Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
64 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):
5
Modified dose descriptor starting point:
NOAEC
Value:
320 mg/m³
Explanation for the modification of the dose descriptor starting point:
Factor of 2 was utilized for oral-to-inhalation route extrapolation for DOWFAX 2A1.
AF for dose response relationship:
1
Justification:
Clear dose response with minimal toxicological findings up to the highest dose
AF for differences in duration of exposure:
1
Justification:
Based on chronic exposure from 2-year study
AF for interspecies differences (allometric scaling):
1
Justification:
ECHA guidance, route-to-route extrapolation addresses allometic scaling
AF for other interspecies differences:
1
Justification:
Substance tested in a number of species without significant adverse effects
AF for intraspecies differences:
5
Justification:
Based on ECHA Guidance for workers
AF for the quality of the whole database:
1
Justification:
ECHA default
AF for remaining uncertainties:
1
Justification:
No additional uncertainties identified
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:
18.2 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):
7
Modified dose descriptor starting point:
NOAEL
Value:
128 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Dermal absorption was assumed to be comparable to oral absorption. No route-to-route adjustment was performed for DOWFAX 2A1.
AF for dose response relationship:
1
Justification:
Clear dose response with minimal toxicological findings up to the highest dose
AF for differences in duration of exposure:
1
Justification:
Based on chronic exposure from 2-year study
AF for interspecies differences (allometric scaling):
1.4
Justification:
Based on allometric scaling from dog to human (ECHA guidance)
AF for other interspecies differences:
1
Justification:
Substance tested in a number of species without significant adverse effects
AF for intraspecies differences:
5
Justification:
Based on ECHA Guidance for workers
AF for the quality of the whole database:
1
Justification:
ECHA default
AF for remaining uncertainties:
1
Justification:
No additional uncertainties identified
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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

This substance is not classified as acutely toxic; therefore, acute/short term systemic dermal DNELs were not calculated. 

Chronic, Systemic, Worker Inhalation DNEL

The starting point for the long-term, systemic inhalation DNEL is the chronic oral NOAEL of 128 mg/kg bw/day from the 2-year dog study. Conservative adjustment factor of 2 was applied to the starting NOAEL (64 mg/kg bw/day) to derive the starting inhalation NOAEC (i.e. ~50% oral absorption was assumed compared to 100% for inhalation absorption for DOWFAX 2A1). Based on the conversion, the starting 8hr worker NOAEC was 320 mg/m3. DNEL may be revised once the results from EOGRTS (OECD 443) study will become available.

Route-to-route extrapolation - 2 (Factor of 2 was utilized for oral (50% absorption assumed) to inhalation (100% absorption assumed) route extrapolation for DOWFAX 2A1).

 

The assessment factors for extrapolating to a DNEL are as follows:

Assessment factor for dose-response relationship- 1: clear dose response with minimal toxicological findings up to the highest dose

Allometric scaling - 1 (route-to-route extrapolation addresses allometic scaling)

'Other differences' - 1: as the registered substance (& its ADPODS category members) was tested in a number of species without significant adverse effects, the 2.5 assessment factors is not necessary.

Worker population variability - 5 (ECHA default)

Time extrapolation - 1 (Based on chronic exposure from 2-year study)

Quality of the database - 1 (ECHA default: the data are consistent and sufficient to conclude on a safe human level of exposure)

Total assessment factor: 5

Application of AF leads to inhalation systemic DNEL (worker) of 64 mg/m3.

Chronic, Systemic, Worker Dermal DNEL

The starting point for the long-term, systemic Dermal DNEL is the chronic oral NOAEL of 128 mg/kg bw/day from the 2-year dog study. DNEL may be revised once the results from EOGRTS (OECD 443) study will become available. As the dermal absorption for DOWFAX 2A1 was assumed to be comparable to oral absorption based on modelling of human bioavailability between the two routes, no adjustment was used to derive the starting dermal systemic NOAEL.

Route-to-route extrapolation - 1

The assessment factors for extrapolating to a DNEL are as follows:

Assessment factor for dose-response relationship- 1: clear dose response with minimal toxicological findings up to the highest dose

Allometric scaling - 1.4 (dog to man)

'Other differences' - 1: as the registered substance (& its ADPODS category members) was tested in a number of species without significant adverse effects, the 2.5 assessment factors is not necessary.

Worker population variability - 5 (ECHA default)

Time extrapolation - 1 (Based on chronic exposure from 2-year study)

Quality of the database - 1 (ECHA default: the data are consistent and sufficient to conclude on a safe human level of exposure)

Total assessment factor: 7

Application of AF leads to dermal systemic DNEL (worker) of 18.2 mg/kg/day.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
16 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):
10
Modified dose descriptor starting point:
NOAEC
Value:
160 mg/m³
Explanation for the modification of the dose descriptor starting point:
Factor of 2 was utilized for oral-to-inhalation route extrapolation for DOWFAX 2A1.
AF for dose response relationship:
1
Justification:
clear dose response with minimal toxicological findings up to the highest dose
AF for differences in duration of exposure:
1
Justification:
Based on chronic exposure from 2-year study
AF for interspecies differences (allometric scaling):
1
Justification:
ECHA guidance, route-to-route extrapolation addresses allometic scaling
AF for other interspecies differences:
1
Justification:
Substance tested in a number of species without significant adverse effects
AF for intraspecies differences:
10
Justification:
Based on ECHA Guidance for general population
AF for the quality of the whole database:
1
Justification:
ECHA default
AF for remaining uncertainties:
1
Justification:
No additional uncertainties identified
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:
9.14 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):
14
Modified dose descriptor starting point:
NOAEL
Value:
128 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Dermal absorption was assumed to be comparable to oral absorption. No adjustment was performed.
AF for dose response relationship:
1
Justification:
Clear dose response with minimal toxicological findings up to the highest dose
AF for differences in duration of exposure:
1
Justification:
Based on chronic exposure from 2-year study
AF for interspecies differences (allometric scaling):
1.4
Justification:
Based on allometric scaling from dog to human (ECHA guidance)
AF for other interspecies differences:
1
Justification:
Substance tested in a number of species without significant adverse effects
AF for intraspecies differences:
10
Justification:
Based on ECHA Guidance for General Population
AF for the quality of the whole database:
1
Justification:
ECHA default
AF for remaining uncertainties:
1
Justification:
No additional uncertainties identified
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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
9.14 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):
14
Modified dose descriptor starting point:
NOAEL
Value:
128 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
1 for oral-to-oral route extrapolation (based on ECHA guidance).
AF for dose response relationship:
1
Justification:
Clear dose response with minimal toxicological findings up to the highest dose
AF for differences in duration of exposure:
1
Justification:
Based on chronic exposure from 2-year study
AF for interspecies differences (allometric scaling):
1.4
Justification:
Based on allometric scaling from dog to human (ECHA guidance)
AF for other interspecies differences:
1
Justification:
Substance tested in a number of species without significant adverse effects
AF for intraspecies differences:
10
Justification:
Based on ECHA Guidance for General Population
AF for the quality of the whole database:
1
Justification:
ECHA default
AF for remaining uncertainties:
1
Justification:
No additional uncertainties identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

This substance is not classified as acutely toxic; therefore, acute/short term systemic DNELs were not calculated.

Chronic, Systemic, General Population Inhalation DNEL

The starting point for the long-term, systemic inhalation DNEL is the chronic oral NOAEL of 128 mg/kg bw/day from the 2-year dog study. Conservative adjustment factor of 2 was applied to the starting NOAEL (64 mg/kg bw/day) to derive the starting inhalation NOAEC (i.e. ~50% oral absorption was assumed compared to 100% for inhalation absorption for DOWFAX 2A1). Based on the conversion, the starting 24hr general public NOAEC was 160 mg/m3. DNEL may be revised once the results from EOGRTS (OECD 443) study will become available.

Route-to-route extrapolation - 2 (Factor of 2 was utilized for oral (50% absorption assumed) to inhalation (100% absorption assumed) route extrapolation for DOWFAX 2A1).

 

The assessment factors for extrapolating to a DNEL are as follows:

Assessment factor for dose-response relationship- 1: clear dose response with minimal toxicological findings up to the highest dose

Allometric scaling - 1 (route-to-route extrapolation addresses allometic scaling)

'Other differences' - 1: as the registered substance (& its ADPODS category members) was tested in a number of species without significant adverse effects, the 2.5 assessment factors is not necessary.

General population variability - 10 (ECHA default)

Time extrapolation - 1 (Based on chronic exposure from 2-year study)

Quality of the database - 1 (ECHA default: the data are consistent and sufficient to conclude on a safe human level of exposure)

Total assessment factor: 10

Application of AF leads to inhalation systemic DNEL (general population) of 16 mg/m3.

Chronic, Systemic, General Population Dermal DNEL

The starting point for the long-term, systemic Dermal DNEL is the chronic oral NOAEL of 128 mg/kg bw/day from the 2-year dog study. DNEL may be revised once the results from EOGRTS (OECD 443) study will become available. As the dermal absorption for DOWFAX 2A1 was assumed to be comparable to oral absorption based on modelling of human bioavailability between the two routes, no adjustment was used to derive the starting dermal systemic NOAEL.

Route-to-route extrapolation - 1

The assessment factors for extrapolating to a DNEL are as follows:

Assessment factor for dose-response relationship- 1: clear dose response with minimal toxicological findings up to the highest dose

Allometric scaling - 1.4 (dog to man)

'Other differences' - 1: as the registered substance (& its ADPODS category members) was tested in a number of species without significant adverse effects, the 2.5 assessment factors is not necessary.

General population variability - 10 (ECHA default)

Time extrapolation - 1 (Based on chronic exposure from 2-year study)

Quality of the database - 1 (ECHA default: the data are consistent and sufficient to conclude on a safe human level of exposure)

Total assessment factor: 14

Application of AF leads to dermal systemic DNEL (general population) of 9.14 mg/kg/day.

Chronic, Systemic, General Population Oral DNEL

Even though there are no consumer uses that require derivation of the oral DNEL value, one has been derived and provided for completeness, but not used in the risk characterization calculations.

The starting point for the long-term, systemic oral DNEL is the 2-year dog oral study NOAEL of 128 mg/kg bw/day.

DNEL may be revised once the results from EOGRTS (OECD 443) study will become available.

The assessment factors for extrapolating to a DNEL are as follows:

Allometric scaling - 1.4 (dog to man)

'Other differences' - 1: as the registered substance (& its ADPODS category members) was tested in a number of species without significant adverse effects, the 2.5 assessment factors is not necessary.

General population variability - 10 (based on ECHA guidance)

Time extrapolation - 1 (Based on chronic exposure from 2-year study)

Quality of the database - 1 (ECHA default)

Total assessment factor: 14

Application of AF leads to an oral DNEL (general population) of 9.14 mg/kg/day.