Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.64 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):
25
Dose descriptor starting point:
NOAEL
Value:
80 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
141.05 mg/m³
Explanation for the modification of the dose descriptor starting point:

No inhalation study available. DNEL computation based on 8 h exposure time. 100% bioavailability via oral route as via the inhalation route, as esters of branched-chain aliphatic acyclic alcohols are rapidly hydrolysed and absorbed from the gastrointestinal tract (Semino, 1998: http://www.inchem.org/documents/jecfa/jecmono/v040je13.htm).

Corrected inhalatory NOAEC = 80 mg/kg/day*(1/0.38 m3/kg/day)*(6.7 m3 (8h)/10 m3 (8h)) = 141.05 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:
2
Justification:
The default extrapolation factor for exposure duration is used: starting point - subchronic (NOAEL oral derived from an OECD 408 study) 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
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:
0.8 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):
100
Dose descriptor starting point:
NOAEL
Value:
80 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
80 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

It is assumed that rat oral and dermal absorptions are equal to human oral and dermal 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:
2
Justification:
The default extrapolation factor for exposure duration is used: starting point - subchronic (NOAEL oral derived from an OECD 408 study) 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
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information

Local effects

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Worker

The primary route of industrial exposure to the test item is by skin contact and inhalation. In an industrial setting, ingestion is not an expected route of exposure.

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

Acute, systemic DNEL

Short-term DNELs are not required as the acute toxicity of the test item is low. The test substance is not classified and labelled for acute systemic toxicity, according to Regulation (EC) 1272/2008 (CLP), based on the test data for acute oral and dermal toxicity. Inhalation toxicity is also regarded as low due to the physico-chemical properties of the test substance.

Acute/long-term, local

No skin sensitization potential was observed in the available experimental data with the test item. The substance is therefore not classified as skin sensitiser according to Regulation (EC) No 1272/2008 (CLP). The substance is classified as skin irritant category 2 according to Regulation (EC) 1272/2008 (CLP). Since there are no data to establish a dose-response relationship a qualitative risk assessment is applied for dermal exposure and a low hazard is assumed. The substance is not classified as eye irritant according to Regulation (EC) 1272/2008 (CLP).

Long-term, systemic DNEL

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

Exposure by inhalation

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

The NOAEL of 80 mg/kg bw/day, assessed in the key repeated dose oral toxicity study (OECD 408, 2016) 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. This worker long-term DNEL is considered to ensure an appropriate level of protection with regard to acute inhalation exposure (no high peaks of exposure expected).

Relevant dose descriptor (NOAEL): 80 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): 1

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

= 80 mg/kg bw/d × 1 × (1 / 0.38 m³/kg bw/d) × (6.7 m³/10 m³)

= 141.05 mg/m³

Step 3: Use of assessment factors: 25

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

Interspecies AF, remaining differences: no evidence for species differences in the general mode of action

Intraspecies AF (worker): 5

Interspecies AF, remaining differences: 2.5

Dose response relationship AF: 1

Exposure duration AF (subchronic to chronic): 2

In conclusion, the long-term inhalation DNEL, worker = 5.64 mg/m3  

 

Dermal exposure

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

The NOAEL of 80 mg/kg bw/day, assessed in the repeated dose oral toxicity study (OECD 408, 2016) was 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 dermal exposure) is derived. Based on the physico-chemical properties of test item a dermal absorption of 100 % is assumed as a worst case scenario.

In conclusion, dermal NOAEL = oral NOAEL

Step 3: Use of assessment factors: 100

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

Interspecies AF, remaining differences: 2.5

Interspecies AF, remaining differences: Interspecies differences are fully covered by the allometric scaling

Intraspecies AF (worker): 5

Dose-response relationship AF: 1

Exposure duration AF (OECD408, exposure period 90 days): 2

In conclusion, long term systemic dermal DNEL, workers = 0.8 mg/kg bw/day

References

(not included as endpoint study record)

- ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version 2. ECHA-2010 -G-19 –EN.  

- ECHA (2014). Guidance on information requirements and chemical safety assessment. Chapter R.7.C: Endpoint specific guidance: Guidance on Toxicokinetics. Nov 2014.  

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

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.4 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:
80 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
69.6 mg/m³
Explanation for the modification of the dose descriptor starting point:

No inhalation study available. DNEL computation based on 24 h exposure time. 100% bioavailability via oral route as via the inhalation route, as esters of branched-chain aliphatic acyclic alcohols are rapidly hydrolysed and absorbed from the gastrointestinal tract (Semino, 1998: http://www.inchem.org/documents/jecfa/jecmono/v040je13.htm). Corrected inhalatory NOAEC = 80 mg/kg bw/day*(1/1.15 m3/kg/day) = 69.6 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:
2
Justification:
The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
1
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
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:
0.4 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:
80 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
80 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

It is assumed that rat oral and dermal absorptions are equal to human oral and dermal absorptions.

 

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:
2
Justification:
The default extrapolation factor for exposure duration is used: subchronic (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
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:
0.4 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:
80 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

no route-to-route extrapolation performed.

 

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:
2
Justification:
The default extrapolation factor for exposure duration is used: subchronic (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:
no hazard identified

Additional information - General Population

General population

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

Acute, systemic DNEL

Short-term DNELs are not required as the acute toxicity of the test item is low. The test substance is not classified and labelled for acute systemic toxicity, according to Regulation (EC) 1272/2008 (CLP), based on the test data for acute oral and dermal toxicity. Inhalation toxicity is also regarded as low due to the physico-chemical properties of the test substance.

Acute/long-term, local

No skin sensitization potential was observed in the available experimental data with the test item. The substance is therefore not classified as skin sensitizer according to Regulation (EC) No 1272/2008 (CLP The substance is classified as skin irritant category 2 according to Regulation (EC) 1272/2008 (CLP). Since there are no data to establish a dose-response relationship a qualitative risk assessment is applied and a low hazard is assumed. The substance is not classified as eye irritant according to Regulation (EC) 1272/2008 (CLP)

Long-term, systemic DNEL for General population

Exposure by inhalation

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

The NOAEL of 80 mg/kg bw/day, assessed in the key repeated dose oral toxicity study (OECD 408, 2016) 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 the same absorption via inhalation than oral absorption.

Relevant dose descriptor (NOAEL): 80 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): 1

Corrected inhalatory NOAEC for general populations

= 80 mg/kg bw/d × (1 / 1.15 m³/kg bw/d)  

= 69.6  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: no evidence for species differences in the general mode of action

Intraspecies AF (general population): 10

Interspecies AF, remaining differences: 2.5

Dose response relationship AF: 1

Exposure duration AF (subchronic to chronic): 2

In conclusion, the long-term inhalation DNEL, general population = 1.4 mg/m3  

 

Dermal exposure

Step 1: Selection of the relevant dose descriptor (starting point): The NOAEL of 80 mg/kg bw/day, assessed in the repeated dose oral toxicity study (OECD 408, 2016) was 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 dermal exposure) is derived. The same dermal absorption as compared to oral absorption is assumed.

In conclusion, dermal NOAEL = oral NOAEL

Step 3: Use of assessment factors: 200

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

Interspecies AF, remaining differences: Interspecies differences are fully covered by the allometric scaling

Intraspecies AF (general population): 10

Interspecies AF, remaining differences: 2.5

Dose response relationship AF: 1

Exposure duration AF (OECD408, exposure period 90 days): 2

In conclusion, long term systemic dermal DNEL, general populations = 0.4 mg/kg bw/day

Oral exposure

An oral DNEL (long term, systemic) for the general population is derived.

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

A 90-day toxicity study according to OECD TG 408 (2016) is selected for DNEL derivation as it is the relevant repeated dose study performed in accordance to OECD guideline and GLP. In this study, the oral NOAEL in rats is 80 mg/kg bw/day.

Step 2: Use of assessment factors: 200

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

Interspecies AF, remaining differences: 2.5

Intraspecies AF (general population): 10

Dose response relationship AF: 1

Exposure duration AF: 2

In conclusion, long term systemic oral DNEL, general population = 0.4 mg/kg bw/day

 

 

References

(not included as endpoint study record)

- ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version 2. ECHA-2010 -G-19 –EN.  

- ECHA (2014). Guidance on information requirements and chemical safety assessment. Chapter R.7.C: Endpoint specific guidance: Guidance on Toxicokinetics. Nov 2014.  

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