Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.18 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
75
Dose descriptor starting point:
NOAEL
DNEL value:
15 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
13.2 mg/m³
Explanation for the modification of the dose descriptor starting point:

For the correction of the NOAEL to NOAEC, the NOAEL should be multiplied by 1/0.38 to correct for exposure time per day, with 6.7/10 to correct for breathing volume of workers and with 1/2 to correct for differences in absorption between routes. The “corrected NOAEC” would then be 15 mg/kg bd/d * 1/0.38 * 6.7/10 * 1/2 = 13 mg/m3.

AF for dose response relationship:
1
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dose…) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a NOAEL, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.
AF for differences in duration of exposure:
6
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. So, as only a sub-acute toxicity study is available, default assessment factor of 6 is to be applied, as a standard procedure.
AF for interspecies differences (allometric scaling):
1
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, as long as route-to-route extrapolation is not needed, allometric scaling should not be applied in cases where doses in experimental animal studies are expressed as concentrations (e.g. in mg/m3 air, ppm in diet, or mg/L in the drinking water) as these are assumed to be already scaled according to the allometric principle, since ventilation rate and food intake directly depend on the basal metabolic rate. In this case the NOAEC is expressed as concentration (mg/m3), therefore a factor for allometric scaling is not needed.
AF for other interspecies differences:
2.5
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: If no substance-specific data are available, the standard procedure for threshold effects is, as a default, to correct for differences in metabolic rate (allometric scaling) and to apply an additional factor of 2.5 for other interspecies differences, i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part).
AF for intraspecies differences:
5
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: If the dose descriptor (e.g. N(L)OAEL, benchmark dose, etc.) has been derived from an animal study, animal intraspecies variation/differences has already to some extent been accounted for in that dose descriptor. Ideally therefore, the intraspecies factor should reflect the additional interspecies variability, i.e. the difference between variability in the human population and variability in the animal population. For workers, as standard procedure for threshold effects a default assessment factor of 5 is to be used, based on the fact that this sub population does not cover the very young, the very old, and the very ill.
AF for the quality of the whole database:
1
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.004 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
37.5
Dose descriptor:
LOAEC
DNEL value:
0.15 mg/m³
AF for dose response relationship:
3
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dose…) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a LOAEC, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 3.
AF for differences in duration of exposure:
1
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: A factor allowing for differences in the experimental exposure duration and the duration of exposure for the population and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. However, a correction for exposure duration for the inhalation rat study is not appropriate as the local effects are mainly driven by the exposure concentration. Therefore, the default assessment factor of 1 is not applied in this instance.
AF for interspecies differences (allometric scaling):
1
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, as long as route-to-route extrapolation is not needed, allometric scaling should not be applied in cases where doses in experimental animal studies are expressed as concentrations (e.g. in mg/m3 air, ppm in diet, or mg/L in the drinking water) as these are assumed to be already scaled according to the allometric principle, since ventilation rate and food intake directly depend on the basal metabolic rate. In this case the BMCL05 is expressed as concentration (mg/m3), therefore a factor for allometric scaling is not needed.
AF for other interspecies differences:
2.5
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: If no substance-specific data are available, the standard procedure for threshold effects is, as a default, to correct for differences in metabolic rate (allometric scaling) and to apply an additional factor of 2.5 for other interspecies differences, i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part).
AF for intraspecies differences:
5
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: If the dose descriptor (e.g. N(L)OAEL, benchmark dose, etc.) has been derived from an animal study, animal intraspecies variation/differences has already to some extent been accounted for in that dose descriptor. Ideally therefore, the intraspecies factor should reflect the additional interspecies variability, i.e. the difference between variability in the human population and variability in the animal population. For workers, as standard procedure for threshold effects a default assessment factor of 5 is to be used, based on the fact that this sub population does not cover the very young, the very old, and the very ill.
AF for the quality of the whole database:
1
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, is to be applied.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.05 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
300
Dose descriptor starting point:
NOAEL
DNEL value:
15 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
15 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Similar bioavailability via the gastrointestinal tract and the skin was assumed resulting in an extrapolated dermal NOAEL of 15 mg/kg bw/day.
AF for dose response relationship:
1
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dose…) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a NOAEL, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.
AF for differences in duration of exposure:
6
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. So, as only a sub-acute toxicity study is available, default assessment factor of 6 is to be applied, as a standard procedure.
AF for interspecies differences (allometric scaling):
4
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, allometric scaling extrapolates doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight to the power of 0.250. This results in a default allometric scaling factor for the rat when compared with humans, namely 4.
AF for other interspecies differences:
2.5
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: If no substance-specific data are available, the standard procedure for threshold effects is, as a default, to correct for differences in metabolic rate (allometric scaling) and to apply an additional factor of 2.5 for other interspecies differences, i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part).
AF for intraspecies differences:
5
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: If the dose descriptor (e.g. N(L)OAEL, benchmark dose, etc.) has been derived from an animal study, animal intraspecies variation/differences has already to some extent been accounted for in that dose descriptor. Ideally therefore, the intraspecies factor should reflect the additional interspecies variability, i.e. the difference between variability in the human population and variability in the animal population. For workers, as standard procedure for threshold effects a default assessment factor of 5 is to be used, based on the fact that this sub population does not cover the very young, the very old, and the very ill.
AF for the quality of the whole database:
1
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
DNEL related information
Justification:
.
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high 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:
0.04 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
150
Dose descriptor starting point:
NOAEL
DNEL value:
15 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
6.5 mg/m³
Explanation for the modification of the dose descriptor starting point:
For the general population, the NOAEL should be multiplied by 1/1.15 (to correct for breathing volume of general workers) and with 1/2 (to correct for differences in absorption between routes). The “corrected NOAEC” would then be 15 mg/kg bw/d * 1/1.15 * 1/2 = 6.52 mg/m3.
AF for dose response relationship:
1
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dose…) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a NOAEL, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.
AF for differences in duration of exposure:
6
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. So, as only a sub-acute toxicity study is available, default assessment factor of 6 is to be applied, as a standard procedure.
AF for interspecies differences (allometric scaling):
1
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, as long as route-to-route extrapolation is not needed, allometric scaling should not be applied in cases where doses in experimental animal studies are expressed as concentrations (e.g. in mg/m3 air, ppm in diet, or mg/L in the drinking water) as these are assumed to be already scaled according to the allometric principle, since ventilation rate and food intake directly depend on the basal metabolic rate. In this case the NOAEC is expressed as concentration (mg/m3), therefore a factor for allometric scaling is not needed.
AF for other interspecies differences:
2.5
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: If no substance-specific data are available, the standard procedure for threshold effects is, as a default, to correct for differences in metabolic rate (allometric scaling) and to apply an additional factor of 2.5 for other interspecies differences, i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part).
AF for intraspecies differences:
10
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: If the dose descriptor (e.g. N(L)OAEL, benchmark dose, etc.) has been derived from an animal study, animal intraspecies variation/differences has already to some extent been accounted for in that dose descriptor. Ideally therefore, the intraspecies factor should reflect the additional interspecies variability, i.e. the difference between variability in the human population and variability in the animal population. For the general population, as standard procedure for threshold effects a default assessment factor of 10 is to be used, based on the fact that this sub population cover the very young, the very old, and the very ill.
AF for the quality of the whole database:
1
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.002 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
75
Dose descriptor:
LOAEC
DNEL value:
0.15 mg/m³
AF for dose response relationship:
3
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dose…) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a LOAEC, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 3.
AF for differences in duration of exposure:
1
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: A factor allowing for differences in the experimental exposure duration and the duration of exposure for the population and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. However, a correction for exposure duration for the inhalation rat study is not appropriate as the local effects are mainly driven by the exposure concentration. Therefore, the default assessment factor of 1 is not applied in this instance.
AF for interspecies differences (allometric scaling):
1
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, as long as route-to-route extrapolation is not needed, allometric scaling should not be applied in cases where doses in experimental animal studies are expressed as concentrations (e.g. in mg/m3 air, ppm in diet, or mg/L in the drinking water) as these are assumed to be already scaled according to the allometric principle, since ventilation rate and food intake directly depend on the basal metabolic rate. In this case the LOAEC is expressed as concentration (mg/m3), therefore a factor for allometric scaling is not needed.
AF for other interspecies differences:
2.5
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: If no substance-specific data are available, the standard procedure for threshold effects is, as a default, to correct for differences in metabolic rate (allometric scaling) and to apply an additional factor of 2.5 for other interspecies differences, i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part).
AF for intraspecies differences:
10
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: If the dose descriptor (e.g. N(L)OAEL, benchmark dose, etc.) has been derived from an animal study, animal intraspecies variation/differences has already to some extent been accounted for in that dose descriptor. Ideally therefore, the intraspecies factor should reflect the additional interspecies variability, i.e. the difference between variability in the human population and variability in the animal population. For general population, as standard procedure for threshold effects a default assessment factor of 10 is to be used, based on the fact that this sub population covers the very young, the very old, and the very ill.
AF for the quality of the whole database:
1
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, is to be applied.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.03 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
600
Dose descriptor starting point:
NOAEL
DNEL value:
15 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
15 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Similar bioavailability via the gastrointestinal tract and the skin was assumed resulting in an extrapolated dermal NOAEL of 15 mg/kg bw/day.
AF for dose response relationship:
1
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dose…) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a NOAEL, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.
AF for differences in duration of exposure:
6
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. So, as only a sub-acute toxicity study is available, default assessment factor of 6 is to be applied, as a standard procedure.
AF for interspecies differences (allometric scaling):
4
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, allometric scaling extrapolates doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight to the power of 0.250. This results in a default allometric scaling factor for the rat when compared with humans, namely 4.
AF for other interspecies differences:
2.5
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: If no substance-specific data are available, the standard procedure for threshold effects is, as a default, to correct for differences in metabolic rate (allometric scaling) and to apply an additional factor of 2.5 for other interspecies differences, i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part).
AF for intraspecies differences:
10
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: If the dose descriptor (e.g. N(L)OAEL, benchmark dose, etc.) has been derived from an animal study, animal intraspecies variation/differences has already to some extent been accounted for in that dose descriptor. Ideally therefore, the intraspecies factor should reflect the additional interspecies variability, i.e. the difference between variability in the human population and variability in the animal population. For general population, as standard procedure for threshold effects a default assessment factor of 10 is to be used, based on the fact that this sub population covers the very young, the very old, and the very ill.
AF for the quality of the whole database:
1
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.03 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
600
Dose descriptor starting point:
NOAEL
DNEL value:
15 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
15 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No route to route extrapolation performed
AF for dose response relationship:
1
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dose…) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a NOAEL, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.
AF for differences in duration of exposure:
6
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. So, as only a sub-acute toxicity study is available, default assessment factor of 6 is to be applied, as a standard procedure.
AF for interspecies differences (allometric scaling):
4
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, allometric scaling extrapolates doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight to the power of 0.250. This results in a default allometric scaling factor for the rat when compared with humans, namely 4.
AF for other interspecies differences:
2.5
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: If no substance-specific data are available, the standard procedure for threshold effects is, as a default, to correct for differences in metabolic rate (allometric scaling) and to apply an additional factor of 2.5 for other interspecies differences, i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part).
AF for intraspecies differences:
10
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: If the dose descriptor (e.g. N(L)OAEL, benchmark dose, etc.) has been derived from an animal study, animal intraspecies variation/differences has already to some extent been accounted for in that dose descriptor. Ideally therefore, the intraspecies factor should reflect the additional interspecies variability, i.e. the difference between variability in the human population and variability in the animal population. For general population, as standard procedure for threshold effects a default assessment factor of 10 is to be used, based on the fact that this sub population covers the very young, the very old, and the very ill.
AF for the quality of the whole database:
1
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - General Population

As the substance is only used in industrial settings, direct exposure of the general public to Gaskamine 240 is not anticipated. DNELs for long-term dermal and inhalation exposure were derived to complete the picture. The physical-chemical and environmental fate properties of the substance may lead to an accumulation of the substance in food webs. Indirect oral exposure of the general public may occur and an appropriate DNEL for chronic oral exposure was derived.