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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.49 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):
25
Dose descriptor starting point:
NOAEL
DNEL value:
10 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
12.3 mg/m³
Explanation for the modification of the dose descriptor starting point:

Starting point is a NOAEL of 10 mg/kg bw/day based on an oral 13 week repeated dose study. This oral rat NOAEL is converted to an inhalatory rat NOAEC by using a default respiratory volume for the rat corresponding to 8 h exposure, which is the relevant duration of worker exposure (0.38 m³/kg bw) and by application of a factor of 2 for route to route extrapolation. The resulting rat inhalatory NOAEC is converted into inhalatory worker NOAEC by correction for respiratory rate based on activity (6.7 m³ for normal light activity versus 10 m³ for worker activity) and by correction for 5 day exposure (7 days versus 5 days): 10 * * (1/0.38) * (1/2) * (6.7/10) * (7/5) = 12.3 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:
2
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-chronic toxicity study is available, a default assessment factor of 2 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 the dose unit (original or transformed) 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 (converted) 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: Characterisation of dose [concentration]-response for human health, Interspecies differences result from variation in the sensitivity of species due to differences in toxicokinetics and toxicodynamics. Some of the toxicokinetic differences can be explained by differences in body size (and related differences in basal metabolic rate). As substance-specific data are available, the standard procedure for threshold effects is followed. As a default, an additional factor of 2.5 for interspecies differences (other than allometric scaling), i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part) is applied.
AF for intraspecies differences:
5
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, intraspecies differences in humans result from a multitude of biological factors such as genetic polymorphism affecting e.g. toxicokinetics/metabolism, age, gender, health status and nutritional status. 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.
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:
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:
0.7 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):
100
Dose descriptor starting point:
NOAEL
DNEL value:
10 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
70 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Starting point is an oral rat NOAEL of 10 mg/kg bw/day (13 weeks study). As explained in the endpoint summary on toxicokinetics, metabolism and distribution, dermal absorption is considered 20% of oral absorption. This value is used to extrapolate the oral rat NOAEL to a dermal rat NOAEL. This rat NOAEL is converted to worker NOAEL by correction for 5 days exposure: 10 * (1/0.20) * (7/5) = 70 mg/kg bw/d.

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:
2
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-chronic toxicity study is available, default assessment factor of 2 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, differences in metabolic rate (allometric scaling) should be accounted for by extrapolation of doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight to the power of 0.75. This results in different default allometric scaling factors for the different animal species when compared with humans. For rats, the default assessment factor, as a standard procedure, is 4.
AF for other interspecies differences:
2.5
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, Interspecies differences result from variation in the sensitivity of species due to differences in toxicokinetics and toxicodynamics. Some of the toxicokinetic differences can be explained by differences in body size (and related differences in basal metabolic rate). As substance-specific data are available, the standard procedure for threshold effects is followed. As a default, an additional factor of 2.5 for interspecies differences (other than allometric scaling), i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part) is applied.
AF for intraspecies differences:
5
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, intraspecies differences in human result from a multitude of biological factors such as genetic polymorphism affecting e.g. toxicokinetics/metabolism, age, gender, health status and nutritional status. 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.
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)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium 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:
0.087 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):
50
Dose descriptor starting point:
NOAEL
DNEL value:
10 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
4.3 mg/m³
Explanation for the modification of the dose descriptor starting point:

Starting point is a NOAEL of 10 mg/kg bw/day based on an oral 13 week repeated dose study. This oral rat NOAEL is converted to an inhalatory rat NOAEC by using a default respiratory volume for the rat corresponding to 24 h exposure, which is the relevant duration for general population, (1.15 m³/kg bw) and by application of a factor of 2 for route to route extrapolation: 10 * (1/2) * (1/1.15) = 4.3 mg/m³. Since both in the experimental situation and in the general population exposure situation exposure is (assumed to be) daily, no correction for days of exposure is needed.

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:
2
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-chronic toxicity study is available, default assessment factor of 2 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 the dose unit (original or transformed) 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 (converted) 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: Characterisation of dose [concentration]-response for human health, Interspecies differences result from variation in the sensitivity of species due to differences in toxicokinetics and toxicodynamics. Some of the toxicokinetic differences can be explained by differences in body size (and related differences in basal metabolic rate). As substance-specific data are available, the standard procedure for threshold effects is followed. As a default, an additional factor of 2.5 for interspecies differences (other than allometric scaling), i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part) is applied.
AF for intraspecies differences:
10
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, intraspecies differences in human result from a multitude of biological factors such as genetic polymorphism affecting e.g. toxicokinetics/metabolism, age, gender, health status and nutritional status. It is usually assumed that a default assessment factor of 10 for the general population is sufficient to protect the larger part of the population, including e.g. children and the elderly. For threshold effects, this factor of 10 is the standard procedure, as a default, when assessing exposure to the general population.
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.
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:
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:
0.25 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):
200
Dose descriptor starting point:
NOAEL
DNEL value:
10 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
50 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Starting point is an oral NOAEL of 10 mg/kg bw/day (13 weeks study). As explained in the endpoint summary on toxicokinetics, metabolism and distribution, dermal absorption is considered 20% of oral absorption. This value is used to extrapolate the oral rat NOAEL to a dermal rat NOAEL: 10 * (1/0.20) = 50

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:
2
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-chronic toxicity study is available, default assessment factor of 2 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, differences in metabolic rate (allometric scaling) should be accounted for by extrapolation of doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight to the power of 0.75. This results in different default allometric scaling factors for the different animal species when compared with humans. For rats, the default assessment factor, as a standard procedure, is 4.
AF for other interspecies differences:
2.5
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, Interspecies differences result from variation in the sensitivity of species due to differences in toxicokinetics and toxicodynamics. Some of the toxicokinetic differences can be explained by differences in body size (and related differences in basal metabolic rate). As substance-specific data are available, the standard procedure for threshold effects is followed. As a default, an additional factor of 2.5 for interspecies differences (other than allometric scaling), i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part) is applied.
AF for intraspecies differences:
10
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, intraspecies differences in human result from a multitude of biological factors such as genetic polymorphism affecting e.g. toxicokinetics/metabolism, age, gender, health status and nutritional status. It is usually assumed that a default assessment factor of 10 for the general population is sufficient to protect the larger part of the population, including e.g. children and the elderly. For threshold effects, this factor of 10 is the standard procedure, as a default, when assessing exposure to the general population.
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.
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:
0.05 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):
200
Dose descriptor starting point:
NOAEL
DNEL value:
10 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Starting point is a NOAEL of 10 mg/kg bw/day based on an oral 13 week repeated dose study. Since the source data and the target DNEL have the same route of exposure and since there is no difference in exposure days (both daily), no conversion of the starting point is necessary.

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:
2
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-chronic toxicity study is available, default assessment factor of 2 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, differences in metabolic rate (allometric scaling) should be accounted for by extrapolation of doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight to the power of 0.75. This results in different default allometric scaling factors for the different animal species when compared with humans. For rats, the default assessment factor, as a standard procedure, is 4.
AF for other interspecies differences:
2.5
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, Interspecies differences result from variation in the sensitivity of species due to differences in toxicokinetics and toxicodynamics. Some of the toxicokinetic differences can be explained by differences in body size (and related differences in basal metabolic rate). As substance-specific data are available, the standard procedure for threshold effects is followed. As a default, an additional factor of 2.5 for interspecies differences (other than allometric scaling), i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part) is applied.
AF for intraspecies differences:
10
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, intraspecies differences in human result from a multitude of biological factors such as genetic polymorphism affecting e.g. toxicokinetics/metabolism, age, gender, health status and nutritional status. It is usually assumed that a default assessment factor of 10 for the general population is sufficient to protect the larger part of the population, including e.g. children and the elderly. For threshold effects, this factor of 10 is the standard procedure, as a default, when assessing exposure to the general population.
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.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population