Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.906 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):
13
Modified dose descriptor starting point:
NOAEC
Value:
37.778 mg/m³
Explanation for the modification of the dose descriptor starting point:
No inhalation study available.
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
Justification:
The factor for exposure duration is not necessary in this case as the observed effects on the male reproductive system are sufficiently taken into account by the subchronic study covering the duration of 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 for intraspecies differences:
5
Justification:
default
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.719 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):
38
DNEL extrapolated from long term DNEL
Modified dose descriptor starting point:
NOAEC
Value:
331.3 mg/m³
Explanation for the modification of the dose descriptor starting point:
No inhalation study available.
AF for dose response relationship:
1
AF for interspecies differences (allometric scaling):
1
Justification:
not applied for the inhalation route
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
5
Justification:
default
AF for the quality of the whole database:
1
AF for remaining uncertainties:
3
Justification:
NOAEC from sub-lethal effects was used as a starting point.

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:
8.242 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):
50
Modified dose descriptor starting point:
NOAEL
Value:
412.1 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No dermal study available.
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
Justification:
The factor for exposure duration is not necessary in this case as the observed effects on the male reproductive system are sufficiently taken into account by the subchronic study covering the duration of spermatogenesis.
AF for interspecies differences (allometric scaling):
4
Justification:
default
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
5
Justification:
default
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
24.725 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):
150
DNEL extrapolated from long term DNEL
Modified dose descriptor starting point:
NOAEL
Value:
3 708.8 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No dermal study available.
AF for dose response relationship:
1
AF for interspecies differences (allometric scaling):
4
Justification:
default
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
5
Justification:
default
AF for the quality of the whole database:
1
AF for remaining uncertainties:
3
Justification:
NOAEC from sub-lethal effects was used as a starting point.

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

Calculation of DNELs for 2,2 -dimethylpropane-1,3 -diyl 2 -ethylhexanoate (CAS 28510 -23 -8)

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 calculation are DNELs derived from available data of the surrogate substance 2-ethylhexanoic acid in a very conservative approach.

Based on the chemical structure of the EHA-esters it can be assumed, that they may undergo enzymatic hydrolysis of the ester bond(s) after human intake. The potential resulting products would be the corresponding alcohol and 2-ethyl hexanoic acid (2-EHA), which is legally classified as Category 2 reproductive toxicant (“Suspected of damaging fertility or the unborn child”). As no data for the EHA-ester regarding reproductive/developmental toxicity were available, the risk assessment of these substances have to be attributed to 2-EHA (as a worst case scenario), where the critical effect for characterization of risk to human health is reproductive and developmental toxicity. Data from analogue substances or the potential alcohol hydrolysis product indicate that no hazard in contrast to 2 -EHA can be expected.

 

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, Dec 2010).

Several animal studies with different species on the reproductive and developmental toxicity of 2-EHA are available. Although the overall results were not consistent, the data clearly provide enough evidence that 2-EHA is a reproductive toxicant and is harmful to the foetus.

 

The lowest identified observed-effect level (LOEL) was seen in one of the public available studies, where effects on the male reproductive system were observed in rats exposed orally to 2-EHA, with the lowest LOEL for reproductive toxicity at 100 mg/kg bw/d (Pennanen et al. 1993). This dose level was based on reduction in sperm motility in male Han Wistar rats exposed via drinking water to 0, 100, 300, or 600 mg/kg bw per day for 10 weeks before mating and 3 weeks during mating.

 

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 LOEL of 100 mg/kg bw/d was used, which has to be corrected as follows:

LOEL rat = 100 mg/kg bw/d

Corrected NOAEL rat = 100 mg/kg bw/d /3 = 33.3 mg/kg bw/d

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, Dec 2010).

Although this document suggested a factor of 2 for the time extrapolation from a subchronic study, in this case this factor is not necessary as the observed effects on the male reproductive system are sufficiently taken into account by the subchronic study covering the duration of spermatogenesis (AGS, 2010). Thus, a factor 1 for the exposure duration is scientifically justified and consequently used for calculation.

 

    Assessment factors used for DNEL calculation

Assessment factor for

Value

Remaining differences

2.5

Interspecies

4

Intraspecies

5 (worker) / 10 (general population)

Exposure duration

1

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-EHA were calculated:

 

DNELs for 2-EHA

DNEL

systemic

Long-term

Acute

Worker

General Population

Worker

General Population

Oral#

-

0.167

-

0.501

Inhalative#

1.174

0.290

3.52

0.870

Dermal#

0.333

0.167

0.999

0.501

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

 

The DNELs for EHA-ester are calculated by considering the different molecular weights and the stoichiometry of 2-EHA compared to the respective EHA-ester according to following formula:

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 for all EHA-ester. 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).

 

CAS

MW

DNEL

systemic

Long-term

Acute

 

 

 

Worker

General Population

Worker

General Population

28510 -23 -8

356.5

Oral

-

0.412

-

1.235

Inhalative

2.906

0.717

8.719

2.151

Dermal

8.242

4.120

24.725

12.361

 

In conclusion, the DNELs derived were based on effects observed with 2 -EHA. This was a very conservative approach based on the fact that enzymatic hydrolysis of 100% (2,2 -dimethylpropane-1,3 -diyl 2 -ethylhexanoate) and oral absorption of 100% (2 -EHA) was assumed. In addition a factor of 3 was applied for the calculation of the corrected starting point (LOEL to the corrected NOAEL), although a NOAEL of 100 mg/kg bw would have been acceptable as a starting point, as no significant adverse effects were reported at the dose level of 100 mg/kg bw. Therefore the exposure calculated with the DNELs also assumes a worst case scenario, rather overestimating the hazards observed.

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within the CSR.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.717 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:
17.93 mg/m³
Explanation for the modification of the dose descriptor starting point:
No inhalation study available.
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
Justification:
The factor for exposure duration is not necessary in this case as the observed effects on the male reproductive system are sufficiently taken into account by the subchronic study covering the duration of spermatogenesis
AF for interspecies differences (allometric scaling):
4
Justification:
default
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
10
Justification:
default
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.151 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):
75
DNEL extrapolated from long term DNEL
Modified dose descriptor starting point:
NOAEC
Value:
161.33 mg/m³
Explanation for the modification of the dose descriptor starting point:
No inhalation study available.
AF for dose response relationship:
1
AF for interspecies differences (allometric scaling):
1
Justification:
Not applied for the inhalation route.
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
10
Justification:
default
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1

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:
4.12 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:
412 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No dermal study available.
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
Justification:
The factor for exposure duration is not necessary in this case as the observed effects on the male reproductive system are sufficiently taken into account by the subchronic study covering the duration of spermatogenesis.
AF for interspecies differences (allometric scaling):
4
Justification:
default
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
10
Justification:
default
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
12.361 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):
300
DNEL extrapolated from long term DNEL
Modified dose descriptor starting point:
NOAEL
Value:
3 708.3 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No dermal study available.
AF for dose response relationship:
1
AF for interspecies differences (allometric scaling):
4
Justification:
default
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
10
Justification:
default
AF for the quality of the whole database:
1
AF for remaining uncertainties:
3
Justification:
NOAEC from sub-lethal effects was used as a starting point.

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
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:
0.412 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:
41.2 mg/kg bw/day
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
Justification:
The factor for exposure duration is not necessary in this case as the observed effects on the male reproductive system are sufficiently taken into account by the subchronic study covering the duration of spermatogenesis.
AF for interspecies differences (allometric scaling):
4
Justification:
default
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
10
Justification:
default
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.235 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):
300
DNEL extrapolated from long term DNEL
Modified dose descriptor starting point:
NOAEL
Value:
370.5 mg/kg bw/day
AF for dose response relationship:
1
AF for interspecies differences (allometric scaling):
4
Justification:
default
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
10
Justification:
default
AF for the quality of the whole database:
1
AF for remaining uncertainties:
3
Justification:
NOAEC from sub-lethal effects was used as a starting point.

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Calculation of DNELs for 2,2 -dimethylpropane-1,3 -diyl 2 -ethylhexanoate(CAS 28510 -23 -8)

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 calculation are DNELs derived from available data of the surrogate substance 2-ethylhexanoic acid in a very conservative approach.

Based on the chemical structure of the EHA-esters it can be assumed, that they may undergo enzymatic hydrolysis of the ester bond(s) after human intake. The potential resulting products would be the corresponding alcohol and 2-ethyl hexanoic acid (2-EHA), which is legally classified as Category 2 reproductive toxicant (“Suspected of damaging fertility or the unborn child”). As no data for the EHA-ester regarding reproductive/developmental toxicity were available, the risk assessment of these substances have to be attributed to 2-EHA (as a worst case scenario), where the critical effect for characterization of risk to human health is reproductive and developmental toxicity. Data from analogue substances or the potential alcohol hydrolysis product indicate that no hazard in contrast to 2 -EHA can be expected.

 

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, Dec 2010).

Several animal studies with different species on the reproductive and developmental toxicity of 2-EHA are available. Although the overall results were not consistent, the data clearly provide enough evidence that 2-EHA is a reproductive toxicant and is harmful to the foetus.

 

The lowest identified observed-effect level (LOEL) was seen in one of the public available studies, where effects on the male reproductive system were observed in rats exposed orally to 2-EHA, with the lowest LOEL for reproductive toxicity at 100 mg/kg bw/d (Pennanen et al. 1993). This dose level was based on reduction in sperm motility in male Han Wistar rats exposed via drinking water to 0, 100, 300, or 600 mg/kg bw per day for 10 weeks before mating and 3 weeks during mating.

 

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 LOEL of 100 mg/kg bw/d was used, which has to be corrected as follows:

LOEL rat = 100 mg/kg bw/d

Corrected NOAEL rat = 100 mg/kg bw/d /3 = 33.3 mg/kg bw/d

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, Dec 2010).

Although this document suggested a factor of 2 for the time extrapolation from a subchronic study, in this case this factor is not necessary as the observed effects on the male reproductive system are sufficiently taken into account by the subchronic study covering the duration of spermatogenesis (AGS, 2010). Thus, a factor 1 for the exposure duration is scientifically justified and consequently used for calculation.

 

    Assessment factors used for DNEL calculation

Assessment factor for

Value

Remaining differences

2.5

Interspecies

4

Intraspecies

5 (worker) / 10 (general population)

Exposure duration

1

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-EHA were calculated:

 

DNELs for 2-EHA

DNEL

systemic

Long-term

Acute

Worker

General Population

Worker

General Population

Oral#

-

0.167

-

0.501

Inhalative#

1.174

0.290

3.52

0.870

Dermal#

0.333

0.167

0.999

0.501

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

 

The DNELs for EHA-ester are calculated by considering the different molecular weights and the stoichiometry of 2-EHA compared to the respective EHA-ester according to following formula:

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 for all EHA-ester. 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).

 

CAS

MW

DNEL

systemic

Long-term

Acute

 

 

 

Worker

General Population

Worker

General Population

28510 -23 -8

356.5

Oral

-

0.412

-

1.235

Inhalative

2.906

0.717

8.719

2.151

Dermal

8.242

4.120

24.725

12.361

 

In conclusion, the DNELs derived were based on effects observed with 2 -EHA. This was a very conservative approach based on the fact that enzymatic hydrolysis of 100% (2,2 -dimethylpropane-1,3 -diyl 2 -ethylhexanoate) and oral absorption of 100% (2 -EHA) was assumed. In addition a factor of 3 was applied for the calculation of the corrected starting point (LOEL to the corrected NOAEL), although a NOAEL of 100 mg/kg bw would have been acceptable as a starting point, as no significant adverse effects were reported at the dose level of 100 mg/kg bw. Therefore the exposure calculated with the DNELs also assumes a worst case scenario, rather overestimating the hazards observed.

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within the CSR.