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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.588 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:
44.079 mg/m³
Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by inhalation. For details on calculations please refer to discussion.

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:
1.667 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:
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. For details on calculations please refer to discussion.

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
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:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

General

DNEL derivation for the substance Citronitril is performed under consideration of the recommendations of ECHA. 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.

 

Workers – Hazard via inhalation route

 

Long term systemic inhalation DNEL, worker

The DNEL long-term, systemic (inhalation) is derived by route-to route extrapolation.

 

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

The NOAEL of 50 mg/kg bw/day, assessed in the key 28-day repeated dose oral toxicity study (2015) is identified as the relevant dose descriptor and starting point.

 

Step 2: Modification into a correct starting point:

Using a conservative approach, a worker DNEL (long-term inhalation exposure) is derived considering a two times higher absorption via inhalation than oral absorption.

 

Relevant dose descriptor (NOAEL): 50 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

= 50 mg/kg bw/day× 0.5 × (1 / 0.38 m³/kg bw/day) × (6.7 m³/10 m³)

= 44.0789 mg/m³

 

Step 3: Use of assessment factors: 75

Interspecies: no allometric scaling factor is applied because an oral-to-inhalation route extrapolation is performed.

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 5

Exposure duration AF: 6

Remaining uncertainties AF: 1

 

In conclusion, long-term systemic inhalation DNEL, workers = 0.5877 mg/m3

 

Short term systemic inhalation DNEL, worker

The test material is not classified and labelled for acute systemic toxicity (inhalation), according to Regulation (EC) No 1272/2008 (CLP). Thus, no DNEL is required.

 

Acute/longterm, local effects, inhalation worker

No data on long-term local toxicity after inhalation is available. Data on acute local toxicity after inhalation is available and showed no specific local effects. As the substance is not classified for acute inhalation and as skin and eye irritating also no adverse effects on the respiratory system are expected (in accordance with "Guidance on information requirements and chemical safety assessment", chapter R8, November 2012). Thus, no DNEL local, long-term and acute (inhalation) is required. Inhalation In addition DNEL for local effects does also not need to be derived as no eye irritation (leading to classification) 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).

 

Workers – Hazard via dermal route

Long term systemic dermal DNEL, worker

The DNEL long-term, systemic (dermal) is derived by route-to route extrapolation from the repeated dose oral toxicity study.

 

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

The 28-day repeated dose toxicity 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 is 50 mg/kg bw/day.

 

Step 2: Modification of the starting point:

The logPow of the test substance was determined to be 2.93. Therefore the dermal uptake is considered to be 10 % of the oral uptake. Therefore the Dermal NOAEL is 10 * oral NOAEL = 500 mg/kg bw/day

 

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

Remaining uncertainties AF: 1

 

In conclusion, long term systemic dermal DNEL, workers = 1.6666 mg/kg bw/day

 

Short-term systemic dermal DNEL, worker

The test material is not classified and labelled for acute dermal toxicity, according to Regulation (EC) No 1272/2008 (CLP). Thus, no DNEL is required.

 

Local effects, long term dermal exposure

The test item is classified as a skin sensitizer, cat. 1A according to Regulation (EC) No 1272/2008 (CLP). Thus, a qualitative risk assessment is conducted (in accordance with "Guidance on information requirements and chemical safety assessment", Part E, November 2012).

 

Local effects, short-term dermal DNEL, worker

Local dermal effects are covered by the long term local risk assessment and no quantitative acute local dermal assessment is required (in accordance with "Guidance on information requirements and chemical safety assessment", Part E, November 2012).

 

Worker – Hazard for the eyes

The test item is not classified for eye irritation or severe eye damage according to Regulation (EC) No 1272/2008 (CLP). Thus, no qualitative risk assessment is required. 

 

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.

- ECHA (2012). Guidance on information requirements and chemical safety assessment.Part E: Risk Characterisation, Version 2.0, November 2012.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.145 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:
21.739 mg/m³
Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by inhalation. For details on calculations please refer to discussion.

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:
0.833 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:
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. For details on calculations please refer to discussion.

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
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.083 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:
50 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No route to route extrapolation was used as one repeated oral exposure study was available. For details on calculations please refer to discussion.

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:
DNEL (Derived No Effect Level)
Value:
0.25 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

General

DNEL derivation for the substance Citronitril is performed under consideration of the recommendations of ECHA. 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.

 

General population – Hazard via inhalation route

Long term systemic inhalation DNEL, General population

The DNEL long-term, systemic (inhalation) is derived by route-to route extrapolation from the repeated dose oral toxicity study.

 

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

The NOAEL of 50 mg/kg bw/day, assessed in the key 28-day repeated dose oral toxicity study (2015) is identified as the relevant dose descriptor and starting point.

 

Step 2: Modification into a correct starting point:

Using a conservative approach, a general population DNEL (long-term inhalation exposure) is derived considering a two times higher absorption via inhalation than oral absorption.

 

Relevant dose descriptor (NOAEL): 50 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

= 50 mg/kg bw/day× 0.5 × (1 / 1.15 m³/kg bw/day)

= 21.7391 mg/m³

 

Step 3: Use of assessment factors: 150

Interspecies: no allometric scaling factor is applied because an oral-to-inhalation route extrapolation is performed.

Interspecies AF, remaining differences: 2.5

Intraspecies AF (general population): 10

Exposure duration AF: 6

Remaining uncertainties AF: 1

 

In conclusion, long-term systemic inhalation DNEL, general population = 0.1449 mg/m3

 

Short term systemic inhalation DNEL, General population

The test material is not classified and labelled for acute systemic toxicity (inhalation), according to Regulation (EC) No 1272/2008 (CLP). Thus, no DNEL is required.

 

Acute/longterm, local effects, General population (inhalation)

No data on long-term local toxicity after inhalation is available. Data on acute local toxicity after inhalation is available and showed no specific local effects. As the substance is not classified for acute inhalation and as skin and eye irritating also no adverse effects on the respiratory system are expected (in accordance with "Guidance on information requirements and chemical safety assessment", chapter R8, November 2012). Thus, no DNEL local, long-term and acute (inhalation) is required. Inhalation In addition DNEL for local effects does also not need to be derived as no eye irritation (leading to classification) 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).

 

General population – Hazard via dermal route

Long term systemic dermal DNEL, General population

The DNEL long-term, systemic (dermal) is derived by route-to route extrapolation from the repeated dose oral toxicity study.

 

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

The 28-day repeated dose toxicity 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 is 50 mg/kg bw/day.

 

Step 2: Modification of the starting point:

The logPow of the test substance was determined to be 2.93. Therefore the dermal uptake is considered to be 10 % of the oral uptake. Therefore the dermal NOAEL is 10* oral NOAEL=500 mg/kg bw/day

 

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

Remaining uncertainties AF: 1

 

In conclusion, long term systemic dermal DNEL, general population = 0.8333 mg/kg bw/day

 

Short-term systemic dermal DNEL, General population

The test material is not classified and labelled for acute dermal toxicity, according to Regulation (EC) No 1272/2008 (CLP). Thus, no DNEL is required.

 

Local effects, long term dermal exposure, General population

The test item is classified as a skin sensitizer, cat. 1A according to Regulation (EC) No 1272/2008 (CLP). Thus, a qualitative risk assessment is conducted (in accordance with "Guidance on information requirements and chemical safety assessment", Part E, November 2012).

 

Local effects, short-term dermal DNEL, General population

Local dermal effects are covered by the long term local risk assessment and no quantitative acute local dermal assessment is required (in accordance with "Guidance on information requirements and chemical safety assessment", Part E, November 2012).

 

General population – Hazard via oral route

Long term systemic oral DNEL, General population

The DNEL long-term, systemic (oral) is derived from the repeated dose oral toxicity study.

 

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

The 28-day repeated dose toxicity 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 is 50 mg/kg bw/day.

 

Step 2: Modification of the starting point:

No modification is used as the same exposure route is considered.

 

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

Remaining uncertainties AF: 1

 

In conclusion, long term systemic oral DNEL, general population = 0.0833 mg/kg bw/day

 

 

Short-term systemic oral DNEL, General population

The test material is classified for acute oral toxicity cat. 4, according to Regulation (EC) No 1272/2008 (CLP). The acute systemic DNEL (oral) is extrapolated from the long term DNEL with multiplication by factor of 3 (in accordance with "Guidance on information requirements and chemical safety assessment", chapter R8, November 2012). The long-term systemic DNEL (oral) is derived from the repeated dose oral toxicity study.

For Steps 1-3 please refer to “Long term systemic oral DNEL, General population”

 

Step 4: extrapolation from the long term DNEL

A factor of 3 is used: long term DNEL*3= short term DNEL

0.08333*3=0.25 mg/kg bw/day

In conclusion, short term systemic oral DNEL, general population = 0.25 mg/kg bw/day

 

General population – Hazard for the eyes

The test item is not classified for eye irritation or severe eye damage according to Regulation (EC) No 1272/2008 (CLP). Thus, no qualitative risk assessment is required. 

 

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.

- ECHA (2012). Guidance on information requirements and chemical safety assessment.Part E: Risk Characterisation, Version 2.0, November 2012.