Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
152 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: See discussion below
Overall assessment factor (AF):
6
Dose descriptor starting point:
NOAEC
DNEL value:
1 812 mg/m³
Modified dose descriptor starting point:
NOAEC
DNEL value:
911 mg/m³
Explanation for the modification of the dose descriptor starting point:

The starting point for the DNEL derivation is the repeat dose inhalation systemic NOAEC from the 90 day sub-chronic study with the read across substance ethoxypropanol (the in vivo hydrolysis product).  The starting point of 1266mg/m3 is extrapolated by molar conversion to an equivalent NOAEC of 1812mg/m3 for ethoxypropyl acetate. This figure is corrected for exposure duration and breathing rate as recommened in the guidance. The correction is 1812 * 6/8 (hrs exposure in study versus duration of working day) * 6.7/10 (breathing rate at rest versus breathing rate at work) = 911 mg/m3

 

AF for dose response relationship:
1
Justification:
No reason to deviate from default.
AF for differences in duration of exposure:
2
Justification:
Default. Sub-chronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Default. Not required for inhalation study
AF for other interspecies differences:
1
Justification:
According to the ECETOC guidance document (ECETOC, 2010) , it is not appropriate in the majority of cases to apply an interspecies factor for ‘residual differences’ and that such a factor should only be supplied should the hazard data indicated a greater or lesser sensitivity of animals compared to man, eg significant differences in the mode of action. If such a factor was required, there would be evidence for it in a comparison of data between different animal species, as opposed to animals and humans. In a comparison of the repeat dose data between rats and mice, the ERASM project (see ECETOC reference) did not find evidence to support use of such a factor on a routine basis and any differences could be accounted for by allometric scaling factors alone. The data presented by ECETOC also support the conclusion that any ‘residual’ interspecies variability following allometric scaling is largely accounted for in the intraspecies factor, reflecting the interdependency of the individual assessment factors and avoiding ‘double counting’ of statistical variability. It should be noted that there is no scientific rationale provided in the ECHA document for the use of such a factor and that the multiplication of separate factors that have no sound scientific rationale behind them and that are not truly independent factors leads to unnecessarily conservative overall assessment factors. In the case of this substance, there is no evidence to support the use of a factor for remaining. For further justification, see attachment to this record.
AF for intraspecies differences:
3
Justification:
According to the ECHA guidance document, where scientific justification exists, one can deviate from the default ECHA assessment factors used in DENL derivation. In deriving DNELS, the assessment factor chosen for Intraspecies variability (worker and general population) has been taken from the ECETOC technical report no, 110 (ECETOC, 2010)as an alternative to the ECHA default. The ECETOC working group performed a detailed assessment of the many publications available on human variability as it pertains to risk assessment. As a consequence of this assessment it was determined that in the majority of cases a factor of 3 for worker or 5 for general population is sufficient to address Intraspecies variability. Specifically considering the p-series glycol ethers, they have a low order of toxicity, with key effects primarily limited to adaptive effects in the liver and kidney (likely associated with either enzyme induction or alpha 2u-globulin formation). These substances also demonstrate very little variability in effect levels and target organs when tested in multiple species and for multiple durations (sub-acute to chronic). As such it is considered that the lower assessment factors proposed by ECETOC should adequately address the Intraspecies variability within the risk assessment. For further justification, see attachment to this record.
AF for the quality of the whole database:
1
Justification:
No reason to deviate from default.
AF for remaining uncertainties:
1
Justification:
No reason to deviate from default.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2 366 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: see information below.
Dose descriptor starting point:
NOAEC
DNEL value:
7 100 mg/m³
Modified dose descriptor starting point:
NOAEC
DNEL value:
7 100 mg/m³
Explanation for the modification of the dose descriptor starting point:

There is no dose reponse information available for the acute toxicity hazard of narcosis for which this substance is currently classified. The data suggests that there is no significant narcosis hazard.  However, since the substance is currently classified for this end point, it is necessary to derive a NOAEL.   For acute, short term systemic effects, the guidance suggests that an acute DNEL can be based on the repeat dose DNEL multiplied by a factor of 1-5.   An alternative approach would be to use the sub-acute, 28 days study with ethoxypropyl acetate and to use the data from this to establish a NOAEL. In this study, no adverse observations of any nature were seen for the first two days of 6 hourly exposures up to a dose of 1200ppm (7100mg/m3). To assess the affect in humans to a single acute exposure of 4hrs, this seems a reasonable starting point. No correction is required as the exposures of the animals are to longer times than required for the human equivalent assessment (conservative approach).

AF for dose response relationship:
1
Justification:
Default
AF for interspecies differences (allometric scaling):
1
Justification:
Default. Not required for inhalation study
AF for other interspecies differences:
1
Justification:
See justification for long term effects above. Narcotic sensitivity between humans and rats is not expected to be signfiicant
AF for intraspecies differences:
3
Justification:
See justification for long term effects above. Intrahuman sensitivity variations for narcotic effects are not expected to be very large.
AF for the quality of the whole database:
1
Justification:
Default

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
103 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
other: See discussion below
Overall assessment factor (AF):
29
Modified dose descriptor starting point:
NOAEL
AF for dose response relationship:
1
Justification:
No reason to deviate from default.
AF for differences in duration of exposure:
2
Justification:
Sub-chronic to chronic
AF for interspecies differences (allometric scaling):
2.5
Justification:
Default allometric scaling factor for Rabbits to humans
AF for other interspecies differences:
1
Justification:
According to the ECHA guidance document, where scientific justification exists, one can deviate from the default ECHA assessment factors used in DENL derivation. In deriving DNELS, the assessment factor chosen for Intraspecies variability (worker and general population) has been taken from the ECETOC technical report no, 110 (ECETOC, 2010)as an alternative to the ECHA default. The ECETOC working group performed a detailed assessment of the many publications available on human variability as it pertains to risk assessment. As a consequence of this assessment it was determined that in the majority of cases a factor of 3 for worker or 5 for general population is sufficient to address Intraspecies variability. Specifically considering the p-series glycol ethers, they have a low order of toxicity, with key effects primarily limited to adaptive effects in the liver and kidney (likely associated with either enzyme induction or alpha 2u-globulin formation). These substances also demonstrate very little variability in effect levels and target organs when tested in multiple species and for multiple durations (sub-acute to chronic). As such it is considered that the lower assessment factors proposed by ECETOC should adequately address the Intraspecies variability within the risk assessment. For further justification, see attachment to this record.
AF for intraspecies differences:
3
Justification:
According to the ECETOC guidance document (ECETOC, 2010) , it is not appropriate in the majority of cases to apply an interspecies factor for ‘residual differences’ and that such a factor should only be supplied should the hazard data indicated a greater or lesser sensitivity of animals compared to man, eg significant differences in the mode of action. If such a factor was required, there would be evidence for it in a comparison of data between different animal species, as opposed to animals and humans. In a comparison of the repeat dose data between rats and mice, the ERASM project (see ECETOC reference) did not find evidence to support use of such a factor on a routine basis and any differences could be accounted for by allometric scaling factors alone. The data presented by ECETOC also support the conclusion that any ‘residual’ interspecies variability following allometric scaling is largely accounted for in the intraspecies factor, reflecting the interdependency of the individual assessment factors and avoiding ‘double counting’ of statistical variability. It should be noted that there is no scientific rationale provided in the ECHA document for the use of such a factor and that the multiplication of separate factors that have no sound scientific rationale behind them and that are not truly independent factors leads to unnecessarily conservative overall assessment factors. In the case of this substance, there is no evidence to support the use of a factor for remaining interspecies differences. For further justification, see attachment to this record.
AF for the quality of the whole database:
2
Justification:
Age of study
AF for remaining uncertainties:
1
Justification:
No reason to deviate from default.
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:
low hazard (no threshold derived)

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
181 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: See discussion below
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEC
Explanation for the modification of the dose descriptor starting point:

The starting point for the DNEL derivation is the repeat dose inhalation systemic NOAEC from the 90 day sub-chronic study with the read across substance ethoxypropanol (the in vivo hydrolysis product).  The starting point of 1266mg/m3 is extrapolated by molar conversion to an equivalent NOAEC of 1812mg/m3 for ethoxypropyl acetate.

According to the guidance on the characterisation of dose response for human health, the NOAEC should be corrected for duration of exposure by a factor of 6/24. This would be appropriate when deriving a DNEL for continuous exposure. For shorter exposures, the guidance on consumer exposure assessment states that the DNEL can be corrected back but in this case using Haber's law rather than the same linear correction. This is a scientifically flawed argument. If a DNEL for short exposures is required, it should be derived directly with a single correction rather than the double correction as stated in the guidance that effectively ends up at the same starting place for exposure but with a lower NOAEC. In this case therefore no correction is made to the starting point and the DNEL derived here is therefore valid for consumer exposures up to 6 hours per day. For durations less than this corrections can be made using the Haber rule as follows (DNEL increased or assessment factor applied:

  • 3hrs: 1.25
  • 2hrs: 1.45
  • 1hr: 1.8
  • 0.5hr: 2.3

For durations longer than this, the DNEL should be reduced linearly:

  • 8hrs: *0.75
  • 24hrs: *0.25 (used for continuous exposures as would be the case for indoor air and environmental background exposures)

For a DNEL for infrequent use, see the next section on acute systemic inhalation exposure.

AF for dose response relationship:
1
Justification:
Default
AF for differences in duration of exposure:
2
Justification:
Sub-chronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Not required for an inhalation study
AF for other interspecies differences:
1
Justification:
According to the ECETOC guidance document (ECETOC, 2010) , it is not appropriate in the majority of cases to apply an interspecies factor for ‘residual differences’ and that such a factor should only be supplied should the hazard data indicated a greater or lesser sensitivity of animals compared to man, eg significant differences in the mode of action. If such a factor was required, there would be evidence for it in a comparison of data between different animal species, as opposed to animals and humans. In a comparison of the repeat dose data between rats and mice, the ERASM project (see ECETOC reference) did not find evidence to support use of such a factor on a routine basis and any differences could be accounted for by allometric scaling factors alone. The data presented by ECETOC also support the conclusion that any ‘residual’ interspecies variability following allometric scaling is largely accounted for in the intraspecies factor, reflecting the interdependency of the individual assessment factors and avoiding ‘double counting’ of statistical variability. It should be noted that there is no scientific rationale provided in the ECHA document for the use of such a factor and that the multiplication of separate factors that have no sound scientific rationale behind them and that are not truly independent factors leads to unnecessarily conservative overall assessment factors. In the case of this substance, there is no evidence to support the use of a factor for remaining interspecies differences. For further justification, see attachment to this record.
AF for intraspecies differences:
5
Justification:
According to the ECHA guidance document, where scientific justification exists, one can deviate from the default ECHA assessment factors used in DENL derivation. In deriving DNELS, the assessment factor chosen for Intraspecies variability (worker and general population) has been taken from the ECETOC technical report no, 110 (ECETOC, 2010)as an alternative to the ECHA default. The ECETOC working group performed a detailed assessment of the many publications available on human variability as it pertains to risk assessment. As a consequence of this assessment it was determined that in the majority of cases a factor of 3 for worker or 5 for general population is sufficient to address Intraspecies variability. Specifically considering the p-series glycol ethers, they have a low order of toxicity, with key effects primarily limited to adaptive effects in the liver and kidney (likely associated with either enzyme induction or alpha 2u-globulin formation). These substances also demonstrate very little variability in effect levels and target organs when tested in multiple species and for multiple durations (sub-acute to chronic). As such it is considered that the lower assessment factors proposed by ECETOC should adequately address the Intraspecies variability within the risk assessment. For further justification, see attachment to this record.
AF for the quality of the whole database:
1
Justification:
No reason to deviate from default.
AF for remaining uncertainties:
1
Justification:
No reason to deviate from default.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 420 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
Overall assessment factor (AF):
5
Dose descriptor starting point:
NOAEC
DNEL value:
7 100 mg/m³
Modified dose descriptor starting point:
NOAEC
DNEL value:
7 100 mg/m³
Explanation for the modification of the dose descriptor starting point:

There is no dose reponse information available for the acute toxicity hazard of narcosis for which this substance is currently classified. The data suggests that there is no significant narcosis hazard.  However, since the substance is currently classified for this end point, it is necessary to derive a NOAEL.   For acute, short term systemic effects, the guidance suggests that an acute DNEL can be based on the repeat dose DNEL multiplied by a factor of 1-5.   An alternative approach would be to use the sub-acute, 28 days study with ethoxypropyl acetate and to use the data from this to establish a NOAEL. In this study, no adverse observations of any nature were seen for the first two days of 6 hourly exposures up to a dose of 1200ppm (7100mg/m3). To assess the affect in humans to a single acute exposure of 4hrs, this seems a reasonable starting point. No correction is required as the exposures of the animals are to longer times than required for the human equivalent assessment (conservative approach).

AF for dose response relationship:
1
Justification:
No reason to deviate from default.
AF for interspecies differences (allometric scaling):
1
Justification:
Not required for an inhalation study
AF for other interspecies differences:
1
Justification:
According to the ECETOC guidance document (ECETOC, 2010) , it is not appropriate in the majority of cases to apply an interspecies factor for ‘residual differences’ and that such a factor should only be supplied should the hazard data indicated a greater or lesser sensitivity of animals compared to man, eg significant differences in the mode of action. If such a factor was required, there would be evidence for it in a comparison of data between different animal species, as opposed to animals and humans. In a comparison of the repeat dose data between rats and mice, the ERASM project (see ECETOC reference) did not find evidence to support use of such a factor on a routine basis and any differences could be accounted for by allometric scaling factors alone. The data presented by ECETOC also support the conclusion that any ‘residual’ interspecies variability following allometric scaling is largely accounted for in the intraspecies factor, reflecting the interdependency of the individual assessment factors and avoiding ‘double counting’ of statistical variability. It should be noted that there is no scientific rationale provided in the ECHA document for the use of such a factor and that the multiplication of separate factors that have no sound scientific rationale behind them and that are not truly independent factors leads to unnecessarily conservative overall assessment factors. In the case of this substance, there is no evidence to support the use of a factor for remaining interspecies differences. For further justification, see attachment to this record.
AF for intraspecies differences:
5
Justification:
According to the ECHA guidance document, where scientific justification exists, one can deviate from the default ECHA assessment factors used in DENL derivation. In deriving DNELS, the assessment factor chosen for Intraspecies variability (worker and general population) has been taken from the ECETOC technical report no, 110 (ECETOC, 2010)as an alternative to the ECHA default. The ECETOC working group performed a detailed assessment of the many publications available on human variability as it pertains to risk assessment. As a consequence of this assessment it was determined that in the majority of cases a factor of 3 for worker or 5 for general population is sufficient to address Intraspecies variability. Specifically considering the p-series glycol ethers, they have a low order of toxicity, with key effects primarily limited to adaptive effects in the liver and kidney (likely associated with either enzyme induction or alpha 2u-globulin formation). These substances also demonstrate very little variability in effect levels and target organs when tested in multiple species and for multiple durations (sub-acute to chronic). As such it is considered that the lower assessment factors proposed by ECETOC should adequately address the Intraspecies variability within the risk assessment. For further justification, see attachment to this record.
AF for the quality of the whole database:
1
Justification:
No reason to deviate from default.
AF for remaining uncertainties:
1
Justification:
No reason to deviate from default.

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
62 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
other: See discussion below
Overall assessment factor (AF):
48
Modified dose descriptor starting point:
NOAEL
AF for dose response relationship:
1
Justification:
No reason to deviate from default.
AF for differences in duration of exposure:
2
Justification:
Sub-chronic to chronic
AF for interspecies differences (allometric scaling):
2.5
Justification:
Rabbit to human
AF for other interspecies differences:
1
Justification:
According to the ECETOC guidance document (ECETOC, 2010) , it is not appropriate in the majority of cases to apply an interspecies factor for ‘residual differences’ and that such a factor should only be supplied should the hazard data indicated a greater or lesser sensitivity of animals compared to man, eg significant differences in the mode of action. If such a factor was required, there would be evidence for it in a comparison of data between different animal species, as opposed to animals and humans. In a comparison of the repeat dose data between rats and mice, the ERASM project (see ECETOC reference) did not find evidence to support use of such a factor on a routine basis and any differences could be accounted for by allometric scaling factors alone. The data presented by ECETOC also support the conclusion that any ‘residual’ interspecies variability following allometric scaling is largely accounted for in the intraspecies factor, reflecting the interdependency of the individual assessment factors and avoiding ‘double counting’ of statistical variability. It should be noted that there is no scientific rationale provided in the ECHA document for the use of such a factor and that the multiplication of separate factors that have no sound scientific rationale behind them and that are not truly independent factors leads to unnecessarily conservative overall assessment factors. In the case of this substance, there is no evidence to support the use of a factor for remaining interspecies differences. For further justification, see attachment to this record.
AF for intraspecies differences:
5
Justification:
According to the ECHA guidance document, where scientific justification exists, one can deviate from the default ECHA assessment factors used in DENL derivation. In deriving DNELS, the assessment factor chosen for Intraspecies variability (worker and general population) has been taken from the ECETOC technical report no, 110 (ECETOC, 2010)as an alternative to the ECHA default. The ECETOC working group performed a detailed assessment of the many publications available on human variability as it pertains to risk assessment. As a consequence of this assessment it was determined that in the majority of cases a factor of 3 for worker or 5 for general population is sufficient to address Intraspecies variability. Specifically considering the p-series glycol ethers, they have a low order of toxicity, with key effects primarily limited to adaptive effects in the liver and kidney (likely associated with either enzyme induction or alpha 2u-globulin formation). These substances also demonstrate very little variability in effect levels and target organs when tested in multiple species and for multiple durations (sub-acute to chronic). As such it is considered that the lower assessment factors proposed by ECETOC should adequately address the Intraspecies variability within the risk assessment. For further justification, see attachment to this record.
AF for the quality of the whole database:
2
Justification:
Age of study
AF for remaining uncertainties:
1
Justification:
No reason to deviate from default.
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:
13.1 mg/kg bw/day
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: See discussion below
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
Explanation for the modification of the dose descriptor starting point:

Extrapolation is by assuming a breathing rate of 0.29m3/kgbw (table R-8.2 of guidance) which equates to 525mg/kgbw, assuming 100% absorption by both inhalation and oral routes based on a starting NOAEL of 1812mg/kg.

AF for dose response relationship:
1
Justification:
No reason to deviate from default.
AF for differences in duration of exposure:
2
Justification:
Sub-chronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Rat to human
AF for other interspecies differences:
1
Justification:
According to the ECETOC guidance document (ECETOC, 2010) , it is not appropriate in the majority of cases to apply an interspecies factor for ‘residual differences’ and that such a factor should only be supplied should the hazard data indicated a greater or lesser sensitivity of animals compared to man, eg significant differences in the mode of action. If such a factor was required, there would be evidence for it in a comparison of data between different animal species, as opposed to animals and humans. In a comparison of the repeat dose data between rats and mice, the ERASM project (see ECETOC reference) did not find evidence to support use of such a factor on a routine basis and any differences could be accounted for by allometric scaling factors alone. The data presented by ECETOC also support the conclusion that any ‘residual’ interspecies variability following allometric scaling is largely accounted for in the intraspecies factor, reflecting the interdependency of the individual assessment factors and avoiding ‘double counting’ of statistical variability. It should be noted that there is no scientific rationale provided in the ECHA document for the use of such a factor and that the multiplication of separate factors that have no sound scientific rationale behind them and that are not truly independent factors leads to unnecessarily conservative overall assessment factors. In the case of this substance, there is no evidence to support the use of a factor for remaining interspecies differences. For further justification, see attachment to this record.
AF for intraspecies differences:
5
Justification:
According to the ECHA guidance document, where scientific justification exists, one can deviate from the default ECHA assessment factors used in DENL derivation. In deriving DNELS, the assessment factor chosen for Intraspecies variability (worker and general population) has been taken from the ECETOC technical report no, 110 (ECETOC, 2010)as an alternative to the ECHA default. The ECETOC working group performed a detailed assessment of the many publications available on human variability as it pertains to risk assessment. As a consequence of this assessment it was determined that in the majority of cases a factor of 3 for worker or 5 for general population is sufficient to address Intraspecies variability. Specifically considering the p-series glycol ethers, they have a low order of toxicity, with key effects primarily limited to adaptive effects in the liver and kidney (likely associated with either enzyme induction or alpha 2u-globulin formation). These substances also demonstrate very little variability in effect levels and target organs when tested in multiple species and for multiple durations (sub-acute to chronic). As such it is considered that the lower assessment factors proposed by ECETOC should adequately address the Intraspecies variability within the risk assessment. For further justification, see attachment to this record.
AF for the quality of the whole database:
1
Justification:
No reason to deviate from default.
AF for remaining uncertainties:
1
Justification:
No reason to deviate from 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:
low hazard (no threshold derived)

Additional information - General Population