Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
101 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: as proposed by ECETOC Technical Report #86.
Overall assessment factor (AF):
6
Modified dose descriptor starting point:
NOAEC
Value:
612 mg/m³
AF for dose response relationship:
1
Justification:
default
AF for differences in duration of exposure:
2
Justification:
default for sub-chronic to chronic extrapolation
AF for interspecies differences (allometric scaling):
1
Justification:
No factor required for inhalation route of exposure
AF for other interspecies differences:
1
Justification:
as proposed by ECETOC Technical Report #86.
AF for intraspecies differences:
3
Justification:
as proposed by ECETOC Technical Report #86.
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:
402 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: See description below
Overall assessment factor (AF):
3
Modified dose descriptor starting point:
NOAEC
Value:
1 225
AF for dose response relationship:
1
Justification:
default
AF for interspecies differences (allometric scaling):
1
Justification:
not required for inhalation route of exposure
AF for other interspecies differences:
1
Justification:
as proposed by ECETOC Technical Report #86.
AF for intraspecies differences:
3
Justification:
as proposed by ECETOC Technical Report #86.
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
default

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
119 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
other: See description below. Read across from another substance using human volunteer data.
Overall assessment factor (AF):
1
Dose descriptor:
NOAEC
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:
364 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: see information below
Overall assessment factor (AF):
24
Modified dose descriptor starting point:
NOAEL
Value:
8 740 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
see detailed description below
AF for dose response relationship:
1
Justification:
default
AF for differences in duration of exposure:
2
Justification:
default for sub-chronic to chronic exposure
AF for interspecies differences (allometric scaling):
4
Justification:
default for rat to human extrapolation
AF for other interspecies differences:
1
Justification:
as proposed by ECETOC Technical Report #86.
AF for intraspecies differences:
3
Justification:
as proposed by ECETOC Technical Report #86.
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
default
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Discussion

According to the REACH “Guidance on information requirements and chemical safety assessment”, a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible.

The DNELs are derived using the scientifically based assessment factors as reported by ECETOC (ECETOC, 2003. Derivation of assessment factors for human health risk assessment. Technical report No. 86, ECETOC, February 2003).

Kinetics

The inhalation and dermal absorption percentages used for DNEL derivation (in case of route-to-route extrapolation) are 50% and 2%, respectively.

Acute toxicity

TAEE is classified for acute toxicity (R67 or Specific Target Organ toxicity – Single exposure, Cat. 3 (H336)) and therefore derivation of a DNELacute is necessary in case peak exposures do occur. The NOAEC for transient signs of CNS depression is 250 ppm (1060 mg/m3), established by read-across from the data on the structural analogue TAME. This NOAEC is derived from acute effects observed in a 28 days inhalation study conducted in rats.

TAEE is irritating to the skin and eyes; however, it is not possible to derive a DNEL on the basis of the available data. It is necessary to stipulate risk management measures that prevent the occurrence of skin and eye irritation.

TAEE does not need to be classified for respiratory tract irritation.

TAEE is not sensitising to the skin. Therefore, no DNEL is derived for this endpoint.

Long-term toxicity

Based on the read-across from structural analogues ETBE and TAME, the overall NOAEC of 250 ppm (1060 mg/m3) is established for the inhalation route of exposure, based on organ (liver, adrenals and kidneys) weight increases in rats and liver effects in mice, observed in the 90-day inhalation studies with TAME. For the oral route of exposure a NOAEL of 100 mg/kg bw/day has been established in the combined repeated dose toxicity study with reproductive and developmental screening test with TAEE, based on the increased ALT activity infemale rats and significant increased relative liver weights accompanied by diffuse enlargement of the hepatocytes without the normal zonal pattern in male rats at mid- and high-dose levels, and increased adrenal weights in both sexes at the high dose level. This NOAEL will be used as a point of departure for DNEL derivation for the oral route of epoxusre.

No repeated dermal toxicity studies for TAEE are available. Regarding local effects, it can be presumed that due to the effective lipid extraction properties of TAEE repeated skin exposure may result in skin fatigue (and consequent risk of toxic eczema), an effect common to a variety of organic solvents. No quantitative data on this effect are available. Therefore a qualitative risk characterisation will be performed for local effects by repeated dermal exposure. For systemic effects, route-to-route extrapolation will be performed to derive long-term DNELs for the dermal route of exposure. 

TAEE is assessed as being non-mutagenic and not carcinogenic. Based on this, no separate risk characterisation for mutagenicity and carcinogenicity is needed.

TAEE did not show effects on fertility or development in the available combined repeated dose toxicity study with reproductive and developmental screening test.As NOAELs for reproductive toxicity, based on the available 2-generation studies with TAME and ETBE, are higher than the NOAELs for systemic toxicity, no DNEL derivation will be performed for this endpoint. Based on data of TAME and ETBE, the lowest NOAEC for developmental toxicity is comparable with the NOAEC for repeated dose toxicity (250 ppm (1060 mg/m3)) which is taken as starting point for the DNEL derivation of TAEE.

There are no indications from the available data that dams are more sensitive regarding systemic effects compared to animals exposed in the repeated dose toxicity studies.

 

Worker DNELs

 

Acute – inhalation, systemic effects

Description

Value

Remark

 

Step 1) Relevant dose-descriptor

NOAEC: 250 ppm (1060 mg/m3)

No appropriate substance specific TAEE data are available. Therefore, the available inhalation toxicity studies on the structural analogues TAME (2-methoxy-2-methylbutane) and ETBE (2-ethoxy-2-methylpropane) will be used for derivation of an acute inhalation DNEL for TAEE. The (lower) inhalation NOAEC reported for TAME, 1060 mg/m3, will be used as starting point. This NOAEC was established in a 90-day neurotoxicity study with rats and based on acute CNS effects:

- depression of central nervous system and neuromuscular junction impairment (FOB observations);

- clinical observations: animals were prostrate and lethargic.

 

Step 2) Modification of starting point

-

This starting point is corrected for molecular weight difference to a starting NOAEC of 1225mg/m3.)

From the available data, it is clear that acute CNS effects occurred during the daily exposures, but it is not clear at which time point during exposure these effects occurred. In the REACH guidance (R.8, Appendix R. 8-8), it is mentioned: ‘If a DNEL for acute toxicity needs to be established, this should be derived only for a specified fraction of the daily exposure duration (usually 15 minutes)’. As it is not clear at which time point during exposure the effects occurred, a calculation to a DNEL for 15 minutes (which results in a higher starting point) cannot be performed.

The REACH guidance prescribes a factor for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m3/10 m3). The application of this factor results in a lower starting point.

Based on a qualitative assessment of the above two subjects, it is considered acceptable that no modification of the starting point will be applied.

 

Step 3) Assessment factors

 

 

 

Interspecies

1

No allometric scaling is needed in case of inhalation exposure because extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans; animal and humans breathe at a rate depending on their caloric requirements.

 

Intraspecies

3

A default assessment factor for workers, as proposed by ECETOC.

 

Exposure duration

not applicable

 

 

Dose response

1

 

 

Quality of database

1

 

 

Application of read-across

116/102

In the available subacute oral studies with TAEE and TAME, the observed NOAELs for systemic toxicity are of the same order of magnitude (100 and 125 mg/kg bw/day, respectively), suggesting a similar potency of both substances. Therefore the introduction of an additional safety factor in order to take into account the uncertainty for using the data on TAME to derive a DNEL for TAEE is considered to be unnecessary in this case, and only correction for molecular weight (102 g/mol for TAMEvs.116 g/mol for TAEE) is applied.

 

DNEL

Value

 

1060 x 116/102 / (1 x 3 x 1 x 1) =402 mg/m3

Long-term – inhalation, systemic effects

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEC: 250 ppm (1060 mg/m3)

No appropriate substance specific TAEE data are available. Therefore, the available inhalation toxicity studies on the structural analogues TAME (2-methoxy-2-methylbutane) and ETBE (2-ethoxy-2-methylpropane) will be used for derivation of a DNEL for TAEE.

The (lower) inhalation NOAEC reported for TAME (250 ppm (1060 mg/m3) based on organ (liver, adrenals and kidneys) weight increases in rats and liver effects in mice) will be used for the derivation of the long-term inhalation DNEL for systemic effects for TAEE.

Step 2) Modification of starting point

6/8

 

 

 

6.7 m3/10 m3

 

This starting point is corrected for molecular weight difference to a starting NOAEC of 1225mg/m3.)

Correction of exposure duration in study (6 hrs/day, 5 days/week) to default worker exposure (8 hrs/day, 5 days/week);

 

Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m3/10 m3).

Step 3) Assessment factors

 

 

Interspecies

1

No allometric scaling is needed in case of inhalation exposure because extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans; animal and humans breathe at a rate depending on their caloric requirements.

Intraspecies

3

A default assessment factor for workers, as proposed by ECETOC.

Exposure duration

2

Extrapolation to chronic exposure based on a 90 days study.

Dose response

1

 

Quality of database

1

 

Application of read-across

116/102

In the available subacute oral studies with TAEE and TAME, the observed NOAELs for systemic toxicity are of the same order of magnitude (100 and 125 mg/kg bw/day, respectively), suggesting a similar potency of both substances. Therefore the introduction of an additional safety factor in order to take into account the uncertainty for using the data on TAME to derive a DNEL for TAEE is considered to be unnecessary in this case, and only correction for molecular weight (102 g/mol for TAMEvs.116 g/mol for TAEE) is applied.

DNEL

Value

 

1060 x 6/8 x 6.7/10 x 116/102 / (1 x 3 x 2 x 1 x 1 x 1) =101 mg/m3

 

Long-term – inhalation, local effects

As bradypnoea and dyspnoea were observed in the available acute inhalation toxicity study with rats, the occurrence of local respiratory effects cannot be excluded after inhalation exposure. However, the design of this study does not allow the derivation of a DNEL for local respiratory tract effects.

For one of the structural analogues of the substance, ETBE (2-ethoxy-2-methylpropane), a DNEL for local effects on the respiratory tract is available, i.e. 105 mg/m3. This value was established as a NOAEC in a study with human volunteers who were exposed to ETBE during light exercises, and therefore no additional assessment factor has been applied for workers. When this value is used as starting point, the following DNEL of TAEE is derived for local effects on the respiratory tract:

105 mg/m3×116/102 (MW correction) = 119 mg/m3.

When comparing this DNEL with the available inhalation DNEL for systemic effects (101 mg/m3), the one for systemic effects appears more critical compared to the local DNEL. Therefore the systemic DNEL of TAEE will be used in the risk characterisation.

 

 

Long-term – dermal, systemic effects (based on the repeated dose inhalation NOAEC)

Route to route extrapolation will be applied to derive a DNEL for the dermal route based on the NOAEC of 250 ppm (1060 mg/m3) from the inhalation repeated dose toxicity study with TAME.

 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEC: 250 ppm (1060 mg/m3)

No appropriate substance specific TAEE data are available. Therefore, the available inhalation toxicity studies on the structural analogues TAME (2-methoxy-2-methylbutane) and ETBE (2-ethoxy-2-methylpropane) will be used for derivation of a DNEL for TAEE.

The (lower) inhalation NOAEC reported for TAME (250 ppm (1060 mg/m3) based on organ (liver, adrenals and kidneys) weight increases in rats and liver effects in mice) will be used for the derivation of the long-term inhalation DNEL for systemic effects for TAEE.

Step 2) Modification of starting point

0.29

 

 

 

50 / 2

Conversion into dermal NAEL (in mg/kg bw/day) by using a 6 h respiratory volume of 0.29 m3/kg bw for the rat.

 

Correction for absorption: 50% inhalation absorption and 2% dermal absorption.

Step 3) Assessment factors

 

 

Interspecies

4

For rats the allometric scaling factor is 4

Intraspecies

3

A default assessment factor for workers, as proposed by ECETOC

Exposure duration

2

Extrapolation to chronic exposure based on a 90 days study

Dose response

1

 

Quality of database

1

 

Application of read-across

116/102

In the available subacute oral studies with TAEE and TAME, the observed NOAELs for systemic toxicity are of the same order of magnitude (100 and 125 mg/kg bw/day, respectively), suggesting a similar potency of both substances. Therefore the introduction of an additional safety factor in order to take into account the uncertainty for using the data on TAME to derive a DNEL for TAEE is considered to be unnecessary in this case, and only correction for molecular weight (102 g/mol for TAMEvs.116 g/mol for TAEE) is applied.

DNEL

Value

 

1060 x 0.29 x 50/2 x 116/102 / (4 x 3 x 2 x 1 x 1 x 1) =364 mg/kg bw/day

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
30 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: See details below
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEC
Value:
306 mg/m³
AF for dose response relationship:
1
Justification:
default
AF for differences in duration of exposure:
2
Justification:
default for sub-chronic to chronic extrapolation
AF for interspecies differences (allometric scaling):
1
Justification:
not required for inhalation route of exposure
AF for other interspecies differences:
1
Justification:
as proposed by ECETOC Technical Report #86.
AF for intraspecies differences:
5
Justification:
as proposed by ECETOC Technical Report #86.
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
default
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
241 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
other: See description below
Overall assessment factor (AF):
5
Modified dose descriptor starting point:
NOAEC
Value:
1 225 mg/m³
AF for dose response relationship:
1
Justification:
default
AF for interspecies differences (allometric scaling):
1
Justification:
not required for inhalation route of exposur
AF for other interspecies differences:
1
Justification:
default intraspecies factor for general population proposed by ECETOC Technical Report #86.
AF for intraspecies differences:
5
Justification:
default intraspecies factor for general population proposed by ECETOC Technical Report #86.
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
default

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
72 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
other: See justification and comments below.
Overall assessment factor (AF):
1.7
Dose descriptor:
NOAEC
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:
218 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: See comments below
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
Value:
8 740 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
See detailed discussion below
AF for dose response relationship:
1
Justification:
default
AF for differences in duration of exposure:
2
Justification:
default for sub-chronic to chronic extrapolation
AF for interspecies differences (allometric scaling):
4
Justification:
default for rat to human extrapolation
AF for other interspecies differences:
1
Justification:
as proposed in the ECETOC Technical Report #86.
AF for intraspecies differences:
5
Justification:
as proposed in the ECETOC Technical Report #86.
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
default
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.83 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other:
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
AF for dose response relationship:
1
Justification:
default
AF for differences in duration of exposure:
6
Justification:
default for sub-acute to chronic extrapolation
AF for interspecies differences (allometric scaling):
4
Justification:
default for rat to human extrapolation
AF for other interspecies differences:
1
Justification:
as proposed by ECETOC Technical Report #86.
AF for intraspecies differences:
5
Justification:
as proposed by ECETOC Technical Report #86.
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
default
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

The DNELs are derived using the scientifically based assessment factors as reported by ECETOC (ECETOC, 2003. Derivation of assessment factors for human health risk assessment. Technical report No. 86, ECETOC, February 2003).

Acute – inhalation, systemic effects

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEC: 250 ppm (1060 mg/m3)

No appropriate substance specific TAEE data are available. Therefore, the available inhalation toxicity studies on the structural analogues TAME (2-methoxy-2-methylbutane) and ETBE (2-ethoxy-2-methylpropane) will be used for derivation of an acute inhalation DNEL for TAEE. The (lower) inhalation NOAEC reported for TAME, 1060 mg/m3, will be used as starting point. This NOAEC was established in a 90-day neurotoxicity study with rats and based on acute CNS effects:

- depression of central nervous system and neuromuscular junction impairment (FOB observations);

- clinical observations: animals were prostrate and lethargic.

Step 2) Modification of starting point

-

 

This starting point is corrected for molecular weight difference to a starting NOAEC of 1225mg/m3.)

From the available data, it is clear that acute CNS effects occurred during the daily exposures, but it is not clear at which time point during exposure these effects occurred. In the REACH guidance (R.8, Appendix R. 8-8), it is mentioned: ‘If a DNEL for acute toxicity needs to be established, this should be derived only for a specified fraction of the daily exposure duration (usually 15 minutes)’. As it is not clear at which time point during exposure the effects occurred, a calculation to a DNEL for 15 minutes (which results in a higher starting point) cannot be performed.

Step 3) Assessment factors

 

 

Interspecies

1

No allometric scaling is needed in case of inhalation exposure because extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans; animal and humans breathe at a rate depending on their caloric requirements.

Intraspecies

5

As general population includes elderly and juvenile citizens, who are considered to be more sensitive, a default assessment factor of 5 is proposed by ECETOC.

Exposure duration

Not applicable

 

Dose response

1

 

Quality of database

1

 

Application of read-across

116/102

In the available subacute oral studies with TAEE and TAME, the observed NOAELs for systemic toxicity are of the same order of magnitude (100 and 125 mg/kg bw/day, respectively), suggesting a similar potency of both substances. Therefore the introduction of an additional safety factor in order to take into account the uncertainty for using the data on TAME to derive a DNEL for TAEE is considered to be unnecessary in this case, and only correction for molecular weight (102 g/mol for TAMEvs.116 g/mol for TAEE) is applied.

DNEL

Value

 

1060 x 116/102 / (1 x 5 x 1 x 1 x 1 x 1) =241 mg/m3

 

Long-term – inhalation, systemic effects

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEC: 250 ppm (1060 mg/m3)

No appropriate substance specific TAEE data are available. Therefore, the available inhalation toxicity studies on the structural analogues TAME (2-methoxy-2-methylbutane) and ETBE (2-ethoxy-2-methylpropane) will be used for derivation of a DNEL for TAEE.

The (lower) inhalation NOAEC reported for TAME (250 ppm (1060 mg/m3) based on organ (liver, adrenals and kidneys) weight increases in rats and liver effects in mice) will be used for the derivation of the long-term inhalation DNEL for systemic effects for TAEE.

Step 2) Modification of starting point

6/24

 

This starting point is corrected for molecular weight difference to a starting NOAEC of 1225mg/m3.)

Correction of exposure duration in study (6 hrs/day) to default general population exposure (24 hrs/day)[1].

Step 3) Assessment factors

 

 

Interspecies

1

No allometric scaling is needed in case of inhalation exposure because extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans; animal and humans breathe at a rate depending on their caloric requirements.

Intraspecies

5

As general population includes elderly and juvenile citizens, who are considered to be more sensitive, a default assessment factor of 5 is proposed by ECETOC.

Exposure duration

2

Extrapolation to chronic exposure based on a 90 days study.

Dose response

1

 

Quality of database

1

 

Application of read-across

116/102

In the available subacute oral studies with TAEE and TAME, the observed NOAELs for systemic toxicity are of the same order of magnitude (100 and 125 mg/kg bw/day, respectively), suggesting a similar potency of both substances. Therefore the introduction of an additional safety factor in order to take into account the uncertainty for using the data on TAME to derive a DNEL for TAEE is considered to be unnecessary in this case, and only correction for molecular weight (102 g/mol for TAMEvs.116 g/mol for TAEE) is applied.

DNEL

Value

 

1060 x 6/24 x 116/102 / (1 x 5 x 1 x 2 x 1 x 1 x 1) =30 mg/m3

 

Long-term – inhalation, local effects

As bradypnoea and dyspnoea were observed in the available acute inhalation toxicity study with rats, the occurrence of local respiratory effects cannot be excluded after inhalation exposure. However, the design of this study does not allow the derivation of a DNEL for local respiratory tract effects.

For one of the structural analogues of the substance, ETBE (2-ethoxy-2-methylpropane), a DNEL for local effects on the respiratory tract is available, i.e. 63 mg/m3. This value was calculated based on the results of a study with human volunteers exposed to ETBE under the conditions of light exercise, by multiplying the established NOAEC of 105 mg/m3by the intraspecies difference factor 5/3, i.e., intraspecies factor for the general population divided by the one for workers. When this value is used as starting point, the following DNEL of TAEE is derived for local effects on the respiratory tract:

63 mg/m3×116/102 (MW correction) = 72 mg/m3

When comparing this DNEL with the available inhalation DNEL for systemic effects (30 mg/m3), the one for systemic effects appears more critical compared to the local DNEL. Therefore the systemic DNEL of TAEE will be used in the risk characterisation.

 

Long-term – dermal, systemic effects (based on the repeated dose inhalation NOAEC)

Route to route extrapolation will be applied to derive a DNEL for the dermal route based on the NOAEC of 250 ppm (1060 mg/m3) from the inhalation repeated dose toxicity study with TAME.

 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEC: 250 ppm (1060 mg/m3)

No appropriate substance specific TAEE data are available. Therefore, the available inhalation toxicity studies on the structural analogues TAME (2-methoxy-2-methylbutane) and ETBE (2-ethoxy-2-methylpropane) will be used for derivation of a DNEL for TAEE.

The (lower) inhalation NOAEC reported for TAME (250 ppm (1060 mg/m3) based on organ (liver, adrenals and kidneys) weight increases in rats and liver effects in mice) will be used for the derivation of the long-term inhalation DNEL for systemic effects for TAEE.

Step 2) Modification of starting point

0.29

 

 

 

50 / 2

Conversion into dermal NAEL (in mg/kg bw/day) by using a 6 h respiratory volume of 0.29 m3/kg bw for the rat.

 

Correction for absorption: 50% inhalation absorption and 2% dermal absorption

Step 3) Assessment factors

 

 

Interspecies

4

For rats the allometric scaling factor is 4

Intraspecies

5

As general population includes elderly and juvenile citizens, who are considered to be more sensitive, a default assessment factor of 5 is proposed by ECETOC.

Exposure duration

2

Extrapolation to chronic exposure based on a 90 days study

Dose response

1

 

Quality of database

1

 

Application of read-across

116/102

In the available subacute oral studies with TAEE and TAME, the observed NOAELs for systemic toxicity are of the same order of magnitude (100 and 125 mg/kg bw/day, respectively), suggesting a similar potency of both substances. Therefore the introduction of an additional safety factor in order to take into account the uncertainty for using the data on TAME to derive a DNEL for TAEE is considered to be unnecessary in this case, and only correction for molecular weight (102 g/mol for TAMEvs.116 g/mol for TAEE) is applied.

DNEL

Value

 

1060 x 0.29 x 50/2 x 116/102 / (4 x 5 x 2 x 1 x 1 x 1) =218mg/kg bw/day

 

Long-term – oral, systemic effects

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 100 mg/kg bw/day

Based on increased ALT activity in female rats and significant increased relative liver weights accompanied by diffuse enlargement of the hepatocytes without the normal zonal pattern in male rats at mid- and high-dose levels, and increased adrenal weights in both sexes at the high dose levelin the subacute toxicity study with TAEE.

Step 2) Modification of starting point

-

-

Step 3) Assessment factors

 

 

Interspecies

4

For rats the allometric scaling factor is 4

Intraspecies

5

As general population includes elderly and juvenile citizens, who are considered to be more sensitive, a default assessment factor of 5 is proposed by ECETOC.

Exposure duration

6

Extrapolation to chronic exposure based on a 28 days study.

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

100 / (4 x 5 x 6 x 1 x 1) =0.83 mg/kg bw/day



[1]Exposure duration for humans indirectly exposed via the environment is assumed to be 24 hours per day, for consumers the exposure duration is assumed to be 1-24 hours per day (depending on the exposure scenario).