Nickel bis(dibutyldithiocarbamate)

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.4 µg/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

Value:

0.2 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

0.18 mg/m³

Explanation for the modification of the dose descriptor starting point:

Starting point is a NOAEL of 0.2 mg/kg bw/day based on an oral OECD 422 study in rats. 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 ratebased on activity (6.7 m³ for normal light activity versus 10 m³ for worker activity): 0.2 * (1/0.38) * (1/2) * (6.7/10) = 0.18 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-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL) 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-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker 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 the most severe NOAEL was found in a sub-acute toxicity study, the 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-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-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-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-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:

There are no remaining uncertainties. Therefore the assessment factor for remaining uncertainties is set at 1

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

333 µg/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

Value:

0.2 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Since no repeated dose dermal study is available, route-to-route extrapolation from the oral exposure route is performed. The starting point is an oral rat NOAEL of 0.2 mg/kg bw/day (OECD 422). The dermal aborption value from read-across substance Ziram was used for absorption via the dermal route. Data on oral absorption is lacking, therefore the default value of 50% was assumed. The modified dose descriptor is therefore: 0.2 * (50/0.1) = 100 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-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL) 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-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker 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 the most severe NOAEL was found in a sub-acute toxicity study, the 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-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-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-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-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:

The dermal penetration of the test substance was based on a structurally related substance ZDMC (CAS 137-30-4) and was conservatively concluded to be 0.1%. Since this value is already conservative and the water solubility of the test substance is much lower than that of ZDMC, which indicates an even lower dermal penetration for the test substance, the assessment factor for remaining uncertainties is set at 1.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.58 µg/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

Value:

0.2 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

0.087 mg/m³

Explanation for the modification of the dose descriptor starting point:

Starting point is a NOAEL of 0.2 mg/kg bw/day based on an oral OECD 422 study in rats. 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 the general population exposure (1.15 m³/kg bw) and by application of a factor of 2 for route to route extrapolation: 0.2 * (1/1.15) * (1/2) = 0.087 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-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL) 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-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker 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 the most severe NOAEL was found in a sub-acute toxicity study, the 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-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-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-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-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:

There are no remaining uncertainties. Therefore the assessment factor for remaining uncertainties is set at 1

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

167 µg/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

Value:

0.2 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Since no repeated dose dermal study is available, route-to-route extrapolation from the oral exposure route is performed. The starting point is an oral rat NOAEL of 0.2 mg/kg bw/day (OECD 422). The dermal aborption value from read-across substance Ziram was used for absorption via the dermal route. Data on oral absorption is lacking, therefore the default value of 50% was assumed. The modified dose descriptor is therefore: 0.2 * (50/0.1) = 100 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-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL) 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-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker 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 the most severe NOAEL was found in a sub-acute toxicity study, the 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-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-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-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-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:

The dermal penetration of the test substance was based on a structurally related substance ZDMC (CAS 137-30-4) and was conservatively concluded to be 0.1%. Since this value is already conservative and the water solubility of the test substance is much lower than that of ZDMC, which indicates an even lower dermal penetration for the test substance, the assessment factor for remaining uncertainties is set at 1.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.33 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

Value:

0.2 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-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL) 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-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker 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 the most severe NOAEL was found in a sub-acute toxicity study, the 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-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-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-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-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:

There are no remaining uncertainties. Therefore the assessment factor for remaining uncertainties is set at 1

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)