1-ethyl-3-methyl-3H-imidazolium dicyanidoamide(1-)

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

6.64 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA REACH guidance and ECETOC guidance for intraspecies differences

Overall assessment factor (AF):

45

Dose descriptor starting point:

NOAEL

Value:

339 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

298.9 mg/m³

Explanation for the modification of the dose descriptor starting point:

The starting point is a NOAEL (oral administration) of 339.0 mg/kg bw. A factor 2 is applied for route to route extrapolation, oral to inhalation. The resulting rat NOAEL was converted into inhalatory worker NOAEC by converting the oral dose to corresponding air concentration (8 hours exposure for workers) and correcting for respiratory rate based on activity (6.7 m³ for normal light activity versus 10 m³ for worker activity): 169.5 * (1/0.38) * (6.7/10) = 298.9 mg/m³

AF for dose response relationship:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – R.8: Characterisation of dose [concentration]-response for human health (v2.1, 2012), 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 R.8 (v2.1, 2012), 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 R.8 (v2.1, 2012), 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. In ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, a similar approach is followed. The rationale here is that allometric scaling should not be applied because in humans inhalation rate is 4-fold lower compared to rat according to the slower metabolic rate and thereby the allometric species difference is already implicitly taken into account.

AF for other interspecies differences:

2.5

Justification:

In accordance with ECHA Guidance R.8 (v2.1, 2012), as long as no substance-specific data are available, an additional factor of 2.5 for other interspecies differences, i.e. toxicokinetic differences not related to metabolic rate and toxicodynamic differences, is applied.

AF for intraspecies differences:

3

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 (2003) and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110 (2010), a default assessment factor for the general population is based on the distributions of human data for various toxicokinetic and toxicodynamic parameters. The upper extreme of the variability in these data was estimated by calculating the 95th percentile of the distribution, which is considered sufficiently conservative to account for intraspecies variability in the general population (the data analysed included both sexes, a variety of disease states and ages). This results in recommended default assessment factor of 5 for the general population. As the worker population is more homogeneous (i.e. younger, healthier, protected from exposures), a default assessment factor of 3 is recommended. This proposal of ECETOC is based on an evaluation of the available scientific literature while the ECHA Guidance R.8 (v2.1, 2012) refers to standard default procedures. Until the scientific basis for using an alternative approach has been established, it is proposed to follow the ECETOC guideline.

AF for the quality of the whole database:

1

Justification:

In accordance with ECHA Guidance R.8 (v2.1, 2012), 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:

default (DNEL derivation based on a GLP and OECD TG study)

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:

1.88 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA REACH guidance and ECETOC guidance for intraspecies differences

Overall assessment factor (AF):

180

Dose descriptor starting point:

NOAEL

Value:

339 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

339 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The starting point is a NOAEL (oral administration) of 339.0 mg/kg bw. In accordance with ECHA Guidance on information requirements and chemical safety assessment – R.8: Characterisation of dose [concentration]-response for human health (v2.1, 2012), in absence of data on absorption via the dermal route, a worst case assumption has to be made. As it is assumed that, in general, dermal absorption will not be higher than oral absorption, no default factor (i.e. factor 1) is introduced.

AF for dose response relationship:

1

Justification:

In accordance with ECHA Guidance R.8 (v2.1, 2012), 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 R.8 (v2.1, 2012), 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 R.8 (v2.1, 2012), 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 0.75. This results a default allometric scaling factor for the rat when compared with humans, namely 4. In ECETOC TR86 Derivation of Assessment Factors for Human Health Risk Assessment (2003) and ECETOC TR110 Guidance on Assessment Factors to Derive a DNEL (2010), a similar approach is followed. Toxicokinetic differences can be explained by basal metabolic rate which can be accounted for by allometric scaling. The underlying principle is that due to the faster metabolic rate of small animals, humans would less effectively detoxify and/or excrete xenobiotics than laboratory animals and thus are more vulnerable. The allometric scaling factor for the rat versus humans is 4.

AF for other interspecies differences:

2.5

Justification:

In accordance with ECHA Guidance R.8 (v2.1, 2012), as long as no substance-specific data are available, an additional factor of 2.5 for other interspecies differences, i.e. toxicokinetic differences not related to metabolic rate and toxicodynamic differences, is applied.

AF for intraspecies differences:

3

Justification:

In accordance with ECETOC TR86 (2003) and ECETOC TR110 (2010), a default assessment factor for the general population is based on the distributions of human data for various toxicokinetic and toxicodynamic parameters. The upper extreme of the variability in these data was estimated by calculating the 95th percentile of the distribution, which is considered sufficiently conservative to account for intraspecies variability in the general population (the data analysed included both sexes, a variety of disease states and ages). This results in recommended default assessment factor of 5 for the general population. As the worker population is more homogeneous (i.e. younger, healthier, protected from exposures), a default assessment factor of 3 is recommended. This proposal of ECETOC is based on an evaluation of the available scientific literature while the ECHA Guidance R.8 (v2.1, 2012) refers to standard default procedures. Until the scientific basis for using an alternative approach has been established, it is proposed to follow the ECETOC guideline.

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:

default

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:

2 166.7 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

other: ECHA REACH guidance and ECETOC guidance

Overall assessment factor (AF):

3

Dose descriptor:

other: human NOEL

Value:

65 000 mg/m³

AF for dose response relationship:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – R.8: Characterisation of dose [concentration]-response for human health (v2.1, 2012), for the LLNA study an assessment factor of 1 is applicable, because 1) the NOAEL is used as a starting point; 2) the doses were well separated (10, 25 and 50%) and; 3) a dose response was observed (stimulation index was 2.27, 2.98 and 3.53% respectively).

AF for differences in duration of exposure:

1

Justification:

In accordance with ECHA Guidance R.8 (v2.1, 2012), for the dose-response relationship, the LLNA is considered to be sufficiently sensitive for assessing skin sensitization; 1) considering presence and absence of skin sensitization and; 2) determining a quantitative value for risk characterization (see note 17 in R.8, Application of AFs to the correct starting point to obtain the induction-specific DNEL, page 125, 1st part). Therefore, an assessment factor of 1 is applicable.

AF for interspecies differences (allometric scaling):

1

Justification:

An assessment factor for interspecies differences is not needed as the starting dose descriptor is the human NOEL for skin sensitisation, which is considered to match to the EC3 in the LLNA in mice; see also explanation for hazard conclusion.

AF for other interspecies differences:

1

Justification:

An assessment factor for other interspecies differences is not needed as the starting dose descriptor is the human NOEL for skin sensitisation, which is considered to match to the EC3 in the LLNA in mice; see also explanation for hazard conclusion.

AF for intraspecies differences:

3

Justification:

In accordance with ECETOC TR86 Derivation of Assessment Factors for Human Health Risk Assessment (2003) and ECETOC TR110 Guidance on Assessment Factors to Derive a DNEL (2010), a default assessment factor for the general population is based on the distributions of human data for various toxicokinetic and toxicodynamic parameters. The upper extreme of the variability in these data was estimated by calculating the 95th percentile of the distribution, which is considered sufficiently conservative to account for intraspecies variability in the general population (the data analysed included both sexes, a variety of disease states and ages). This results in recommended default assessment factor of 5 for the general population. As the worker population is more homogeneous (i.e. younger, healthier, protected from exposures), a default assessment factor of 3 is recommended. This proposal of ECETOC is based on an evaluation of the available scientific literature while the ECHA Guidance R.8 (v2.1, 2012) refers to standard default procedures. Until the scientific basis for using an alternative approach has been established, it is proposed to follow the ECETOC guideline.

AF for the quality of the whole database:

1

Justification:

In accordance with ECHA Guidance R.8 (v2.1, 2012), 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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.97 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA REACH guidance and ECETOC guidance for intraspecies differences

Overall assessment factor (AF):

75

Dose descriptor starting point:

NOAEL

Value:

339 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

147.39 mg/m³

Explanation for the modification of the dose descriptor starting point:

The starting point is a NOAEL (oral administration) of 339.0 mg/kg bw. A factor 2 is applied for route to route extrapolation, oral to inhalation. The resulting rat NOAEL was converted into inhalatory consumer NOAEC by converting the oral dose to corresponding air concentration. NOAEC = NOAEL (oral, rat, OECD422) *abs oral/inhal *1/1.15 m3/kg/d = 339 mg/kg *50/100 *1/1.15m3/kg/d = 147.39 mg/m3

 

AF for dose response relationship:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – R.8: Characterisation of dose [concentration]-response for human health (v2.1, 2012), 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 R.8 (v2.1, 2012), 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 R.8 (v2.1, 2012), 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. In ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, a similar approach is followed. The rationale here is that allometric scaling should not be applied because in humans inhalation rate is 4-fold lower compared to rat according to the slower metabolic rate and thereby the allometric species difference is already implicitly taken into account.

AF for other interspecies differences:

2.5

Justification:

In accordance with ECHA Guidance R.8 (v2.1, 2012), as long as no substance-specific data are available, an additional factor of 2.5 for other interspecies differences, i.e. toxicokinetic differences not related to metabolic rate and toxicodynamic differences, is applied.

AF for intraspecies differences:

5

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 (2003) and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110 (2010), a default assessment factor for the general population is based on the distributions of human data for various toxicokinetic and toxicodynamic parameters. The upper extreme of the variability in these data was estimated by calculating the 95th percentile of the distribution, which is considered sufficiently conservative to account for intraspecies variability in the general population (the data analysed included both sexes, a variety of disease states and ages). This results in recommended default assessment factor of 5 for the general population. As the worker population is more homogeneous (i.e. younger, healthier, protected from exposures), a default assessment factor of 3 is recommended. This proposal of ECETOC is based on an evaluation of the available scientific literature while the ECHA Guidance R.8 (v2.1, 2012) refers to standard default procedures. Until the scientific basis for using an alternative approach has been established, it is proposed to follow the ECETOC guideline.

AF for the quality of the whole database:

1

Justification:

In accordance with ECHA Guidance R.8 (v2.1, 2012), 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:

default (DNEL derivation based on a GLP and OECD TG study)

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:

1.13 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA REACH guidance and ECETOC guidance for intraspecies differences

Overall assessment factor (AF):

300

Dose descriptor starting point:

NOAEL

Value:

339 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The starting point is a NOAEL (oral administration) of 339.0 mg/kg bw. In accordance with ECHA Guidance on information requirements and chemical safety assessment – R.8: Characterisation of dose [concentration]-response for human health (v2.1, 2012), in absence of data on absorption via the dermal route, a worst case assumption has to be made. As it is assumed that, in general, dermal absorption will not be higher than oral absorption, no default factor (i.e. factor 1) is introduced.

AF for dose response relationship:

1

Justification:

In accordance with ECHA Guidance R.8 (v2.1, 2012), 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 R.8 (v2.1, 2012), 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 R.8 (v2.1, 2012), 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 0.75. This results a default allometric scaling factor for the rat when compared with humans, namely 4. In ECETOC TR86 Derivation of Assessment Factors for Human Health Risk Assessment (2003) and ECETOC TR110 Guidance on Assessment Factors to Derive a DNEL (2010), a similar approach is followed. Toxicokinetic differences can be explained by basal metabolic rate which can be accounted for by allometric scaling. The underlying principle is that due to the faster metabolic rate of small animals, humans would less effectively detoxify and/or excrete xenobiotics than laboratory animals and thus are more vulnerable. The allometric scaling factor for the rat versus humans is 4.

AF for other interspecies differences:

2.5

Justification:

In accordance with ECHA Guidance R.8 (v2.1, 2012), as long as no substance-specific data are available, an additional factor of 2.5 for other interspecies differences, i.e. toxicokinetic differences not related to metabolic rate and toxicodynamic differences, is applied.

AF for intraspecies differences:

5

Justification:

n accordance with ECETOC TR86 (2003) and ECETOC TR110 (2010), a default assessment factor for the general population is based on the distributions of human data for various toxicokinetic and toxicodynamic parameters. The upper extreme of the variability in these data was estimated by calculating the 95th percentile of the distribution, which is considered sufficiently conservative to account for intraspecies variability in the general population (the data analysed included both sexes, a variety of disease states and ages). This results in recommended default assessment factor of 5 for the general population. As the worker population is more homogeneous (i.e. younger, healthier, protected from exposures), a default assessment factor of 3 is recommended. This proposal of ECETOC is based on an evaluation of the available scientific literature while the ECHA Guidance R.8 (v2.1, 2012) refers to standard default procedures. Until the scientific basis for using an alternative approach has been established, it is proposed to follow the ECETOC guideline.

AF for the quality of the whole database:

1

Justification:

n 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:

default (DNEL derivation based on a GLP and OECD TG study)

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:

1 300 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

other: ECHA REACH guidance and ECETOC guidance

Overall assessment factor (AF):

5

Dose descriptor:

other: human NOEL

Value:

65 000 mg/m³

AF for dose response relationship:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – R.8: Characterisation of dose [concentration]-response for human health (v2.1, 2012), for the LLNA study an assessment factor of 1 is applicable, because 1) the NOAEL is used as a starting point; 2) the doses were well separated (10, 25 and 50%) and; 3) a dose response was observed (stimulation index was 2.27, 2.98 and 3.53% respectively).

AF for differences in duration of exposure:

1

Justification:

In accordance with ECHA Guidance R.8 (v2.1, 2012), for the dose-response relationship, the LLNA is considered to be sufficiently sensitive for assessing skin sensitization; 1) considering presence and absence of skin sensitization and; 2) determining a quantitative value for risk characterization (see note 17 in R.8, Application of AFs to the correct starting point to obtain the induction-specific DNEL, page 125, 1st part). Therefore, an assessment factor of 1 is applicable.

AF for interspecies differences (allometric scaling):

1

Justification:

An assessment factor for interspecies differences is not needed as the starting dose descriptor is the human NOEL for skin sensitisation, which is considered to match to the EC3 in the LLNA in mice; see also explanation for hazard conclusion.

AF for other interspecies differences:

1

Justification:

An assessment factor for other interspecies differences is not needed as the starting dose descriptor is the human NOEL for skin sensitisation, which is considered to match to the EC3 in the LLNA in mice; see also explanation for hazard conclusion.

AF for intraspecies differences:

5

Justification:

In accordance with ECETOC TR86 Derivation of Assessment Factors for Human Health Risk Assessment (2003) and ECETOC TR110 Guidance on Assessment Factors to Derive a DNEL (2010), a default assessment factor for the general population is based on the distributions of human data for various toxicokinetic and toxicodynamic parameters. The upper extreme of the variability in these data was estimated by calculating the 95th percentile of the distribution, which is considered sufficiently conservative to account for intraspecies variability in the general population (the data analysed included both sexes, a variety of disease states and ages). This results in recommended default assessment factor of 5 for the general population. As the worker population is more homogeneous (i.e. younger, healthier, protected from exposures), a default assessment factor of 3 is recommended. This proposal of ECETOC is based on an evaluation of the available scientific literature while the ECHA Guidance R.8 (v2.1, 2012) refers to standard default procedures. Until the scientific basis for using an alternative approach has been established, it is proposed to follow the ECETOC guideline.

AF for the quality of the whole database:

1

Justification:

In accordance with ECHA Guidance R.8 (v2.1, 2012), 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

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.13 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA REACH guidance and ECETOC guidance for intraspecies differences

Dose descriptor starting point:

NOAEL

Value:

339 mg/kg bw/day

AF for dose response relationship:

1

Justification:

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:

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 R.8 (v2.1, 2012), 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. In ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, a similar approach is followed. The rationale here is that allometric scaling should not be applied because in humans inhalation rate is 4-fold lower compared to rat according to the slower metabolic rate and thereby the allometric species difference is already implicitly taken into account.

AF for other interspecies differences:

2.5

Justification:

In accordance with ECHA Guidance R.8 (v2.1, 2012), as long as no substance-specific data are available, an additional factor of 2.5 for other interspecies differences, i.e. toxicokinetic differences not related to metabolic rate and toxicodynamic differences, is applied.

AF for intraspecies differences:

5

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 (2003) and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110 (2010), a default assessment factor for the general population is based on the distributions of human data for various toxicokinetic and toxicodynamic parameters. The upper extreme of the variability in these data was estimated by calculating the 95th percentile of the distribution, which is considered sufficiently conservative to account for intraspecies variability in the general population (the data analysed included both sexes, a variety of disease states and ages). This results in recommended default assessment factor of 5 for the general population. As the worker population is more homogeneous (i.e. younger, healthier, protected from exposures), a default assessment factor of 3 is recommended. This proposal of ECETOC is based on an evaluation of the available scientific literature while the ECHA Guidance R.8 (v2.1, 2012) refers to standard default procedures. Until the scientific basis for using an alternative approach has been established, it is proposed to follow the ECETOC guideline.

AF for the quality of the whole database:

1

Justification:

In accordance with ECHA Guidance R.8 (v2.1, 2012), 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:

default (DNEL derivation based on a GLP and OECD TG study)

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population

There are no consumer uses known for EMIM DCA. However, for the assessment of the AC13, the DNELs for the general population were derived.