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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
70.52 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:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
1 763 mg/m³
Explanation for the modification of the dose descriptor starting point:

No long-term repeated dose toxicity study via inhalation with the test substance is available. In the 90 days repeated dose oral toxicity study with the test substance, a subchronic NOAEL of 1000 mg/kg bw/day (actual ingested, via gavage) was observed in both female and male rats (OECD 408; Wood, 2019; key). No adverse effects were observed in the study, where following doses were administered: 0, 10, 100, 1000 mg/kg bw/day for 90 consecutive days. This NOAEL of 1000 mg/kg bw/day was confirmed in an extended one-generation reproductive toxicity study in rats (OECD443, K1; Labcorp Early Development Laboratories Ltd, 2021) where the daily doses were 150, 450 or 1000 mg/kg bw/day. 


For the route-to-route extrapolation from oral to inhalation, the dose descriptor starting point = 1000 mg/kg bw/day x 1/(0.38 m³/kg bw/d) x 6.7 m³/10 m³ = 1763 mg/m³. The oral dose for rats was converted to the corresponding air concentration using a standard breathing volume for the rat (0.38


m³/ kg for 8 hours exposure of workers). For workers the resulting air concentration needs to be additionally corrected for the difference between basal caloric demand and caloric demand under light activity. This correction factor derives from the inhalative volumes in 8 hours under the respective conditions (6.7 m³ for base level, 10 m³ for light activity). No additional correction factor is needed as the bioavailability via both the inhalation and the oral route is considered 100%.

AF for dose response relationship:
1
Justification:
NOAEL used as starting point
AF for differences in duration of exposure:
2
Justification:
difference in duration, subchronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
included in route-to-route extrapolation
AF for other interspecies differences:
2.5
Justification:
default value
AF for intraspecies differences:
5
Justification:
worker population
AF for the quality of the whole database:
1
Justification:
no need for further assessment factor
AF for remaining uncertainties:
1
Justification:
no need for further assessment factor
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:
10 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:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No long-term repeated dose toxicity study via dermal application is available with the test substance. In the 90 days repeated dose oral toxicity study with the test substance, a subchronic NOAEL of 1000 mg/kg bw/day (actual ingested, via gavage) was observed in both female and male rats (OECD 408; Wood, 2019; key). No adverse effects were observed in the study, where following doses were administered: 0, 10, 100, 1000 mg/kg bw/day for 90 consecutive days. This NOAEL of 1000 mg/kg bw/day was confirmed in an extended one-generation reproductive toxicity study in rats (OECD443, K1; Labcorp Early Development Laboratories Ltd, 2021) where the daily doses were 150, 450 or 1000 mg/kg bw/day. 


Based on this information, the chronic NOAEL of 1000 mg/kg bw/d was used as a starting point for the calculation of the dermal, long-term, systemic DNEL for workers. No additional correction factor is needed as the bioavailability via both the dermal and the oral route is considered 100%.

AF for dose response relationship:
1
Justification:
NOAEL is used as a starting point
AF for differences in duration of exposure:
2
Justification:
difference in duration, subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
rat to human
AF for other interspecies differences:
2.5
Justification:
default value
AF for intraspecies differences:
5
Justification:
worker population
AF for the quality of the whole database:
1
Justification:
no need for further assessment factor
AF for remaining uncertainties:
1
Justification:
no need for further assessment factor
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
17.4 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:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
870 mg/m³
Explanation for the modification of the dose descriptor starting point:

On the basis of the 90 days repeated dose oral toxicity study with the test substance, a chronic NOAEL of 1000 mg/kg bw/day (actual ingested, via gavage) was observed in both female and male rats. No adverse effects were observed in the study, where following doses were administered: 0, 10, 100, 1000 mg/ kg bw/day for 90 consecutive days. The study was performed according to OECD guideline 408. This study is used a pivotal study to derive the DNEL. In a combined reproduction / developmental toxicity screening study, rats were exposed to 1000 mg/kg bw/ d for a minimum of four weeks according to OECD Guideline 421. No adverse effects were observed in the parental animals nor in the F1 progeny. This NOAEL of 1000 mg/kg bw/day was confirmed in an extended one-generation reproductive toxicity study in rats (OECD443, K1; Labcorp Early Development Laboratories Ltd, 2021) where the daily doses were 150, 450 or 1000 mg/kg bw/day. 


For the route-to-route extrapolation from oral to inhalation, the dose descriptor starting point = 1000 mg/ kg bw/d x 1/1.15 m³/kg/d = 870 mg/m³. The oral dose for rats was converted to the corresponding air concentration using a standard breathing volume for the rat (1.15 m³/kg for 24 hours exposure). No additional correction factor is needed as the bioavailability via both the inhalation and the oral route is considered 100%.

AF for dose response relationship:
1
Justification:
NOAEL is used as starting point
AF for differences in duration of exposure:
2
Justification:
subchronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
included in route-to-route extrapolation
AF for other interspecies differences:
2.5
Justification:
default value
AF for intraspecies differences:
10
Justification:
general population
AF for the quality of the whole database:
1
Justification:
no need for further assessment factor
AF for remaining uncertainties:
1
Justification:
no need for further assessment factor
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:
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:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

On the basis of the 90 days repeated dose oral toxicity study with the test substance, a chronic NOAEL of 1000 mg/kg bw/day (actual ingested, via gavage) was observed in both female and male rats. No adverse effects were observed in the study, where following doses were administered: 0, 10, 100, 1000 mg/ kg bw/day for 90 consecutive days. The study was performed according to OECD guideline 408. This study is used a pivotal study to derive the DNEL. In a reproduction / developmental toxicity screening study, rats were exposed to 1000 mg/kg bw/d for a minimum of four weeks according to OECD Guideline 421. No adverse effects were observed in the parental animals nor in the F1 progeny. This NOAEL of 1000 mg/kg bw/day was confirmed in an extended one-generation reproductive toxicity study in rats (OECD443, K1; Labcorp Early Development Laboratories Ltd, 2021) where the daily doses were 150, 450 or 1000 mg/kg bw/day.  Based on this information, the chronic NOAEL of 1000 mg/kg bw/was used as a starting point for the calculation of the dermal, long-term, systemic DNEL. No additional correction factor is needed as the bioavailability via both the dermal and the oral route is considered 100%.

AF for dose response relationship:
1
Justification:
NOAEL as starting point
AF for differences in duration of exposure:
2
Justification:
subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
rat to human
AF for other interspecies differences:
2.5
Justification:
default value
AF for intraspecies differences:
10
Justification:
general population
AF for the quality of the whole database:
1
Justification:
no need for further assessment factor
AF for remaining uncertainties:
1
Justification:
no need for further assessment factor
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):
200
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

On the basis of the 90 days repeated dose oral toxicity study with the test substance, a chronic NOAEL of 1000 mg/kg bw/day (actual ingested, via gavage) was observed in both female and male rats. No adverse effects were observed in the study, where following doses were administered: 0, 10, 100, 1000 mg/ kg bw/day for 90 consecutive days. The study was performed according to OECD guideline 408. In a reproduction / developmental toxicity screening study, rats were exposed to 1000 mg/kg bw/day for a minimum of four weeks according to OECD Guideline 421. No adverse effects were observed in the parental animals nor in the F1 progeny. Based on this information, the chronic NOAEL of 1000 mg/kg bw/day was used as a starting point.

AF for dose response relationship:
1
Justification:
NOAEL was used as starting point
AF for differences in duration of exposure:
2
Justification:
subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
rat to human
AF for other interspecies differences:
2.5
Justification:
default value
AF for intraspecies differences:
10
Justification:
general population
AF for the quality of the whole database:
1
Justification:
no need for further assessment factor
AF for remaining uncertainties:
1
Justification:
no need for further assessment factor
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population