors to Derive a DNEL
Overall assessment factor (AF):
45
DNEL extrapolated from long term DNEL
Modified dose descriptor starting point:
NOAEC
DNEL value:
88.16 mg/m³
Explanation for the modification of the dose descriptor starting point:

See above.

AF for dose response relationship:
1
Justification:
See above.
AF for interspecies differences (allometric scaling):
1
Justification:
See above.
AF for other interspecies differences:
2.5
Justification:
See above.
AF for intraspecies differences:
1
Justification:
See above.
AF for the quality of the whole database:
1
Justification:
See above.
AF for remaining uncertainties:
6
Justification:
An assessment factor of 6 has been applied in order to consider the differences in the duration of the exposure between the oral reproductive/developmental toxicity study and a chronic exposure.

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Guidance on Assessment Factors to Derive a DNEL
Overall assessment factor (AF):
45
Dose descriptor:
NOAEC
AF for dose response relationship:
1
Justification:
See above.
AF for differences in duration of exposure:
6
Justification:
See above.
AF for interspecies differences (allometric scaling):
1
Justification:
See above.
AF for other interspecies differences:
2.5
Justification:
See above.
AF for intraspecies differences:
3
Justification:
See above.
AF for the quality of the whole database:
1
Justification:
See above.
AF for remaining uncertainties:
1
Justification:
See above.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Guidance on Assessment Factors to Derive a DNEL
Overall assessment factor (AF):
45
Dose descriptor starting point:
NOAEC
AF for dose response relationship:
1
Justification:
See above.
AF for interspecies differences (allometric scaling):
1
Justification:
See above.
AF for other interspecies differences:
2.5
Justification:
See above.
AF for intraspecies differences:
3
Justification:
See above.
AF for the quality of the whole database:
1
Justification:
See above.
AF for remaining uncertainties:
6
Justification:
See above.

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.4 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Guidance on Assessment Factors to Derive a DNEL
Overall assessment factor (AF):
72
Modified dose descriptor starting point:
NOAEL
DNEL value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Repeated toxicity studies are available only for the oral route. Effects observed in the acute toxicity study by oral route are more severe than effects observed in the acute dermal toxicity study. Therefore a route-to-route extrapolation is considered appropriate and even conservative with respect to the expected hazard for dermal route.

AF for dose response relationship:
1
Justification:
The starting point for the DNEL calculation was a NOAEL, therefore the default assessment factor, as a standard procedure, is 1.
AF for differences in duration of exposure:
6
Justification:
An assessment factor of 6 has been applied in order to consider the differences in the duration of the exposure between the oral reproductive/developmental toxicity study and a chronic exposure.
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling for rats involves a default assessment factor of 4.
AF for other interspecies differences:
1
Justification:
An additional AF for interspecies differences is considered not necessary, because allometric scaling will be conservative enough.
AF for intraspecies differences:
3
Justification:
Intraspecies AF for workers population, according to ECETOC guidelines
AF for the quality of the whole database:
1
Justification:
The available data are sufficient to correctly derive the inhalation DNEL
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are foreseen.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.09 mg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Guidance on Assessment Factors to Derive a DNEL
Overall assessment factor (AF):
18
Dose descriptor:
other: LOAEL
AF for dose response relationship:
2
Justification:
A good dose-response relationship was possible to asses because in the LLNA study, but, considering the use of LOAEL instead of a NOAEL, an AF of 2 has been evaluated as appropriate.
AF for differences in duration of exposure:
1
Justification:
No assessment factor for the duration and frequency of exposure was considered necessary. Repeated exposure to the substance will not worsen the sensitizing effects.
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling is needed for local effects.
AF for other interspecies differences:
1
Justification:
An additional AF for interspecies differences is considered not necessary, because allometric scaling will be conservative enough.
AF for intraspecies differences:
3
Justification:
Intraspecies AF for workers population, according to ECETOC guidelines
AF for the quality of the whole database:
1
Justification:
The available data are sufficient to correctly derive the inhalation DNEL
AF for remaining uncertainties:
3
Justification:
An assessment factor of 3 has been used in order to consider possible differences in matrix effects.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.09 mg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Guidance on Assessment Factors to Derive a DNEL
Overall assessment factor (AF):
18
Dose descriptor starting point:
other: LOAEL
AF for dose response relationship:
2
Justification:
No dose-response relationship was possible to asses because the LOAEL derived from a single exposure toxicity study, but the irritation effect observed at the dose of 2,000 mg/kg was considered consistent with the non-irritating properties of the substance according to the skin irritation/corrosion endpoint studies. According to the above considerations and considering the use of a LOAEL instead of a NOAEL, an AF of 2 has been evaluated as appropriate.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling for mice involves a default assessment factor of 7.
AF for other interspecies differences:
1
Justification:
No allometric scaling is needed for local effects.
AF for intraspecies differences:
3
Justification:
Intraspecies AF for workers population, according to ECETOC guidelines
AF for the quality of the whole database:
1
Justification:
The available data are sufficient to correctly derive the inhalation DNEL
AF for remaining uncertainties:
3
Justification:
An assessment factor of 3 has been used in order to consider possible differences in matrix effects.

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

DNELs for inhalation and dermal routes of exposure have been derived. The DNEL derived for inhalation route systemic effects after long term-exposure has been used also to cover the hazards relater to local effects and short-term exposure because it has been considered conservative enough to protect workers also from other hazards related to inhalation exposure. These DNELs derive from the NOAEL observed in the reproduction/developmental toxicity screening test, performed by oral route. Also the DNEL for systemic effects after a dermal repeated exposure has been derived from the same oral toxicity study, therefore a route-to-route extrapolation have been deemed necessary in order to obtain the correct starting points for the derivation of the inhalation and dermal DNELs.

DNELs for local effects after dermal exposure have been derived from the skin sensitization study, in which theEC3value has been calculatedat 6.51%. As the starting dose descriptor was expressed as a percentage, a correction has been calculated in order to obtain the correct starting point in mg/cm2of skin.

The correct starting points were then divided by an overall assessment factor, which was a result of various consideration on uncertainties on inter-and intra-species variations, and on differences in the duration of exposure between test animals and humans. Moreover also the whole quality of the database was considered.

No DNEL was derived for systemic effects after short-term dermal exposure, because no hazard has been identified (i.e. the studies performed for the skin irritation/corrosion endpoint gave non-irritant results) and no DNEL have been derived for the eye irritation effects, for which a qualitative approach has been followed, leading to a low hazard for this endpoint.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.6 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Guidance on Assessment Factors to Derive a DNEL
Overall assessment factor (AF):
75
Modified dose descriptor starting point:
NOAEC
DNEL value:
43.5 mg/m³
Explanation for the modification of the dose descriptor starting point:

Repeated toxicity studies are available only for the oral route. Effects observed in the acute toxicity studies by oral and inhalation routes are similar, and therefore a route-to-route extrapolation in considered appropriate.

AF for dose response relationship:
1
Justification:
The starting point for the DNEL calculation was a NOAEL, therefore the default assessment factor, as a standard procedure, is 1.
AF for differences in duration of exposure:
6
Justification:
An assessment factor of 6 has been applied in order to consider the differences in the duration of the exposure between the oral reproductive/developmental toxicity study and a chronic exposure.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling does not apply in case of oral-inhalation route to route extrapolation.
AF for other interspecies differences:
2.5
Justification:
As no allometric factor has been used, an assessment factor for other interspecies differences has been chosen
AF for intraspecies differences:
5
Justification:
Intraspecies AF for general population, according to ECETOC guidelines
AF for the quality of the whole database:
1
Justification:
The available data are sufficient to correctly derive the inhalation DNEL
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are foreseen.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.6 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Guidance on Assessment Factors to Derive a DNEL
Overall assessment factor (AF):
75
DNEL extrapolated from long term DNEL
Modified dose descriptor starting point:
NOAEC
DNEL value:
43.5 mg/m³
Explanation for the modification of the dose descriptor starting point:

See above.

AF for dose response relationship:
1
Justification:
See above.
AF for interspecies differences (allometric scaling):
1
Justification:
See above.
AF for other interspecies differences:
2.5
Justification:
See above.
AF for intraspecies differences:
5
Justification:
See above.
AF for the quality of the whole database:
1
Justification:
See above.
AF for remaining uncertainties:
6
Justification:
An assessment factor of 6 has been applied in order to consider the differences in the duration of the exposure between the oral reproductive/developmental toxicity study and a chronic exposure.

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.6 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Guidance on Assessment Factors to Derive a DNEL
Overall assessment factor (AF):
75
Dose descriptor:
NOAEC
AF for dose response relationship:
1
Justification:
See above.
AF for differences in duration of exposure:
6
Justification:
See above.
AF for interspecies differences (allometric scaling):
1
Justification:
See above.
AF for other interspecies differences:
2.5
Justification:
See above.
AF for intraspecies differences:
5
Justification:
See above.
AF for the quality of the whole database:
1
Justification:
See above.
AF for remaining uncertainties:
1
Justification:
See above.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.6 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Guidance on Assessment Factors to Derive a DNEL
Overall assessment factor (AF):
75
DNEL extrapolated from long term DNEL
Dose descriptor starting point:
NOAEC
AF for dose response relationship:
1
Justification:
See above.
AF for interspecies differences (allometric scaling):
1
Justification:
See above.
AF for other interspecies differences:
2.5
Justification:
See above.
AF for intraspecies differences:
3
Justification:
See above.
AF for the quality of the whole database:
1
Justification:
See above.
AF for remaining uncertainties:
6
Justification:
See above.

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.8 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Guidance on Assessment Factors to Derive a DNEL
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
DNEL value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Repeated toxicity studies are available only for the oral route. Effects observed in the acute toxicity study by oral route are more severe than effects observed in the acute dermal toxicity study. Therefore a route-to-route extrapolation is considered appropriate and even conservative with respect to the expected hazard for dermal route.

AF for dose response relationship:
1
Justification:
The starting point for the DNEL calculation was a NOAEL, therefore the default assessment factor, as a standard procedure, is 1.
AF for differences in duration of exposure:
6
Justification:
An assessment factor of 6 has been applied in order to consider the differences in the duration of the exposure between the oral reproductive/developmental toxicity study and a chronic exposure.
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling for rats involves a default assessment factor of 4.
AF for other interspecies differences:
1
Justification:
An additional AF for interspecies differences is considered not necessary, because allometric scaling will be conservative enough.
AF for intraspecies differences:
5
Justification:
Intraspecies AF for general population, according to ECETOC guidelines
AF for the quality of the whole database:
1
Justification:
The available data are sufficient to correctly derive the inhalation DNEL
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are foreseen.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.05 mg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Guidance on Assessment Factors to Derive a DNEL
Overall assessment factor (AF):
30
Dose descriptor:
other: LOAEL
AF for dose response relationship:
2
Justification:
A good dose-response relationship was possible to asses because in the LLNA study, but, considering the use of LOAEL instead of a NOAEL, an AF of 2 has been evaluated as appropriate.
AF for differences in duration of exposure:
1
Justification:
No assessment factor for the duration and frequency of exposure was considered necessary. Repeated exposure to the substance will not worsen the sensitizing effects.
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling is needed for local effects.
AF for other interspecies differences:
1
Justification:
An additional AF for interspecies differences is considered not necessary, because allometric scaling will be conservative enough.
AF for intraspecies differences:
5
Justification:
Intraspecies AF for general population, according to ECETOC guidelines
AF for the quality of the whole database:
1
Justification:
The available data are sufficient to correctly derive the inhalation DNEL
AF for remaining uncertainties:
3
Justification:
An assessment factor of 3 has been used in order to consider possible differences in matrix effects.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.05 mg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Guidance on Assessment Factors to Derive a DNEL
Overall assessment factor (AF):
30
Dose descriptor starting point:
other: LOAEL
AF for dose response relationship:
2
Justification:
A good dose-response relationship was possible to asses because in the LLNA study, but, considering the use of LOAEL instead of a NOAEL, an AF of 2 has been evaluated as appropriate.
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling is needed for local effects.
AF for other interspecies differences:
1
Justification:
An additional AF for interspecies differences is considered not necessary, because allometric scaling will be conservative enough.
AF for intraspecies differences:
5
Justification:
Intraspecies AF for general population, according to ECETOC guidelines
AF for the quality of the whole database:
1
Justification:
The available data are sufficient to correctly derive the inhalation DNEL
AF for remaining uncertainties:
3
Justification:
An assessment factor of 3 has been used in order to consider possible differences in matrix effects.

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.8 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Guidance on Assessment Factors to Derive a DNEL
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
DNEL value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

None.

AF for dose response relationship:
1
Justification:
The starting point for the DNEL calculation was a NOAEL, therefore the default assessment factor, as a standard procedure, is 1.
AF for differences in duration of exposure:
6
Justification:
An assessment factor of 6 has been applied in order to consider the differences in the duration of the exposure between the oral reproductive/developmental toxicity study and a chronic exposure.
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling for rats involves a default assessment factor of 4.
AF for other interspecies differences:
1
Justification:
An additional AF for interspecies differences is considered not necessary, because allometric scaling will be conservative enough.
AF for intraspecies differences:
5
Justification:
Intraspecies AF for general population, according to ECETOC guidelines
AF for the quality of the whole database:
1
Justification:
The available data are sufficient to correctly derive the inhalation DNEL
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are foreseen.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.8 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Guidance on Assessment Factors to Derive a DNEL
Overall assessment factor (AF):
120
DNEL extrapolated from long term DNEL
Modified dose descriptor starting point:
NOAEL
DNEL value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

None.

AF for dose response relationship:
1
Justification:
The starting point for the DNEL calculation was a NOAEL, therefore the default assessment factor, as a standard procedure, is 1.
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling for rats involves a default assessment factor of 4.
AF for other interspecies differences:
1
Justification:
An additional AF for interspecies differences is considered not necessary, because allometric scaling will be conservative enough.
AF for intraspecies differences:
5
Justification:
Intraspecies AF for general population, according to ECETOC guidelines
AF for the quality of the whole database:
1
Justification:
The available data are sufficient to correctly derive the inhalation DNEL
AF for remaining uncertainties:
6
Justification:
An assessment factor of 6 has been applied in order to consider the differences in the duration of the exposure between the oral reproductive/developmental toxicity study and a chronic exposure.

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

DNELs for inhalation, dermal and oral routes of exposure have been derived. The DNEL derived for inhalation route systemic effects after long term-exposure has been used also to cover the hazards relater to local effects and short-term exposure because it has been considered conservative enough to protect general population also from other hazards related to inhalation exposure. These DNELs derive from the NOAEL observed in the reproduction/developmental toxicity screening test, performed by oral route. Also the DNEL for systemic effects after a dermal repeated exposure has been derived from the same oral toxicity study, therefore a route-to-route extrapolation have been deemed necessary in order to obtain the correct starting point for the derivation of the inhalation and dermal DNELs.

DNELs for local effects after dermal exposure have been derived from the skin sensitization study, in which theEC3value has been calculatedat 6.51%. As the starting dose descriptor was expressed as a percentage, a correction has been calculated in order to obtain the correct starting point in mg/cm2of skin.

Also DNELs for the oral exposure derive from the reproduction/developmental toxicity screening test but, in this case, no route-to-route extrapolation have been considered necessary.

The correct starting points were then divided by an overall assessment factor, which was a result of various consideration on uncertainties on inter-and intra-species variations, and on differences in the duration of exposure between test animals and humans. Moreover also the whole quality of the database was considered.

No DNEL was derived for systemic effects after short-term dermal exposure, because no hazard has been identified (i.e. the studies performed for the skin irritation/corrosion endpoint gave non-irritant results) and no DNEL have been derived for the eye irritation effects, for which a qualitative approach has been followed, leading to a low hazard for this endpoint.