Registration Dossier

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
80 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: informed assessment factors
Overall assessment factor (AF):
6
Modified dose descriptor starting point:
NOAEC
Value:
479.82 mg/m³
Explanation for the modification of the dose descriptor starting point:
Long term inhalation studies are not available. The long term systemic DNEL for inhalation has been derived from the 90 d oral repeated dose toxicity study. For derivation of the dose descriptor starting point a factor of 2 has been included for route-to-route extrapolation from oral to inhalative.
AF for dose response relationship:
1
Justification:
Default ECHA AF for NOAEL used as starting point. The original NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
2
Justification:
The NOAEL is based on a 90 day study. Default AF for extrapolation from sub-acute to chronic (ECHA 2008).
AF for interspecies differences (allometric scaling):
1
Justification:
Default corrections for respiratory rate and respiratory volume have been included in route-to-route extrapolation
AF for other interspecies differences:
1
Justification:
The substance is metabolised via general metabolic pathways that are common and very similar to rodents and humans. Moreover, the absence of any specific target organs indicating a specific MOA at high concentrations shows that there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
AF for intraspecies differences:
3
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems makes a lower variability likely, hence the AF of 3 by ECETOC (2010) is sufficiently conservative for workers.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
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:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
45 833.33 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: informed assessment factors
Overall assessment factor (AF):
24
Modified dose descriptor starting point:
NOAEL
Value:
1 100 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Long term dermal studies are not available. The long term systemic DNEL for dermal exposure has been derived from the 90 d oral repeated dose toxicity study.
AF for dose response relationship:
1
Justification:
Default ECHA AF for NOAEL used as starting point. The original NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
2
Justification:
The NOAEL is based on a 90 day study. Default AF for extrapolation from sub-acute to chronic (ECHA 2008).
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to humans AF 4 (ECHA 2008).
AF for other interspecies differences:
1
Justification:
The substance is metabolised via general metabolic pathways that are common and very similar to rodents and humans. Moreover, the absence of any specific target organs indicating a specific MOA at high concentrations shows that there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
AF for intraspecies differences:
3
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems makes a lower variability likely, hence the AF of 3 by ECETOC (2010) is sufficiently conservative for workers.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
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:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Oral absorption

No experimental studyon Bis(2-ethylhexyl) carbonate available.However, Bis(2-ethylhexyl) carbonate undergoes hydrolysis in the gastrointestinal tract resulting in carbonic acid and 2-Ethylhexanol. 

Carbonate moiety:

Independent from their absorption rate, the resulting Carbonic acid, respectively the Carbonate anion and carbon dioxide are uncritical from a toxicological view due to natural regulation mechanisms (c.f. standard textbooks on pharmacology and physiology). Synopses have been elaborated within the OECD work on investigation of high production volume chemicals. The description given in the following are excerpts of the OECD SIDS Initial Assessment Reports on Bicarbonate special. However, comparable information is also given in the OECD SIDS Initial Assessment Reports on Sodium carbonate, Sodium bicarbonate and Ammonium hydrogencarbonate (assessment reports available via Inernet:http://www.oecd.org/document/63/0,3343,en_2649_34379_1897983_1_1_1_1,00.html) and have been quoted in REACH Registrations on Carbonates:

The major extra-cellular buffer in the blood and the interstitial fluid of vertebrates is the bicarbonate buffer system, described by the following equation:

H2O + CO2<=> H2CO3<=> H++ HCO3-

Carbon dioxide from the tissues diffuses rapidly into red blood cells, where it is hydrated with water to form carbonic acid. This reaction is accelerated by carbonic anhydrase, an enzyme present in high concentrations in red blood cells. The carbonic acid formed dissociates into bicarbonate and hydrogen ions. Most of the bicarbonate ions diffuse into the plasma. Since the ratio of H2CO3 to dissolved CO2 is constant at equilibrium, pH may be expressed in terms of bicarbonate ion concentration and partial pressure of CO2 by means of Henderson-Hasselbalch equation:

          pH = pK + log [HCO3-]/αPCO2

Human blood plasma has normally a pH of 7.40. Should the pH fall below 7.0 or rise above 7.8, irreversible damage may occur. Compensatory mechanisms for acid-base disturbances function altering the ratio of [HCO3-] to PCO2, and returning the pH of the blood to normal. Thus, metabolic acidosis may be compensated for by hyper-ventilation and increased renal absorption of HCO3-. Metabolic alkalosis may be compensated for by hypo-ventilation and the excess of excretion of HCO3 - in urine. Renal mechanisms are usually sufficient to restore the acid-balance.

 

Alcohol moiety:

The released alcohol moiety 2-Ethylhexanol is systemically absorbed and thus might have an systemic effect. According to the information given in the respective REACH registration 2-Ethylhexanol was efficiently absorbed following oral administration to rats, excretion of [14C] within 28 hrs after oral administration to rats (% of dose): 6-7 %CO2, 80-82 % in urine, 8-9 % in faeces. AGI absortion rate of 100% after oral exposure is taken into account for DNEL derivation. As experimental data show a resorption of almost 100%, this deviation from ECHA default value for oral absorption of 50% is justified.

 

Dermal absorption

Bis(2-ethylhexyl) carbonate does not penetrate the human skinin vitro(c.f. IUCLID entry Dermal absorption: 14858-73-2_8.8.1_THG_2007_OECD 428). Thus, actually it is not necessary to derive dermal DNELs systemic effects, as no systemic exposure will occur after dermal exposure.

To calculate a DNEL with an absorption rate of zero is not possible, respectively will result in an infinite value. To calculate dermal DNELs, thedetection limit of the dermal absorption study may be used as worst case dermal absorption rate. (Application volume 40 µL(= 40 mg, assuming a density of 1 (measured density = 0.998 c.f. 14858-73-2_7.4_THG_2005_OECD 109), detection limit 10 µg/mL, resulting in a worst case absorption rate of 0.025 %.)

Inhalatory absorption

For inhalatory exposure as a worst case assumption a 100% absorption is assumed in absence of any experimental data (TGD R8).As the metabolite 2-Ethylhexanol is efficiently absorbed after oral administration, no further assessment factor for oral-to-inhalatory route-to-route extrapolation is required.

 

Dose descriptors identified for the endpoints of concern:

Endpoint

Quantitative dose descriptor or other information on potency

Associated relevant effect

Remarks on the study

Local effect

Systemic effect

Acute Toxicity

oral

-

> 2000 mg/kg bw

No lethality at highest dose

Rat acute study

dermal

No effects

> 2000 mg/kg bw

No lethality at highest dose

Rat acute study

 

Irritation/corrosivity

Eye

Slight transient irritation (not leading to classification)

 

No systemic effect

No irritation

Rabbit study

 

Skin

Irritation (Classification R38; Skin Irrit. 2, H315) 

 

No systemic effect

Local irritation, NOAEL not available, no SCL available

Rabbit study

 

Skin sensitisation

Skin

positive (most probably false positive) response in the 1st LLNA;

negative results in 2nd LLNA, Buehler test and M&K study

-

Not sensitising

2 LLNA

Buehler test

M&K

 

Repeated dose toxicity (sub-acute/sub-chronic)

oral

-

NOAEL 1000 mg/kg bw/d

No effects relevant to human health at limit dose

28 day gavage study rat

oral

-

NOAEL 250 mg/kg bw/d (2-Ethylhexanol); recalculated based on molecular weight NOAEL = 275 mg/kg bw/d (as Bis(2-ethylhexyl) carbonate)

 

90 day gavage study rat

Developmental toxicity

oral

-

NOAEL embryotoxicity=130 mg/kg bw/d (2-Ethylhexanol); recalculated based on molecular weight NOAEL = 143 mg/kg bw/d (as Bis(2-ethylhexyl) carbonate)

decreased fetal weight; increased number of fetuses with skeletal variations and retardations

OECD414, gavage rat

Modification of the relevant dose descriptors to the correct starting point (NOAEL from oral 90 d repeated dose study):

Assessment factors

Uncertainties

AF

REACH

Justification

Allometric scaling (inhalation)

1

Default corrections for respiratory rate and respiratory volume have been included in route-to-route extrapolation

Allometric scaling (dermal)

4

Allometric scaling rat to humans AF 4 (ECHA 2008)

Interspecies differences

1

The substance is metabolised via general metabolic pathways that are common and very similar to rodents and humans. Moreover, the absence of any specific target organs indicating a specific MOA at high concentrations shows that there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.

Intraspecies differences

3

Known mode of action involving ubiquitous and non-specific enzyme systems makes a lower variability likely, hence the AF of 3 by ECETOC (2010) is sufficiently conservative for workers.

Differences in duration of exposure

2

The NOAEL is based on a 90 day study. DefaultAF for extrapolation from sub-chronic to chronic (ECHA 2008).

Dose response and endpoint specific/severity

 

1

Default ECHA AF for NOAEL used as starting point. The original NOAEL is reliable. No adjustment is required.

Quality of whole database

1

The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

Remaining uncertainties

1

no remaining uncertainties

 

Long term inhalation studies are not available. The long term systemic DNEL for inhalation has been derived from the 90 d oral repeated dose toxicity study.

 

Worker-DNEL long-term for inhalation route (systemic)

Bis(2-ethylhexyl)carbonate has a very low vapour pressure and no use pattern which will generate inhalative exposure. Thus, actually it is not necessary to derive inhalative DNELs systemic effects, as this way of exposure is not relevant.

For workers the corrected inhalatory NOEC is calculated according to the following equation:

 

corrected inhalatory NOAEC  = oral NOAEL x 1/sRVratx ABSoral-rat/ ABSinh-humanx sRVhuman/ wRV

                                             = 275 x 1/0.384 x 100/100 x 6.7/10

The corrected inhalatory NOAECworker(8h) is therefore:

                                             = 479.82 mg/m3(8h-TWA)

DNEL worker, chronic inhalative systemic: 80.00mg/m³

Start value: 275 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 479.82 mg/m³

Overall AF: 1*1*3*2*1*1*1 = 6

 

Worker-DNEL long-term for dermal route (systemic)

The corrected dermal NOAEL for Bis(2-ethylhexyl) carbonate as worst case assumption is therefore:

275 x 100/0.025 = 1,100,000 mg/kg bw/day

DNEL worker, chronic dermal systemic: 45,833.33 mg/kg bw/d

Start value: 275 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation:1,100,000mg/kg bw/d

Overall AF: 4*1*3*2*1*1*1 = 24

 

Modification of the relevant dose descriptors to the correct starting point (NOAEL from oral 28 d repeated dose study):

Assessment factors

Uncertainties

AF

REACH

Justification

Allometric scaling (inhalation)

1

Default corrections for respiratory rate and respiratory volume have been included in route-to-route extrapolation

Allometric scaling (dermal)

4

Allometric scaling rat to humans AF 4 (ECHA 2008)

Interspecies differences

1

The substance is metabolised via general metabolic pathways that are common and very similar to rodents and humans. Moreover, the absence of any specific target organs indicating a specific MOA at high concentrations shows that there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.

Intraspecies differences

3

Known mode of action involving ubiquitous and non-specific enzyme systems makes a lower variability likely, hence the AF of 3 by ECETOC (2010) is sufficiently conservative for workers.

Differences in duration of exposure

6

The NOAEL is based on a 28 day study. DefaultAF for extrapolation from sub-acute to chronic (ECHA 2008).

Dose response and endpoint specific/severity

 

1

Default ECHA AF for NOAEL used as starting point. The original NOAEL is reliable. No adjustment is required.

Quality of whole database

1

The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

Remaining uncertainties

1

no remaining uncertainties

 

Long term inhalation studies are not available. The long term systemic DNEL for inhalation has been derived from the 28 d oral repeated dose toxicity study.

 

Worker-DNEL long-term for inhalation route (systemic)

Bis(2-ethylhexyl)carbonate has a very low vapour pressure and no use pattern which will generate inhalative exposure.Thus, actually it is not necessary to derive inhalative DNELs systemic effects, as this way of exposure is not relevant.

For workers the corrected inhalatory NOEC is calculated according to the following equation:

 

corrected inhalatory NOAEC  = oral NOAEL x 1/sRVratx ABSoral-rat/ ABSinh-humanx sRVhuman/ wRV

                                             = 1000 x 1/0.384 x 100/100 x 6.7/10

The corrected inhalatory NOAECworker(8h) is therefore:

                                             =1744.79 mg/m3(8h-TWA)

DNEL worker, chronic inhalative systemic: 96.93 mg/m³

Start value: 1000 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 1744.79 mg/m³

Overall AF: 1*1*3*6*1*1*1 = 18

 

Worker-DNEL long-term for dermal route (systemic)

The corrected dermal NOAEL for Bis(2-ethylhexyl) carbonate as worst case assumption is therefore:

1000 x 100/0.025 = 4,000,000 mg/kg bw/day

DNEL worker, chronic dermal systemic: 55,555.56 mg/kg bw/d

Start value: 1000 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 4,000,000 mg/kg bw/d

Overall AF: 4*1*3*6*1*1*1 = 72

 

The DNELs derived from the 28 d study conducted with Bis(2-ethylhexyl) carbonate are higher than those derived from the 90 d study with the metabolite 2-Ethylhexanol. As both are in a similar range, the more protective value is used.

 

Modification of the relevant dose descriptors to the correct starting point (NOAEL from oralDevelopmental toxicitystudy):

Assessment factors

Uncertainties

AF

REACH

Justification

Allometric scaling (inhalation)

1

Default corrections for respiratory rate and respiratory volume have been included in route-to-route extrapolation

Allometric scaling (dermal)

4

Allometric scaling rat to humans AF 4 (ECHA 2008)

Interspecies differences

1

The substance is metabolised via general metabolic pathways that are common and very similar to rodents and humans. Moreover, the absence of any specific target organs indicating a specific MOA at high concentrations shows that there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.

Intraspecies differences

3

Known mode of action involving ubiquitous and non-specific enzyme systems makes a lower variability likely, hence the AF of 3 by ECETOC (2010) is sufficiently conservative for workers.

Differences in duration of exposure

1

No time extrapolation is required since the susceptible window is fully covered (OECD guideline 414 study)

Dose response and endpoint specific/severity

 

1

Default ECHA AF for NOAEL used as starting point. The original NOAEL is reliable. No adjustment is required.

Quality of whole database

1

The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

Remaining uncertainties

1

no remaining uncertainties

 

Worker-DNEL long-term for inhalation route (systemic)

For workers the corrected inhalatory NOEC is calculated according to the following equation:

 

corrected inhalatory NOAEC  = oral NOAEL x 1/sRVratx ABSoral-rat/ ABSinh-humanx sRVhuman/ wRV

                                             = 143 x 1/0.384 x 100/100 x 6.7/10

The corrected inhalatory NOAECworker(8h) is therefore:

                                             = 249.51 mg/m3(8h-TWA)

DNEL worker, chronic inhalative systemic: 83.17mg/m³

Start value: 143 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 249.51 mg/m³

Overall AF: 1*1*3*1*1*1*1 = 3

 

Worker-DNEL long-term for dermal route (systemic)

The corrected dermal NOAEL for Bis(2-ethylhexyl) carbonate as worst case assumption is therefore:

143 x 100/0.025 = 572,000 mg/kg bw/day

DNEL worker, chronic dermal systemic: 47,666.67 mg/kg bw/d

Start value: 143 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 572,000 mg/kg bw/d

Overall AF: 4*1*3*1*1*1*1 = 12

 

The DNELs derived from the OECD guideline 414 study are higher than those from the 90 day study. The DNELs for repeated dose toxicity are thus also protective for development.

 

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
23.87 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: informed assessment factors
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEC
Value:
238.72 mg/m³
Explanation for the modification of the dose descriptor starting point:
Long term inhalation studies are not available. The long term systemic DNEL for inhalation has been derived from the 90 d oral repeated dose toxicity study. For derivation of the dose descriptor starting point a factor of 2 has been included for route-to-route extrapolation from oral to inhalative.
AF for dose response relationship:
1
Justification:
Default ECHA AF for NOAEL used as starting point. The original NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
2
Justification:
The NOAEL is based on a 90 day study. Default AF for extrapolation from sub-acute to chronic (ECHA 2008).
AF for interspecies differences (allometric scaling):
1
Justification:
Default corrections for respiratory rate and respiratory volume have been included in route-to-route extrapolation
AF for other interspecies differences:
1
Justification:
The substance is metabolised via general metabolic pathways that are common and very similar to rodents and humans. Moreover, the absence of any specific target organs indicating a specific MOA at high concentrations shows that there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
AF for intraspecies differences:
5
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems makes a lower variability likely, hence the AF of 5 by ECETOC (2010) is sufficiently conservative for general population.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
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:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
27 500 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: informed assessment factors
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
Value:
1 100 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Long term dermal studies are not available. The long term systemic DNEL for dermal exposure has been derived from the 90 d oral repeated dose toxicity study.
AF for dose response relationship:
1
Justification:
Default ECHA AF for NOAEL used as starting point. The original NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
2
Justification:
The NOAEL is based on a 90 day study. Default AF for extrapolation from sub-acute to chronic (ECHA 2008).
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to humans AF 4 (ECHA 2008).
AF for other interspecies differences:
1
Justification:
The substance is metabolised via general metabolic pathways that are common and very similar to rodents and humans. Moreover, the absence of any specific target organs indicating a specific MOA at high concentrations shows that there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
AF for intraspecies differences:
5
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems makes a lower variability likely, hence the AF of 5 by ECETOC (2010) is sufficiently conservative for general population.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
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:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
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:
6.88 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: informed assessment factors
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
Value:
275 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
no route to route extrapolation: original study via oral route
AF for dose response relationship:
1
Justification:
Default ECHA AF for NOAEL used as starting point. The original NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
2
Justification:
The NOAEL is based on a 90 day study. Default AF for extrapolation from sub-acute to chronic (ECHA 2008).
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to humans AF 4 (ECHA 2008).
AF for other interspecies differences:
1
Justification:
The substance is metabolised via general metabolic pathways that are common and very similar to rodents and humans. Moreover, the absence of any specific target organs indicating a specific MOA at high concentrations shows that there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
AF for intraspecies differences:
5
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems makes a lower variability likely, hence the AF of 5 by ECETOC (2010) is sufficiently conservative for general population.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
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

Oral absorption

No experimental studyon Bis(2-ethylhexyl) carbonate available.However, Bis(2-ethylhexyl) carbonate undergoes hydrolysis in the gastrointestinal tract resulting in carbonic acid and 2-Ethylhexanol. 

Carbonate moiety:

Independent from their absorption rate, the resulting Carbonic acid, respectively the Carbonate anion and carbon dioxide are uncritical from a toxicological view due to natural regulation mechanisms (c.f. standard textbooks on pharmacology and physiology). Synopses have been elaborated within the OECD work on investigation of high production volume chemicals. The description given in the following are excerpts of the OECD SIDS Initial Assessment Reports on Bicarbonate special. However, comparable information is also given in the OECD SIDS Initial Assessment Reports on Sodium carbonate, Sodium bicarbonate and Ammonium hydrogencarbonate (assessment reports available via Internet:http://www.oecd.org/document/63/0,3343,en_2649_34379_1897983_1_1_1_1,00.html) and have been quoted in REACH Registrations on Carbonates:

The major extra-cellular buffer in the blood and the interstitial fluid of vertebrates is the bicarbonate buffer system, described by the following equation:

H2O + CO2<=> H2CO3<=> H++ HCO3-

Carbon dioxide from the tissues diffuses rapidly into red blood cells, where it is hydrated with water to form carbonic acid. This reaction is accelerated by carbonic anhydrase, an enzyme present in high concentrations in red blood cells. The carbonic acid formed dissociates into bicarbonate and hydrogen ions. Most of the bicarbonate ions diffuse into the plasma. Since the ratio of H2CO3to dissolved CO2 is constant at equilibrium, pH may be expressed in terms of bicarbonate ion concentration and partial pressure of CO2 by means of Henderson-Hasselbalch equation:

          pH = pK + log [HCO3-]/αPCO2

Human blood plasma has normally a pH of 7.40. Should the pH fall below 7.0 or rise above 7.8, irreversible damage may occur. Compensatory mechanisms for acid-base disturbances function altering the ratio of [HCO3-] to PCO2, and returning the pH of the blood to normal. Thus, metabolic acidosis may be compensated for by hyper-ventilation and increased renal absorption ofHCO3-. Metabolic alkalosis may be compensated for by hypo-ventilation and the excess of excretion ofHCO3-in urine. Renal mechanisms are usually sufficient to restore the acid-balance.

 

Alcohol moiety:

The released alcohol moiety 2-Ethylhexanol is systemically absorbed and thus might have an systemic effect. According to the information given in the respective REACH registration 2-Ethylhexanol was efficiently absorbed following oral administration to rats, excretion of [14C] within 28 hrs after oral administration to rats (% of dose): 6-7 %CO2, 80-82 % in urine, 8-9 % in faeces. AGI absortion rate of 100% after oral exposure is taken into account for DNEL derivation. As experimental data show a resorption of almost 100%, this deviation from ECHA default value for oral absorption of 50% is justified.

 

Dermal absorption

Bis(2-ethylhexyl) carbonate does not penetrate the human skinin vitro(c.f. IUCLID entry Dermal absorption: 14858-73-2_8.8.1_THG_2007_OECD 428). Thus, actually it is not necessary to derive dermal DNELs systemic effects, as no systemic exposure will occur after dermal exposure.

To calculate a DNEL with an absorption rate of zero is not possible, respectively will result in an infinite value. To calculate dermal DNELs, thedetection limit of the dermal absorption study may be used as worst case dermal absorption rate. (Application volume 40 µL(= 40 mg, assuming a density of 1 (measured density = 0.998 c.f. 14858-73-2_7.4_THG_2005_OECD 109), detection limit 10 µg/mL, resulting in a worst case absorption rate of 0.025 %.)

Inhalatory absorption

For inhalatory exposure as a worst case assumption a 100% absorption is assumed in absence of any experimental data (TGD R8).As the metabolite 2-Ethylhexanol is efficiently absorbed after oral administration, no further assessment factor for oral-to-inhalatory route-to-route extrapolation is required.

 

Dose descriptors identified for the endpoints of concern:

Endpoint

Quantitative dose descriptor or other information on potency

Associated relevant effect

Remarks on the study

Local effect

Systemic effect

Acute Toxicity

oral

-

> 2000 mg/kg bw

No lethality at highest dose

Rat acute study

dermal

No effects

> 2000 mg/kg bw

No lethality at highest dose

Rat acute study

 

Irritation/corrosivity

Eye

Slight transient irritation (not leading to classification)

 

No systemic effect

No irritation

Rabbit study

 

Skin

Irritation (Classification R38; Skin Irrit.2, H315) 

 

No systemic effect

Local irritation, NOAEL not available, no SCL available

Rabbit study

 

Skin sensitisation

Skin

positive (most probably false positive) response in the 1st LLNA;

negative results in 2nd LLNA, Buehler test and M&K study

-

Not sensitising

2 LLNA

Buehler test

M&K

 

Repeated dose toxicity (sub-acute/sub-chronic)

oral

-

NOAEL 1000 mg/kg bw/d

No effects relevant to human health at limit dose

28 day gavage study rat

oral

-

NOAEL 250 mg/kg bw/d (2-Ethylhexanol); recalculated based on molecular weight NOAEL = 275 mg/kg bw/d (as Bis(2-ethylhexyl) carbonate)

 

90 day gavage study rat

Developmental toxicity

oral

-

NOAEL embryotoxicity=130 mg/kg bw/d (2-Ethylhexanol); recalculated based on molecular weight NOAEL = 143 mg/kg bw/d (as Bis(2-ethylhexyl) carbonate)

decreased fetal weight; increased number of fetuses with skeletal variations and retardations

OECD414, gavage rat

 

Modification of the relevant dose descriptors to the correct starting point (NOAEL from oral 90 d repeated dose study):

Assessment factors

Uncertainties

AF

REACH

Justification

Allometric scaling (inhalation)

1

Default corrections for respiratory rate and respiratory volume have been included in route-to-route extrapolation

Allometric scaling (dermal, oral)

4

Allometric scaling rat to humans AF 4 (ECHA 2008)

Interspecies differences

1

The substance is metabolised via general metabolic pathways that are common and very similar to rodents and humans. Moreover, the absence of any specific target organs indicating a specific MOA at high concentrations shows that there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.

Intraspecies differences

5

Known mode of action involving ubiquitous and non-specific enzyme systems makes a lower variability likely, hence the AF of 5 by ECETOC (2010) is sufficiently conservative for general population.

Differences in duration of exposure

2

The NOAEL is based on a 90 day study. DefaultAF for extrapolation from sub-chronic to chronic (ECHA 2008).

Dose response and endpoint specific/severity

 

1

Default ECHA AF for NOAEL used as starting point. The original NOAEL is reliable. No adjustment is required.

Quality of whole database

1

The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

Remaining uncertainties

1

no remaining uncertainties

 

 

General population-DNEL long-term for inhalation route (systemic)

For general population the corrected inhalatory NOEC is calculated according to the following equation:

corrected inhalatory NOAEC  = oral NOAEL x 1/sRVratx ABSoral-rat/ ABSinh-human

                                             = 275 x 1/1.152 x 100/100

The corrected inhalatory NOAECgeneral population(24 h) is therefore:

                                             = 238.72 mg/m3(24 h)

DNELgeneral population, chronic inhalative systemic:23.87mg/m³

Start value: 275 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 238.72 mg/m³

Overall AF: 1*1*5*2*1*1 = 10

 

general population-DNEL long-term for dermal route (systemic)

The corrected dermal NOAEL for Bis(2-ethylhexyl) carbonate as worst case assumption is therefore:

275 x 100/0.025 = 1,100,000 mg/kg bw/day

DNELgeneral population, chronic dermal systemic: 27,500 mg/kg bw/d

Start value: 275 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation:1,100,000mg/kg bw/d

Overall AF: 4*1*5*2*1*1 = 40

 

general population-DNEL long-term for oral route (systemic)

DNELgeneral population, chronic oral systemic: 6.88 mg/kg bw/d

Start value: 275 mg/kg bw/d

Route of original study: oral

Overall AF: 4*1*5*2*1*1 = 40

 

 

Modification of the relevant dose descriptors to the correct starting point (NOAEL from oral 28 d repeated dose study):

Assessment factors

Uncertainties

AF

REACH

Justification

Allometric scaling (inhalation)

1

Default corrections for respiratory rate and respiratory volume have been included in route-to-route extrapolation

Allometric scaling (dermal, oral)

4

Allometric scaling rat to humans AF 4 (ECHA 2008)

Interspecies differences

1

The substance is metabolised via general metabolic pathways that are common and very similar to rodents and humans. Moreover, the absence of any specific target organs indicating a specific MOA at high concentrations shows that there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.

Intraspecies differences

5

Known mode of action involving ubiquitous and non-specific enzyme systems makes a lower variability likely, hence the AF of 5 by ECETOC (2010) is sufficiently conservative for general population.

Differences in duration of exposure

6

The NOAEL is based on a 28 day study. DefaultAF for extrapolation from sub-acute to chronic (ECHA 2008).

Dose response and endpoint specific/severity

 

1

Default ECHA AF for NOAEL used as starting point. The original NOAEL is reliable. No adjustment is required.

Quality of whole database

1

The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

Remaining uncertainties

1

no remaining uncertainties

 

General population-DNEL long-term for inhalation route (systemic)

For general population the corrected inhalatory NOEC is calculated according to the following equation:

corrected inhalatory NOAEC  = oral NOAEL x 1/sRVratx ABSoral-rat/ ABSinh-human

                                             = 1000 x 1/1.152 x 100/100

The corrected inhalatory NOAECgeneral population(24 h) is therefore:

                                             = 868.06 mg/m3(24 h)

DNELgeneral population, chronic inhalative systemic: 28.93 mg/m³

Start value: 1000 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 868.06 mg/m³

Overall AF: 1*1*5*6*1*1*1 = 30

 

general population-DNEL long-term for dermal route (systemic)

The corrected dermal NOAEL for Bis(2-ethylhexyl) carbonate as worst case assumption is therefore:

1000 x 100/0.025 = 4,000,000 mg/kg bw/day

DNELgeneral population, chronic dermal systemic: 33,333.33 mg/kg bw/d

Start value: 1000 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation:4,000,000mg/kg bw/d

Overall AF: 4*1*5*6*1*1*1 = 120

 

general population-DNEL long-term for oral route (systemic)

DNELgeneral population, chronic oral systemic: 8.33 mg/kg bw/d

Start value: 1000 mg/kg bw/d

Route of original study: oral

Overall AF: 4*1*5*6*1*1*1 = 120

 

The DNELs derived from the 28 d study conducted with Bis(2-ethylhexyl) carbonate are higher than those derived from the 90 d study with the metabolite 2-Ethylhexanol. As both are in a similar range, the more protective value is used.

 

Modification of the relevant dose descriptors to the correct starting point (NOAEL from oralDevelopmental toxicitystudy):

Assessment factors

Uncertainties

AF

REACH

Justification

Allometric scaling (inhalation)

1

Default corrections for respiratory rate and respiratory volume have been included in route-to-route extrapolation

Allometric scaling (dermal, oral)

4

Allometric scaling rat to humans AF 4 (ECHA 2008)

Interspecies differences

1

The substance is metabolised via general metabolic pathways that are common and very similar to rodents and humans. Moreover, the absence of any specific target organs indicating a specific MOA at high concentrations shows that there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.

Intraspecies differences

5

Known mode of action involving ubiquitous and non-specific enzyme systems makes a lower variability likely, hence the AF of 5 by ECETOC (2010) is sufficiently conservative for general population.

Differences in duration of exposure

1

No time extrapolation is required since the susceptible window is fully covered (OECD guideline 414 study)

Dose response and endpoint specific/severity

 

1

Default ECHA AF for NOAEL used as starting point. The original NOAEL is reliable. No adjustment is required.

Quality of whole database

1

The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

Remaining uncertainties

1

no remaining uncertainties

 

 

general population-DNEL long-term for inhalation route (systemic)

For general population the corrected inhalatory NOEC is calculated according to the following equation:

corrected inhalatory NOAEC  = oral NOAEL x 1/sRVratx ABSoral-rat/ ABSinh-human

                                             = 143 x 1/1.152 x 100/100

The corrected inhalatory NOAECgeneral population(24 h) is therefore:

                                             = 124.13 mg/m3(24 h)

DNELgeneral population, chronic inhalative systemic: 24.83 mg/m³

Start value: 143 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 124.13 mg/m³

Overall AF: 1*1*5*1*1*1*1 = 5

 

general population-DNEL long-term for dermal route (systemic)

The corrected dermal NOAEL for Bis(2-ethylhexyl) carbonate as worst case assumption is therefore:

143 x 100/10 = 572,000 mg/kg bw/day

DNELgeneral population, chronic dermal systemic: 28,600 mg/kg bw/d

Start value: 143 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 572,000 mg/kg bw/d

Overall AF: 4*1*5*1*1*1*1 = 20

 

general population-DNEL long-term for oral route (systemic)

DNELgeneral population, chronic oral systemic: 7.15 mg/kg bw/d

Start value: 143 mg/kg bw/d

Route of original study: oral

Overall AF: 4*1*5*1*1*1*1 = 20

 

The DNELs derived from the OECD guideline 414 study are higher than those from the 90 day study. The DNELs for repeated dose toxicity are thus also protective for development.

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