Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
35.263 mg/m³
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
Value:
881.6 mg/m³
Explanation for the modification of the dose descriptor starting point:
No inhalation study available.
AF for dose response relationship:
1
Justification:
DNEL is based on a NOAEL
AF for differences in duration of exposure:
2
Justification:
The factor for exposure duration of 2 was chosen to take into consideration that the study length did not cover a full cycle of rat male spermatogenesis.
AF for interspecies differences (allometric scaling):
1
Justification:
not applied for the inhalation route
AF for other interspecies differences:
2.5
Justification:
Default AF
AF for intraspecies differences:
5
Justification:
Default AF for workers
AF for the quality of the whole database:
1
Justification:
DNEL is based on a high-quality study
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
105.79 mg/m³
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL
Explanation for the modification of the dose descriptor starting point:
No inhalation study available.

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
100 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Value:
10 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No dermal study available.
AF for dose response relationship:
1
Justification:
DNEL is based on a NOAEL
AF for differences in duration of exposure:
2
Justification:
The factor for exposure duration of 2 was chosen to take into consideration that the study length did not cover a full cycle of rat male spermatogenesis.
AF for interspecies differences (allometric scaling):
4
Justification:
Default AF for rats
AF for other interspecies differences:
2.5
Justification:
Default AF
AF for intraspecies differences:
5
Justification:
Default AF for workers
AF for the quality of the whole database:
1
Justification:
DNEL is based on a high-quality study
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
300 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL
Explanation for the modification of the dose descriptor starting point:
No dermal study available.

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Calculation of DNELs for Multi constituent ester of pentaerythritol 2-ethylhexanoate

 

Justification

A substance-tailored exposure-driven testing was followed for the hazard assessment of repeated dose toxicity and toxicity to reproduction. No significant exposure is expected throughout all relevant exposure scenarios according to Annex XI, section 3.2(a) (i), therefore testing for repeated dose toxicity and reproductive toxicity is omitted in accordance with Annex VIII column 2 section 8.6.1 and 8.7.1 for the registered substance itself. The justification is based on an exposure assessment in accordance with section 5 of Annex I. The basis for the exposure calculations are DNELs derived from available data of the test substance, when tested in an OECD 422 study.

 

Derivation of DNEL

In general, the calculation of a DNEL is based on the no observed adverse effect level which has to be modified as described in “Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health” (ECHA, 2012).

An OECD 422 study is available for the surrogate substance Hexanoic acid, 2-ethyl-, 2,2-bis [ [(2-ethyl-1-oxohexyl)oxy] methyl] -1,3-propanediyl ester, a tetraester of 2-ethylhexanoic acid with pentaerythritol.

Dermal and inhalative intakes are the possible exposure routes for workers, whereas oral, dermal and inhalative intakes are the possible exposure routes for the general population.

As no local effects were observed, only DNELs for acute and long-term systemic effects are relevant.

For the derivation of the DNELs, the NOAEL of ≥ 1000 mg/kg bw/d was used as the starting point.

The DNEL is calculated according to the formula DNEL = (corrected NOAEL) / (overall assessment factors).

 

The overall assessment factor is based on the factors suggested in “Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health” (ECHA, 2012).

 

Assessment factors used for DNEL calculation

Assessment factor for

Value

Remaining differences

2.5

Interspecies

4

Intraspecies

5 (worker) / 10 (general population)

Exposure duration

2

Dose-response

1

Quality of whole database

1

The DNELs (systemic, acute) are derived using the additional default factor of 3 in combination with the DNELs systemic long-term.

 

For calculation of the DNELs for inhalative systemic effects, the interspecies difference between rat and human has to be taken into account. Therefore, the corrected NOAEL has to be corrected by the risk assessor 6.7/10 regarding breathing volume and frequency. Another factor of 2 is also used to account for the absorption difference between oral and inhalative uptake (Chapter R.8. p.19).

 

Based on the corrected NOAEL and the different factors described above, following DNELs for 2,2-bis[[(2-ethyl-1-oxohexyl)oxy]methyl]propane-1,3-diyl bis(2-ethylhexanoate) were calculated:

 

 

DNEL

systemic

Long-term

Acute

Worker

General Population

Worker

General Population

Oral#

-

5

-

15

Inhalative#

35.263

8.696

105.79

26.01

Dermal#

100

50

300

150

 # Oral, dermal: mg/kg bw/d; Inhalative: mg/m³

 

As the DNELs for the dermal route are calculated by route-to-route extrapolation from data for the oral route, a factor of 0.1 for the dermal absorption is taken into account. This factor is based on the maximum estimated dermal absorption of 10% compared to the oral absorption by each substance as calculated by the software Dermwin™, a part of the EpiSuite 4.1 software package (US EPA, 2012). 

 

References:   

ECHA (2012). Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health.

 

US EPA (2012). Estimation Programs Interface Suite™ for Microsoft® Windows, v 4.10.Environmental, DC

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.696 mg/m³
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEC
Value:
434.8 mg/m³
Explanation for the modification of the dose descriptor starting point:
No inhalation study available.
AF for dose response relationship:
1
Justification:
DNEL is based on a NOAEL
AF for differences in duration of exposure:
2
Justification:
The factor for exposure duration of 2 was chosen to take into consideration that the study length did not cover a full cycle of rat male spermatogenesis.
AF for interspecies differences (allometric scaling):
1
Justification:
AF not used for inhalation route
AF for other interspecies differences:
2.5
Justification:
Default AF
AF for intraspecies differences:
10
Justification:
Default AF for general population
AF for the quality of the whole database:
1
Justification:
DNEL is based on a high-quality study
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
26.01 mg/m³
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL
Explanation for the modification of the dose descriptor starting point:
No inhalation study available.

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
50 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
NOAEL
Value:
10 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No dermal study available.
AF for dose response relationship:
1
Justification:
DNEL is based on a NOAEL
AF for differences in duration of exposure:
2
Justification:
The factor for exposure duration of 2 was chosen to take into consideration that the study length did not cover a full cycle of rat male spermatogenesis.
AF for interspecies differences (allometric scaling):
4
Justification:
Default AF for rats
AF for other interspecies differences:
2.5
Justification:
Default AF
AF for intraspecies differences:
10
Justification:
Default AF for general population
AF for the quality of the whole database:
1
Justification:
DNEL is based on a high-quality study
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
150 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL
Explanation for the modification of the dose descriptor starting point:
No dermal study available.

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
AF for dose response relationship:
1
Justification:
DNEL is based on a NOAEL
AF for differences in duration of exposure:
2
Justification:
The factor for exposure duration of 2 was chosen to take into consideration that the study length did not cover a full cycle of rat male spermatogenesis.
AF for interspecies differences (allometric scaling):
4
Justification:
Default AF for rats
AF for other interspecies differences:
2.5
Justification:
Default AF
AF for intraspecies differences:
10
Justification:
Default AF for general polulation
AF for the quality of the whole database:
1
Justification:
DNEL is based on a high-quality study
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
15 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Calculation of DNELs forMulti constituent ester of pentaerythritol 2-ethylhexanoate

 

Justification

A substance-tailored exposure-driven testing was followed for the hazard assessment of repeated dose toxicity and toxicity to reproduction. No significant exposure is expected throughout all relevant exposure scenarios according to Annex XI, section 3.2(a) (i), therefore testing for repeated dose toxicity and reproductive toxicity is omitted in accordance with Annex VIII column 2 section 8.6.1 and 8.7.1 for the registered substance itself. The justification is based on an exposure assessment in accordance with section 5 of Annex I. The basis for the exposure calculations are DNELs derived from available data of the test substance, when tested in an OECD 422 study.

 

Derivation of DNEL

In general, the calculation of a DNEL is based on the no observed adverse effect level which has to be modified as described in “Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health” (ECHA, 2012).

An OECD 422 study is available for the surrogate substance Hexanoic acid, 2-ethyl-, 2,2-bis [ [(2-ethyl-1-oxohexyl)oxy] methyl] -1,3-propanediyl ester, a tetraester of 2-ethylhexanoic acid with pentaerythritol.

Dermal and inhalative intakes are the possible exposure routes for workers, whereas oral, dermal and inhalative intakes are the possible exposure routes for the general population.

As no local effects were observed, only DNELs for acute and long-term systemic effects are relevant.

For the derivation of the DNELs, the NOAEL of ≥ 1000 mg/kg bw/d was used as the starting point.

The DNEL is calculated according to the formula DNEL = (corrected NOAEL) / (overall assessment factors).

 

The overall assessment factor is based on the factors suggested in “Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health” (ECHA, 2012).

 

Assessment factors used for DNEL calculation

Assessment factor for

Value

Remaining differences

2.5

Interspecies

4

Intraspecies

5 (worker) / 10 (general population)

Exposure duration

2

Dose-response

1

Quality of whole database

1

The DNELs (systemic, acute) are derived using the additional default factor of 3 in combination with the DNELs systemic long-term.

 

For calculation of the DNELs for inhalative systemic effects, the interspecies difference between rat and human has to be taken into account. Therefore, the corrected NOAEL has to be corrected by the risk assessor 6.7/10 regarding breathing volume and frequency. Another factor of 2 is also used to account for the absorption difference between oral and inhalative uptake (Chapter R.8. p.19).

 

Based on the corrected NOAEL and the different factors described above, following DNELs for 2,2-bis[[(2-ethyl-1-oxohexyl)oxy]methyl]propane-1,3-diyl bis(2-ethylhexanoate) were calculated:

 

 

DNEL

systemic

Long-term

Acute

Worker

General Population

Worker

General Population

Oral#

-

5

-

15

Inhalative#

35.263

8.696

105.79

26.01

Dermal#

100

50

300

150

 # Oral, dermal: mg/kg bw/d; Inhalative: mg/m³

 

As the DNELs for the dermal route are calculated by route-to-route extrapolation from data for the oral route, a factor of 0.1 for the dermal absorption is taken into account. This factor is based on the maximum estimated dermal absorption of 10% compared to the oral absorption by each substance as calculated by the software Dermwin™, a part of the EpiSuite 4.1 software package (US EPA, 2012). 

 

References:   

ECHA (2012). Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health.

 

US EPA (2012). Estimation Programs Interface Suite™ for Microsoft® Windows, v 4.10.Environmental, DC