Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

80 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

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

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Hazard assessment conclusion:

hazard unknown (no further information necessary)

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 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

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Hazard assessment conclusion:

no hazard identified

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 H₂CO₃to dissolved CO₂is constant at equilibrium, pH may be expressed in terms of bicarbonate ion concentration and partial pressure of CO₂by 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
Endpoint	Local effect	Systemic effect	Associated relevant effect	Remarks on the study
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/sRV_ratx ABS_oral-rat/ ABS_inh-humanx sRV_human/ wRV

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

The corrected inhalatory NOAEC_worker(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/sRV_ratx ABS_oral-rat/ ABS_inh-humanx sRV_human/ wRV

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

The corrected inhalatory NOAEC_worker(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/sRV_ratx ABS_oral-rat/ ABS_inh-humanx sRV_human/ wRV

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

The corrected inhalatory NOAEC_worker(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.

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 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

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Hazard assessment conclusion:

hazard unknown (no further information necessary)

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 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

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

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 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

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

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 CO₂is constant at equilibrium, pH may be expressed in terms of bicarbonate ion concentration and partial pressure of CO₂by 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
Endpoint	Local effect	Systemic effect	Associated relevant effect	Remarks on the study
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/sRV_ratx ABS_oral-rat/ ABS_inh-human

= 275 x 1/1.152 x 100/100

The corrected inhalatory NOAEC_{general 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/sRV_ratx ABS_oral-rat/ ABS_inh-human

= 1000 x 1/1.152 x 100/100

The corrected inhalatory NOAEC_{general 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/sRV_ratx ABS_oral-rat/ ABS_inh-human

= 143 x 1/1.152 x 100/100

The corrected inhalatory NOAEC_{general 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.

Registration Dossier

Registration Dossier

Data platform availability banner - registered substances factsheets

Diss Factsheets

Bis(2-ethylhexyl) carbonate

Toxicological Summary

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

Acute/short term exposure

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

Acute/short term exposure

Workers - Hazard for the eyes

Local effects

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

Acute/short term exposure

General Population - Hazard via oral route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

General Population - Hazard for the eyes

Local effects

Additional information - General Population