Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.32 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):
187.5
Dose descriptor starting point:
NOAEL
Value:
200 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
246.9 mg/m³
Explanation for the modification of the dose descriptor starting point:

Corrected NOAEC (inhalation) for workers:

= 200 mg/kg bw/day x 0.5 x 1/0.38 m3/kg bw/day x (6.7 m3/10 m3) x 1.4

= 246.9 mg/m3

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:
Default for subacute to chronic is applied.
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scalling is applied for inhalation as the inhalative data is standardized with reference to the respiratory rates. Respiratory rates depend directly on caloric demand, therefore inhalative study results are already extrapolated to humans on the basis of metabolic rate scaling (=allometric scaling).
AF for other interspecies differences:
2.5
Justification:
The recommended AF for other interspecies differences is applied.
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 OECD TG 422 toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
2.5
Justification:
The OECD 422 is designed to be a screening study on Reproduction/Developmental Toxicity and does not provide in detail examinations on these endpoints. Therefore, a conservative assessment factor of 2.5 reflects the remaining uncertainty based on the study design.
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:
0.37 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):
750
Dose descriptor starting point:
NOAEL
Value:
200 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
280 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Corrected NOAEL (dermal) for workers:

= 200 mg/kg bw/day x 1.4

= 280 mg/kg bw/day

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:
Default for subacute to chronic is applied.
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is applied.
AF for other interspecies differences:
2.5
Justification:
The recommended AF for other interspecies differences is applied.
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 OECD TG 422 toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
2.5
Justification:
The OECD 422 is designed to be a screening study on Reproduction/Developmental Toxicity and does not provide in detail examinations on these endpoints. Therefore, a conservative assessment factor of 2.5 reflects the remaining uncertainty based on the study design.
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:
medium hazard (no threshold derived)

Additional information - workers

General

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA, Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose-response for human health (Version: 2.1, November 2012).

Inhalation

Long term, systemic DNEL – exposure via inhalation (workers)

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

No repeated dose inhalation toxicity study with the test item is available. Therefore, long-term inhalation DNEL was derived by route-to-route extrapolation from an oral repeated dose toxicity study:

Based on an OECD TG 422 study with the test item, daily oral administration to Wistar rats revealed signs of systemic toxicity in the high and mid dose tested i. e. and 2000/1000 and 600 mg/kg bw/d. The NOAEL for systemic toxicity was therefore considered to be 200 mg/kg bw/day. NOAEL for fertility and developmental toxicity was determined to be 200 mg/kg bw/d, respectively as well based on the conditions of this study. This NOAEL is therefore used as Point of Departure for DNEL derivation since it can be considered reflecting a worst case assumption.

Step 1: PoD: NOAEL = 200 mg/kg bw/day

Step 2: Modification of PoD:

Standard respiratory volume, human (sRVhuman) for 8 h per person (70 kg): 6.7 m3

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

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

Oral absorption of the rat/ inhalation absorption of humans (ABS oral-rat / ABS inh-human): 1/2 (default)

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker

Corrected NOAEC (inhalation) for workers:

= 200 mg/kg bw/day x 0.5 x 1/0.38 m3/kg bw/day x (6.7 m3/10 m3) x 1.4

= 246.9 mg/m3

Step 3: Overall AF= 187.5

Intraspecies AF (worker): 5
The default value for the relatively homogenous group "worker" is used.

Interspecies AF, remaining differences: 2.5
The recommended AF for other interspecies differences is applied.

Allometric scaling AF: 1
No allometric scalling is applied for inhalation as the inhalative data is standardized with reference to the respiratory rates. Respiratory rates depend directly on caloric demand, therefore inhalative study results are already extrapolated to humans on the basis of metabolic rate scaling (=allometric scaling).

Dose response relationship AF: 1
The dose response relationship is considered unremarkable, therefore no additional factor is used.

Exposure duration AF: 6
Default for subacute to chronic is applied.

Whole database AF: 1
The OECD TG 422 toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

Remaining uncertainties: 2.5
The OECD 422 is designed to be a screening study on Reproduction/Developmental Toxicity and does not provide in detail examinations on these endpoints. Therefore, a conservative assessment factor of 2.5 reflects the remaining uncertainty based on the study design.

In conclusion, long term systemic inhalation DNEL, workers = 1.32 mg/m3

Acute, systemic DNEL- exposure via inhalation (workers)

There is no short-term or long-term toxicity study via inhalation route available for the test item. Even though the test item has a high vapour pressure (15.6 hPa), exposure via inhalation route cannot not excluded. However, the test item is not classified as acutely toxic. Therefore, long-term DNELs are considered sufficient to ensure that acute effects do not occur. Thus no short-term DNEL inhalation is derived.

Long term & acute, local DNEL- exposure via inhalation (workers)

The test item is not classified for skin or eye irritation according to Regulation (EC) No 1272/2008 (CLP). Therefore, it is not considered to pose a hazard for local effects on the mucous membranes of respiratory tract when inhaled.

 

Dermal

Long term, systemic DNEL- exposure via dermal route (workers)

No dermal repeated dose toxicity study with the test item is available. Therefore, long-term dermal DNEL was derived by route-to-route extrapolation.

The NOAEL of 200 mg/kg bw/day derived from an OECD TG 422 study performed with the test item was used as the Point of Departure.

Step 1: PoD: NOAEL = 200 mg/kg bw/day

Step 2: Modification into a correct starting point:

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker.

There are no relevant experimental data on repeated dermal exposure. A conservative approach is used assuming identical dermal and oral absorption values.

Corrected NOAEL (dermal) for workers:

= 200 mg/kg bw/day x 1.4

= 280 mg/kg bw/day

Step 3: Overall AF= 750

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

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

 

Interspecies AF, remaining differences: 2.5

The recommended AF for other interspecies differences is applied.

 

Intraspecies AF (worker): 5

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

 

Dose-response relationship AF: 1

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

 

Exposureduration AF: 6
Default for subacute to chronic is applied.

Remaining uncertainties: 2.5
The OECD 422 is designed to be a screening study on Reproduction/Developmental Toxicity and does not provide in detail examinations on these endpoints.
 Therefore, a conservative assessment factor of 2.5 reflects the remaining uncertainty based on the study design.

 

In conclusion, long term systemic dermal DNEL, workers = 0.37 mg/kg bw/day

Acute, systemic DNEL- dermal exposure (workers)

An acute dermal toxicity study is available for the test item. Based on the results the test item is not classified for acute dermal toxicity according to Regulation (EC) No 1272/2008 (CLP). Thus, the acute systemic dermal DNEL was not derived. Further, long-term DNELs are considered sufficient to ensure that acute effects do not occur.

 

Long term & acute, local DNEL- dermal exposure (workers)

The test substance is not classified for skin irritation or skin sensitization. Thus, the local dermal DNEL was not derived.

 

Hazard to the eye-local effects (worker)

The test item is classified for eye irritation (H319) according to Regulation (EC) No 1272/2008 (CLP).

 

References

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 (2016). Guidance on information requirements and chemical safety assessment. Part E: Risk Characterisation, Version 3.0, May 2016

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.23 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):
375
Dose descriptor starting point:
NOAEL
Value:
200 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
86.96 mg/m³
Explanation for the modification of the dose descriptor starting point:

Corrected NOAEC (inhalation) for general population:

= 200 mg/kg bw/day x 0.5 x 1/1.15 m3/kg bw/day

= 86.96 mg/m3

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:
Default for subacute to chronic is applied.
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scalling is applied for inhalation as the inhalative data is standardized with reference to the respiratory rates. Respiratory rates depend directly on caloric demand, therefore inhalative study results are already extrapolated to humans on the basis of metabolic rate scaling (=allometric scaling).
AF for other interspecies differences:
2.5
Justification:
The recommended AF for other interspecies differences is applied.
AF for intraspecies differences:
10
Justification:
The default value for the relatively heterogeneous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
The OECD TG 422 toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
2.5
Justification:
The OECD 422 is designed to be a screening study on Reproduction/Developmental Toxicity and does not provide in detail examinations on these endpoints. Therefore, a conservative assessment factor of 2.5 reflects the remaining uncertainty based on the study design.
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:
0.13 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):
1 500
Dose descriptor starting point:
NOAEL
Value:
200 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
200 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Correction for difference between human and experimental exposure conditions: 7 d rat, 24 h/7 d, 24h general population = 1

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:
Default for subacute to chronic is applied.
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is applied.
AF for other interspecies differences:
2.5
Justification:
The recommended AF for other interspecies differences is applied.
AF for intraspecies differences:
10
Justification:
The default value for the relatively heterogeneous group "general population" is applied
AF for the quality of the whole database:
1
Justification:
The OECD TG 422 toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
2.5
Justification:
The OECD 422 is designed to be a screening study on Reproduction/Developmental Toxicity and does not provide in detail examinations on these endpoints. Therefore, a conservative assessment factor of 2.5 reflects the remaining uncertainty based on the study design.
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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.13 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):
1 500
Dose descriptor starting point:
NOAEL
Value:
200 mg/kg bw/day
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:
Default for subacute to chronic is applied.
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is applied.
AF for other interspecies differences:
2.5
Justification:
The recommended AF for other interspecies differences is applied.
AF for intraspecies differences:
10
Justification:
The default value for the relatively heterogeneous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
The OECD TG 422 toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
2.5
Justification:
The OECD 422 is designed to be a screening study on Reproduction/Developmental Toxicity and does not provide in detail examinations on these endpoints. Therefore, a conservative assessment factor of 2.5 reflects the remaining uncertainty based on the study design.
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

General Population

Inhalation

Long term, systemic DNEL – exposure by inhalation (general population)

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

No repeated dose inhalation toxicity study with the test item is available. Therefore, long-term dermal DNEL was derived by route-to-route extrapolation from an oral repeated dose toxicity study:

Based on an OECD TG 422 study with the test item, daily oral administration to Wistar rats revealed signs of systemic toxicity in the high and mid dose tested i. e. and 2000/1000 and 600 mg/kg bw/d. The NOAEL for systemic toxicity was therefore considered to be 200 mg/kg bw/day. NOAEL for fertility and developmental toxicity was determined to be 200 mg/kg bw/d, respectively as well based on the conditions of this study. This NOAEL is therefore used as Point of Departure for DNEL derivation since it can be considered reflecting a worst case assumption.

Step 1: PoD: NOAEL = 200 mg/kg bw/day

Step 2: Modification of PoD:

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

Oral absorption of the rat/ inhalation absorption of humans (ABS oral-rat / ABS inh-human): 1/2 (default)

Corrected NOAEC (inhalation) for general population:

= 200 mg/kg bw/day x 0.5 x 1/1.15 m3/kg bw/day

= 86.96 mg/m3

Step 3: Overall AF= 375

Intraspecies AF (General population): 10
The default value for the relatively heterogeneous group "general population" is used

Interspecies AF, remaining differences: 2.5
The recommended AF for other interspecies differences is applied.

Allometric scaling AF: 1
No allometric scalling is applied for inhalation as the inhalative data is standardized with reference to the respiratory rates. Respiratory rates depend directly on caloric demand, therefore inhalative study results are already extrapolated to humans on the basis of metabolic rate scaling (=allometric scaling).

Dose response relationship AF: 1
The dose response relationship is considered unremarkable, therefore no additional factor is used.

Exposure duration AF: 6
Default for subacute to chronic is applied.

Whole database AF: 1
The OECD TG 422 toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

Remaining uncertainties: 2.5
The OECD 422 is designed to be a screening study on Reproduction/Developmental Toxicity and does not provide in detail examinations on these endpoints.
 Therefore, a conservative assessment factor of 2.5 reflects the remaining uncertainty based on the study design.

In conclusion, long term systemic inhalation DNEL, general population = 0.23 mg/m3

Acute, systemic DNEL- exposure via inhalation (general population)

There is no short-term or long-term toxicity study via inhalation route available for the test item. Even though the test item has a high vapour pressure (15.6 hPa), exposure via inhalation route cannot not excluded. However, the test item is not classified as acutely toxic. Therefore, long-term DNELs are considered sufficient to ensure that acute effects do not occur. Thus no short-term DNEL inhalation is derived.

Long-term and short-term, local DNEL- exposure via inhalation (general population)

The test item is not classified for skin or eye irritation according to Regulation (EC) No 1272/2008 (CLP). Therefore, it is not considered to pose a hazard for local effects on the mucous membranes of respiratory tract when inhaled.

 

Dermal

Long term, systemic DNEL- exposure via dermal route (general population)

No repeated dose dermal toxicity study with the test item is available. Therefore, long-term dermal DNEL was derived by route-to-route extrapolation. The NOAEL of 200 mg/kg bw/day derived from an OECD TG 422 study performed with the test item was used as the Point of Departure.

Step 1: PoD: NOAEL= 200 mg/kg bw/day

Step 2: Modification into a correct starting point:
Correction for difference between human and experimental exposure conditions: 7 d rat, 24 h/7 d, 24h general population = 1

Step 3: Overall AF= 1500

Interspecies AF, allometric scaling (rat to human): 4
The default allometric scaling factor for the differences between rats and humans is applied.

 

Interspecies AF, remaining differences: 2.5
The recommended AF for other interspecies differences is applied.

 

Intraspecies AF (general population): 10
The default value for the relatively heterogeneous group "general population" is applied

 

Dose-response relationship AF: 1
The dose response relationship is considered unremarkable, therefore no additional factor is used.

 

Exposure duration AF: 6
Default for subacute to chronic is applied.

Remaining uncertainties: 2.5
The OECD 422 is designed to be a screening study on Reproduction/Developmental Toxicity and does not provide in detail examinations on these endpoints.
 Therefore, a conservative assessment factor of 2.5 reflects the remaining uncertainty based on the study design.

In conclusion, long term systemic dermal DNEL, general population = 0.13 mg/kg bw/day

Acute, systemic DNEL- dermal exposure (general population)

An acute dermal toxicity study is available for the test item. Based on the results the test item is not classified for acute dermal toxicity according to Regulation (EC) No 1272/2008 (CLP). Thus, the acute systemic dermal DNEL was not derived. Further, long-term DNELs are considered sufficient to ensure that acute effects do not occur.

Long term & acute, local DNEL- dermal exposure (general population)

The test substance is not classified for skin irritation or skin sensitization. Thus, the local dermal DNEL was not derived.

Long term, systemic DNEL- exposure by oral route (general population)

An oral repeated dose toxicity study with the test item is available. Based on an OECD TG 422 study with the test item, daily oral administration to Wistar rats revealed signs of systemic toxicity in the high and mid dose tested i. e. and 2000/1000 and 600 mg/kg bw/d. The NOAEL for systemic toxicity was therefore considered to be 200 mg/kg bw/day. NOAEL for fertility and developmental toxicity was determined to be 200 mg/kg bw/d, respectively as well based on the conditions of this study. This NOAEL is therefore used as Point of Departure for DNEL derivation since it can be considered reflecting a worst case assumption.

Step 1: PoD: NOAEL = 200 mg/kg bw/day

Step 2: Overall AF= 1500

Interspecies AF, allometric scaling (rat to human): 4
The default allometric scaling factor for the differences between rats and humans is applied.

 

Interspecies AF, remaining differences: 2.5
The recommended AF for other interspecies differences is applied.

 

Intraspecies AF (general population): 10
The default value for the relatively heterogeneous group "general population" is used.

 

Dose-response relationship AF: 1
The dose response relationship is considered unremarkable, therefore no additional factor is used.

 

Exposure duration AF: 6
Default for subacute to chronic is applied.

Remaining uncertainties: 2.5
The OECD 422 is designed to be a screening study on Reproduction/Developmental Toxicity and does not provide in detail examinations on these endpoints.
 Therefore, a conservative assessment factor of 2.5 reflects the remaining uncertainty based on the study design.

In conclusion, long term systemic oral DNEL, general population 0.13 mg/kg bw/day

 

Acute, systemic DNEL- exposure by oral route (general population)

An acute oral toxicity study with the test item is available. Based on the experimental results the test item is not classified for acute oral toxicity under Regulation (EC) No. 1272/2008 (CLP). Thus, the acute systemic oral DNEL was not derived. Further, long-term DNELs are considered sufficient to ensure that acute effects do not occur

Hazard to the eye-local effects (general population)

The test item is classified for eye irritation (H319) according to Regulation (EC) No 1272/2008 (CLP).

References

ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8:

Characterization of dose [concentration]-response for human health. Version 2.1, November 2012

ECHA (2016). Guidance on information requirements and chemical safety assessment. Part E: Risk Characterization, Version 3.0, May 2016