Reaction mass of Sodiumbis[1-[(2-hydroxy-5-nitrophenyl)azo]-2-naphtholato(2-)]chromate(1-) and Sodium [1-[(2-hydroxy-4-nitrophenyl)azo]-2-naphtholato(2-)][1-[(2-hydroxy-5-nitrophenyl)azo]-2-naphtholato(2-)]chromate(1-) and Sodiumbis[1-[(2-hydroxy-4-nitrophenyl)azo]-2-naphtholato(2-)]chromate(1-)

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.64 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Dose descriptor starting point:

NOAEL

Value:

350 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

432 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:

4

Justification:

A conservative 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:

medium hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

24.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Dose descriptor starting point:

NOAEL

Value:

350 mg/kg bw/day

Value:

4 900 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated dermal exposure available. Taken into account the physico-chemical properties of the substance, dermal absorption 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:

4

Justification:

An extrapolation factor for exposure duration is used: subacute screening (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

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - workers

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA (2012). Regarding the data used for evaluation, the "quality of whole database factors" and "dose-response factors" are considered each to a value of 1, and are not shown in the calculations presented below.

 

Acute, systemic DNEL

Short term DNELs are not required as the acute toxicity of the test substance is low. The test substance is not classified and labeled for acute systemic toxicity, according to Regulation 1272/2008/EC (CLP), based on the test data for acute oral and dermal toxicity. Acute short term inhalation toxicity is also regarded as low due to the physico-chemical properties of the test substance (assumed vapor pressure < 10^-6 hPa, melting point not available, decompses at 260 °C).

 

Acute/long-term, local

The test substance is classified and labeled as irritating to the eyes (category 2, H319). Therefore, a qualitative approach for hazard assessment is deemed necessary. The test substance is further considered as sensitizing based on available data (category 1B, H317).

 

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.

 

Exposure by inhalation

 

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

In order to derive a long-term inhalation DNEL, an inhalation NOEC was derived from NOEL oral value (determined in a reproductive/developmental screening study according to OECD Guideline 422), as no repeated dose inhalation study was available. Oral NO(A)EL of 350 mg/kg bw/day was converted to an inhalation NO(A)EC, assuming 100 % absorption via the lung and 50 % absorption via the oral route.

 

Step 2: Modification into a correct starting point:

The oral NO(A)EL was converted into an inhalation NO(A)EC according to the following formula assuming a daily exposure period of 8 hours during light activity:

 

Relevant dose descriptor (NO(A)EL): 350 mg/kg bw/day

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

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

Frequency of exposure in study: 7 days/week

Frequency of worker exposure: 5 days/week

Corrected inhalatory NOAEC for workers

= 350 mg/kg bw/day × (1 / 0.38 m³/kg bw/day) × 0.5 × (6.7 m³/10 m³) x (7/5)

= 432 mg/m³

 

Step 3: Use of assessment factors: 50

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 5

Exposure duration AF: 4

 

In conclusion, long term systemic inhalation DNEL, workers = 8.64 mg/m³

 

 

Dermal exposure

 

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

In order to derive a long-term dermal DNEL, a dermal NOEL was derived from NOEL oral value (determined in a 59-d repeated dose toxicity study with female rats), as no repeated dose dermal study was available. The oral NO(A)EL of 350 mg/kg bw/day was used as starting point.

 

Step 2: Modification into a correct starting point:

Correction for dermal absorption rates of the test substance (based on Guidance on information requirements and chemical safety assessment, R. 7C, 2014, Chapter R 7.12):

Dermal absorption is supposed to be low regarding the molecular weight of 689.5 g/mol and the moderate water solubility. The barrier function of the skin for ionic substances further decreases the penetration of the test substance. In addition, the results of the acute dermal toxicity support a low absorption via dermal route. Therefore, oral NO(A)EL of 350 mg/kg bw/day was converted to a dermal NO(A)EL, considering a conservative 10 % absorption through the skin.

Frequency of exposure in study: 7 days/week

Frequency of worker exposure: 5 days/week

In conclusion, dermal NO(A)EL = 350 x (100/10) x (7/5)= 4900 mg/kg bw/d.

 

Step 3: Use of assessment factors: 200

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

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 5

Exposure duration AF: 4

 

In conclusion, long term systemic dermal DNEL, workers = 24.5 mg/kg bw/day.

 

References

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

- ECHA (2014). Guidance on information requirements and chemical safety assessment.Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.52 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):

100

Dose descriptor starting point:

NOAEL

Value:

350 mg/kg bw/day

Value:

152.2 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:

4

Justification:

An extrapolation factor for exposure duration is used: subacute screening (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 more heterogenous 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:

medium hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.75 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):

400

Dose descriptor starting point:

NOAEL

Value:

350 mg/kg bw/day

Value:

3 500 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 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:

4

Justification:

An extrapolation factor for exposure duration is used: subacute screenin (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 more heterogenous 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:

medium hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.875 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):

400

Dose descriptor starting point:

NOAEL

Value:

350 mg/kg bw/day

Value:

350 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:

4

Justification:

An extrapolation factor for exposure duration is used: subacute screening (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 more heterogenous 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

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA (2012). Regarding the data used for evaluation, the "quality of whole database factors" and "dose-response factors" are considered each to a value of 1 and are not shown in the calculations presented below.

 

Acute, systemic DNEL

Short term DNELs are not required as the acute toxicity of the test substance is low. The test substance is not classified and labeled for acute systemic toxicity, according to Regulation 1272/2008/EC (CLP), based on the test data for acute oral and dermal toxicity. Acute short term inhalation toxicity is also regarded as low due to the physico-chemical properties of the test substance (assumed vapor pressure < 10^-6 hPa, melting point not available, decompses at 260 °C).

 

Acute/long-term, local

The test substance is classified and labeled as irritating to eyes (category 2). Therefore, a qualitative approach for hazard assessment is deemed necessary. The test substance is further considered as sensitizing based on available data (category 1B, H317).

 

Long term, systemic DNEL

 

Exposure by inhalation

 

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

In order to derive a long-term inhalation DNEL, an inhalation NOEC was derived from NOEL oral value (determined in a reproductive/developmental screening study according to OECD 422), as no repeated dose inhalation study was available. Oral NO(A)EL of 350 mg/kg bw/day was converted to an inhalation NOEC, assuming 100 % absorption via the lung and 50 % absorption via the oral route.

 

Step 2: Modification into a correct starting point:

Relevant dose descriptor (NO(A)EL): 350 mg/kg bw/day

Standard respiratory volume of the rat (sRVrat) for 8 hours: 1.15 m³/kg bw/day

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

 

Corrected inhalatory NOAEC for general population

= 350 mg/kg bw/day × (1 / 1.15 m³/kg bw/day) × 0.5

= 152.2 mg/m³

 

Step 3: Use of assessment factors: 100

Interspecies AF, remaining differences: 2.5

Intraspecies AF (general population): 10

Exposure duration AF: 4

 

In conclusion, long term systemic inhalation DNEL, general population = 1.52 mg/m³

 

Dermal exposure

 

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

In order to derive a long-term dermal DNEL, a dermal NOEL was derived from NOEL oral value (determined in a reproductive/developmental screening study according to OECD 422), as no repeated dose dermal study was available. The oral NO(A)EL of 350 mg/kg bw/day was used as starting point.

 

Step 2: Modification into a correct starting point:

Correction for dermal absorption rates of the test substance (based on Guidance on information requirements and chemical safety assessment, R. 7C, 2014, Chapter R 7.12):

Dermal absorption is supposed to be low regarding the molecular weight of 689.5 g/mol and the moderate water solubility. The barrier function of the skin for ionic substances further decreases the penetration of the test substance. In addition, the results of the acute dermal toxicity support a low absorption via dermal route. Therefore, oral NOEL of 1000 mg/kg bw/day was converted to a dermal NOEL, considering a conservative 10 % absorption through the skin.

In conclusion, dermal NO(A)EL = 350 x (100/10) = 3500 mg/kg bw/d.

 

Step 3: Use of assessment factors: 400

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

Interspecies AF, remaining differences: 2.5

Intraspecies AF (general population): 10

Exposure duration AF: 4

 

In conclusion, long term systemic dermal DNEL, general population = 8.75 mg/kg bw/day.

 

Oral exposure

 

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

In order to derive a long-term oral DNEL, an oral NO(A)EL determined in the 59-d repeated dose toxicity study with female rats was identified as the relevant dose descriptor (350 mg/kg bw/day).

 

Step 2: Use of assessment factors: 400

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

Interspecies AF, remaining differences: 2.5

Intraspecies AF (general population): 10

Exposure duration AF: 4

 

In conclusion, long term systemic oral DNEL, general population = 0.875 mg/kg bw/day.

 

 

References

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

- ECHA (2014). Guidance on information requirements and chemical safety assessment. Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics.