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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.145 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
Modified dose descriptor starting point:
NOAEC
DNEL value:
3.64 mg/m³
Explanation for the modification of the dose descriptor starting point:

APPENDIX R. 8-2 Bioavailability, route-to-route extrapolation and allometric scaling of Chapter R.8: Characterisation of dose [concentration]-response for human health provides for modification of the dose descriptor in calculating DNEL for repeat dose inhalation toxicity.

AF for dose response relationship:
1
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for differences in duration of exposure:
2
Justification:
Duration of exposure: subchronic to chronic
Justification:
10.5 mg/m3 (8.33/4 * 70/20 x 0.5 [rat oral abs 50%/human inhalation abs 100%])
AF for intraspecies differences:
5
Justification:
intraspecies – workers
AF for the quality of the whole database:
1
Justification:
quality of data base
AF for remaining uncertainties:
2.5
Justification:
remaining differences
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
700 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12.5
Modified dose descriptor starting point:
other: LD50 - oral
DNEL value:
8 750 mg/m³
Explanation for the modification of the dose descriptor starting point:

It is acceptable to use the value where a limit test has been conducted, and no adverse effects on health have been observed, then the limit dose can be regarded as the dose descriptor in setting the DNEL. Due to the low vapour pressure are negligible.  Any substance ingested will remain in the mouth/nose with the potential for subsequent oral exposure.  Hence LD50 for oral toxicity is considered the appropriate endpoint for hazard assessment in the absence of specific information on inhalation toxicity.

AF for dose response relationship:
1
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling factor: 4 BW(human) = 70 kg, Hrv = Human respiration rate = 10 m3 / person. = 5000 / 4 * 70/10 = 3500 mg/m3
AF for intraspecies differences:
5
Justification:
intraspecies – workers
AF for the quality of the whole database:
1
Justification:
quality of data base
AF for remaining uncertainties:
2.5
Justification:
remaining differences

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:
0.416 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
Modified dose descriptor starting point:
NOAEL
DNEL value:
41.65 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

APPENDIX R. 8-2 Bioavailability, route-to-route extrapolation and allometric scaling of Chapter R.8: Characterisation of dose [concentration]-response for human health provides for modification of the dose descriptor in calculating DNEL

AF for dose response relationship:
1
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for differences in duration of exposure:
2
Justification:
duration of exposure: subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for intraspecies differences:
5
Justification:
intraspecies – workers
AF for the quality of the whole database:
1
Justification:
quality of database
AF for remaining uncertainties:
2.5
Justification:
remaining differences
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2 000 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
other: LD50, dermal
DNEL value:
10 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Guidance on information requirements and chemical safety assessment; Chapter R.7a: Endpoint specific guidance, section R.7.4.5.2 Concluding on suitability for Chemical Safety Assessment for acute toxicity states that when a limit test has been conducted, and no adverse effects on health have been observed, then the limit dose can be regarded as the NOAEL.

AF for dose response relationship:
1
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for other interspecies differences:
4
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for intraspecies differences:
5
Justification:
intraspecies – workers
AF for the quality of the whole database:
1
Justification:
quality of database
AF for remaining uncertainties:
2.5
Justification:
remaining differences

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
16 mg/cm²
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
DNEL derivation method:
other: Standard derivation
Overall assessment factor (AF):
5
Dose descriptor starting point:
other: NOAEL
AF for intraspecies differences:
5
Justification:
intraspecies - workers

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

The test substance does not have any local irritating or sensitizing effects in animals. By extrapolation it is possible to calculate systemic and local DNELS for short term and some long term exposure; however calculation of long term local DNELS for local effects on the basis of the available data does not seem to be reasonable, as the substance is not classified for acute toxicological effects. The assessment factors applied for long term systemic effects are deemed to provide suitable exposure modelling for risk assessment.

The same toxicological endpoints chosen for setting the DNELs for workers have been used for setting DNELs for the general population. The increased assessment factor for interspecies sensitivity is considered sufficiently protective.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Value:
0.07 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEC
DNEL value:
3.62 mg/m³
Explanation for the modification of the dose descriptor starting point:

APPENDIX R. 8-2 Bioavailability, route-to-route extrapolation and allometric scaling of Chapter R.8: Characterisation of dose [concentration]-response for human health provides for modification of the dose descriptor in calculating DNEL for repeat dose inhalation toxicity.

AF for dose response relationship:
1
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for differences in duration of exposure:
2
Justification:
duration of exposure – subchronic to chronic
Justification:
Corrected dose descriptor: 3.62 mg/kg bw (8.33 mg/kg bw/day x 1/1.15 x 0.5 [rat oral abs 50%/human inhalation abs 100%])
AF for intraspecies differences:
10
Justification:
intraspecies – general population
AF for the quality of the whole database:
1
Justification:
Quality of the database
AF for remaining uncertainties:
2.5
Justification:
remaining differences
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
350 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: LD50 oral
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
DNEL value:
8 750 mg/m³
Explanation for the modification of the dose descriptor starting point:

It is acceptable to use the value where a limit test has been conducted, and no adverse effects on health have been observed, then the limit dose can be regarded as the dose descriptor in setting the DNEL. Due to the low vapour pressure are negligible.  Any substance ingested will remain in the mouth/nose with the potential for subsequent oral exposure.  Hence LD50 for oral toxicity is considered the appropriate endpoint for hazard assessment in the absence of specific information on inhalation toxicity.

AF for dose response relationship:
1
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for intraspecies differences:
10
Justification:
intraspecies – general population
AF for the quality of the whole database:
1
Justification:
quality of the database
AF for remaining uncertainties:
2.5
Justification:
remaining differences

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:
0.208 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
Modified dose descriptor starting point:
NOAEL
DNEL value:
41.65 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

APPENDIX R. 8-2 Bioavailability, route-to-route extrapolation and allometric scaling of Chapter R.8: Characterisation of dose [concentration]-response for human health provides for modification of the dose descriptor in calculating DNEL

AF for dose response relationship:
1
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for differences in duration of exposure:
2
Justification:
duration of exposure – subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for intraspecies differences:
10
Justification:
intraspecies – general population
AF for the quality of the whole database:
1
Justification:
quality of the database
AF for remaining uncertainties:
2.5
Justification:
remaining differences
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
100 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
DNEL value:
10 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Guidance on information requirements and chemical safety assessment; Chapter R.7a: Endpoint specific guidance, section R.7.4.5.2 Concluding on suitability for Chemical Safety Assessment for acute toxicity states that when a limit test has been conducted, and no adverse effects on health have been observed, then the limit dose can be regarded as the NOAEL.

AF for dose response relationship:
1
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for interspecies differences (allometric scaling):
4
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for intraspecies differences:
10
Justification:
intraspecies – general population
AF for the quality of the whole database:
1
Justification:
quality of database
AF for remaining uncertainties:
2.5
Justification:
remaining differences

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8 mg/cm²
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
DNEL derivation method:
other: Standard derivation
Overall assessment factor (AF):
10
Dose descriptor starting point:
other: NOAEL
AF for intraspecies differences:
10
Justification:
intraspecies – general population

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.04 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
Modified dose descriptor starting point:
NOAEL
DNEL value:
8.33 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

APPENDIX R. 8-2 Bioavailability, route-to-route extrapolation and allometric scaling of Chapter R.8: Characterisation of dose [concentration]-response for human health provides for modification of the dose descriptor in calculating DNEL

AF for dose response relationship:
1
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for differences in duration of exposure:
2
Justification:
duration of exposure – subacute to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for intraspecies differences:
10
Justification:
intraspecies – general population
AF for the quality of the whole database:
1
Justification:
quality of database
AF for remaining uncertainties:
2.5
Justification:
remaining differences
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
50 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
DNEL value:
5 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

As discussed above, it is acceptable to use the value where a limit test has been conducted, and no adverse effects on health have been observed, then the limit dose can be regarded as the dose descriptor in setting the DNEL. Hence LD50 for oral toxicity is considered the appropriate endpoint for hazard assessment

AF for dose response relationship:
1
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for interspecies differences (allometric scaling):
4
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for intraspecies differences:
10
Justification:
intraspecies – general population
AF for the quality of the whole database:
1
Justification:
quality of database
AF for remaining uncertainties:
2.5
Justification:
remaining differences

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

The test substance does not have any local irritating or sensitizing effects in animals. By extrapolation it is possible to calculate systemic and local DNELS for short term and some long term exposure; however calculation of long term local DNELS for local effects on the basis of the available data does not seem to be reasonable, as the substance is not classified for acute toxicological effects. The assessment factors applied for long term systemic effects are deemed to provide suitable exposure modelling for risk assessment.

The same toxicological endpoints chosen for setting the DNELs for workers have been used for setting DNELs for the general population. The increased assessment factor for interspecies sensitivity is considered sufficiently protective.