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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.93 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:
125 mg/kg bw/day
Modified dose descriptor starting point:
other: NAEC
DNEL value:
220.1 mg/m³
Explanation for the modification of the dose descriptor starting point:

NAEC worker (8h) = (125 mg/kg bw/0.38 m³/kg bw) * 6.7 m³/10 m³

[where: NAEC is the modified starting point; 125 mg/kg bw is the NOAEL for repeated dose toxicity; 0.38 m³/kg bw is the default respiratory volume for the rat corresponding to the daily duration of human exposure; for workers a further correction is needed for the difference between respiratory rates under standard conditions and under conditions of light activity. This correction factor derives from the inhalation volumes in 8 hours under the respective conditions (6.7 m³ for base level, 10 m³ for light activity)]

AF for dose response relationship:
1
Justification:
data well supported
AF for differences in duration of exposure:
6
Justification:
subacute to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
scaling issues just evaluated in modified starting point
AF for other interspecies differences:
2.5
Justification:
remaining differences
AF for intraspecies differences:
5
Justification:
worker population
AF for the quality of the whole database:
1
Justification:
good quality and reliability
AF for remaining uncertainties:
1
Justification:
based on a worst-case approach, 100 % adsorption for inhalation route for animal and human is assumed
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:
0.42 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:
125 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Based on the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral-to-dermal extrapolation.

AF for dose response relationship:
1
Justification:
data well supported
AF for differences in duration of exposure:
6
Justification:
subacute to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
allometric factor rat to man
AF for other interspecies differences:
2.5
Justification:
remaining differences
AF for intraspecies differences:
5
Justification:
worker population
AF for the quality of the whole database:
1
Justification:
good quality and reliability
AF for remaining uncertainties:
1
Justification:
based on a worst-case approach, 100 % adsorption for dermal route for animal and human is assumed
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:
no hazard identified

Additional information - workers

The Derived No Effect Level for inhalation long-term exposure is estimated from the No Observed Effect Level obtained from the combined repeated dose /reproductive-developmental toxicity experiment.

The NOAEL for repeated dose toxicity was established as 125 mg/kg body weight/day. During the experiment, the most relevant effect observed was the colouration; at 125 mg/kg bw/day frequency of pigment presence was negligible and it was found only in organs directly related to the route of the test substance administration (digestive system and in regional lymph nodes). Accumulation of pigment was found in epithelium of renal cortical tubules and lymph nodes of males and females at the dose levels 500 and 1000 mg/kg/day; at the higher dose, the accumulation resulted to be irreversible. Presence of blue pigment was never accompanied by inflammatory or degenerative changes, at all the tested doses.

 

The calculation of DNELs is based on the NOAEL identified and has to be corrected for the differences between effect assessment data and the real human exposure situation, taking into account variability and uncertainty within and between species. In order to correct the interspecies difference between rat and human the no observed effect level has to be corrected as mentioned below.

 

INHALATION ROUTE - Systemic effects long term exposure

Corrected starting point for the inhalation route for workers:

NAEC worker (8h) = (125 mg/kg bw/0.38 m³/kg bw) * (6.7 m³/ 10 m³)

[where: NAEC is the modified starting point; 125 mg/kg bw is the NOAEL for repeated dose toxicity; 0.38 m³/kg bw is the default respiratory volume for the rat corresponding to the daily duration of human exposure; for workers a further correction is needed for the difference between respiratory rates under standard conditions and under conditions of light activity. This correction factor derives from the inhalation volumes in 8 hours under the respective conditions (6.7 m3 for base level, 10 m3 for light activity)]

 

Thus, the corrected starting point NAEC was estimated to be 220.1 mg/m³. Subsequently other assessment factors have been used to derived the DNEL:

- differences in duration of exposure 6, because the starting value resulted from a subacute study

- remaining differences 2.5

- intraspecies differences 5, for worker population

 

DERMAL ROUTE - Systemic effects long term exposure

Based on the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral-to-dermal extrapolation, thus NOAEL has been used as starting point, without any further correction. Subsequently other assessment factors have been used to derived the DNEL:

- differences in duration of exposure 6, because the starting value resulted from a subacute study

- because the NOAEL was recorded in a study conducted on rats, for interspecies differences the allometric scaling of 4 has been used

- remaining differences 2.5

- intraspecies differences 5, for worker population

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.72 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:
125 mg/kg bw/day
Modified dose descriptor starting point:
other: NAEC
DNEL value:
108.7 mg/m³
Explanation for the modification of the dose descriptor starting point:

NAEC general population (24h) = 125 mg/kg bw/1.15 m³/kg bw

[where: NAEC is the modified starting point; 125 mg/kg bw is the NOAEL for repeated dose toxicity; 1.15 m³/kg bw is the default respiratory volume for the rat corresponding to the daily duration of human exposure]

AF for dose response relationship:
1
Justification:
data well supported
AF for differences in duration of exposure:
6
Justification:
subacute to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
scaling issues just evaluated in modified starting point
AF for other interspecies differences:
2.5
Justification:
remaining differences
AF for intraspecies differences:
10
Justification:
general population
AF for the quality of the whole database:
1
Justification:
good quality and reliability
AF for remaining uncertainties:
1
Justification:
based on a worst-case approach, 100 % adsorption for inhalation route for animal and human is assumed
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:
0.21 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:
125 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Based on the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral-to-dermal extrapolation.

AF for dose response relationship:
1
Justification:
data well supported
AF for differences in duration of exposure:
6
Justification:
subacute to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
allometric factor rat to man
AF for other interspecies differences:
2.5
Justification:
remaining differences
AF for intraspecies differences:
10
Justification:
general population
AF for the quality of the whole database:
1
Justification:
good quality and reliability)
AF for remaining uncertainties:
1
Justification:
based on a worst-case approach, 100 % adsorption for dermal route for animal and human is assumed
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:
0.21 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:
125 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No default factor should be introduced when performing on the same route; 125 mg/kg bw is the NOAEL for repeated dose toxicity.

AF for dose response relationship:
1
Justification:
data well supported
AF for differences in duration of exposure:
6
Justification:
subacute to chronic)
AF for interspecies differences (allometric scaling):
4
Justification:
allometric factor rat to man
AF for other interspecies differences:
2.5
Justification:
remaining differences)
AF for intraspecies differences:
10
Justification:
general population
AF for the quality of the whole database:
1
Justification:
good quality and reliability
AF for remaining uncertainties:
1
Justification:
100 % adsorption for oral route for animal and human is assumed
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 Derived No Effect Level for inhalation long-term exposure is estimated from the No Observed Effect Level obtained from the combined repeated dose /reproductive-developmental toxicity experiment.

The NOAEL was established as 125 mg/kg body weight/day. During the experiment, the most relevant effect observed was the colouration; at 125 mg/kg bw/day frequency of pigment presence was negligible and it was found only in organs directly related to the route of the test substance administration (digestive system and in regional lymph nodes). Accumulation of pigment was found in epithelium of renal cortical tubules and lymph nodes of males and females at the dose levels 500 and 1000 mg/kg/day; at the higher dose, the accumulation resulted to be irreversible. Presence of blue pigment was never accompanied by inflammatory or degenerative changes, at all the tested doses.

 

The calculation of DNELs is based on the NOAEL identified and has to be corrected for the differences between effect assessment data and the real human exposure situation, taking into account variability and uncertainty within and between species. In order to correct the interspecies difference between rat and human the no observed effect level has to be corrected as mentioned below.

 

INHALATION ROUTE - Systemic effects long term exposure

Corrected starting point for the inhalation route for general population:

NAEC general population (24h) = 125 mg/kg bw/ 1.15 m³/kg bw

[where: NAEC is the modified starting point; 125 mg/kg bw is the NOAEL for repeated dose toxicity; 1.15 m³/kg bw is the default respiratory volume for the rat corresponding to the daily duration of human exposure]

 

Thus, the corrected starting point NAEC was estimated to be 108.7 mg/m³. Subsequently other assessment factors have been used to derived the DNEL:

- differences in duration of exposure 6, because the starting value resulted from a subacute study

- remaining differences 2.5

- intraspecies differences 10 for general population

 

DERMAL ROUTE - Systemic effects long term exposure

Based on the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral-to-dermal extrapolation, thus NOAEL has been used as starting point, without any further correction.

 

Subsequently other assessment factors have been used to derived the DNEL:

- differences in duration of exposure 6, because the starting value resulted from a subacute study

- because the NOAEL was recorded in a study conducted on rats, for interspecies differences the allometric scaling of 4 has been used

- remaining differences 2.5

- intraspecies differences 10, for general population

 

ORAL ROUTE - Systemic effects long term exposure

No default factor should be introduced when performing on the same route, thus NOAEL has been used as starting point, without any further correction.

 

Subsequently other assessment factors have been used to derived the DNEL:

- differences in duration of exposure 6, because the starting value resulted from a subacute study

- because the NOAEL was recorded in a study conducted on rats, for interspecies differences the allometric scaling of 4 has been used

- remaining differences 2.5

- intraspecies differences 10, for general populatio- intraspecies differences 10, for general population