Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.9 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
DNEL value:
200 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
246.84 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:
As the NOAEL of a repeated dose toxicity study (OECD 422) with an exposure time of approx. 50 days (males: 50 days; females: 2 weeks prior to mating until Postpartum Day 13) was used as point of departure an AF of 4 is considered as adequate for the exposure duration extrapolation.
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:
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
Most sensitive endpoint:
acute toxicity
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:
14 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
DNEL value:
200 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
2 800 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated dermal exposure. Based on physicochemical data dermal absorption is possible. According to “Guidance on information requirements and chemical safety assessment chapter R7c: Endpoint specific Guidance”, especially water solubility is high enough to enable dermal penetration. The log Pow lies in the range between -1 and 4, although it is <2 and therefore not in the optimal range. The molecular weight of the substance is above 100 g/mol, but based on the structure of the molecule it might hydrolyse upon skin contact, facilitating dermal absorption. Nevertheless, penetration through skin is anticipated to be less extensive than oral absorption and an absorption rate of 10 % of oral absorption was taken for calculation.

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:
As the NOAEL of a repeated dose toxicity study (OECD 422) with an exposure time of approx. 50 days (males: 50 days; females: 2 weeks prior to mating until Postpartum Day 13) was used as point of departure an AF of 4 is considered as adequate for the exposure duration extrapolation.
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
Most sensitive endpoint:
acute toxicity
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 substance 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 from the repeated dose oral toxicity study.

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

The combined repeated dose oral toxicity study OECD 422 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 systemic NOAEL is 200 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 considering a two times higher absorption via inhalation than oral absorption.

 

Relevant dose descriptor (NOAEL): 200 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

Frequency of exposure in study: 7 days/week

Frequency of worker exposure: 5 days/week

 

Corrected inhalatory NOAEC for workers

= 200 mg/kg bw/day* 0.5 * (1 / 0.38 m³/kg bw/day) * (6.7 m³/10 m³) * (7/5)

= 246.84 mg/m³

 

Step 3: Use of assessment factors: 50

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: 4

Remaining uncertainties AF: 1

 

In conclusion, long term systemic inhalation DNEL, workers = 4.9 mg/m3

 

Short term systemic inhalation DNEL, worker

No data for the classification and labelling of the test substance for acute systemic toxicity (inhalation) is available. The substance is not classified for acute oral toxicity and acute dermal toxicity, therefore no adverse result for inhalation toxicity is expected (in accordance with "Guidance on information requirements and chemical safety assessment", chapter R8). Thus, no DNEL is required.

 

Short and long term local inhalation DNEL, worker

No data on respiratory irritation is available. However, the test substance is not classified for eye irritation according to Regulation (EC) No 1272/2008 (CLP). This implies that no potential damage to mucosal tissue may occur by an inhalation exposure.

 

 

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 (OECD 422).

 

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

The combined repeated dose toxicity study (OECD 422) 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 200 mg/kg bw/day.

 

Step 2: Modification of the starting point:

There are no relevant experimental data on repeated dermal exposure. Based on physicochemical data dermal absorption is possible. According to “Guidance on information requirements and chemical safety assessment chapter R7c: Endpoint specific Guidance”, especially water solubility is high enough to enable dermal penetration. The log Pow lies in the range between -1 and 4, although it is <2 and therefore not in the optimal range. The molecular weight of the substance is above 100 g/mol, but based on the structure of the molecule it might hydrolyse upon skin contact, facilitating dermal absorption. Nevertheless, penetration through skin is anticipated to be less extensive than oral absorption and an absorption rate of 10 % of oral absorption was taken for calculation.

 

Relevant dose descriptor (NOAEL): 200 mg/kg bw/day

Frequency of exposure in study: 7 days/week

Frequency of worker exposure: 5 days/week

Oral absorption of the rat / dermal absorption of humans (ABSoral-rat / ABSinh-human): 100/10

 

Corrected dermal NOAEL for workers

200 mg/kg bw/day * (100%/10%) * (7/5) = 2800 mg/kg bw/day

 

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

Remaining uncertainties AF: 1

 

In conclusion, long term systemic dermal DNEL, workers = 14 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.

 

Long term and short term local dermal DNEL, worker

The test item is not classified for skin sensitization or skin irritation/corrosion according to Regulation (EC) No 1272/2008 (CLP). Thus, no qualitative risk assessment has to be conducted.

   

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

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

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

- ECHA (2017). Guidance on information requirements and chemical safety assessment chapter R7c: Endpoint specific Guidance, June 2017.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.74 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
DNEL value:
200 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
74.07 mg/m³
Explanation for the modification of the dose descriptor 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.

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:
As the NOAEL of a repeated dose toxicity study (OECD 422) with an exposure time of approx. 50 days (males: 50 days; females: 2 weeks prior to mating until Postpartum Day 13) was used as point of departure an AF of 4 is considered as adequate for the exposure duration extrapolation.
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:
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

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:
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):
400
Dose descriptor starting point:
NOAEL
DNEL value:
200 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
2 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated dermal exposure. Based on physicochemical data dermal absorption is possible. According to “Guidance on information requirements and chemical safety assessment chapter R7c: Endpoint specific Guidance”, especially water solubility is high enough to enable dermal penetration. The log Pow lies in the range between -1 and 4,

although it is <2 and therefore not in the optimal range. The molecular weight of the substance is above 100 g/mol, but based on the structure of the molecule it might hydrolyse upon skin contact, facilitating dermal absorption. Nevertheless, penetration through skin is anticipated to be less extensive than oral absorption and an absorption rate of 10 % of oral absorption was taken for calculation.
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:
As the NOAEL of a repeated dose toxicity study (OECD 422) with an exposure time of approx. 50 days (males: 50 days; females: 2 weeks prior to mating until Postpartum Day 13) was used as point of departure an AF of 4 is considered as adequate for the exposure duration extrapolation.
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

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:
0.5 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):
400
Dose descriptor starting point:
NOAEL
DNEL value:
200 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
200 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

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

 

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:
As the NOAEL of a repeated dose toxicity study (OECD 422) with an exposure time of approx. 50 days (males: 50 days; females: 2 weeks prior to mating until Postpartum Day 13) was used as point of departure an AF of 4 is considered as adequate for the exposure duration extrapolation.
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 substance 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 combined repeated dose oral toxicity study OECD 422 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 systemic NOAEL is 200 mg/kg bw/day.

 

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): 200 mg/kg bw/day

Standard respiratory volume of the rat (sRVrat) for 24 hours: 1.35 m³/kg bw/d

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

Frequency of exposure in study: 7 days/week

Frequency of general population exposure: 7 days/week

 

Corrected inhalatory NOAEC for workers

= 200 mg/kg bw/day* 0.5 * (1 / 1.35 m³/kg bw/day) * (7/7)

= 74.07 mg/m³

 

Step 3: Use of assessment factors: 100

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: 4

Remaining uncertainties AF: 1

 

In conclusion, long term systemic inhalation DNEL, general population = 0.74 mg/m3

 

Short term systemic inhalation DNEL, general population

No data for the classification and labelling of the test substance for acute systemic toxicity (inhalation) is available. The substance is not classified for acute oral toxicity and acute dermal toxicity, therefore no adverse result for inhalation toxicity is expected (in accordance with "Guidance on information requirements and chemical safety assessment", chapter R8). Thus, no DNEL is required.

 

Short and long term local inhalation DNEL, general population

No data on respiratory irritation is available. However, the test substance is not classified for eye irritation according to Regulation (EC) No 1272/2008 (CLP). This implies that no potential damage to mucosal tissue may occur by an inhalation exposure.

 

 

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 (OECD 422).

 

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

The combined repeated dose toxicity study (OECD 422) 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 200 mg/kg bw/day.

 

Step 2: Modification of the starting point:

There are no relevant experimental data on repeated dermal exposure. Based on physicochemical data dermal absorption is possible. According to “Guidance on information requirements and chemical safety assessment chapter R7c: Endpoint specific Guidance”, especially water solubility is high enough to enable dermal penetration. The log Pow lies in the range between -1 and 4

, although it is <2 and therefore not in the optimal range. The molecular weight of the substance is above 100 g/mol, but based on the structure of the molecule it might hydrolyse upon skin contact, facilitating dermal absorption. Nevertheless, penetration through skin is anticipated to be less extensive than oral absorption and an absorption rate of 10 % of oral absorption was taken for calculation.

 

Relevant dose descriptor (NOAEL): 200 mg/kg bw/day

Frequency of exposure in study: 7 days/week

Frequency of general population exposure: 7 days/week

 

Corrected dermal NOAEL for general population

200 mg/kg bw/day * (100%/10%) * (7/7) = 2000 mg/kg bw/day

 

Step 3: Use of assessment factors: 400

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

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 10

Exposure duration AF: 4

Remaining uncertainties AF: 1

 

In conclusion, long term systemic dermal DNEL, general population = 5 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.

 

Long term and short term local dermal DNEL, general population

The test item is not classified for skin sensitization or skin irritation/corrosion according to Regulation (EC) No 1272/2008 (CLP). Thus, no qualitative risk assessment has to be conducted.

   

General population – Hazard via oral route

Long term systemic oral DNEL, general population

The DNEL long term, systemic (oral) is derived from the combined repeated dose oral toxicity study (OECD 422).

 

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

The combined repeated dose toxicity study (OECD 422) 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 200 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: 400

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

Interspecies AF, remaining differences: 2.5

Intraspecies AF (general population): 10

Exposure duration AF: 4

Remaining uncertainties AF: 1

 

In conclusion, long term systemic oral DNEL, general population = 0.5 mg/kg bw/day

 

Short term systemic oral DNEL, General population

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

 

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

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

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

- ECHA (2017). Guidance on information requirements and chemical safety assessment chapter R7c: Endpoint specific Guidance, June 2017.