Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

15 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

60

Modified dose descriptor starting point:

NOAEC

Value:

882 mg/m³

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by inhalation

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 NOAEC, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

6

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. So, as only a sub-acute toxicity study is available, default assessment factor of 6 is to be applied, as a standard procedure.

AF for interspecies differences (allometric scaling):

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, as long as route-to-route extrapolation is not needed, allometric scaling should not be applied in cases where doses in experimental animal studies are expressed as concentrations (e.g. in mg/m3 air, ppm in diet, or mg/L in the drinking water) as these are assumed to be already scaled according to the allometric principle, since ventilation rate and food intake directly depend on the basal metabolic rate. In this case the NOAEC is expressed as concentration (mg/m3), therefore a factor for allometric scaling is not needed. 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 rats according to the slower metabolic rate and thereby the allometric species difference is already implicitly taken into account.

AF for other interspecies differences:

1

Justification:

As no adverse effect has been observed up to the limit dose of 1000 mg/kg bw/d there is no rationale for an additional factor of 2.5 for remaining differences.

AF for intraspecies differences:

5

Justification:

Default assessment factor for worker

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:

2

Justification:

Read-across

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.2 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

240

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on the systemic effects as a results of dermal exposure.

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 NOAEC, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

6

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. So, as only a sub-acute toxicity study is available, default assessment factor of 6 is to be applied, as a standard procedure.

AF for interspecies differences (allometric scaling):

4

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, allometric scaling extrapolates doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight to the power of 0.75. This results a default allometric scaling factor for the rat when compared with humans, namely 4. 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. 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:

1

Justification:

As no adverse effect has been observed up to the limit dose of 1000 mg/kg bw/d there is no rationale for an additional factor of 2.5 for remaining differences.

AF for intraspecies differences:

5

Justification:

Default assessment factor for worker

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:

2

Justification:

Read-across

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Kinetics (absorption for oral, dermal and inhalation route of exposure)

No data on absorption are available. According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information on the starting route, to include a default factor of 2 in the case of oral-to-inhalation extrapolation. This approach was taken forward to DNEL derivation. For dermal absorption, based on the physical-chemical properties of the substance (molecular weight > 500 g/mol [891-989g/mol], log Kow < -1 [-6 at 20°C], water solubility > 10000 mg/L [>200 - <300 g/L] low uptake is expected. Low dermal absorption is supported by the absence of adverse effects in the acute dermal toxicity study with Direct Orange 102 similar. Based on the above physical-chemical properties, oral absorption is also expected to be low. The absence of systemic effects at the high doses tested in the available oral toxicity studies with Direct Orange 102 similarsupports low oral absorption. As both oral and dermal absorption are expected to be low a default factor of 1 for oral-to-dermal extrapolation was used for DNEL derivation.

Acute toxicity

Direct Orange 102 similar does not have to be classified for acute toxicity and therefore derivation of a DNEL_acuteis not necessary.

Repeated dose toxicity

A subacute oral toxicity study is available for the read-across substance analogue substance 1. In this study, male and female rats received the substance by oral gavage at 1000 mg/kg bw/day on 5 days per week over a 30-day period. The treatment period was followed by a 2-wk recovery period. No treatment-related reactions were observed with respect to clinical symptoms, mortality, food consumption, body weight, clinical laboratory investigations and pathology. Furthermore, eye examination did not reveal any ocular changes and no loss of hearing ability was observed. The NOAEL from this study was 1000 mg/kg bw/day. This NOAEL is supported by the absence of adverse effects at 1000 mg/kg bw/day, the highest dose tested, in an oral reproduction/developmental toxicity screening study with Direct Red 239. Hence, a NOAEL of 1000 mg/kg bw/day for systemic effects was used as starting point for the DNEL derivation.

Mutagenicity

Direct Orange 102 similar was not mutagenic in the Ames test. No chromosome aberration or gene mutation test in mammalian cells is available for Direct Orange 102 similar. However, for a structural analogue of Direct Orange 102 similar (analogue substance 1) a gene mutation test in mouse lymphoma L5178Y cells is available. This gene mutation test also covers chromosome aberrations because during evaluation small and large colonies were distinguished. Under the conditions of this gene mutation test with the structural analogue, the test substance was non-mutagenic and non-clastogenic.

Reproduction toxicity

No adverse effects on parents or offspring were observed in a reproduction/developmental toxicity screening test (OECD 421) in which rats received analogue substance 2 by oral gavage at 0, 100, 300 or 1000 mg/kg bw/day. Thus, the NOAEL for reproductive toxicity was 1000 mg/kg bw/day. As this NOAEL is the same as that for repeated dose toxicity (derived from the subacute oral toxicity study with analogue substance 1), no specific DNEL has to be derived for developmental and reproductive toxicity.

DNEL derivation

Short-term toxicity (systemic and local):

No DNEL needs to be derived for all routes of exposure.

Long-term toxicity:

Inhalation long-term exposure, systemic effects

In the absence of route-specific information, route-to-route extrapolation was performed for DNEL calculation. A default factor of 2 for oral-to-inhalation extrapolation was used as proposed in Chapter R.8.4.2 of the REACH Guidance on information requirements and chemical safety assessment. It was assumed that there is no first pass effect (data to demonstrate this are lacking). The NOAEL from the repeated-dose oral toxicity study with the read across substance was used for derivation of the DNEL_long-termor the inhalation route.

Inhalation long-term exposure, local effects

No data are available based on which a DNEL for local effects can be derived. There are also no data to suggest that the substance may cause local effects by inhalation exposure.

Dermal long-term exposure, systemic effects

In the absence of route-specific information, route-to-route extrapolation was performed for DNEL calculation. A default factor of 1 for oral-to-dermal extrapolation was used as proposed in Chapter R.8.4.2 of the REACH Guidance on information requirements and chemical safety assessment. It was assumed that there is no first pass effect (data to demonstrate this are lacking). The NOAEL from the repeated-dose oral toxicity study with the read across substance was used for derivation of the DNEL_long-termfor the dermal route.

Dermal long-term exposure, local effects

No data are available based on which a DNEL for local effects can be derived. As the substance is not irritating or sensitizing to skin, no local effects are expected for repeated dermal exposure.

Oral long-term exposure, systemic effects

The NOAEL of 1000 mg/kg bw/day for systemic toxicity obtained in the repeated dose oral toxicity study with analogue substance 1, which was supported by the results of the reproduction / developmental toxicity screening test (OECD TG 421) with analogue substance 2, was used for DNEL derivation.

Worker DNELs

Long-term –inhalation, systemic effects(based on repeated dose oral toxicity study with read across substance in rats)

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 1000 mg/kg bw/day	Highest dose tested. No effects observed.
Step 2) Modification of starting point	2 0.38 m³/kg bw 6.7 m³/10 m³	Ratio of inhalation to oral absorption (default value, as proposed in the REACH guidance (R.8.4.2) Standard respiratory volume of a rat, corrected for 8 h exposure, as proposed in the REACH Guidance (R.8.4.2) Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m³/10 m³).
Modified dose-descriptor	(1000 / 2 / 0.38) x (6.7/10) = 882 mg/m³
Step 3) Assessment factors
Interspecies	1	No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation.
Intraspecies	5	Default assessment factor for worker
Exposure duration	6	Extrapolation from subacute to chronic
Dose response	1
Quality of database and remaining uncertainties	2	Read-across
DNEL	Value
	882 / (1 x 5 x 6 x 1 x 2) = 882 / 60 = 15 mg/m³

Long-term – dermal, systemic effects(based on repeated dose oral toxicity study with read across substance in rats)

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 1000 mg/kg bw/day	Highest dose tested. No effects observed.
Step 2) Modification of starting point	1	As both oral and dermal absorption are expected to be low adefault factor of 1 for oral-to-dermal extrapolation was used.
Step 3) Assessment factors
Interspecies	4	Assessment factor for allometric scaling
Intraspecies	5	Default assessment factor for worker
Exposure duration	6	Extrapolation from subacute to chronic
Dose response	1
Quality of database and remaining uncertainties	2	Read-across
DNEL	Value
	1000 / (4 x 5 x 6 x 1 x 2) =1000 / 240 = 4.2 mg/kg bw/day

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.6 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

120

Modified dose descriptor starting point:

NOAEC

Value:

435 mg/m³

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by inhalation

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 NOAEC, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

6

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. So, as only a sub-acute toxicity study is available, default assessment factor of 6 is to be applied, as a standard procedure.

AF for interspecies differences (allometric scaling):

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, as long as route-to-route extrapolation is not needed, allometric scaling should not be applied in cases where doses in experimental animal studies are expressed as concentrations (e.g. in mg/m3 air, ppm in diet, or mg/L in the drinking water) as these are assumed to be already scaled according to the allometric principle, since ventilation rate and food intake directly depend on the basal metabolic rate. In this case the NOAEC is expressed as concentration (mg/m3), therefore a factor for allometric scaling is not needed. 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 rats according to the slower metabolic rate and thereby the allometric species difference is already implicitly taken into account.

AF for other interspecies differences:

1

Justification:

As no adverse effect has been observed up to the limit dose of 1000 mg/kg bw/d there is no rationale for an additional factor of 2.5 for remaining differences.

AF for intraspecies differences:

10

Justification:

Default assessment factor for 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.

AF for remaining uncertainties:

2

Justification:

Read-across

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.1 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

480

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on the systemic effects as a results of dermal exposure.

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 NOAEC, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

6

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. So, as only a sub-acute toxicity study is available, default assessment factor of 6 is to be applied, as a standard procedure.

AF for interspecies differences (allometric scaling):

4

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, allometric scaling extrapolates doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight to the power of 0.75. This results a default allometric scaling factor for the rat when compared with humans, namely 4. 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. 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:

1

Justification:

As no adverse effect has been observed up to the limit dose of 1000 mg/kg bw/d there is no rationale for an additional factor of 2.5 for remaining differences.

AF for intraspecies differences:

10

Justification:

Default assessment factor for 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.

AF for remaining uncertainties:

2

Justification:

Read-across

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.1 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

480

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

no route to route extrapolation

AF for dose response relationship:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dose…) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a NOAEL, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

6

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. So, as only a sub-acute toxicity study is available, default assessment factor of 6 is to be applied, as a standard procedure.

AF for interspecies differences (allometric scaling):

4

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, allometric scaling extrapolates doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight to the power of 0.75. This results a default allometric scaling factor for the rat when compared with humans, namely 4. 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. 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:

1

Justification:

As no adverse effect has been observed up to the limit dose of 1000 mg/kg bw/d there is no rationale for an additional factor of 2.5 for remaining differences.

AF for intraspecies differences:

10

Justification:

Default assessment factor for 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.

AF for remaining uncertainties:

2

Justification:

Read-across

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Kinetics (absorption for oral, dermal and inhalation route of exposure)

No data on absorption are available. According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information on the starting route, to include a default factor of 2 in the case of oral-to-inhalation extrapolation. This approach was taken forward to DNEL derivation. For dermal absorption, based on the physical-chemical properties of the substance (molecular weight > 500 g/mol [891-989g/mol], log Kow < -1 [-6 at 20°C], water solubility > 10000 mg/L [>200 - <300 g/L] low uptake is expected. Low dermal absorption is supported by the absence of adverse effects in the acute dermal toxicity study with Direct Orange 102 similar. Based on the above physical-chemical properties, oral absorption is also expected to be low. The absence of systemic effects at the high doses tested in the available oral toxicity studies with Direct Orange 102 similarsupports low oral absorption. As both oral and dermal absorption are expected to be low a default factor of 1 for oral-to-dermal extrapolation was used for DNEL derivation.

Acute toxicity

Direct Orange 102 similar does not have to be classified for acute toxicity and therefore derivation of a DNEL_acuteis not necessary.

Repeated dose toxicity

A subacute oral toxicity study is available for the read-across substance analogue substance 1. In this study, male and female rats received the substance by oral gavage at 1000 mg/kg bw/day on 5 days per week over a 30-day period. The treatment period was followed by a 2-wk recovery period. No treatment-related reactions were observed with respect to clinical symptoms, mortality, food consumption, body weight, clinical laboratory investigations and pathology. Furthermore, eye examination did not reveal any ocular changes and no loss of hearing ability was observed. The NOAEL from this study was 1000 mg/kg bw/day. This NOAEL is supported by the absence of adverse effects at 1000 mg/kg bw/day, the highest dose tested, in an oral reproduction/developmental toxicity screening study with Direct Red 239. Hence, a NOAEL of 1000 mg/kg bw/day for systemic effects was used as starting point for the DNEL derivation.

Mutagenicity

Direct Orange 102 similar was not mutagenic in the Ames test. No chromosome aberration or gene mutation test in mammalian cells is available for Direct Orange 102 similar. However, for a structural analogue of Direct Orange 102 similar (analogue substance 1) a gene mutation test in mouse lymphoma L5178Y cells is available. This gene mutation test also covers chromosome aberrations because during evaluation small and large colonies were distinguished. Under the conditions of this gene mutation test with the structural analogue, the test substance was non-mutagenic and non-clastogenic.

Reproduction toxicity

No adverse effects on parents or offspring were observed in a reproduction/developmental toxicity screening test (OECD 421) in which rats received analogue substance 2 by oral gavage at 0, 100, 300 or 1000 mg/kg bw/day. Thus, the NOAEL for reproductive toxicity was 1000 mg/kg bw/day. As this NOAEL is the same as that for repeated dose toxicity (derived from the subacute oral toxicity study with analogue substance 1), no specific DNEL has to be derived for developmental and reproductive toxicity.

DNEL derivation

Short-term toxicity (systemic and local):

No DNEL needs to be derived for all routes of exposure.

Long-term toxicity:

Inhalation long-term exposure, systemic effects

In the absence of route-specific information, route-to-route extrapolation was performed for DNEL calculation. A default factor of 2 for oral-to-inhalation extrapolation was used as proposed in Chapter R.8.4.2 of the REACH Guidance on information requirements and chemical safety assessment. It was assumed that there is no first pass effect (data to demonstrate this are lacking). The NOAEL from the repeated-dose oral toxicity study with the read across substance was used for derivation of the DNEL_long-termor the inhalation route.

Inhalation long-term exposure, local effects

No data are available based on which a DNEL for local effects can be derived. There are also no data to suggest that the substance may cause local effects by inhalation exposure.

Dermal long-term exposure, systemic effects

In the absence of route-specific information, route-to-route extrapolation was performed for DNEL calculation. A default factor of 1 for oral-to-dermal extrapolation was used as proposed in Chapter R.8.4.2 of the REACH Guidance on information requirements and chemical safety assessment. It was assumed that there is no first pass effect (data to demonstrate this are lacking). The NOAEL from the repeated-dose oral toxicity study with the read across substance was used for derivation of the DNEL_long-termfor the dermal route.

Dermal long-term exposure, local effects

No data are available based on which a DNEL for local effects can be derived. As the substance is not irritating or sensitizing to skin, no local effects are expected for repeated dermal exposure.

Oral long-term exposure, systemic effects

The NOAEL of 1000 mg/kg bw/day for systemic toxicity obtained in the repeated dose oral toxicity study with analogue substance 1, which was supported by the results of the reproduction / developmental toxicity screening test (OECD TG 421) with analogue substance 2, was used for DNEL derivation.

General population DNELs

Long-term – oral, systemic effects (based on repeated dose oral toxicity study with read across substance in rats)

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 1000 mg/kg bw/day	Highest dose tested. No effects observed.
Step 2) Modification of starting point	-	-
Step 3) Assessment factors
Interspecies	4	Assessment factor for allometric scaling.
Intraspecies	10	Default assessment factor for general population
Exposure duration	6	Extrapolation from subacute to chronic
Dose response	1
Quality of database	2	Read across
DNEL	Value
	1000 / (4 x 10 x 6 x 1 x 2) =1000 / 480 = 2.1 mg/kg bw/day

Long-term – inhalation, systemic effects (based on repeated dose oral toxicity study with read across substance in rats)

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 1000 mg/kg bw/day	Highest dose tested. No effects observed.
Step 2) Modification of starting point	2 1.15 m³/kg bw	Ratio of inhalation to oral absorption (default value, as proposed in the REACH guidance (R.8.4.2) Standard respiratory volume of a rat, corrected for 24 h exposure, as proposed in the REACH Guidance (R.8.4.2)
Modified dose-descriptor	(1000 / 2) x (1/1.15) = 435 mg/m³
Step 3) Assessment factors
Interspecies	1	No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation.
Intraspecies	10	Default assessment factor for general population
Exposure duration	6	Extrapolation from subacute to chronic
Dose response	1
Quality of database and remaining uncertainties	2	Read-across
DNEL	Value
	435 / (1 x 10 x 6 x 1 x 2) = 435 / 120 = 3.6 mg/m³

Long-term – dermal, systemic effects (based on repeated dose oral toxicity study with read across substance in rats)

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 1000 mg/kg bw/day	Highest dose tested. No effects observed.
Step 2) Modification of starting point	1	As both oral and dermal absorption are expected to be low adefault factor of 1 for oral-to-dermal extrapolation was used
Step 3) Assessment factors
Interspecies	4	Assessment factor for allometric scaling.
Intraspecies	10	Default assessment factor for general population
Exposure duration	6	Extrapolation from subacute to chronic
Dose response	1
Quality of database and remaining uncertainties	2	Read-across
DNEL	Value
	1000 / (4 x 10 x 6 x 1 x 2) =1000 / 480 = 2.1 mg/kg bw/day

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