1,2-Benzenedicarboxylic acid, benzyl isononyl alkyl esters

Toxicological Summary

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.