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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
24.7 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):
25
Dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
617.1 mg/m³
Explanation for the modification of the dose descriptor starting point:

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


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


Corrected NOAEC (inhalation) for workers:


NOECcorr = NOAELoral x 1/0.38 m³/kg bw/day x 6.7 m³/10m³ x 7d/5d x ABSoral/ABSinh


NOECcorr = 500 mg/kg bw/day x 1/0.38 m³/kg bw/day x 6.7 m³/10m³ x 7d/5d x 1/2

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:
Extrapolation from subchronic to chronic exposure.
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 408 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:
1
Justification:
DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties is applied.
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:
7 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:
500 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
700 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Oral absorption of the rat/ dermal absorption of humans (ABS oral-rat / ABS derm-human): 1/1


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


Corrected NOAEL (dermal) for workers:


NOAELcorr = NOAELoral x 7d/5d x ABSoral/ABSinh


NOAELcorr = 500 mg/kg bw/day x 7d/5d x 1/1

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:
2
Justification:
Extrapolation from subchronic to chronic exposure.
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.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 408 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:
1
Justification:
DNEL derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties is applied.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
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)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

Systemic long-term DNEL for inhalation exposure


The respective NOAEC is based on a NOAEL of 500 mg/kg bw/day from a subchronic oral rat study with the analogue substance (CAS 18479-58-8) and considering an oral bioavailability of 100%. It was modified  using a human standard respiratory volume (sRVhuman) of 6.7 m3 for 8 hours per person (70 kg), a rat standard respiratory volume (sRVrat) of 0.38 m3/kg bw for 8 hours, a worker respiratory volume (wRV) of 10 m³ for 8 hours with light physical activity, the default quotient of ½ for oral absorption of the rat and inhalation absorption of humans (ABS oral-rat / ABS inh-human) and a correction for difference between human and experimental exposure conditions (7 days exposure of the rats/5 days exposure of worker per week) to 617.1mg/m3 using the equation provided in the Guidance Document on Information Requirement, Chapter R8:


NOECcorr = NOAELoral x 1/0.38 m³/kg bw/day x 6.7 m³/10m³ x 7d/5d x ABSoral/ABSinh


Using assessment factors of (i) 2 for duration of exposure, (ii) 2.5 for remaining species differences and (iii) 5 for intraspecies extrapolation, a DNEL of 24.7 mg/m3 for long-term, systemic inhalative exposure was calculated.


 


Systemic acute DNEL for inhalation exposure


In accordance with column 2 of REACH Annex VIII, an acute inhalation toxicity study (required in section 8.5.3) does not need to be conducted as the oral and dermal routes are more relevant for exposure and no adverse systemic effects were observed in the acute oral toxicity study and in in vivo skin irritation/sensitisation studies. Due to the physico-chemical properties of the substance (especially the low volatility; vapour pressure =20 Pa), high peak-inhalation exposure is not considered relevant. Moreover, the LD50 of the test item as well as the read-across substance (CAS 18479-58-8) in rats by the oral route was more than 2000 mg/kg bw and therefore acute toxicity is of low concern. Long-term DNELs are considered sufficient to ensure that acute effects do not occur.


 


Local long-term and acute DNELs for inhalation exposure


No study on respiratory irritation is available, but, due to the physico-chemical properties of the substance (especially the low volatility; vapour pressure = 20 Pa), inhalation exposure is considered unlikely. Furthermore, the test item was not classified for skin sensitisation. Therefore, although the test item is classified for skin and eye irritation (cat. 2) according to Regulation (EC) No 1272/2008 (CLP), long-term local effects in the respiratory tract are not expected.


 


Systemic long-term DNEL for dermal exposure


The NOAEL of 500 mg/kg bw/day from a subchronic oral toxicity study with the analogue substance (CAS 18479-58-8) according to OECD guideline 408 is used as POD. It was modified using a correction for difference between human and experimental exposure conditions (7 days exposure of the rats/5 days exposure of worker per week) to 700 mg/kg bw/day using the equation provided in the Guidance Document on Information Requirement, Chapter R8:


NOAELcorr = NOAELdermal x 7d/5d


Using assessment factors of (i) 2 for duration of exposure, (ii) 4 for interspecies differences (allometric scaling), (iii) 2.5 for remaining interspecies differences and (iiii) 5 for intraspecies extrapolation, a DNEL of 7 mg/kg bw/day for long-term, systemic dermal exposure was calculated.


 


Systemic acute DNEL for dermal exposure


No acute dermal toxicity study is available. In accordance with column 2 of REACH Annex VIII, an acute dermal toxicity study (required in section 8.5.3) does not need to be conducted as no adverse systemic effects were observed in the acute oral toxicity study and in in vivo skin irritation/ sensitisation studies. Long-term DNELs are considered sufficient to ensure that acute effects do not occur.


 


Local long-term and acute DNELs for dermal exposure


The substance is irritating to skin and eyes but is not classified for skin sensitisation. Therefore, appropriate qualitative risk managements measures should be implemented to avoid exposure. A qualitative risk assessment is applied and the substance is assigned to the low hazard band in accordance with ECHA Guidance on information requirements and chemical safety assessment Part E: Risk Characterisation (2016).


 


Hazard for the eyes


According to CLP Regulation (EC 1272/2008), the test substance is classified as eye irritant (category 2). Thus, a qualitative risk assessment is conducted. Appropriate qualitative risk managements measures should be implemented to avoid exposure. The substance is assigned to the low hazard band in accordance with ECHA Guidance on information requirements and chemical safety assessment Part E: Risk Characterisation (2016).


 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.35 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:
500 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
217.5 mg/m³
Explanation for the modification of the dose descriptor starting point:

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


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


Corrected NOAEC (inhalation) for general population:


NOECcorr = NOAELoral x 1/1.15 m³/kg bw/day x ABSoral/ABSinh


NOECcorr = 500 mg/kg bw/day x 0.87 m³/kg bw/day x 1/2

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:
Extrapolation from subchronic to chronic exposure.
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 heterogenous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
The OECD TG 408 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:
1
Justification:
DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties is applied.
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:
2.5 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):
200
Dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No corrections are needed as a similar absorption through the oral and dermal route is assumed.

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:
Extrapolation from subchronic to chronic exposure.
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 heterogenous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
The study was conducted with only minor deviations from OECD TG 408 which did not affect the quality of the results. The 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:
1
Justification:
DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties is applied.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.5 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):
200
Dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No modification is needed as the same route of exposure is assessed and the same exposure period is assumed.

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:
Extrapolation from subchronic to chronic exposure.
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 heterogenous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
The study was conducted according to OECD TG 408. The 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:
1
Justification:
DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties is applied.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

Systemic long-term DNEL for inhalation exposure


The respective NOAEC is based on a NOAEL of 500 mg/kg bw/day from a subchronic oral rat study and considering an oral bioavailability of 100%. It was modified  using a rat standard respiratory volume (sRVrat) of 1.15 m3/kg bw/day for 24 hours and the default quotient of ½ for oral absorption of the rat and inhalation absorption of humans (ABS oral-rat / ABS inh-human) to 217.5 mg/m³ using the equation provided in the Guidance Document on Information Requirement, Chapter R8.


NOECcorr = NOAELoral x 1/1.15 m³/kg bw/day x ABSoral/ABSinh


Using assessment factors of (i) 2 for duration of exposure, (ii) 2.5 for remaining species differences and (iii) 10 for intraspecies extrapolation, a DNEL of 4.35 mg/m3 for long-term, systemic inhalative exposure was calculated.


 


Systemic acute DNEL for inhalation exposure


In accordance with column 2 of REACH Annex VIII, an acute inhalation toxicity study (required in section 8.5.3) does not need to be conducted as the oral and dermal routes are more relevant for exposure and no adverse systemic effects were observed in the acute oral toxicity study and in in vivo skin irritation/sensitisation studies. Due to the physico-chemical properties of the substance (especially the low volatility; vapour pressure =20 Pa), high peak-inhalation exposure is not considered relevant. Moreover, the LD50 of the test item as well as the read-across substance (CAS 18479-58-8) in rats by the oral route was more than 2000 mg/kg bw and therefore acute toxicity is of low concern. Long-term DNELs are considered sufficient to ensure that acute effects do not occur.


 


Local long-term and acute DNELs for inhalation exposure


No study on respiratory irritation is available, but, due to the physico-chemical properties of the substance (especially the low volatility; vapour pressure = 20 Pa), inhalation exposure is considered unlikely. Furthermore, the test item was not classified for skin sensitisation. Therefore, although the test item is classified for skin and eye irritation (cat. 2) according to Regulation (EC) No 1272/2008 (CLP), long-term local effects in the respiratory tract are not expected.


 


Systemic long-term DNEL for dermal exposure


The NOAEL of 500 mg/kg bw/day from a subchronic oral toxicity study with the analogue substance (CAS 18479-58-8) according to OECD guideline 408 is used as POD. It was modified using a correction for difference between human and experimental exposure conditions (7 days exposure of the rats/5 days exposure of worker per week) to 700 mg/kg bw/day using the equation provided in the Guidance Document on Information Requirement, Chapter R8:


NOAELcorr = NOAELdermal x 7d/5d


Using assessment factors of (i) 2 for duration of exposure, (ii) 4 for interspecies differences (allometric scaling), (iii) 2.5 for remaining interspecies differences and (iiii) 10 for intraspecies extrapolation, a DNEL of 2.5 mg/kg bw/day for long-term, systemic dermal exposure was calculated.


 


Systemic acute DNEL for dermal exposure


No acute dermal toxicity study is available. In accordance with column 2 of REACH Annex VIII, an acute dermal toxicity study (required in section 8.5.3) does not need to be conducted as no adverse systemic effects were observed in the acute oral toxicity study and in in vivo skin irritation/ sensitisation studies. Long-term DNELs are considered sufficient to ensure that acute effects do not occur.


 


Local long-term and acute DNELs for dermal exposure


The substance is irritating to skin and eyes but is not classified for skin sensitisation. Therefore, appropriate qualitative risk managements measures should be implemented to avoid exposure. A qualitative risk assessment is applied and the substance is assigned to the low hazard band in accordance with ECHA Guidance on information requirements and chemical safety assessment Part E: Risk Characterisation (2016).


 


Systemic long-term DNEL for oral exposure


The NOAEL of 500 mg/kg bw/day from a subchronic oral toxicity study with an analogue substance (CAS 18479-58-8) according to OECD guideline 408 is used as POD considering a 100% oral absorption. It did not have to be modified according to Guidance Document on Information Requirement, Chapter R8


Using assessment factors of (i) 2 for duration of exposure, (ii) 4 for interspecies differences (allometric scaling), (iii) 2.5 for remaining interspecies differences and (iiii) 10 for intraspecies extrapolation, a DNEL of 2.5 mg/kg bw/day for long-term, systemic dermal exposure was calculated.


 


Systemic acute DNEL for oral exposure


The LD50 of the test substance as well as for the read-across substance (CAS 18479-58-8) in rats by the oral route was more than 2000 mg/kg bw and therefore acute toxicity is of a low concern. Long-term DNELs are considered sufficient to ensure that acute effects do not occur.


 


Hazard for the eyes


According to CLP Regulation (EC 1272/2008), the test substance is classified as eye irritant (category 2). Thus, a qualitative risk assessment is conducted. Appropriate qualitative risk managements measures should be implemented to avoid exposure. The substance is assigned to the low hazard band in accordance with ECHA Guidance on information requirements and chemical safety assessment Part E: Risk Characterisation (2016).