Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
302 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
Modified dose descriptor starting point:
NOAEC
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:
608 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Modified dose descriptor starting point:
NOAEC

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 disdcussion below
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEC
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:
365 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
Overall assessment factor (AF):
5
Modified dose descriptor starting point:
NOAEC
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