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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:
1.32 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
Modified dose descriptor starting point:
NOAEC
Value:
98.74 mg/m³
AF for dose response relationship:
1
Justification:
default
AF for differences in duration of exposure:
6
Justification:
default for subacute to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
default for inhalation
AF for other interspecies differences:
2.5
Justification:
default residual
AF for intraspecies differences:
5
Justification:
default for workers
AF for the quality of the whole database:
1
Justification:
default
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

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.8 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
Modified dose descriptor starting point:
NOAEL
Value:
840 mg/kg bw/day
AF for dose response relationship:
1
Justification:
default
AF for differences in duration of exposure:
6
Justification:
default for subacute to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
default for rat
AF for other interspecies differences:
2.5
Justification:
default for residual
AF for intraspecies differences:
5
Justification:
default for workers
AF for the quality of the whole database:
1
Justification:
default
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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

General

The DNELs presented in this section have been developed following REACH technical guidance on route-to route extrapolation and assessment factors (ECHA, 2008).

ECHA (2008) Guidance of information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health.

Acute toxicity - Workers

A DNEL for acute toxicity should be derived if an acute hazard leading to acute toxicity (e.g. classified under DSD or CLP) has been identified and there is a potential for high peak exposures. If no hazard has been identified then a DNEL for acute toxicity is unnecessary as the long-term DNEL will be sufficient to ensure that adverse effects do no occur. S261A is neither acutely toxic nor is it an irritant (eye, skin or respiratory tract) and therefore no acute DNELs (systemic or local) have been calculated.

Long-term systemic toxicity - Workers

A reliable 3-week feeding study in male rats with a NOAEL of 60 mg/kg bw/d is available for S261A, together with longer-term studies on the structurally related compounds DINP (2-year study) and BBP (90-day study) which provided NOAELs of 17 and 151 mg/kg bw/day, respectively. DNELs for long-term systemic toxicity will be developed for both S261A and DINP, with the one giving the lowest value considered most appropriate.

Inhalation DNEL (systemic) based on DINP

Dose descriptor

A rat chronic (2-year) oral NOAEL of 17 mg/kg bw/d will be used as the starting point.

Modification of dose descriptor

The equivalent rat inhalation NOAEC will be derived using route-to-route extrapolation. Uptake of 75% after inhalation and 50% after ingestion has been assumed (see discussion of toxicokinetics). The inhalatory NOAEC is calculated as follows (ECHA (2008); Figure R.8-3):

NOAECinhalation = NOAELoral x 1/sRVrat 8hr x ABSoral-rat/ABSinh-human x sRVhuman/wRVhuman

= 17 x 1/0.38 x 50/75 x 6.7/10 = 19.98 mg/m3

The NOAEC is then adjusted for differences in exposure pattern (5 d/wk for workers, 7 d/wk for the underlying rat chronic study):

NOAECinhalation = 7/5 x 19.98 = 27.97 mg/m3

Assessment factors

Uncertainty

AF

Justification

Interspecies differences

1

2.5

default for inhalation route

residual

Intraspecies differences

5

default AF for workers

Differences in duration of exposure

1

default for chronic exposure

Dose response and endpoint specific/severity issues

1

default AF

Quality of database

1

default AF

Overall AF

12.5

 

 

DNELl-t inhal-systemic = 27.97 / 12.5 = 2.24 mg/m3

Inhalation DNEL (systemic) based on S261A

Dose descriptor

A rat sub-acute (3-week) oral NOAEL of 60 mg/kg bw/d will be used as the starting point.

Modification of dose descriptor

The equivalent rat inhalation NOAEC will be derived using route-to-route extrapolation. Uptake of 75% after inhalation and 50% after ingestion has been assumed (see discussion of toxicokinetics). The inhalatory NOAEC is calculated as follows (ECHA (2008); Figure R.8-3):

NOAECinhalation = NOAELoral x 1/sRVrat 8hr x ABSoral-rat/ABSinh-human x sRVhuman/wRVhuman

= 60 x 1/0.38 x 50/75 x 6.7/10 = 70.53 mg/m3

The NOAEC is then adjusted for differences in exposure pattern (5 d/wk for workers, 7 d/wk for the underlying rat sub-acute study):

NOAECinhalation = 7/5 x 70.53 = 98.74 mg/m3

Assessment factors

Uncertainty

AF

Justification

Interspecies differences

1

2.5

default for inhalation route

residual

Intraspecies differences

5

default AF for workers

Differences in duration of exposure

6

default for sub-acute to chronic extrapolation

Dose response and endpoint specific/severity issues

1

default AF

Quality of database

1

default AF

Overall AF

75

 

 

DNELl-t inhal-systemic = 98.74 / 75 = 1.32 mg/m3

The inhalation long-term systemic DNEL for S261A will therefore be based on results from a substance-specific sub-acute feeding study (more conservative outcome), and a DNEL of 5.48 mg/m3 used for risk characterisation.

Dermal DNEL (systemic) based on DINP

Dose descriptor

A rat chronic (2-year) oral NOAEL of 17 mg/kg bw/d will be used as the starting point. Modification of dose descriptor The equivalent rat dermal NOAEL will be derived using route-to-route extrapolation. Uptake of 5% by the skin and 50% after ingestion has been assumed (see discussion of toxicokinetics). The dermal NOAEL may be calculated as follows:

NOAELdermal = NOAELoral x ABSoral-rat/ABSdermal-human

= 17 x 50/5 = 170 mg/kg bwt/d

The NOAEL is then adjusted for differences in exposure pattern (5 d/wk for workers, 7 d/wk for the underlying rat chronic study):

NOAELdermal = 7/5 x 170 = 238 mg/kg bwt/d

Assessment factors

Uncertainty

AF

Justification

Interspecies differences

4

2.5

default for rat

residual

Intraspecies differences

5

default AF for workers

Differences in duration of exposure

1

default for chronic exposure

Dose response and endpoint specific/severity issues

1

default AF

Quality of database

1

default AF

Overall AF

50

 

 

DNELl-t dermal-systemic = 238 / 50 = 4.76 mg/kg bw/d

Dermal DNEL (systemic) based on S261A

Dose descriptor

A rat sub-acute (3-week) oral NOAEL of 60 mg/kg bw/d will be used as the starting point.

Modification of dose descriptor

The equivalent rat dermal NOAEL will be derived using route-to-route extrapolation. Uptake of 5% by the skin and 50% after ingestion has been assumed (see discussion of toxicokinetics) The dermal NOAEL may be calculated as follows:

NOAELdermal = NOAELoral x ABSoral-rat/ABSdermal-human

= 60 x 50/5 = 600 mg/kg bwt/d

The NOAEL is then adjusted for differences in exposure pattern (5 d/wk for workers, 7 d/wk for the underlying rat sub-acute study):

NOAELdermal = 7/5 x 600 = 840 mg/kg bwt/d

Assessment factors

Uncertainty

AF

Justification

Interspecies differences

4

2.5

default for rat

residual

Intraspecies differences

5

default AF for workers

Differences in duration of exposure

6

default for sub-acute to chronic extrapolation

Dose response and endpoint specific/severity issues

1

default AF

Quality of database

1

default AF

Overall AF

300

 

 

DNELl-t dermal-systemic = 840 / 300 = 2.8 mg/kg bw/d

The dermal long-term systemic DNEL for S261A will therefore be based on results from a substance-specific sub-acute feeding study (more conservative outcome), and a DNEL of 2.8 mg/kg bw/d used for risk characterisation.

Long-term local effects

No long-term local effects have been reported for S261A or related phthalate esters, hence no long-term local DNELs have been calculated.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.23 µg/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
Modified dose descriptor starting point:
NOAEC
Value:
34.78 mg/m³
AF for dose response relationship:
1
Justification:
default
AF for differences in duration of exposure:
6
Justification:
default for subacute to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
default for inhalation route
AF for other interspecies differences:
2.5
Justification:
default residual
AF for intraspecies differences:
10
Justification:
default for general population
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
no remaining uncertanties
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:
1 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
Modified dose descriptor starting point:
NOAEL
Value:
600 mg/kg bw/day
AF for dose response relationship:
1
Justification:
default
AF for differences in duration of exposure:
6
Justification:
default for subacute to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
default for rat
AF for other interspecies differences:
2.5
Justification:
default residual
AF for intraspecies differences:
10
Justification:
default for general opoulation
AF for the quality of the whole database:
1
Justification:
default
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-threshold effect and/or no dose-response information available
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:
0.1 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
Modified dose descriptor starting point:
NOAEL
Value:
60 mg/kg bw/day
AF for dose response relationship:
1
Justification:
default
AF for differences in duration of exposure:
6
Justification:
default for subacute to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
default for rat
AF for other interspecies differences:
2.5
Justification:
default residual
AF for intraspecies differences:
10
Justification:
default for general population
AF for the quality of the whole database:
1
Justification:
default
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:
no hazard identified

Additional information - General Population

General

The DNELs presented in this section have been developed following REACH technical guidance on route-to route extrapolation and assessment factors (ECHA, 2008).

ECHA (2008) Guidance of information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health.

Acute toxicity – General population

A DNEL for acute toxicity should be derived if an acute hazard leading to acute toxicity (e.g. classified under DSD or CLP) has been identified and there is a potential for high peak exposures. If no hazard has been identified then a DNEL for acute toxicity is unnecessary as the long-term DNEL will be sufficient to ensure that adverse effects do no occur. S261A is neither acutely toxic nor is it an irritant (eye, skin or respiratory tract) and therefore no acute DNELs (systemic or local) have been calculated.

Long-term systemic toxicity – General population

For consistency with the preceding analysis for workers, long-term systemic DNELs for the general population with be based on a substance-specific sub-acute NOAEL of 60 mg/kg bw/d obtained for S261A.

Inhalation DNEL (systemic)

Dose descriptor

A rat sub-acute (3-week) oral NOAEL of 60 mg/kg bw/d will be used as the starting point. Modification of dose descriptor The equivalent rat inhalation NOAEC will be derived using route-to-route extrapolation. Uptake of 75% after inhalation and 50% after ingestion has been assumed (see discussion of toxicokinetics). The inhalatory NOAEC is calculated as follows (ECHA (2008); Figure R.8-3):

NOAECinhalation = NOAELoral x 1/sRVrat 24hr x ABSoral-rat/ABSinh-human x ABSinh-rat/ABSinh-human

= 60 x 1/1.15 x 50/75 = 34.78 mg/m3

No additional correction is required for differences in exposure pattern (7 d/wk for general population, 7 d/wk for the underlying rat sub-acute study.

Assessment factors

Uncertainty

AF

Justification

Interspecies differences

1

2.5

default for inhalation route

residual

Intraspecies differences

10

default AF for general population

Differences in duration of exposure

6

default for sub-acute to chronic extrapolation

Dose response and endpoint specific/severity issues

1

default AF

Quality of database

1

default AF

Overall AF

150

 

 

DNELl-t inhal-systemic = 34.78 / 150 = 0.23 mg/m3

Dermal DNEL (systemic)

Dose descriptor

A rat sub-acute (3-week) oral NOAEL of 60 mg/kg bw/d will be used as the starting point.

Modification of dose descriptor

The equivalent rat dermal NOAEL will be derived using route-to-route. Uptake of 5% by the skin and 50% after ingestion has been assumed (see discussion of toxicokinetics). The dermal NOAEL may be calculated as follows:

NOAELdermal = NOAELoral x ABSoral-rat/ABSdermal-human

= 60 x 50/5 = 600 mg/kg bwt/d

No additional correction is required for differences in exposure pattern (7 d/wk for general population, 7 d/wk for the underlying rat sub-acute study).

Assessment factors

Uncertainty

AF

Justification

Interspecies differences

4

2.5

default for rat

residual

Intraspecies differences

10

default AF for workers

Differences in duration of exposure

6

default for sub-acute to chronic extrapolation

Dose response and endpoint specific/severity issues

1

default AF

Quality of database

1

default AF

Overall AF

600

 

 

DNELl-t dermal-systemic = 600 / 600 = 1.00 mg/kg bw/d

Oral DNEL (systemic)

Dose descriptor

A rat sub-acute (3-week) oral NOAEL of 60 mg/kg bw/d will be used as the starting point.

Modification of dose descriptor The extent of uptake from the gastrointestinal tract will be assumed to be identical for rats and humans. No additional correction is required (7 d/wk for general population, 7 d/wk for the underlying rat sub-acute study)

Assessment factors

Uncertainty

AF

Justification

Interspecies differences

4

2.5

default for rat

residual

Intraspecies differences

10

default AF for workers

Differences in duration of exposure

6

default for sub-acute to chronic extrapolation

Dose response and endpoint specific/severity issues

1

default AF

Quality of database

1

default AF

Overall AF

600

 

 

DNELl-t dermal-systemic = 60 / 600 = 0.10 mg/kg bw/d

Long-term local effects

No long-term local effects have been reported for S261A or related phthalate esters, hence no long-term local DNELs have been calculated.