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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
9.32 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
3
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
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-threshold effect and/or no dose-response information available
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
19.83 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
12
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
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-threshold effect and/or no dose-response information available

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 (ECHA, 2008), and ECETOC guidance on assessment factors (ECETOC, 2003).

Scientific justification for this approach reflects REACH guidance which notes that the overall assessment factor applied to an experimental NOAEL when developing a DNEL is multiplicative in nature, and that care should be taken to avoid double counting several aspects when multiplying the individual factors (ECHA, 2008). As a consequence, no additional factor has been included in these DNELs to address “residual” interspecies variation present following allometric scaling since this is largely accounted for in the default assessment factor proposed by ECETOC for intraspecies variability; and an assessment factor of 3 was considered appropriate to account for variability present in worker groups, while a value of 5 is considered appropriate for the general population, since these approximate the 90th percentile and 95th percentile, respectively, of human data analysed by ECETOC.

ECETOC (2003) Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86, ECETOC Brussels, February 2003.

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

Acute toxicity

A DNEL for acute toxicity should be derived if an acute hazard leading to acute toxicity (e.g. classified under DSD) 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. S278 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

While no repeated dose oral toxicity data are available on S278, oral studies on three other phthalates, Santicizer 261 (3-week study), DINP (2-year study) and BBP (90-day study), returned NOAELs of 60, 17 and 151 mg/kg bw/day, respectively. The NOAEL for DINP will be used as a surrogate for the derivation of a long-term systemic DNEL for S278 since (i) the information originates from a modern chronic exposure study, and (ii) the magnitude of the NOAEL is relatively low. In recognition of the likely conservative nature of the resulting DNEL, no additional assessment factor will be applied to account for uncertainties associated with read-across from DINP to S278.

Inhalation DNEL (systemic)

Dose descriptor

A rat chronic (2-year) 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 (ECETOC)

Justification

Interspecies differences

1

-

default for inhalation route

residual

Intraspecies differences

3

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

3

 

 

DNELl-t inhal-systemic = 27.97 / 3 = 9.32 mg/m3

Dermal DNEL (systemic)

Dose descriptor

A rat chronic (2-year) 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 (ECETOC)

Justification

Interspecies differences

4

-

default for rat

residual

Intraspecies differences

3

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

 

 

DNELl-t dermal-systemic = 238 / 12 = 19.83 mg/kg bw/d

Long-term local effects

No long-term local effects have been reported for S278 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:
1.97 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
5
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
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-threshold effect and/or no dose-response information available
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
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-threshold effect and/or no dose-response information available

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.85 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
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 (ECHA, 2008), and ECETOC guidance on assessment factors (ECETOC, 2003).

Scientific justification for this approach reflects REACH guidance which notes that the overall assessment factor applied to an experimental NOAEL when developing a DNEL is multiplicative in nature, and that care should be taken to avoid double counting several aspects when multiplying the individual factors (ECHA, 2008). As a consequence, no additional factor has been included in these DNELs to address “residual” interspecies variation present following allometric scaling since this is largely accounted for in the default assessment factor proposed by ECETOC for intraspecies variability; and an assessment factor of 3 was considered appropriate to account for variability present in worker groups, while a value of 5 is considered appropriate for the general population, since these approximate the 90th percentile and 95th percentile, respectively, of human data analysed by ECETOC.

ECETOC (2003) Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86, ECETOC Brussels, February 2003.

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

Acute toxicity

A DNEL for acute toxicity should be derived if an acute hazard leading to acute toxicity (e.g. classified under DSD) 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. S278 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

While no repeated dose oral toxicity data are available on S278, oral studies on three other phthalates, Santicizer 261 (3-week study), DINP (2-year study) and BBP (90-day study), returned NOAELs of 60, 17 and 151 mg/kg bw/day, respectively. The NOAEL for DINP will be used as a surrogate for the derivation of a long-term systemic DNEL for S278 since (i) the information originates from a modern chronic exposure study, and (ii) the magnitude of the NOAEL is relatively low. In recognition of the likely conservative nature of the resulting DNEL, no additional assessment factor will be applied to account for uncertainties associated with read-across from DINP to S278.

Inhalation DNEL (systemic)

Dose descriptor

A rat chronic (2-year) 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 24hr x ABSoral-rat/ABSinh-human x ABSinh-rat/ABSinh-human

= 17 x 1/1.15 x 50/75 = 9.86 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 chronic study).

Assessment factors

Uncertainty

AF (ECETOC)

Justification

Interspecies differences

1

-

default for inhalation route

residual

Intraspecies differences

5

default AF for general population

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

5

 

 

DNELl-t inhal-systemic = 9.86 / 5 = 1.97 mg/m3

Dermal DNEL (systemic)

Dose descriptor

A rat chronic (2-year) 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

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

Assessment factors

Uncertainty

AF (ECETOC)

Justification

Interspecies differences

4

-

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

20

 

 

DNELl-t dermal-systemic = 170 / 20 = 8.5 mg/kg bw/d

Oral DNEL (systemic)

Dose descriptor

A rat chronic (2-year) NOAEL of 17 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 chronic study)

Assessment factors

Uncertainty

AF (ECETOC)

Justification

Interspecies differences

4

-

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

20

 

 

DNELl-t dermal-systemic = 17 / 20 = 0.85 mg/kg bw/d

Long-term local effects

No long-term local effects have been reported for S278 or related phthalate esters, hence no long-term local DNELs have been calculated.

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