Cuprate(4-), [.mu.-[[3,3'-[(1-oxido-1,2-diazenediyl)bis[[2-(hydroxy-.kappa.O)-4,1-phenylene]-2,1-diazenediyl-.kappa.N1]]bis[4-(hydroxy-.kappa.O)-2,7-naphthalenedisulfonato]](8-)]]di-, ammonium sodium

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.17 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

75

Modified dose descriptor starting point:

NOAEC

Value:

88.2 mg/m³

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by inhalation. A conservative approach is used assuming a two times higher absorption via the inhalation route (end route) as compared to the oral route (starting route).

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

1

Justification:

Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.

AF for other interspecies differences:

2.5

Justification:

Recommended AF for other interspecies differences.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

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:

3.33 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):

300

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 repeated dermal exposure. Taken into account the physico-chemical and toxic properties of the substance, dermal absoption is anticipated to be 10 % of oral absorption.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

2.5

Justification:

Recommended AF for other interspecies differences.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

General

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA (2010).

 

Acute, systemic DNEL

The test substance is not classified and labelled for acute systemic toxicity according to Regulation (EC) No 1272/2008 (CLP), based on the test data for acute oral toxicity. No data on acute toxicity after inhalation is available. Inhalation is not the route of exposure due to the use of the substance (see section 3.5). Thus, the derivation of a DNEL for acute/short term exposure is not required.

   

Acute/long term DNEL for local effects

 

Inhalation:Inhalation DNEL for local effects does not need to be derived as no skin and eye irritating (leading to C&L) and in conclusion no indication of local mucosal membranes damage has been identified (in accordance with "Guidance on information requirements and chemical safety assessment", chapter R8, November 2012). Thus, no DNEL is required.

 

Skin irritation/corrosion: The test substance is not classified for skin irritation/corrosion according to Regulation (EC) No 1272/2008 (CLP) based on the available experimental data. Therefore, no qualitative assessment is conducted.

 

Eye irritation:The test substance is not classified for eye irritation according to Regulation (EC) No 1272/2008 (CLP) based on the available experimental data. Therefore, no qualitative assessment is conducted.

 

Respiratory irritation:No data on respiratory irritation is available. As the substance is not classified as skin and eye irritating also no adverse effects on respiratory system is expected.No DNEL was derived. 

 

Long term, systemic DNEL

Occupational exposure to the test substance occurs mainly by dermal route, and may also occur by inhalation exposure. Therefore two long-term DNELs are calculated for workers. In view of the data used for evaluation, the "quality of whole database factor" and "dose-response factor" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.

 

Exposure by inhalation

Step 1: Selection of the relevant dose descriptor (starting point):

For risk characterisation an inhalation NOAEC was derived by route to route extrapolation. The OECD TG 407 study is selected for DNEL derivation as it is the relevant repeated dose study performed in accordance to OECD guideline and GLP. In this study, the oral NOAEL in rats is 100 mg/kg bw/day.

 

Step 2: Modification into a correct starting point:

Using a conservative approach, a worker DNEL (long-term inhalation exposure) is derived. This worker DNEL is considered to ensure an appropriate level of protection with regard to acute inhalation exposure (no high peaks of exposure expected).

 

Relevant dose descriptor (NOAEL): 100 mg/kg bw/day

Standard respiratory volume of the rat (sRVrat) for 8 hours: 0.38 m³/kg bw/d

Oral absorption of the rat / inhalation absorption of humans (ABSoral-rat / ABSinh-human): 0.5

Standard respiratory volume of humans (sRVhuman) for 8 hours: 6.7 m³

Worker respiratory volume (wRV) for 8 hours with light physical activity: 10 m³

 

Corrected inhalatory NOAEC for workers

= 100 mg/kg bw/d × 0.5 × (1 / 0.38 m³/kg bw/d) × (6.7 m³/10 m³)

= 88.2 mg/m³ 

 

Step 3: Use of assessment factors: 75

Interspecies: Respiratory interspecies differences are fully covered by the modification of the NOAEC

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 5

Exposure duration AF: 6 (subacute)

 

In conclusion, long term systemic inhalation DNEL, workers = 1.17 mg/m³. 

Dermal exposure

Step 1: Selection of the relevant dose descriptor (starting point):

The OECD TG 407 study is selected for DNEL derivation as it is the relevant repeated dose study performed in accordance to OECD guideline and GLP. In this study, the oral NOAEL in rats is 100 mg/kg bw/day.

 

Step 2: Modification of the starting point:

Using a conservative approach, a worker DNEL (long-term dermal exposure) is derived. Based on the physico-chemical (MW 1080 - 1100 g/mol) and toxic properties of the test substance dermal absorption is anticipated to be low. The test substance is not a skin irritant or corrosive and is not classified as skin sensitizer and therefore no damage to the skin surface may enhance penetration. Thus, a dermal absorption of 10% of oral absorption is assumed as worst case.

 

In conclusion, dermal NOAEL = oral NOAEL x [ABS oral rat/ABS dermal human] = 100 mg/kg bw/day x (100/10) = 1000 mg/kg bw/d. 

 

Step 3: Use of assessment factors: 300

Interspecies AF, allometric scaling (rat to human): 4

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 5

Exposure duration AF: 6

 

In conclusion, long term systemic dermal DNEL, workers = 3.33 mg/kg bw/day

 

References

(not included as endpoint study record)

 

- ECHA (2010). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version 2. ECHA-2010 -G-19 –EN.

 

- ECHA (2010). Guidance on information requirements and chemical safety assessment. Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics. May 2008

 

- ECHA (2012) Practical Guide 15: How to undertake a qualitative human health assessment and document it in a chemical safety report, November 2012.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.29 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

150

Modified dose descriptor starting point:

NOAEC

Value:

43.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by inhalation. A conservative approach is used assuming a two times higher absorption via the inhalation route (end route) as compared to the oral route (starting route).

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

1

Justification:

Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.

AF for other interspecies differences:

2.5

Justification:

Recommended AF for other interspecies differences.

AF for intraspecies differences:

10

Justification:

The default value for the relatively homogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

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:

1.67 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

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 repeated dermal exposure. Taken into account the physico-chemical and toxic properties of the substance, dermal absoption is anticipated to be 10 % of oral absorption.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

2.5

Justification:

Recommended AF for other interspecies differences.

AF for intraspecies differences:

10

Justification:

The default value for the relatively homogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.17 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

Modified dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No route to route extrapolation is required since a repeated dose oral toxicity study is available.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

2.5

Justification:

Recommended AF for other interspecies differences.

AF for intraspecies differences:

10

Justification:

The default value for the relatively homogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

General

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA (2010). In view of the data used for evaluation, the "quality of whole database factors" and "dose-response factors" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.

 

Acute, systemic DNEL

The test substance is not classified and labelled for acute systemic toxicity, according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP), based on the test data for acute oral toxicity. No data on acute toxicity after inhalation is available. Thus, the derivation of a DNEL for acute/short term exposure is not required.

   

Acute/long term DNEL for local effects

 

Inhalation:Inhalation DNEL for local effects does not need to be derived as no skin and eye irritating (leading to C&L) and in conclusion no indication of local mucosal membranes damage has been identified (in accordance with "Guidance on information requirements and chemical safety assessment", chapter R8, November 2012). Thus, no DNEL is required.

 

Skin irritation/corrosion: The test substance is not classified for skin irritation/corrosion according to Regulation (EC) No 1272/2008 (CLP) based on the available experimental data. Therefore, no qualitative assessment is conducted.

 

Eye irritation:The test substance is not classified for eye irritation according to Regulation (EC) No 1272/2008 (CLP) based on the available experimental data. Therefore, no qualitative assessment is conducted.

 

Respiratory irritation:No data on respiratory irritation is available. As the substance is not classified as skin and eye irritating also no adverse effects on respiratory system is expected. No DNEL was derived. 

 

Long term, systemic DNEL

Exposure by inhalation

Step 1: Selection of the relevant dose descriptor (starting point):

For risk characterisation an inhalation NOAEC was derived by route to route extrapolation. The OECD TG 407 study is selected for DNEL derivation as it is the relevant repeated dose study performed in accordance to OECD guideline and GLP. In this study, the oral NOAEL in rats is 100 mg/kg bw/day.

 

Step 2: Modification into a correct starting point:

Using a conservative approach, a DNEL (long-term inhalation exposure) for general population is derived. This worker DNEL is considered to ensure an appropriate level of protection with regard to acute inhalation exposure (no high peaks of exposure expected).

 

Relevant dose descriptor (NOAEL): 100 mg/kg bw/day

Standard respiratory volume of the rat (sRVrat) for 24 hours: 1.15 m³/kg bw/d

Oral absorption of the rat / inhalation absorption of humans (ABSoral-rat / ABSinh-human): 0.5

 

Corrected inhalatory NOAEC for general population

= 100 mg/kg bw/d × 1/1.15 m³/kg bw/d x 0.5

= 43.5 mg/m³ 

 

Step 3: Use of assessment factors: 150

Interspecies AF (allometric scaling): Respiratory interspecies differences are fully covered by the modification of the NOAEC

Interspecies AF, remaining differences: 2.5

Intraspecies AF (general population): 10

Exposure duration AF: 6 (subacute study)

 

In conclusion, long term systemic inhalation DNEL, general population = 0.29 mg/m3

 

Dermal exposure

Step 1: Selection of the relevant dose descriptor (starting point):

There are no relevant experimental data on repeated exposure via dermal route. Thus, the OECD TG 407 study is selected for DNEL derivation as it is the relevant dose study performed in accordance to OECD guideline and GLP. In this study, the NOAEL in rats is 100 mg/kg bw/d.

 

Step 2: Modification into a correct starting point:

Using a conservative approach, a worker DNEL (long-term dermal exposure) is derived. Based on the physico-chemical (MW 1080 - 1100 g/mol) and toxic properties of the test substance dermal absorption is anticipated to be low. The test substance is not a skin irritant or corrosive and is not classified as skin sensitizer and therefore no damage to the skin surface may enhance penetration. Thus, a dermal absorption of 10% of oral absorption is assumed as worst case.

 

In conclusion, dermal NOAEL = oral NOAEL x [ABS oral rat/ABS dermal human] = 100 mg/kg bw/day x (100/50) = 1000 mg/kg bw/d.

 

Step 3: Use of assessment factors: 600

Interspecies AF, allometric scaling (rat to human): 4

Interspecies AF, remaining differences: 2.5

Intraspecies AF (general population): 10

Exposure duration AF: 6 (subacute study)

 

In conclusion, long term systemic dermal DNEL, general population = 1.67 mg/kg bw/day

 

Oral exposure

Step 1: Selection of the relevant dose descriptor (starting point):

A subacute study in rats is selected for DNEL derivation as it is the relevant repeated dose study performed in accordance to OECD guideline and GLP. In this study, the oral NOAEL in rats is 100 mg/kg bw/day.

 

Step 2: Modification of the starting point:

Not required.

 

Step 3: Use of assessment factors: 600

Interspecies AF, allometric scaling (rat to human): 4

Interspecies AF, remaining differences: 2.5

Intraspecies AF (general population): 10

Exposure duration AF: 6 (subacute study)

 

In conclusion, long term systemic oral DNEL, general population = 0.17 mg/kg bw/day

 

References

 

(not included as endpoint study record)

 

- ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version 2.1. November 2012.

 

- ECHA (2012). Guidance on information requirements and chemical safety assessment.Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics. November 2012.

 

- ECHA (2012) Practical Guide 15: How to undertake a qualitative human health assessment and document it in a chemical safety report, November 2012.