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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.23 mg/m³
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Dose descriptor starting point:
NOAEL
Value:
25 mg/kg bw/day
Value:
30.8 mg/m³
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
2
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
1
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
5
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
AF for remaining uncertainties:
1
Justification:
None known
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:
0.35 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Dose descriptor starting point:
NOAEL
Value:
25 mg/kg bw/day
Value:
35 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
2
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
4
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
5
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
AF for remaining uncertainties:
1
Justification:
None known
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

The inhalation DNEL for long term exposure (systemic effects) was based on the OECD 415 oral study, in which a NOAEL of 25 mg/kg/day for fertility was established, this was then corrected for inhalation via route to route extrapolation to give a starting point of 30.8 mg/m3. The assessment factors were used according to ECHA Guidance Chapter R8:

AF differences in exposure: 2,

AF for allometric scaling: 1 (accounted for in route to route extrapolation),

AF for other interspecies differences: 2.5,

AF for intraspecies differences: 5

The dermal DNEL for long term exposure (systemic effects) was based on the OECD 415 oral study, in which a NOAEL of 25 mg/kg/day for fertility was established. The assessment factors were used according to ECHA Guidance Chapter R8:

AF differences in exposure: 2,

AF for allometric scaling: 4 (rat),

AF for other interspecies differences: 2.5,

AF for intraspecies differences: 5

Regarding systemic acute effects, it is assumed that the systemic DNEL for long term effects is sufficient to ensure acute effects do not occur.

For the workers DNELs calculation, default AFs from ECHA were used according to ECHA Guidance Chapter R8, leading

to the following overall assessment factors:

-For inhalation DNEL long term systemic effects: 25

-For dermal DNEL long term systemic effects: 100

However, ECETOC has reviewed the default AFs proposed by ECHA in its technical reports (Technical Reports No 86 [2003], No 110 [2010] and No 136 [2020]). These reviews revealed that the available scientific data, while supporting several of the AF being recommended in the ECHA R.8 guidance, did not support all of them. ECETOC has proposed alternative AFs ("informed AFs"), lower than the default AFs from ECHA, based on the available scientific data. Specifically, the following AFs were proposed:

-AFs for intraspecies differences: 3 for the workers (instead of 5 as proposed by ECHA) and 5 for the general population (instead of 10 as proposed by ECHA)

-no AF of 2.5 for other interspecies differences (remaining uncertainties for Toxicodynamics) (instead of 2.5 as proposed by ECHA)

-AF of 1.5 for differences in exposure (subchronic > chronic) when the source study is of good quality (instead of 2 as proposed by ECHA)

Taking into account ECETOC proposal, the overall assessment factors for Cyclamen Aldehyde would be:

-For inhalation DNEL long term systemic effects: 4.5 (versus 25 with ECHA approach)

-For dermal DNEL long term systemic effects: 18 (versus 100 with ECHA approach)

Therefore, the ECETOC approach would allow dividing by more than 5 the total assessment factor, leading to DNEL five times higher than the ones calculated from ECHA approach:

-Inhalation DNEL long term systemic effects: 6.86 mg/kg bw/d with ECETOC approach versus 1.23 mg/kg bw/d with ECHA approach

-Dermal DNEL long term systemic effects: 1.94 mg/kg bw/d with ECETOC approach versus 0.35 mg/kg bw/d with ECHA approach

This has a consequent impact on the risk characterization ratios that are subsequently calculated for the Chemical Safety Report.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.22 mg/m³
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Dose descriptor starting point:
NOAEL
Value:
25 mg/kg bw/day
Value:
10.9 mg/m³
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
2
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
1
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
10
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
AF for remaining uncertainties:
1
Justification:
None Known
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:
0.13 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Dose descriptor starting point:
NOAEL
Value:
25 mg/kg bw/day
Value:
25 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
2
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
4
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
10
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
AF for remaining uncertainties:
1
Justification:
None known
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.13 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Dose descriptor starting point:
NOAEL
Value:
25 mg/kg bw/day
Value:
25 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
2
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
4
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
10
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
AF for remaining uncertainties:
1
Justification:
None known
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 inhalation DNEL for long term exposure (systemic effects) was based on the OECD 415 oral study, in which a NOAEL of 25 mg/kg/day for fertility was established, this was then corrected for inhalation via route to route extrapolation to give a starting point of 10.9 mg/m3 for general population. The assessment factors were used according to ECHA Guidance Chapter R8:

AF differences in exposure: 2,

AF for allometric scaling: 1 (accounted for in route to route extrapolation),

AF for other interspecies differences: 2.5,

AF for intraspecies differences: 10

 

The dermal DNEL for long term exposure (systemic effects) was based on the OECD 415 oral study, in which a NOAEL of 25 mg/kg/day for fertility was established. The assessment factors were used according to ECHA Guidance Chapter R8:

AF differences in exposure: 2,

AF for allometric scaling: 4 (rat),

AF for other interspecies differences: 2.5,

AF for intraspecies differences: 10

 

The oral DNEL for long term exposure (systemic effects) was based on the OECD 415 oral study, in which a NOAEL of 25 mg/kg/day for fertility was established. The assessment factors were used according to ECHA Guidance Chapter R8:

AF differences in exposure: 2,

AF for allometric scaling: 4 (rat),

AF for other interspecies differences: 2.5,

AF for intraspecies differences: 10

  

Regarding systemic acute effects, it is assumed that the systemic DNEL for long term effects is sufficient to ensure acute effects do not occur.

For the general population DNELs calculation, default AFs from ECHA were used according to ECHA Guidance Chapter R8,

leading to the following overall assessment factors:

-For inhalation DNEL long term systemic effects: 50

-For dermal DNEL long term systemic effects: 200

-For oral DNEL long term systemic effects: 200

However, ECETOC has reviewed the default AFs proposed by ECHA in its technical reports (Technical Reports No 86 [2003], No 110 [2010] and No 136 [2020]). These reviews revealed that the available scientific data, while supporting several of the AF being recommended in the ECHA R.8 guidance, did not support all of them. ECETOC has proposed alternative AFs ("informed AFs"), lower than the default AFs from ECHA, based on the available scientific data. Specifically, the following AFs were proposed:

-AFs for intraspecies differences: 3 for the workers (instead of 5 as proposed by ECHA) and 5 for the general population (instead of 10 as proposed by ECHA)

-no AF of 2.5 for other interspecies differences (remaining uncertainties for Toxicodynamics) (instead of 2.5 as proposed by ECHA)

-AF of 1.5 for differences in exposure (subchronic > chronic) when the source study is of good quality (instead of 2 as proposed by ECHA)

Taking into account ECETOC proposal, the overall assessment factors for Cyclamen Aldehyde would be:

-For inhalation DNEL long term systemic effects: 7.5 (versus 50 with ECHA approach)

-For dermal DNEL long term systemic effects: 30 (versus 200 with ECHA approach)

-For oral DNEL long term systemic effects: 30 (versus 200 with ECHA approach)

Therefore, the ECETOC approach would allow dividing by more than 6 the total assessment factor, leading to DNEL six times higher than the ones calculated from ECHA approach:

-Inhalation DNEL long term systemic effects: 1.45 mg/kg bw/d with ECETOC approach versus 0.22 mg/kg bw/d with ECHA approach

-Dermal DNEL long term systemic effects: 0.83 mg/kg bw/d with ECETOC approach versus 0.13 mg/kg bw/d with ECHA approach

-Oral DNEL long term systemic effects: 0.83 mg/kg bw/d with ECETOC approach versus 0.13 mg/kg bw/d with ECHA approach

This has a consequent impact on the risk characterization ratios that are subsequently calculated for the Chemical Safety Report.

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