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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
35.3 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):
5
Modified dose descriptor starting point:
NOAEC
Value:
176.3 mg/m³
Explanation for the modification of the dose descriptor starting point:

There is one repeated dose inhalation study available (BASF, 2013). However, the duration of exposure of this study (5 days) is too short to serve as a reasonable starting point for a longterm DNEL derivation. There are no other relevant experimental data on repeated exposure by inhalation.

Hence, an oral study with dose descriptor modification was used as a starting point (see discussion for further information). 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:
1
Justification:
NOAEL taken from 2 generation study
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:
1
Justification:
Effects are secondary to altered/enhanced liver metabolism. No organ damage was observed. An additional factor for remaining toxicodynamic differences is not deemed necessary.
AF for intraspecies differences:
5
Justification:
Default factor
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:
DNEL (Derived No Effect Level)
Value:
5 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
5
Dose descriptor:
NOAEC
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:
1
Justification:
Local effects are related to the deposited concentration rather than the total dose (AUC). Therefore, no AF for exposure duration is applied.
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:
1
Justification:
Interspecies differences including toxicokinetics are fully covered by the allometric scaling. There is no additional evidence for species differences including toxicodynamics. Therefore, no additional factor is used.
AF for intraspecies differences:
5
Justification:
Default factor
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

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
125 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):
20
Modified dose descriptor starting point:
NOAEL
Value:
2 500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on repeated dermal exposure. Taken into account the available toxicokinetic data, dermal absoption is anticipated to be 4 % and oral absoption is estimated to be 50%.
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:
1
Justification:
NOAEL taken from 2 generation study
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:
1
Justification:
Effects are secondary to altered/enhanced liver metabolism. No organ damage was observed. An additional factor for remaining toxicodynamic differences is not deemed necessary.
AF for intraspecies differences:
5
Justification:
Default factor
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

General

DNEL derivation for the substance is performed under consideration of the recommendations of ECHA REACH Guidance. In view of the data used for evaluation, the "quality of whole database factors" and the “factor for remaining uncertainties“ is considered to amount to a value of 1. Based on the available experimental data there is no evidence for interspecies differences in the general mode of action or kinetics. The observed effects are considered secondary to altered / enhanced liver metabolism, which is already covered by the factors for allometric scaling.

 

Acute/short-term exposure - systemic effects

The guidance on dose/concentration response regarding human health (section R8.1.2.5 of chapter R.8 of the Guidance on Information Requirements and Chemical Safety Assessment) indicates that acute DNELs do not need to be calculated for substances that are not classified for an acute toxicity hazard according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP). As this substance is not classified, no acute systemic DNELs need to be calculated.

 

Acute/short-term and long-term exposure-local effects

 

Skin and eye irritation/corrosion and sensitization:

The skin and eye irritation and sensitization potential of the test item was assessed in several in vivo studies. The test item has been demonstrated to be neither irritating nor sensitising.

 

Respiratory irritation:

A short-term inhalation toxicity study (BASF SE, 2013) revealed that the test substance has irritating properties in the respiratory tract. Based on these findings a long-term inhalation DNEL for local effects is derived. The NOAEC of 50 mg/m³ is identified as the relevant dose descriptor and starting point.

 

Modification into a correct starting point:

Using a conservative approach, a worker DNEL (long-term inhalation exposure) is derived. This worker DNEL is considered to ensure an appropriate level of protection with regard to acute inhalation exposure.

 

Relevant dose descriptor (NOAEC): 50 mg/m³

Exposure duration rat: 6 h/d

Exposure duration worker: 8 h/d

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/m³ × (6 h/d/8 h/d) × (6.7 m³/10 m³)

= 25.1 mg/m³

 

Assessment factors:

Dose response differences: 1

Differences in exposure duration: 1

Interspecies differences (allometric scaling): 1

Intraspecies differences (worker): 5

 

Taking the above mentioned assessment factors into account, the following worker long term inhalation DNEL for local effects is:

25.1 mg/m³ / (1 x 1 x 1 x 5 ) = 25.1 mg/m³ / 5

= 5 mg/m³

 

Long-term exposure-systemic effects  

In a 90-day oral repeated dose toxicity study (BASF, 1995) and an oral 2 generation study (BASF, 2009) in rats, similar NOAELs were identified. Both studies showed peroxisomal proliferation, altered liver metabolism and associated secondary changes in blood parameters, and reduced body weight gain. As peroxisomal proliferation is not relevant for human health hazard the NOAEL relevant for human health is 196 mg/kg bw/day (90 -day study) and 200 mg/kg (2 -generation study). Since a significant increase in exposure time (from 90 to 120 -130 days) did not alter the NOAEL or lead to more severe effects, an additional factor for exposure duration is not required.

Considering the appropriate modification and assessment factors, the worker DNEL (long-term inhalation exposure) is calculated as follows:

Inhalation exposure 

Modification into a correct starting point:

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

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

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

= 200 mg/kg bw/day × 0.5 × (1 / 0.38 m³/kg bwI) × (6.7 m³/10 m³)

= 176.3 mg/m³

 

Assessment factors:

Dose response differences: 1

Differences in exposure duration: 1

Interspecies differences (allometric scaling): 1

Intraspecies differences: 5

 

Taking the above mentioned assessment factors into account, the following worker long term inhalation DNEL for systemic effects is:

176.3 mg/m³ / (1 x 1 x 1 x 5) = 176.3 mg/m³ / 5

= 35.3 mg/m³

 

As the inhalation DNEL for long term local effects is lower than the inhalation DNEL for long term systemic effects, systemic effects are fully covered by the DNEL for long term local effects.

 

Dermal exposure

 

Modification into a correct starting point:

Dose descriptor of relevant study: The dermal absorption is considered to be 4%, the oral absorption is considered to be 50%.

 

Relevant starting point NOAEL dermal = (200 mg/kg bw/day x 0.5) / 0.04 = 2500 mg/kg bw/day

 

Assessment factors:

Dose response differences: 1

Differences in exposure duration: 1

Interspecies differences (allometric scaling): 4

Intraspecies differences (worker): 5

 

Taking the above mentioned assessment factors into account, the following worker long- term dermal DNEL for systemic effects is:

2500 mg/kg bw/d / (1 x 1 x 4 x 5) = 2500 mg/kg bw/day / 20

= 125 mg/kg bw/day

 

References  

- ECHA (2010). 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.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.7 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):
10
Modified dose descriptor starting point:
NOAEC
Value:
87 mg/m³
Explanation for the modification of the dose descriptor starting point:

There is one repeated dose inhalation study available (BASF, 2013). However, the duration of exposure of this study (5 days) is too short to serve as a reasonable starting point for a longterm DNEL derivation. There are no other relevant experimental data on repeated exposure by inhalation.

Hence, an oral study with dose descriptor modification was used as a starting point (see discussion for further information). 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:
1
Justification:
NOAEL taken from 2 generation study
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:
1
Justification:
Effects are secondary to altered/enhanced liver metabolism. No organ damage was observed. An additional factor for remaining toxicodynamic differences is not deemed necessary.
AF for intraspecies differences:
10
Justification:
Default factor
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:
DNEL (Derived No Effect Level)
Value:
1.25 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
10
Dose descriptor:
NOAEC
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:
1
Justification:
Local effects are related to the deposited concentration rather than the total dose (AUC). Therefore, no AF for exposure duration is applied.
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:
1
Justification:
Interspecies differences including toxicokinetics are fully covered by the allometric scaling. There is no additional evidence for species differences including toxicodynamics. Therefore, no additional factor is used.
AF for intraspecies differences:
10
Justification:
Default factor
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 via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
62.5 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):
40
Modified dose descriptor starting point:
NOAEL
Value:
2 500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on repeated dermal exposure. Taken into account the available toxicokinetic data, dermal absoption is anticipated to be 4 % and oral absoption is estimated to be 50%.
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:
1
Justification:
NOAEL taken from 2 generation study
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:
1
Justification:
Interspecies differences including toxicokinetics are fully covered by the allometric scaling. There is no additional evidence for species differences including toxicodynamics. Therefore, no additional factor is used.
AF for intraspecies differences:
10
Justification:
Default factor
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

General Population - Hazard via oral 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):
40
Modified dose descriptor starting point:
NOAEL
Value:
200 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No route to route extrapolation is required since a repeated dose oral toxicity study is available.
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
1
Justification:
NOAEL taken from 2 generation study
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:
1
Justification:
Interspecies differences including toxicokinetics are fully covered by the allometric scaling. There is no additional evidence for species differences including toxicodynamics. Therefore, no additional factor is used.
AF for intraspecies differences:
10
Justification:
Default factor
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

DNEL derivation for the substance is performed under consideration of the recommendations of ECHA REACH Guidance (2010). In view of the data used for evaluation, the "quality of whole database factors" and the “factor for remaining uncertainties“ is considered to amount to a value of 1. Based on the available experimental data there is no evidence for interspecies differences in the general mode of action or kinetics. The observed effects are considered secondary to altered / enhanced liver metabolism, which is already covered by the factors for allometric scaling.

 

Acute/short-term exposure - systemic effects

The guidance on dose/concentration response regarding human health (section R8.1.2.5 of chapter R.8 of the Guidance on Information Requirements and Chemical Safety Assessment) indicates that acute DNELs do not need to be calculated for substances that are not classified for an acute toxicity hazard. As this substance is not classified, no acute DNELs need to be calculated.

 

Acute/short-term and long-term exposure -local effects

 

Skin and eye irritation/corrosion and sensitization:

The skin and eye irritation and sensitization potential of the test item was assessed in several in vivo studies. The test item has been demonstrated to be neither irritating nor sensitising.

 

Respiratory irritation:

A short-term inhalation toxicity study (BASF SE, 2013) revealed that the test substance has irritating properties in the respiratory tract. Based on these findings a long-term inhalation DNEL for local effects is derived. The NOAEC of 50 mg/m³ is identified as the relevant dose descriptor and starting point.

 

Modification into a correct starting point:

Using a conservative approach, a general population DNEL (long-term inhalation exposure) is derived.

 

Relevant dose descriptor (NOAEC): 50 mg/m³

Exposure duration rat: 6 h/d

Exposure duration general population: 24 h/d

 

Corrected inhalatory NOAEC for general population

= 50 mg/m³ × (6 h/d/24 h/d)

= 12.5 mg/m³

 

Assessment factors:

Dose response differences: 1

Differences in exposure duration: 1

Interspecies differences (allometric scaling): 1

Intraspecies differences (general population): 10

 

Taking the above mentioned assessment factors into account, the following general population long term inhalation DNEL for local effects is:

12.5 mg/m³ / (1 x 1 x 1 x 10) = 12.5 mg/m³ / 10

= 1.25 mg/m³

 

Long-term exposure - systemic effects

In a 90-day oral repeated dose toxicity study (BASF, 1995) and an oral 2 generation study (BASF, 2009) in rats, similar NOAELs were identified. Both studies showed peroxisomal proliferation, altered liver metabolism and associated secondary changes in blood parameters, and reduced body weight gain. As peroxisomal proliferation is not relevant for human health hazard the NOAEL relevant for human health is 196 mg/kg bw/day (90 -day study) and 200 mg/kg (2 -generation study). Since a significant increase in exposure time (from 90 to 120 -130 days) did not alter the NOAEL or lead to more severe effects, an additional factor for exposure duration is not required.

Considering the appropriate modification and assessment factors, the worker DNEL (long-term inhalation exposure) is calculated as follows:

Inhalation exposure

Modification into a correct starting point:

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

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

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

 

Corrected inhalatory NOAEC for general population

= 200 mg/kg bw/day × 0.5 / 1.15 m³/kg bw

= 87 mg/m³

 

Assessment factors:

Dose response differences: 1

Differences in exposure duration: 1

Interspecies differences (allometric scaling): 1

Intraspecies differences (general population): 10

 

Taking the above mentioned assessment factors into account, the following worker long term inhalation DNEL for systemic effects is:

87 mg/m³ / (1 x 1 x 1 x 10) = 87 mg/m³ / 10

= 8.7 mg/m³

 

As the inhalation DNEL for long term local effects is lower than the inhalation DNEL for long term systemic effects, systemic effects are fully covered by the DNEL for long term local effects.

 

Dermal exposure

Modification of the dose descriptor

Dose descriptor of relevant study: The dermal absorption is considered to be 4%, the oral absorption is considered to be 50%.

 

Relevant starting point NOAEL dermal = (200 mg/kg bw/day x 0.5) / 0.04 = 2500 mg/kg bw/day

 

Assessment factors:

Dose response differences: 1

Differences in exposure duration: 1

Interspecies differences (allometric scaling): 4

Intraspecies differences (general population): 10

 

Taking the above mentioned assessment factors into account, the following general population DNEL

(dermal exposure) is 2500 mg/kg bw/d / (1 x 1 x 4 x 10) = 2500 mg/kg bw/day / 40

= 62.5 mg/kg bw/day    

 

Oral exposure

Relevant starting point NOAEL oral = 200 mg/kg bw/day

 

Assessment factors:

Dose response differences: 1

Differences in exposure duration: 1

Interspecies differences (allometric scaling): 4

Intraspecies differences (general population): 10

 

Taking the above mentioned assessment factors into account, the following general population DNEL

(oral exposure) is 200 mg/kg bw/d / (1 x 1 x 4 x 10) = 200 mg/kg bw/day / 40

= 5 mg/kg bw/day  

 

References  

- ECHA (2010). 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.