Registration Dossier
Registration Dossier
Diss Factsheets
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EC number: 211-309-7 | CAS number: 637-92-3
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data

Toxicological Summary
- Administrative data
- Workers - Hazard via inhalation route
- Workers - Hazard via dermal route
- Workers - Hazard for the eyes
- Additional information - workers
- General Population - Hazard via inhalation route
- General Population - Hazard via dermal route
- General Population - Hazard via oral route
- General Population - Hazard for the eyes
- Additional information - General Population
Administrative data
Workers - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 352 mg/m³
- Most sensitive endpoint:
- repeated dose toxicity
DNEL related information
- Overall assessment factor (AF):
- 3
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 1 050 mg/m³
- AF for dose response relationship:
- 1
- AF for differences in duration of exposure:
- 1
- Justification:
- chronic study
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- not required for inhalation study
- AF for other interspecies differences:
- 1
- Justification:
- see discussion
- AF for intraspecies differences:
- 3
- Justification:
- see discussion
- AF for the quality of the whole database:
- 1
- AF for remaining uncertainties:
- 1
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 2 800 mg/m³
- Most sensitive endpoint:
- neurotoxicity
DNEL related information
- Overall assessment factor (AF):
- 3
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 8 400 mg/m³
- AF for dose response relationship:
- 1
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- not required for inhalation study
- AF for other interspecies differences:
- 1
- Justification:
- see discussion
- AF for intraspecies differences:
- 3
- Justification:
- see discussion
- AF for the quality of the whole database:
- 1
- AF for remaining uncertainties:
- 1
Local effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 105 mg/m³
- Most sensitive endpoint:
- irritation (respiratory tract)
DNEL related information
- Overall assessment factor (AF):
- 1
- Dose descriptor:
- NOAEC
- AF for dose response relationship:
- 1
- AF for differences in duration of exposure:
- 1
- AF for interspecies differences (allometric scaling):
- 1
- AF for other interspecies differences:
- 1
- AF for intraspecies differences:
- 1
- AF for the quality of the whole database:
- 1
- AF for remaining uncertainties:
- 1
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:
- 6 767 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
DNEL related information
- Overall assessment factor (AF):
- 12
- Modified dose descriptor starting point:
- NOAEL
- Value:
- 81 200 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
- From inhalation data. Assume rat respiratory volume 0.29m3/kgbw/6hr. Inhalation absorption efficiency 40%, dermal absorption 0.3%.
- AF for dose response relationship:
- 1
- AF for differences in duration of exposure:
- 1
- Justification:
- Chronic study used as a basis for DNEL derivation
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- rat to human
- AF for other interspecies differences:
- 1
- Justification:
- see discussion
- AF for intraspecies differences:
- 3
- Justification:
- see discussion
- AF for the quality of the whole database:
- 1
- AF for remaining uncertainties:
- 1
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
Workers - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- no hazard identified
Additional information - workers
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 (2010).
ECETOC (2010) Guidance on assessment factors to derive a DNEL. Technical report No. 110, ECETOC, Brussels, October 2010.
Kinetics
The inhalation and dermal absorption percentages used for DNEL derivation (in case of route-to-route extrapolation) are 40% and 0.3%, respectively.
Acute toxicity
ETBE is labelled for acute toxicity (R67 or Specific Target Organ toxicity – Single exposure, Cat. 3 (H336)) and therefore derivation of a DNELacute is necessary for situations where peak exposures may occur. The NOAEC for transient signs of CNS depression is 2000 ppm (8400 mg/m3). This NOAEC is derived from acute effects observed in a 28 day inhalation study conducted in rats.
ETBE is not irritating to the skin, eyes and respiratory tract and not sensitising to the skin. Therefore, no DNELs are derived for these endpoints.
Long-term toxicity
Based on the available 90-days studies, the overall NOAEC for rats and mice is 500 ppm based on changes in liver (female mice, 1750 and 5000 ppm (7350 and 21000 mg/m3)) over 90-days and reduced survival and serum enzyme alterations (rats, 1500 and 5000 ppm (6300 and 21000 mg/m3)) over 2-years.
No repeated dermal toxicity studies for ETBE are available, and appropriate DNELs will therefore be developed using route-to-route extrapolation from the available chronic inhalation toxicity data. This is considered acceptable given the negligible first-pass hepatic metabolism associated with both of these routes of exposure.
Regarding local effects, the human data on ETBE (Nihlen et al 1998b) indicate the occurrence of possible subjective symptoms of mild nasal discomfort with reports of unpleasant taste and odour experienced by volunteers exposed to 50 ppm ETBE. Based on these data a NOAEC of 25 ppm is established, however it is recognised that this is likely to be quite a conservative conclusion.
It can also be presumed that repeated skin exposure may result in skin fatigue (due to the effective lipid extraction properties of ETBE 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.
ETBE is assessed as being non-mutagenic and not carcinogenic. Based on this, no separate risk characterisation for mutagenicity and carcinogenicity is needed.
ETBE did not show effects on fertility in an oral two-generation study with rats. No DNEL has to be derived for reproductive toxicity.
No developmental toxicity was observed in an oral prenatal developmental toxicity study in rats. No DNEL has to be derived for developmental toxicity.
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.
Acute – inhalation, systemic effects
The DNEL is based on findings of transient CNS depression recorded in a rat 28-day inhalation study, which returned a NOAEC of 2000 ppm (8400 mg/m3).
Description |
Value |
Remark |
Step 1) Relevant dose-descriptor |
NOAEC: 2000 ppm (8400 mg/m3) |
Based on acute (transient) CNS effects in a 28-day inhalation study with rats: general sedation, reduced motor activity, mild to moderate ataxia. |
Step 2) Modification of starting point |
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) ’. The acute transient CNS effects were completely disappeared within 15 minutes after exposure for 6 hours to 4000 ppm. The half-life in the blood of rats has been estimated to be 0.4 hours (DeKant et al, 2001) which means that ETBE is cleared rapidly from the body. The acute CNS effects are assumed to be caused by filling of the brain compartment. As the acute DNEL is derived for only 15 minutes, filling of the brain compartment is considered less compared to 6 hours of exposure resulting a higher starting point.
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 (ECETOC, 2010a). No additional assessment factor is required for “remaining differences” since inter- and intraspecies variability are not independent variables, with any remaining uncertainty accounted for already through the use of allometric scaling (where appropriate) and in the intraspecies assessment factor (ECETOC, 2010a).The systemic toxic effects have been thoroughly studied for ETBE and there are no indications that humans in comparison to animal test species would significantly differ in their responses, hence the additional adjustment factor of 2.5 is not warranted. |
Intraspecies |
3 |
An informed assessment factor of 3 is proposed (ECETOC, 2010a) based on an analysis of the available scientific literature rather than the adoption of standard defaults. Intraspecies sensitivity extrapolation from rat to man is done by extrapolation from the already interspecies extrapolated rodent EC05 (=NOAEL) to an assumed human EC05 (=NOAEL). Assuming the ratio between the EC95 and EC5 in a rat is 10, observed in many studies, and applying the ECHA intraspecies factor of 5 on the interspecies extrapolated rat EC05 in order to achieve the worker EC05 means that the ratio between the EC95 and EC05 in workers is assumed to be 250. A factor of 250 for the ratio between the worker EC95 and EC05 is far outside general clinical evidence. Therefore the ECETOC intraspecies assessment factors should be preferred. |
Exposure duration |
not applicable |
|
Dose response |
1 |
|
Quality of database |
1 |
|
DNEL |
Value |
|
|
8400 / (1 x 3 x 1 x 1) =2800 mg/m3 |
Long-term – inhalation, systemic effects
The DNEL is based upon a NOAEC of 500 ppm (2100 mg/m3) reflecting findings of reduced survival, slight haematological changes, altered clinical chemistry parameters and liver effects after chronic exposure to higher exposure concentrations.
Description |
Value |
Remark |
Step 1) Relevant dose-descriptor |
NOAEC: 500 ppm (2100 mg/m3) |
Based onreduced survival, slight haematological changes, altered clinical chemistry parameters and liver effectsafter chronic exposure to higher exposure concentrations.
|
Step 2) Modification of starting point |
6/8
6.7 m3/10 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 (ECETOC, 2010a). No additional assessment factor is required for “remaining differences” since inter- and intraspecies variability are not independent variables, with any remaining uncertainty accounted for already through the use of allometric scaling (where appropriate) and in the intraspecies assessment factor (ECETOC, 2010a).The systemic toxic effects have been thoroughly studied for ETBE and there are no indications that humans in comparison to animal test species would significantly differ in their responses, hence the additional adjustment factor of 2.5 is not warranted. |
Intraspecies |
3 |
An informed assessment factor of 3 is proposed (ECETOC, 2010a) based on an analysis of the available scientific literature rather than the adoption of standard defaults. Intraspecies sensitivity extrapolation from rat to man is done by extrapolation from the already interspecies extrapolated rodent EC05 (=NOAEL) to an assumed human EC05 (=NOAEL). Assuming the ratio between the EC95 and EC5 in a rat is 10, observed in many studies, and applying the ECHA intraspecies factor of 5 on the interspecies extrapolated rat EC05 in order to achieve the worker EC05 means that the ratio between the EC95 and EC05 in workers is assumed to be 250. A factor of 250 for the ratio between the worker EC95 and EC05 is far outside general clinical evidence. Therefore the ECETOC intraspecies assessment factors should be preferred. |
Exposure duration |
1 |
A factor of 1 is applied since the results were obtained from a chronic study. |
Dose response |
1 |
|
Quality of database |
1 |
|
DNEL |
Value |
|
|
2100 x 6/8 x 6.7/10 / (1 x 3 x 1 x 1 x 1) =352 mg/m3 |
Long-term – inhalation, local effects
Eight male human subjects were exposed to 0, 5, 25, 50 ppm concentrations of ETBE for 2 hours (Nihlen et al 1998b). There were a total of 4 exposures to each subject to the 4 exposure concentrations (exposed once to each exposure concentration). Subjective discomfort of the throat and airways was increased significantly after exposure to 50 ppm ETBE, and remained elevated for the remainder of the 2 hr exposure period. Symptoms had resolved 80 min after exposure ceased. The taste and odour of the test atmosphere was unpleasant. The authors state that subjective symptoms of ocular and nasal discomfort, fatigue, nausea dizziness and intoxication were greater in the 50 ppm group, but no dose-response relationship or statistically significant difference was present. The intensity of the response at 50 ppm appeared to be very mild (stated to be between "not at all" and "hardly at all").
There was no statistically significant effect on eye redness, tear-film break-up, conjunctival damage or blinking frequency. Nasal volume was decreased by 6-15% (P = 0.001) in all groups, including controls, compared to pre-exposure values. Exposure to ETBE vapour was without effect on the composition of nasal lavage fluid (i. e. leukocytes, epithelial cells, inflammatory markers etc).
A small (3-4%) but significant (P<0.05) decrease in forced vital capacity (FVC) and vital capacity (VC) in subjects exposed to 25 or 50 ppm ETBE vapour, however short-term changes in lung function of <5% are likely to reflect normal variation and are therefore of no clinical significance. The authors also state that one-second forced expiratory volume (FEV1) and the transfer factor (TLco) were also decreased (approx. 2% and 2 -4%, respectively) after exposure, but this finding was not statistically significant. The slightly decreased lung function changes were mild in nature and minor in extent, and likely to reflect normal variation rather than an effect of ETBE vapour on lung function.
Subjective symptoms of mild nasal discomfort and reports of unpleasant taste and odour experienced by volunteers exposed to 50 ppm ETBE will be taken into account for risk characterisation of long-term local effects after inhalation, leading to a conservative NOAEC and DNEL of 25 ppm (105 mg/m3). This value will be used directly with no modification, and is lower than the systemic DNEL of 84 ppm (352 mg/m3) based on animal inhalation data (discussed above).
Long-term – dermal, systemic effects (based on the repeated dose inhalation NOAEC)
As dermal repeated dose toxicity studies with ETBE are not available, route to route extrapolation will be applied to derive a DNEL for the dermal route, based on the NOAEC of 500 ppm (2100 mg/m3) from the available inhalation repeated dose toxicity studies. This point of departure is used in preference to the oral NOAEL since ingestion leads to first-pass metabolism in the liver whereas more widespread systemic exposure and no first-pass hepatic metabolism occurs after inhalation and/or dermal exposure.
Description |
Value |
Remark |
Step 1) Relevant dose-descriptor |
NOAEC: 500 ppm (2100 mg/m3) |
Based onreduced survival, slight haematological changes, altered clinical chemistry parameters and liver effectsafter chronic exposure to higher exposure concentrations.
|
Step 2) Modification of starting point |
0.29
40 / 0.3 |
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: 40% inhalation absorption and 0.3% dermal absorption. |
Step 3) Assessment factors |
|
|
Interspecies |
4 |
Assessment factor for allometric scaling from rats to humans as proposed by ECETOC (2010a). No additional assessment factor is required for “remaining differences” since inter- and intraspecies variability are not independent variables, with any remaining uncertainty accounted for already through the use of allometric scaling (where appropriate) and in the intraspecies assessment factor (ECETOC, 2010a). The systemic toxic effects have been thoroughly studied for ETBE and there are no indications that humans in comparison to animal test species would significantly differ in their responses, hence the additional adjustment factor of 2.5 is not warranted. |
Intraspecies |
3 |
An informed assessment factor of 3 is proposed (ECETOC, 2010a) based on an analysis of the available scientific literature rather than the adoption of standard defaults. Intraspecies sensitivity extrapolation from rat to man is done by extrapolation from the already interspecies extrapolated rodent EC05 (=NOAEL) to an assumed human EC05 (=NOAEL). Assuming the ratio between the EC95 and EC5 in a rat is 10, observed in many studies, and applying the ECHA intraspecies factor of 5 on the interspecies extrapolated rat EC05 in order to achieve the worker EC05 means that the ratio between the EC95 and EC05 in workers is assumed to be 250. A factor of 250 for the ratio between the worker EC95 and EC05 is far outside general clinical evidence. Therefore the ECETOC intraspecies assessment factors should be preferred. |
Exposure duration |
1 |
A factor of 1 is applied since the results were obtained from a chronic study. |
Dose response |
1 |
|
Quality of database |
1 |
|
DNEL |
Value |
|
|
2100 x 0.29 x 40/0.3 / (4 x 3 x 1 x 1 x 1) =6767 mg/kg bw/day |
Explanation of ECETOC Assessment Factors
The ECHA default interspecies assessment factors are useful for an isolated study for only one toxicological endpoint. In all other cases the ECETOC factors should be preferred for the following reasons: In case of existing high production volume chemicals there is at least one study for each toxicological endpoint and many times more studies for the same toxicological endpoint. So the confidence in the real No Observed Adverse Effect Level (NOAEL) is much higher than in case of an isolated study for only one toxicological endpoint. Also developmental and reproductive toxicity studies and studies focused on neurotoxicity contribute to the evidence of the true NOAEL.
ECETOC interspecies extrapolation to human is based on allometric scaling. Comparison of tolerable repeated dose levels in rodents and humans for many substances has revealed, that allometric scaling provided the appropriate adjustment of rodent tolerable repeated dose levels to human repeated dose levels.
Intraspecies sensitivity extrapolation from rat to man is done by extrapolation from the already interspecies extrapolated rodent EC05 (= EC05 interspecies adjusted rat to human) to an assumed human EC05 (= NOAEL human). It is assumed, that the rodent EC05 is a NOAEL and is conservatively 3.16 times smaller than the rodent EC50 and 10 times smaller than the rodent EC95. So the ratio between the rat EC95 and EC05 is assumed to be a factor of 10. This is in agreement with the applied dose range in a rodent study being at least a factor of 10 (see the long term NTP rodent studies).
* The ECETOC intraspecies factor of 3, applied to the interspecies extrapolated rodent EC05 (= EC05 interspecies adjusted rat to human) means that the ratio between worker EC95 and EC05 is assumed to be 90.
* The ECETOC intraspecies factor of 5, applied to the interspecies extrapolated rodent EC05 (= EC05 interspecies adjusted rat to human) means that the ratio between consumer EC95 and EC05 is assumed to be 250.
* The ECHA intraspecies factor of 5, applied to the interspecies extrapolated rodent EC05 (= EC05 interspecies adjusted rat to human) means that the ratio between worker EC95 and EC05 is assumed to be 250.
* The ECHA intraspecies factor of 10, applied to the interspecies extrapolated rodent EC05 (= EC05 interspecies adjusted rat to human) means that the ratio between consumer EC95 and EC05 is assumed to be 1000.
In the general population the ratio between the EC95 and EC05 is about a factor of 25. That is larger than that in the rat. The intraspecies assessment factors of ECETOC account for this factor of 25 and, in addition, for statistical uncertainty in the comparison between human and animal studies on repeated tolerable dose levels. Therefore, the ECETOC intraspecies assessment factors are conservative for deriving a DNEL for workers and for consumers (=general population).
General Population - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 105 mg/m³
- Most sensitive endpoint:
- repeated dose toxicity
DNEL related information
- Overall assessment factor (AF):
- 5
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 525 mg/m³
- AF for dose response relationship:
- 1
- AF for differences in duration of exposure:
- 1
- Justification:
- chronic study
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- not required for inhalation study
- AF for other interspecies differences:
- 1
- Justification:
- see discussion
- AF for intraspecies differences:
- 5
- Justification:
- see discussion
- AF for the quality of the whole database:
- 1
- AF for remaining uncertainties:
- 1
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 1 680 mg/m³
- Most sensitive endpoint:
- neurotoxicity
DNEL related information
- Overall assessment factor (AF):
- 5
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 8 400 mg/m³
- AF for dose response relationship:
- 1
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- not required for inhalation study
- AF for other interspecies differences:
- 1
- AF for intraspecies differences:
- 5
- AF for the quality of the whole database:
- 1
- AF for remaining uncertainties:
- 1
Local effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 63 mg/m³
- Most sensitive endpoint:
- irritation (respiratory tract)
DNEL related information
- Overall assessment factor (AF):
- 1.7
- Dose descriptor:
- NOAEC
- AF for dose response relationship:
- 1
- AF for differences in duration of exposure:
- 1
- AF for interspecies differences (allometric scaling):
- 1
- AF for other interspecies differences:
- 1
- AF for intraspecies differences:
- 1.7
- Justification:
- see discussion
- AF for the quality of the whole database:
- 1
- AF for remaining uncertainties:
- 1
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
General Population - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 4 060 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
DNEL related information
- Overall assessment factor (AF):
- 20
- Modified dose descriptor starting point:
- NOAEL
- Value:
- 81 200 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
- From inhalation data. Assume rat respiratory volume 0.29m3/kgbw/6hr. Inhalation absorption efficiency 40%, dermal absorption 0.3%
- AF for dose response relationship:
- 1
- AF for differences in duration of exposure:
- 1
- Justification:
- chronic study
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- rat to human
- AF for other interspecies differences:
- 1
- Justification:
- see discussion
- AF for intraspecies differences:
- 5
- Justification:
- see discussion
- AF for the quality of the whole database:
- 1
- AF for remaining uncertainties:
- 1
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
General Population - Hazard via oral route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 6 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
DNEL related information
- Overall assessment factor (AF):
- 20
- Modified dose descriptor starting point:
- NOAEL
- Value:
- 121 mg/kg bw/day
- AF for dose response relationship:
- 1
- AF for differences in duration of exposure:
- 1
- Justification:
- chronic study
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- rat to human
- AF for other interspecies differences:
- 1
- Justification:
- see discussion
- AF for intraspecies differences:
- 5
- Justification:
- see discussion
- AF for the quality of the whole database:
- 1
- AF for remaining uncertainties:
- 1
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
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 (2010).
ECETOC (2010) Guidance on assessment factors to derive a DNEL. Technical report No. 110, ECETOC, Brussels, October 2010.
Kinetics
The inhalation and dermal absorption percentages used for DNEL derivation (in case of route-to-route extrapolation) are 40% and 0.3%, respectively.
Acute toxicity
ETBE is labelled for acute toxicity (R67 or Specific Target Organ toxicity – Single exposure, Cat. 3 (H336)) and therefore derivation of a DNELacute is necessary for situations where peak exposures may occur. The NOAEC for transient signs of CNS depression is 2000 ppm (8400 mg/m3). This NOAEC is derived from acute effects observed in a 28 day inhalation study conducted in rats.
ETBE is not irritating to the skin, eyes and respiratory tract and not sensitising to the skin. Therefore, no DNELs are derived for these endpoints.
Long-term toxicity
Based on the available 90-days studies, the overall NOAEC for rats and mice is 500 ppm based on changes in liver (female mice, 1750 and 5000 ppm (7350 and 21000 mg/m3)) over 90-days and reduced survival and serum enzyme alterations (rats, 1500 and 5000 ppm (6300 and 21000 mg/m3)) over 2-years.
No repeated dermal toxicity studies for ETBE are available, and appropriate DNELs will therefore be developed using route-to-route extrapolation from the available chronic inhalation toxicity data. This is considered acceptable given the negligible first-pass hepatic metabolism associated with both of these routes of exposure.
Regarding oral exposure, the most critical NOAEL, 121 mg/kg bw/day, is derived from a rat 2-year drinking water study where changes in clinical chemistry parameters were observed at received doses of 540-560 mg/kg bw/day.
Regarding local effects, the human data on ETBE (Nihlen et al 1998b) indicate the occurrence of possible subjective symptoms of mild nasal discomfort with reports of unpleasant taste and odour experienced by volunteers exposed to 50 ppm ETBE. Based on these data a NOAEC of 25 ppm is established, however it is recognised that this is likely to be quite a conservative conclusion.
It can also be presumed that repeated skin exposure may result in skin fatigue (due to the effective lipid extraction properties of ETBE 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.
ETBE is assessed as being non-mutagenic and not carcinogenic. Based on this, no separate risk characterisation for mutagenicity and carcinogenicity is needed.
ETBE did not show effects on fertility in an oral two-generation study with rats. No DNEL has to be derived for reproductive toxicity.
No developmental toxicity was observed in an oral prenatal developmental toxicity study in rats. No DNEL has to be derived for developmental toxicity.
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.
In the available oral gavage studies, ptyalism (excessive salivation) was observed at all dose levels (i. e., from 250 mg/kg bw/day onwards). This is considered related to unpalatable nature of the dosing solutions / to the unpalatable 'taste' of ETBE. In the draft EU RAR this effect is not taken into account as an adverse effect, therefore, this effect is not considered a significant health effect.
The DNEL is based on findings of transient CNS depression recorded in a rat 28-day inhalation study, which returned a NOAEC of 2000 ppm (8400 mg/m3).
Description |
Value |
Remark |
Step 1) Relevant dose-descriptor |
NOAEC: 2000 ppm (8400 mg/m3) |
Based on acute (transient) CNS effects in a 28-day inhalation study with rats: general sedation, reduced motor activity, mild to moderate ataxia. |
Step 2) Modification of starting point |
- |
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) ’. The acute transient CNS effects were completely disappeared within 15 minutes after exposure for 6 hours to 4000 ppm. The half-life in the blood of rats has been estimated to be 0.4 hours (DeKant et al, 2001) which means that ETBE is cleared rapidly from the body. The acute CNS effects are assumed to be caused by filling of the brain compartment. As the acute DNEL is derived for only 15 minutes, filling of the brain compartment is considered less compared to 6 hours of exposure resulting a higher starting point. Therefore, 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 (ECETOC, 2010a). No additional assessment factor is required for “remaining differences” since inter- and intraspecies variability are not independent variables, with any remaining uncertainty accounted for already in the intraspecies assessment factor (ECETOC, 2010a). The systemic toxic effects have been thoroughly studied for ETBE and there are no indications that humans in comparison to animal test species would significantly differ in their responses, hence the additional adjustment factor of 2.5 is not warranted. |
Intraspecies |
5 |
An informed assessment factor of 5 is proposed (ECETOC, 2010a) based on an analysis of the available scientific literature rather than the adoption of standard defaults. This is considered adequate to protect the general population as well as the elderly and young. Intraspecies sensitivity extrapolation from rat to man is done by extrapolation from the already interspecies extrapolated rodent EC05 (=NOAEL) to an assumed human EC05 (=NOAEL). Assuming the ratio between the EC95 and EC5 in a rat is 10, observed in many studies, and applying the ECHA intraspecies factor of 10 on the interspecies extrapolated rat EC05 in order to achieve the consumer EC05 means that the ratio between the EC95 and EC05 in consumers is assumed to be 1000. A factor of 1000 for the ratio between the consumer EC95 and EC05 is far outside general clinical evidence. Therefore the ECETOC intraspecies assessment factors should be preferred. |
Exposure duration |
not applicable |
|
Dose response |
1 |
|
Quality of database |
1 |
|
DNEL |
Value |
|
|
8400 / (1 x 5 x 1 x 1) =1680 mg/m3 |
Long-term – inhalation, systemic effects
The DNEL is based upon a NOAEC of 500 ppm (2100 mg/m3 ) reflecting findings of reduced survival, slight haematological changes, altered clinical chemistry parameters and liver effects after chronic exposure to higher exposure concentrations.
Description |
Value |
Remark |
Step 1) Relevant dose-descriptor |
NOAEC: 500 ppm (2100 mg/m3) |
Based onreduced survival, slight haematological changes, altered clinical chemistry parameters and liver effectsafter chronic exposure.
|
Step 2) Modification of starting point |
6/24 |
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 (ECETOC, 2010). No additional assessment factor is required for “remaining differences” since inter- and intraspecies variability are not independent variables, with any remaining uncertainty accounted for in the intraspecies assessment factor (ECETOC, 2010a). The systemic toxic effects have been thoroughly studied for ETBE and there are no indications that humans in comparison to animal test species would significantly differ in their responses, hence the additional adjustment factor of 2.5 is not warranted. |
Intraspecies |
5 |
An informed assessment factor of 5 is proposed (ECETOC, 2010a) based on an analysis of the available scientific literature rather than the adoption of standard defaults. This is considered adequate to protect the general population as well as the elderly and young. Intraspecies sensitivity extrapolation from rat to man is done by extrapolation from the already interspecies extrapolated rodent EC05 (=NOAEL) to an assumed human EC05 (=NOAEL). Assuming the ratio between the EC95 and EC5 in a rat is 10, observed in many studies, and applying the ECHA intraspecies factor of 10 on the interspecies extrapolated rat EC05 in order to achieve the consumer EC05 means that the ratio between the EC95 and EC05 in consumers is assumed to be 1000. A factor of 1000 for the ratio between the consumer EC95 and EC05 is far outside general clinical evidence. Therefore the ECETOC intraspecies assessment factors should be preferred. |
Exposure duration |
1 |
A factor of 1 is applied since the results were obtained from a chronic study. |
Dose response |
1 |
|
Quality of database |
1 |
|
DNEL |
Value |
|
|
2100 x 6/24 / (1 x 5 x 1 x 1 x 1) =105 mg/m3 |
Long-term – inhalation, local effects
Based on the results of Nihlen et al (1998b), a conservative NOAEC of 25 ppm (105 mg/m3) is established. This level is considered a DNEL for local effects for workers. The taste and odour of ETBE and slight irritation of the respiratory tract are more critical for the worker DNEL than prevention against systemic effects in humans. Application of an assessment factor for intraspecies differences (5/3, i. e., intraspecies factor for the general population divided by the one for workers) results in a DNEL for the general population of 25 ppm (105 mg/m3) / (5/3) = 15 ppm (63 mg/m3).
Long-term – dermal, systemic effects (based on the repeated dose inhalation NOAEC)
As dermal repeated dose toxicity studies with ETBE are not available, route to route extrapolation will be applied to derive a DNEL for the dermal route, based on the NOAEC of 500 ppm (2100 mg/m3) from the available inhalation repeated dose toxicity studies. This point of departure is used in preference to the oral NOAEL since ingestion leads to first-pass metabolism in the liver whereas more widespread systemic exposure occurs after inhalation and dermal exposure.
Description |
Value |
Remark |
Step 1) Relevant dose-descriptor |
NOAEC: 500 ppm (2100 mg/m3) |
Based on reduced survival, slight haematological changes, altered clinical chemistry parameters and liver effectsafter chronic exposure.
|
Step 2) Modification of starting point |
0.29
40 / 0.3 |
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: 40% inhalation absorption and 0.3% dermal absorption. |
Step 3) Assessment factors |
|
|
Interspecies |
4 |
Assessment factor for allometric scaling from rats to humans as proposed by ECETOC (2010a). No additional assessment factor is required for “remaining differences” since inter- and intraspecies variability are not independent variables, with any remaining uncertainty accounted for already through the use of allometric scaling (where appropriate) and in the intraspecies assessment factor (ECETOC, 2010a).The systemic toxic effects have been thoroughly studied for ETBE and there are no indications that humans in comparison to animal test species would significantly differ in their responses, hence the additional adjustment factor of 2.5 is not warranted. |
Intraspecies |
5 |
An informed assessment factor of 5 is proposed (ECETOC, 2010a) based on an analysis of the available scientific literature rather than the adoption of standard defaults. This is considered adequate to protect the general population as well as the elderly and young. Intraspecies sensitivity extrapolation from rat to man is done by extrapolation from the already interspecies extrapolated rodent EC05 (=NOAEL) to an assumed human EC05 (=NOAEL). Assuming the ratio between the EC95 and EC5 in a rat is 10, observed in many studies, and applying the ECHA intraspecies factor of 10 on the interspecies extrapolated rat EC05 in order to achieve the consumer EC05 means that the ratio between the EC95 and EC05 in consumers is assumed to be 1000. A factor of 1000 for the ratio between the consumer EC95 and EC05 is far outside general clinical evidence. Therefore the ECETOC intraspecies assessment factors should be preferred. |
Exposure duration |
1 |
A factor of 1 is applied since the results were obtained from a chronic study. |
Dose response |
1 |
|
Quality of database |
1 |
|
DNEL |
Value |
|
|
2100 x 0.29 x 40/0.3 / (4 x 5 x 1 x 1 x 1) =4060 mg/kg bw/day |
Long-term – oral, systemic effects
The DNEL is based on a NOAEL of 121 mg/kg bw/day that was obtained from a 2-year drinking water study where alterations in clinical chemistry parameters were noted in male and female rats. This NOAEL is quite conservative given the occurrence of reduced water consumption (and probable dehydration) in the higher treatment groups, an observation considered related to the unpleasant taste of ETBE.
Description |
Value |
Remark |
Step 1) Relevant dose-descriptor |
NOAEL: 121 mg/kg bw/day |
Based on alterations in clinical chemistry parameters in male and female rats. This NOAEL is quite conservative given the occurrence of reduced water consumption (and probable dehydration) noted in the higher treatment groups, an observation considered related to the unpleasant taste of ETBE.
|
Step 2) Modification of starting point |
Not applicable |
|
Step 3) Assessment factors |
|
|
Interspecies |
4 |
Assessment factor for allometric scaling from rats to humans as proposed by ECETOC (2010a). No additional assessment factor is required for “remaining differences” since inter- and intraspecies variability are not independent variables, with any remaining uncertainty accounted for already through the use of allometric scaling (where appropriate) and in the intraspecies assessment factor (ECETOC, 2010a). The systemic toxic effects have been thoroughly studied for ETBE and there are no indications that humans in comparison to animal test species would significantly differ in their responses, hence the additional adjustment factor of 2.5 is not warranted. |
Intraspecies |
5 |
An informed assessment factor of 5 is proposed (ECETOC, 2010a) based on an analysis of the available scientific literature rather than the adoption of standard defaults. This is considered adequate to protect the general population as well as the elderly and young. Intraspecies sensitivity extrapolation from rat to man is done by extrapolation from the already interspecies extrapolated rodent EC05 (=NOAEL) to an assumed human EC05 (=NOAEL). Assuming the ratio between the EC95 and EC5 in a rat is 10, observed in many studies, and applying the ECHA intraspecies factor of 10 on the interspecies extrapolated rat EC05 in order to achieve the consumer EC05 means that the ratio between the EC95 and EC05 in consumers is assumed to be 1000. A factor of 1000 for the ratio between the consumer EC95 and EC05 is far outside general clinical evidence. Therefore the ECETOC intraspecies assessment factors should be preferred. |
Exposure duration |
1 |
A factor of 1 is applied since the results were obtained from a chronic drinking water study. This duration and route of exposure is highly appropriate for humans exposed via drinking water. |
Dose response |
1 |
|
Quality of database |
1 |
|
DNEL |
Value |
|
|
121 / (4 x 5 x 1 x 1 x 1) =6.0 mg/kg bw/day |
Explanation of ECETOC Assessment Factors
The ECHA default interspecies assessment factors are useful for an isolated study for only one toxicological endpoint. In all other cases the ECETOC factors should be preferred for the following reasons: In case of existing high production volume chemicals there is at least one study for each toxicological endpoint and many times more studies for the same toxicological endpoint. So the confidence in the real No Observed Adverse Effect Level (NOAEL) is much higher than in case of an isolated study for only one toxicological endpoint. Also developmental and reproductive toxicity studies and studies focused on neurotoxicity contribute to the evidence of the true NOAEL.
ECETOC interspecies extrapolation to human is based on allometric scaling. Comparison of tolerable repeated dose levels in rodents and humans for many substances has revealed, that allometric scaling provided the appropriate adjustment of rodent tolerable repeated dose levels to human repeated dose levels.
Intraspecies sensitivity extrapolation from rat to man is done by extrapolation from the already interspecies extrapolated rodent EC05 (= EC05 interspecies adjusted rat to human) to an assumed human EC05 (= NOAEL human). It is assumed, that the rodent EC05 is a NOAEL and is conservatively 3.16 times smaller than the rodent EC50 and 10 times smaller than the rodent EC95. So the ratio between the rat EC95 and EC05 is assumed to be a factor of 10. This is in agreement with the applied dose range in a rodent study being at least a factor of 10 (see the long term NTP rodent studies).
* The ECETOC intraspecies factor of 3, applied to the interspecies extrapolated rodent EC05 (= EC05 interspecies adjusted rat to human) means that the ratio between worker EC95 and EC05 is assumed to be 90.
* The ECETOC intraspecies factor of 5, applied to the interspecies extrapolated rodent EC05 (= EC05 interspecies adjusted rat to human) means that the ratio between consumer EC95 and EC05 is assumed to be 250.
* The ECHA intraspecies factor of 5, applied to the interspecies extrapolated rodent EC05 (= EC05 interspecies adjusted rat to human) means that the ratio between worker EC95 and EC05 is assumed to be 250.
* The ECHA intraspecies factor of 10, applied to the interspecies extrapolated rodent EC05 (= EC05 interspecies adjusted rat to human) means that the ratio between consumer EC95 and EC05 is assumed to be 1000.
In the general population the ratio between the EC95 and EC05 is about a factor of 25. That is larger than that in the rat. The intraspecies assessment factors of ECETOC account for this factor of 25 and, in addition, for statistical uncertainty in the comparison between human and animal studies on repeated tolerable dose levels. Therefore, the ECETOC intraspecies assessment factors are conservative for deriving a DNEL for workers and for consumers (=general population).
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.

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