Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.49 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):
50
Dose descriptor starting point:
NOAEL
DNEL value:
20 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
24.67 mg/m³
AF for dose response relationship:
1
Justification:
Default AF for NOAEL as starting point
AF for differences in duration of exposure:
2
Justification:
For NOAEL from 90 d study as starting point: default assessment factor for extrapolation from subchronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
No additional factor for allometry is required for the inhalation DNELs as allometric scaling is already included in the respiratory volumes
AF for other interspecies differences:
2.5
Justification:
Default AF for remaining interspecies differences
AF for intraspecies differences:
5
Justification:
Default AF for workers
AF for the quality of the whole database:
1
Justification:
The available studies were conducted according to modern regulatory standards and are adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
2
Justification:
After adjustment for relative S-content and study duration, the effect levels in the repeated dose toxicity studies were mostly within a factor of approx. 2. Thus, an additional factor of 2 has been applied to account for any uncertainties associated with read-across. A higher AF is not considered to be appropriate, as the multiplication of AF would ultimately lead to overly conservative DNELs.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.14 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):
200
Dose descriptor starting point:
NOAEL
DNEL value:
20 mg/m³
Modified dose descriptor starting point:
NOAEL
DNEL value:
20 mg/kg bw/day
AF for dose response relationship:
1
Justification:
Default AF for NOAEL as starting point
AF for differences in duration of exposure:
2
Justification:
For NOAEL from 90 d study as starting point: default assessment factor for extrapolation from subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to humans AF 4 (ECHA 2008).
AF for other interspecies differences:
2.5
Justification:
Default AF for remaining interspecies differences
AF for intraspecies differences:
5
Justification:
Default AF for workers
AF for the quality of the whole database:
1
Justification:
The available studies were conducted according to modern regulatory standards and are adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
2
Justification:
After adjustment for relative S-content and study duration, the effect levels in the repeated dose toxicity studies were mostly within a factor of approx. 2. Thus, an additional factor of 2 has been applied to account for any uncertainties associated with read-across. A higher AF is not considered to be appropriate, as the multiplication of AF would ultimately lead to overly conservative DNELs.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard for the eyes

Additional information - workers

Identification of starting point

The most critical NOAELs were obtained in the 13 wk repeated dose toxicity study and the 2-generation study with NaTG:

NOAEL = 20 mg/kg bw/d (13 wk repeated dose toxicity study, oral, rat, NaTG)

NOAEL = 20 mg/kg bw/d (2-generation reproduction toxicity study, oral, rat, NaTG)

 

Route-to-route extrapolation

Oral absorption

For chemical safety assessment an oral absorption rate of 100% is assumed as a worst case default value in the absence of other data.

 

Dermal absorption

On the assumption that, in general, dermal absorption will not be higher than oral absorption, no AF (i.e. factor 1) should be introduced when performing oral-to-dermal extrapolation in the absence of other data. (REACH ECHA Guidance R8))

 

Inhalation absorption

For chemical safety assessment an inhalation absorption rate of 100% is assumed as a worst case default value in the absence of other data. By default an assessment factor of 2 for extrapolation oral to inhalation is introduced.

 

Corrections of the dose descriptor

The following default correction factors were applied to the NOAEL:

 

Correction

Factor

Differences in respiratory volume (worker)

2.63

Light activity at work (worker, inhalation)

0.67

Differences between human and experimental animal exposure conditions (worker)

1.4

Route-to-route extrapolation oral-inhalation

2

Route-to-route extrapolation oral-dermal

1

 

Assessment factors

 

Uncertainties

AF

 

Justification

Allometric scaling (dermal, oral)

4

Allometric scaling rat to humans AF 4 (ECHA 2008).

No additional factor for allometry is required for the inhalation DNELs as allometric scaling is already included in the respiratory volumes

Remaining interspecies differences

2.5

Default AF for remaining interspecies differences

Intraspecies differences

5

Default AF for workers

Differences in duration of exposure

2

For NOAEL from 90 d studyas starting point:default assessment factor for extrapolation from subchronic to chronic

1

For NOAEL from 2-generation study as starting point: no time extrapolation is required as the susceptible window is fully covered

Dose response and endpoint specific/severity

1

Default AF for NOAEL as starting point

Quality of whole database

1

The available studies were conducted according to modern regulatory standards and are adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

Remaining uncertainties

2

After adjustment for relative S-content and study duration, the effect levels in the repeated dose toxicity studies were mostly within a factor of approx. 2. Thus, an additional factor of 2 has been applied to account for any uncertainties associated with read-across. A higher AF is not considered to be appropriate, as the multiplication of AF would ultimately lead to overly conservative DNELs.

 

 

DNELs

DNELS derived from the 13 wk NOAEL (OECD TG 408):

 

DNEL worker, chronic dermal systemic: 0.14 mg/kg bw/d

Start value: 20 mg/kg bw/d

Route of original study: oral 

Dose descriptor starting point after route-to-route extrapolation and corrections: 28 mg/kg bw/d

Overall AF: 200

 

DNEL worker, chronic inhalation systemic: 0.49 mg/m³

Start value: 20 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation and corrections: 24.67 mg/m³

Overall AF: 50

 

 

DNELS derived from the reproduction NOAEL (OECD TG 416):

 

DNEL worker, chronic dermal systemic: 0.28 mg/kg bw/d

Start value: 20 mg/kg bw/d

Route of original study: oral 

Dose descriptor starting point after route-to-route extrapolation and corrections: 28 mg/kg bw/d

Overall AF: 100

 

DNEL worker, chronic inhalation systemic: 0.98 mg/m³

Start value: 20 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation and corrections: 24.67 mg/m³

Overall AF: 25

 

The DNELs based on reproduction toxicity are higher than those based on repeated dose toxicity. Thus, the repeated dose toxicity-based DNELs are also protective for reproduction.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.074 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):
100
Dose descriptor starting point:
NOAEL
DNEL value:
20 mg/m³
Modified dose descriptor starting point:
NOAEC
DNEL value:
7.4 mg/m³
AF for dose response relationship:
1
Justification:
Default AF for NOAEL as starting point
AF for differences in duration of exposure:
2
Justification:
For NOAEL from 90 d study as starting point: default assessment factor for extrapolation from subchronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
No additional factor for allometry is required for the inhalation DNELs as allometric scaling is already included in the respiratory volumes
AF for other interspecies differences:
2.5
Justification:
Default AF for remaining interspecies differences
AF for intraspecies differences:
10
Justification:
Default AF for general population
AF for the quality of the whole database:
1
Justification:
The available studies were conducted according to modern regulatory standards and are adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
2
Justification:
After adjustment for relative S-content and study duration, the effect levels in the repeated dose toxicity studies were mostly within a factor of approx. 2. Thus, an additional factor of 2 has been applied to account for any uncertainties associated with read-across. A higher AF is not considered to be appropriate, as the multiplication of AF would ultimately lead to overly conservative DNELs.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.05 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):
400
Dose descriptor starting point:
NOAEL
DNEL value:
20 mg/m³
Modified dose descriptor starting point:
NOAEL
DNEL value:
20 mg/kg bw/day
AF for dose response relationship:
1
Justification:
Default AF for NOAEL as starting point
AF for differences in duration of exposure:
2
Justification:
For NOAEL from 90 d study as starting point: default assessment factor for extrapolation from subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to humans AF 4 (ECHA 2008).
AF for other interspecies differences:
2.5
Justification:
Default AF for remaining interspecies differences
AF for intraspecies differences:
10
Justification:
Default AF for general population
AF for the quality of the whole database:
1
Justification:
The available studies were conducted according to modern regulatory standards and are adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
2
Justification:
After adjustment for relative S-content and study duration, the effect levels in the repeated dose toxicity studies were mostly within a factor of approx. 2. Thus, an additional factor of 2 has been applied to account for any uncertainties associated with read-across. A higher AF is not considered to be appropriate, as the multiplication of AF would ultimately lead to overly conservative DNELs.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.05 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):
400
Dose descriptor starting point:
NOAEL
DNEL value:
20 mg/kg bw/day
AF for dose response relationship:
1
Justification:
Default AF for NOAEL as starting point
AF for differences in duration of exposure:
2
Justification:
For NOAEL from 90 d study as starting point: default assessment factor for extrapolation from subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to humans AF 4 (ECHA 2008).
AF for other interspecies differences:
2.5
Justification:
Default AF for remaining interspecies differences
AF for intraspecies differences:
10
Justification:
Default AF for general population
AF for the quality of the whole database:
1
Justification:
The available studies were conducted according to modern regulatory standards and are adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
2
Justification:
After adjustment for relative S-content and study duration, the effect levels in the repeated dose toxicity studies were mostly within a factor of approx. 2. Thus, an additional factor of 2 has been applied to account for any uncertainties associated with read-across. A higher AF is not considered to be appropriate, as the multiplication of AF would ultimately lead to overly conservative DNELs.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

Identification of starting point

The most critical NOAELs were obtained in the 13 wk repeated dose toxicity study and the 2-generation study with NaTG:

NOAEL = 20 mg/kg bw/d (13 wk repeated dose toxicity study, oral, rat, NaTG)

NOAEL = 20 mg/kg bw/d (2-generation reproduction toxicity study, oral, rat, NaTG)

 

Route-to-route extrapolation

Oral absorption

For chemical safety assessment an oral absorption rate of 100% is assumed as a worst case default value in the absence of other data.

 

Dermal absorption

On the assumption that, in general, dermal absorption will not be higher than oral absorption, no AF (i.e. factor 1) should be introduced when performing oral-to-dermal extrapolation in the absence of other data. (REACH ECHA Guidance R8))

 

Inhalation absorption

For chemical safety assessment an inhalation absorption rate of 100% is assumed as a worst case default value in the absence of other data. By default an assessment factor of 2 for extrapolation oral to inhalation is introduced.

 

Corrections of the dose descriptor

The following default correction factors were applied to the NOAEL:

 

Correction

Factor

Differences in respiratory volume (general population)

0.74

Differences between human and experimental animal exposure conditions (general population)

1

Route-to-route extrapolation oral-inhalation

2

Route-to-route extrapolation oral-dermal

1

 

Assessment factors

 

Uncertainties

AF

 

Justification

Allometric scaling (dermal, oral)

4

Allometric scaling rat to humans AF 4 (ECHA 2008).

No additional factor for allometry is required for the inhalation DNELs as allometric scaling is already included in the respiratory volumes

Remaining interspecies differences

2.5

Default AF for remaining interspecies differences

Intraspecies differences

10

Default AF for general population

Differences in duration of exposure

2

For NOAEL from 90 d studyas starting point:default assessment factor for extrapolation from subchronic to chronic

1

For NOAEL from 2-generation study as starting point: no time extrapolation is required as the susceptible window is fully covered

Dose response and endpoint specific/severity

1

Default AF for NOAEL as starting point

Quality of whole database

1

The available studies were conducted according to modern regulatory standards and are adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

Remaining uncertainties

2

After adjustment for relative S-content and study duration, the effect levels in the repeated dose toxicity studies were mostly within a factor of approx. 2. Thus, an additional factor of 2 has been applied to account for any uncertainties associated with read-across. A higher AF is not considered to be appropriate, as the multiplication of AF would ultimately lead to overly conservative DNELs.

 

DNELs

DNELS derived from the 13 wk NOAEL (OECD TG 408):

 

DNEL general population, chronic dermal systemic: 0.05 mg/kg bw/d

Start value: 20 mg/kg bw/d

Route of original study: oral 

Dose descriptor starting point after route-to-route extrapolation and corrections: 20 mg/kg bw/d

Overall AF: 400

 

DNEL general population, chronic oral systemic: 0.05 mg/kg bw/d

Start value: 20 mg/kg bw/d

Route of original study: oral 

Overall AF: 400

 

DNEL general population, chronic inhalation systemic: 0.074 mg/m³

Start value: 20 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation and corrections: 7.4 mg/m³

Overall AF: 100

 

 

 

DNELS derived from the reproduction NOAEL (OECD TG 416):

 

DNEL general population, chronic dermal systemic: 0.1 mg/kg bw/d

Start value: 20 mg/kg bw/d

Route of original study: oral 

Dose descriptor starting point after route-to-route extrapolation and corrections: 20 mg/kg bw/d

Overall AF: 200

 

DNEL general population, chronic oral systemic: 0.1 mg/kg bw/d

Start value: 20 mg/kg bw/d

Route of original study: oral 

Overall AF: 200

 

DNEL general population, chronic inhalation systemic: 0.148 mg/m³

Start value: 20 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation and corrections: 7.4 mg/m³

Overall AF: 50

 

The DNELs based on reproduction toxicity are higher than those based on repeated dose toxicity. Thus, the repeated dose toxicity-based DNELs are also protective for reproduction.