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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.588 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
Value:
50 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
44.1 mg/m³
Explanation for the modification of the dose descriptor starting point:

Absorption: ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 section R8.4.2 (2012) states that in the absence of reliable data for both the starting route (oral) and the end route (inhalation), worst-case assumptions should be made. It was therefore assumed that limited absorption occurs by the oral route, leading to a low (conservative) internal NOAEL. To secure a conservative external NOAEL, maximum absorption should be assumed for the inhalation route (i.e. 100%) leading to a low external NOAEL. Thus, in the case of oral-to-inhalation extrapolation, it is proposed to include a default factor of 2 (i.e. the absorption percentage by the oral route is half that of the inhalation absorption) 

 

Physiological Parameters: To convert the oral NOAEL into an inhalatory NOAEC, the following physiological parameters were applied.

 Symbol  Parameter  Value/Reference
 
 Systemic NOAELlong-term Oral systemic NOAEL from OECD422 in rats  50 mg/kg bw/day
 sRVrat standard Respiratory Volume - rat, 8h exposure period  0.38 m3/kg/day
 sRVhuman standard Respiratory Volume - human, 8h exposure period  6.7 m3
 wRV worker Respiratory Volume, 8h exposure period, light activity  10 m3

NB. For workers a correction was added for the difference between respiratory rates under standard conditions (sRVhuman) and under conditions of light activity (wRV).

 

Calculation: The corrected dose descriptor for inhalation is determined using the following equation:

 

Corrected Inhalatory NOAEClong-term = Systemic NOAELlong-term x [(1/sRVrat) x (ABSoral-rat/ABSinh-human) x (sRVhuman/wRV)].

Corrected Inhalatory NOAEClong-term = 50 mg/kg bw/day X  [(1/0.38 m3/kg bw/day) X (1/2) X (6.7 m3/10m3)].

Corrected Inhalatory NOAEClong-term = 44.1 mg/m3 

Therefore, the corrected dose descriptor for inhalation is 44.1 mg/m3 for workers.

AF for dose response relationship:
1
Justification:
Table R.8-6 ECHA REACH Guidance 'dose-response': the dose-descriptor is a NOAEL therefore default value for systemic effects is 1.
AF for differences in duration of exposure:
6
Justification:
Table R.8-6 ECHA REACH Guidance 'Exposure duration': default value for sub-acute to chronic is 6.
AF for interspecies differences (allometric scaling):
1
Justification:
Table R.8-4 ECHA REACH Guidance: An assessment factor or interspecies differences is not to be used for inhalation exposure since the differences in the metabolic rate/bw have already been taken into account in the corrected dose descriptor starting point.
AF for other interspecies differences:
2.5
Justification:
Table R.8-6 ECHA REACH Guidance 'interspecies': after correction for differences in metabolic rate per bodyweight, remaining differences are corrected with an AF of 2.5
AF for intraspecies differences:
5
Justification:
Table R.8-6 ECHA REACH Guidance 'intraspecies': default factor for worker is 5.
AF for the quality of the whole database:
1
Justification:
Table R.8-6 ECHA REACH Guidance 'quality of whole database': 1 is the default for a good quality database, taking into account completeness and consistency of the available data for the standard information requirements at the relevant tonnage band.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
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:
0.167 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
Value:
50 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

For systemic hazard assessment via the dermal route of exposure, route-to-route extrapolation from the oral NOAEL value was considered appropriate.

 

ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 section R8.4.2 states that when data on dermal penetration is available, dermal absorption is considered to be the same as oral absorption (i.e. 100 %). Therefore no default factor should be introduced when performing oral-to-dermal extrapolation & the oral NOAEL is considered to be the same as the dermal NOAEL.

AF for dose response relationship:
1
Justification:
Table R.8-6 ECHA REACH Guidance 'dose-response': the dose-descriptor is a NOAEL therefore default value for systemic effects is 1.
AF for differences in duration of exposure:
6
Justification:
Table R.8-6 ECHA REACH Guidance 'Exposure duration': default value for sub-acute to chronic is 6.
AF for interspecies differences (allometric scaling):
4
Justification:
Table R8.3 ECHA REACH Guidance R8 'Allometric scaling factors for different species as compared to humans': Rat AS factor is 4.
AF for other interspecies differences:
2.5
Justification:
Table R.8-6 ECHA REACH Guidance 'interspecies': after correction for differences in metabolic rate per bodyweight, remaining differences are corrected with an AF of 2.5
AF for intraspecies differences:
5
Justification:
Table R.8-6 ECHA REACH Guidance 'intraspecies': default factor for worker is 5.
AF for the quality of the whole database:
1
Justification:
Table R.8-6 ECHA REACH Guidance 'quality of whole database': 1 is the default for a good quality database, taking into account completeness and consistency of the available data for the standard information requirements at the relevant tonnage band.
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:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

N-Phenyl-diethanolamine, reaction products with formaldehyde is not classified as a non-threshold mutagen/carcinogen, therefore relevant classifications & dose descriptors were considered from the available toxicity information as follows: 

 

The substance is classified as a Sensitiser (category 1), a non-threshold effect. As such, for scenarios involving local dermal exposure, a qualitative hazard assessment was undertaken in line with ECHA Guidance on Information Requirements and Chemical Safety Assessment.

 

For Acute toxicity, no classifications were assigned, therefore there were no DNELs derived for short term/acute exposure periods. 

 

For systemic long term scenarios, a combined repeated dose toxicity with reproductive/developmental toxicity screening study was available (OECD TG422). From this, the following NOAELs were available: 

  • parenteral NOAEL = 50mg/kg bw/day (linked to kidney effects classified as STOT RE2 (kidney)
  • reproductive NOAEL = ≥650mg/kg bw/day
  • developmental NOAEL = ≥650mg/kg bw/day

As no effects on reproduction and development were present, the most sensitive NOAEL for derivation of DNELs was considered to be the parenteral NOAEL linked to kidney toxicity. 

 

 

General Population - 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):
150
Dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
21.7 mg/m³
Explanation for the modification of the dose descriptor starting point:

Absorption: ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 section R8.4.2 (2012) states that in the absence of reliable data for both the starting route (oral) and the end route (inhalation), worst-case assumptions should be made. It was therefore assumed that limited absorption occurs by the oral route, leading to a low (conservative) internal NOAEL. To secure a conservative external NOAEL, maximum absorption should be assumed for the inhalation route (i.e. 100%) leading to a low external NOAEL. Thus, in the case of oral-to-inhalation extrapolation, it is proposed to include a default factor of 2 (i.e. the absorption percentage by the oral route is half that of the inhalation absorption) 

 

Physiological Parameters: To convert the oral NOAEL into an inhalatory NOAEC, the following physiological parameters were applied:

 Symbol  Parameter  Value/Reference
    
 Systemic NOAELlong-term Oral systemic NOAEL from OECD422 in rats  50 mg/kg bw/day
 sRVrat standard Respiratory Volume - rat, 24h exposure period  1.15 m3/kg/day

 

Calculation: The corrected dose descriptor for inhalation is determined using the following equation:

 

Corrected Inhalatory NOAEClong-term = Systemic NOAELlong-term x [(1/sRVrat) x (ABSoral-rat/ABSinh-rat) x (ABSinh-rat/ABSinh-human)].

Corrected Inhalatory NOAEClong-term = 50 mg/kg bw/day X  [(1/1.15 m3/kg bw/day) X (1/2) X (2/2)].

Corrected Inhalatory NOAEClong-term = 50 mg/kg bw/day X 0.435

Corrected Inhalatory NOAEClong-term = 21.7 mg/m3 

Therefore, the corrected dose descriptor for inhalation is 21.7 mg/m3 for the general population.

AF for dose response relationship:
1
Justification:
Table R.8-6 ECHA REACH Guidance 'dose-response': the dose-descriptor is a NOAEL therefore default value for systemic effects is 1.
AF for differences in duration of exposure:
6
Justification:
Table R.8-6 ECHA REACH Guidance 'Exposure duration': default value for sub-acute to chronic is 6.
AF for interspecies differences (allometric scaling):
1
Justification:
Table R.8-4 ECHA REACH Guidance: An assessment factor or interspecies differences is not to be used for inhalation exposure since the differences in the metabolic rate/bw have already been taken into account in the corrected dose descriptor starting point.
AF for other interspecies differences:
2.5
Justification:
Table R.8-6 ECHA REACH Guidance 'interspecies': after correction for differences in metabolic rate per bodyweight, remaining differences are corrected with an AF of 2.5
AF for intraspecies differences:
10
Justification:
Table R.8-6 ECHA REACH Guidance 'intraspecies': default factor for general population is 10.
AF for the quality of the whole database:
1
Justification:
Table R.8-6 ECHA REACH Guidance 'quality of whole database': 1 is the default for a good quality database, taking into account completeness and consistency of the available data for the standard information requirements at the relevant tonnage band.
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
Value:
50 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

For systemic hazard assessment via the dermal route of exposure, route-to-route extrapolation from the oral NOAEL value was considered appropriate.

 

ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 section R8.4.2 states that when data on dermal penetration is available, dermal absorption is considered to be the same as oral absorption (i.e. 100 %). Therefore no default factor should be introduced when performing oral-to-dermal extrapolation & the oral NOAEL is considered to be the same as the dermal NOAEL.

AF for dose response relationship:
1
Justification:
Table R.8-6 ECHA REACH Guidance 'dose-response': the dose-descriptor is a NOAEL therefore default value for systemic effects is 1.
AF for differences in duration of exposure:
6
Justification:
Table R.8-6 ECHA REACH Guidance 'Exposure duration': default value for sub-acute to chronic is 6.
AF for interspecies differences (allometric scaling):
4
Justification:
Table R8.3 ECHA REACH Guidance R8 'Allometric scaling factors for different species as compared to humans': Rat AS factor is 4.
AF for other interspecies differences:
2.5
Justification:
Table R.8-6 ECHA REACH Guidance 'interspecies': after correction for differences in metabolic rate per bodyweight, remaining differences are corrected with an AF of 2.5
AF for intraspecies differences:
10
Justification:
Table R.8-6 ECHA REACH Guidance 'intraspecies': default factor for general population is 10.
AF for the quality of the whole database:
1
Justification:
Table R.8-6 ECHA REACH Guidance 'quality of whole database': 1 is the default for a good quality database, taking into account completeness and consistency of the available data for the standard information requirements at the relevant tonnage band.
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:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)

General Population - Hazard via oral 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
Value:
50 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No modification of the dose descriptor starting point was required. The endpoint used to derive the DNEL uses the oral exposure route.

AF for dose response relationship:
1
Justification:
Table R.8-6 ECHA REACH Guidance 'dose-response': the dose-descriptor is a NOAEL therefore default value for systemic effects is 1.
AF for differences in duration of exposure:
6
Justification:
Table R.8-6 ECHA REACH Guidance 'Exposure duration': default value for sub-acute to chronic is 6.
AF for interspecies differences (allometric scaling):
4
Justification:
Table R8.3 ECHA REACH Guidance R8 'Allometric scaling factors for different species as compared to humans': Rat AS factor is 4.
AF for other interspecies differences:
2.5
Justification:
Table R.8-6 ECHA REACH Guidance 'interspecies': after correction for differences in metabolic rate per bodyweight, remaining differences are corrected with an AF of 2.5
AF for intraspecies differences:
10
Justification:
Table R.8-6 ECHA REACH Guidance 'intraspecies': default factor for general population is 10.
AF for the quality of the whole database:
1
Justification:
Table R.8-6 ECHA REACH Guidance 'quality of whole database': 1 is the default for a good quality database, taking into account completeness and consistency of the available data for the standard information requirements at the relevant tonnage band.
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:
low hazard (no threshold derived)

Additional information - General Population

N-Phenyl-diethanolamine, reaction products with formaldehyde is not classified as a non-threshold mutagen/carcinogen, therefore relevant classifications & dose descriptors were considered from the available toxicity information as follows: 

 

The substance is classified as a Sensitiser (category 1), a non-threshold effect. As such, for scenarios involving local dermal exposure, a qualitative hazard assessment was undertaken in line with ECHA Guidance on Information Requirements and Chemical Safety Assessment.

 

For Acute toxicity, no classifications were assigned, therefore there were no DNELs derived for short term/acute exposure periods. 

 

For systemic long term scenarios, a combined repeated dose toxicity with reproductive/developmental toxicity screening study was available (OECD TG422). From this, the following NOAELs were available: 

  • parenteral NOAEL = 50mg/kg bw/day (linked to kidney effects classified as STOT RE2 (kidney)
  • reproductive NOAEL = ≥650mg/kg bw/day
  • developmental NOAEL = ≥650mg/kg bw/day

As no effects on reproduction and development were present, the most sensitive NOAEL for derivation of DNELs was considered to be the parenteral NOAEL linked to kidney toxicity. 

 

 

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