Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.2 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:
NOAEL
DNEL value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
88.16 mg/m³
Explanation for the modification of the dose descriptor starting point:

NOAEL(oral) converted to NOAEC(inhal)

= 100 mg/kg/day x 1/0.38 (sRV rat) × 50% / 100% (oral abs. rat / inhal abs. human) × 6.7 / 10 (resting/work human respiratory rate)

= 88.16 mg/m3

AF for dose response relationship:
1
Justification:
Default value in line with Section R.8.4.3.1 of Chapter R.8 of Guidance on information requirements and chemical safety assessment
AF for differences in duration of exposure:
6
Justification:
Extrapolation from subacute study to chronic exposure value in line with Table R.8-5 of Chapter R.8 of Guidance on information requirements and chemical safety assessment
AF for interspecies differences (allometric scaling):
1
Justification:
Interspecies differences addressed in calculation of dose descriptor starting point
AF for other interspecies differences:
2.5
Justification:
Default factor for remaining interspecies differences.
AF for intraspecies differences:
5
Justification:
Default value in line with Section R.8.4.3.1 of Chapter R.8 of Guidance on information requirements and chemical safety assessment
AF for the quality of the whole database:
1
Justification:
Sufficient data for tonnage.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
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:
0.17 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:
NOAEL
DNEL value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
50 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

It is assumed that absorption via the tested route (oral) is greater that of the route of interest (dermal). i.e. oral absorption is 100% and dermal absorption is 50%. This gives a modified dose descriptor starting point of 100 mg/kg/day x 50% / 100% = 50 mg/kg/day

AF for dose response relationship:
1
Justification:
Clear NOELs derived. No uncertainty about dose response
AF for differences in duration of exposure:
6
Justification:
Sub-acute to chronic default factor.
AF for interspecies differences (allometric scaling):
4
Justification:
Rat to human default factor.
AF for other interspecies differences:
2.5
Justification:
Default factor for remaining interspecies differences
AF for intraspecies differences:
5
Justification:
Default factor for workers.
AF for the quality of the whole database:
1
Justification:
Sufficient data for tonnage.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.01 mg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
375
Dose descriptor:
other: EC3
DNEL value:
4.1 mg/m³
AF for dose response relationship:
3
Justification:
Default factor for correction of EC3 to EC1.
AF for differences in duration of exposure:
10
Justification:
LLNA to chronic exposure.
AF for interspecies differences (allometric scaling):
1
Justification:
Not required for local effects.
AF for other interspecies differences:
2.5
Justification:
Default factor for remaining interspecies differences.
AF for intraspecies differences:
5
Justification:
Default factor for workers
AF for the quality of the whole database:
1
Justification:
Sufficient data for tonnage.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

The substance is not acutely toxic via the oral or dermal routes, with LD50 values greater than 3000 mg/kg bw and 2000 mg/kg bw, respectively. There were no effects in the GLP compliant OECD 422 study (klimisch 1) that would indicate there was a potential for adverse local effects. In addition, the substance is not irritating to skin or eyes. On this basis no acute DNELs were considered necessary either for systemic or local effects. However, the substance is a skin sensitiser. Therefore, a dermal, long term, local effects DNEL has been set. Risk Management Measures to prevent exceedance of the long term dermal DNEL are considered to protect against acute exposure with respect to skin sensitisation potential.

 

Based on a complete set of in vitro genotoxicity studies, it is concluded that the substance has no genotoxic properties.

 

In a fully GLP compliant OECD 422 study (Klimisch 1), the overall NOAEL for the study was 100 mg/kg/day based on involution of the acinus in the mammary glands (inguinal region) in the female 300 mg/kg/day dose group and a high value in albumin in the male 300 mg/kg/day dose group. This study was used for setting long-term systemic DNELs.

For the purposes of human risk assessment there is sufficient information to consider that the substance would be fully absorbed (100%) by the oral route, and metabolised and excreted. Human dermal absorption is assumed at 50% and inhalation absorption is assumed to be complete.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.29 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:
NOAEL
DNEL value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
43.48 mg/m³
Explanation for the modification of the dose descriptor starting point:

NOAEL(oral) converted to NOAEC(inhal)

= 100 mg/kg/day x 1/1.15 (sRV rat)×50% / 100% (oral abs. rat / inhal abs. human)

= 43.48 mg/m3

AF for dose response relationship:
1
Justification:
Default value in line with Section R.8.4.3.1 of Chapter R.8 of Guidance on information requirements and chemical safety assessment
AF for differences in duration of exposure:
6
Justification:
Extrapolation from subacute study to chronic exposure value in line with Table R.8-5 of Chapter R.8 of Guidance on information requirements and chemical
AF for interspecies differences (allometric scaling):
1
Justification:
Interspecies differences addressed in calculation of dose descriptor starting point
AF for other interspecies differences:
2.5
Justification:
Default factor for remaining interspecies differences.
AF for intraspecies differences:
10
Justification:
Default value in line with Section R.8.4.3.1 of Chapter R.8 of Guidance on information requirements and chemical safety assessment
AF for the quality of the whole database:
1
Justification:
Sufficient data for tonnage.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.

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:
0.083 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:
NOAEL
DNEL value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
50 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

It is assumed that absorption via the tested route (oral) is greater that of the route of interest (dermal). i.e. oral absorption is 100% and dermal absorption is 50%. This gives a modified dose descriptor starting point of 100 mg/kg/day x50% / 100% = 50 mg/kg/day

AF for dose response relationship:
1
Justification:
Default value in line with Section R.8.4.3.1 of Chapter R.8 of Guidance on information requirements and chemical safety assessment
AF for differences in duration of exposure:
6
Justification:
Extrapolation from subacute study to chronic exposure value in line with Table R.8-5 of Chapter R.8 of Guidance on information requirements and chemical safety assessment
AF for interspecies differences (allometric scaling):
4
Justification:
Default for allometric scaling between rat and man
AF for other interspecies differences:
2.5
Justification:
Default factor for remaining interspecies differences.
AF for intraspecies differences:
10
Justification:
Default value in line with Section R.8.4.3.1 of Chapter R.8 of Guidance on information requirements and chemical safety assessment
AF for the quality of the whole database:
1
Justification:
Sufficient data for tonnage.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.005 mg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
750
Dose descriptor:
other: EC50
DNEL value:
4.1 mg/m³
AF for dose response relationship:
3
Justification:
Default factor for correction of EC3 to EC1.
AF for differences in duration of exposure:
10
Justification:
LLNA to chronic exposure.
AF for interspecies differences (allometric scaling):
1
Justification:
Not required for local effects.
AF for other interspecies differences:
2.5
Justification:
Default factor for remaining interspecies differences.
AF for intraspecies differences:
10
Justification:
Default factor for the general population
AF for the quality of the whole database:
1
Justification:
Sufficient data for tonnage.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.17 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:
NOAEL
DNEL value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No modification

AF for dose response relationship:
1
Justification:
Default value in line with Section R.8.4.3.1 of Chapter R.8 of Guidance on information requirements and chemical safety assessment
AF for differences in duration of exposure:
6
Justification:
Extrapolation from subacute study to chronic exposure value in line with Table R.8-5 of Chapter R.8 of Guidance on information requirements and chemical safety assessment
AF for interspecies differences (allometric scaling):
4
Justification:
Default factor for extrapolating from rat to man
AF for other interspecies differences:
2.5
Justification:
Default factor for remaining interspecies differences.
AF for intraspecies differences:
10
Justification:
Default value in line with Section R.8.4.3.1 of Chapter R.8 of Guidance on information requirements and chemical safety assessment
AF for the quality of the whole database:
1
Justification:
Sufficient data for tonnage.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
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

The substance is not acutely toxic via the oral or dermal routes, with LD50 values greater than 3000 mg/kg bw and 2000 mg/kg bw, respectively. There were no effects in the GLP compliant OECD 422 study (klimisch 1) that would indicate there was a potential for adverse local effects. In addition, the substance is not irritating to skin or eyes. On this basis no acute DNELs were considered necessary either for systemic or local effects. However, the substance is a skin sensitiser. Therefore, a dermal, long term, local effects DNEL has been set. Risk Management Measures to prevent exceedance of the long term dermal DNEL are considered to protect against acute exposure with respect to skin sensitisation potential.

 

Based on a complete set of in vitro genotoxicity studies, it is concluded that the substance has no genotoxic properties.

 

In a fully GLP compliant OECD 422 study (Klimisch 1), the overall NOAEL for the study was 100 mg/kg/day based on involution of the acinus in the mammary glands (inguinal region) in the female 300 mg/kg/day dose group and a high value in albumin in the male 300 mg/kg/day dose group. This study was used for setting long-term systemic DNELs.

For the purposes of human risk assessment there is sufficient information to consider that the substance would be fully absorbed (100%) by the oral route, and metabolised and excreted. Human dermal absorption is assumed at 50% and inhalation absorption is assumed to be complete.