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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.2 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Dose descriptor starting point:
NOAEC
Value:
207 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
104 mg/m³
Explanation for the modification of the dose descriptor starting point:

DNEL derivation is based on a 90-day toxicity study by inhalation administration to rats (TNO 2017). The starting concentration for DNEL calculation is a NOAEC of 207 mg/m3 (25.1 ppm).  The NAEC (8h) derived for workers is 104 mg/m3 (207 mg/m3 x 6h/8h x 6.7 m3/10 m3) after correction for difference in exposure conditions and between respiratory rates under standard conditions and under conditions of light activity.  

AF for dose response relationship:
1
Justification:
This factor is applied because the dose-descriptor starting point is a NOAEC.
AF for differences in duration of exposure:
2
Justification:
DNEL is based on a subchronic study (90-day).
AF for interspecies differences (allometric scaling):
1
Justification:
AF not used for inhalation. Allometric scaling is implicitly taken into account in the factor for remaining differences.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 is applied for remaining differences.
AF for intraspecies differences:
5
Justification:
A factor of 5 is applied for worker DNELs.
AF for the quality of the whole database:
1
Justification:
The key study chosen for DNEL calculation is considered as a reliable study.
AF for remaining uncertainties:
1
Justification:
No other assessment factor is applied.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
irritation (respiratory tract)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.5 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):
100
Dose descriptor starting point:
NOAEL
Value:
25 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
350 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Dermal DNEL derivation is based on the oral extended one generation reproduction toxicity study (OECD 443, CRL 2021) because the extrapolation between oral and dermal routes is more relevant that the dermal and inhalation routes based on the toxicokinetics.


The starting dose for the dermal DNEL calculation is an oral NOAEL of 25 mg/kg/day. 


Based on the TK assessment, a dermal absorption of 10% and an oral absorption of 100% were used.


Correction factor for difference between human and experimental exposure conditions : 7/5 (In the study, animals were exposed 7 days per week, and workers work 5 days per week).


Dermal NOAEL = oral NOAEL x 100/10 x 7/5= 25 x 100/10 x 7/5 = 350 mg/kg bw/day

AF for dose response relationship:
1
Justification:
This factor is applied because the dose-descriptor starting point is a NOAEL.
AF for differences in duration of exposure:
2
Justification:
DNEL is based on a subchronic study : in the EOGRTS, males and females were exposed at least 16 weeks.
AF for interspecies differences (allometric scaling):
4
Justification:
An allometric scaling factor of 4 must be applied because the key study was performed on rats.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 is applied for remaining differences.
AF for intraspecies differences:
5
Justification:
A factor of 5 is applied for worker DNELs.
AF for the quality of the whole database:
1
Justification:
The key study chosen for DNEL calculation is considered as a reliable study.
AF for remaining uncertainties:
1
Justification:
No other assessment factor is applied.
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:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
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

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:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Dose descriptor starting point:
NOAEC
Value:
207 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
37 mg/m³
Explanation for the modification of the dose descriptor starting point:

DNEL derivation is based on a 90-day toxicity study by inhalation administration to rats (TNO 2017). The starting dose for DNEL calculation is a NOAEC of 207 mg/m3. The NOAEC (24h) derived for the general population is 37 mg/m3 (207 mg/m3 x 6h/24h x 5d/7d) after correction for difference in exposure conditions.

AF for dose response relationship:
1
Justification:
This factor is applied because the dose-descriptor starting point is a NOAEC.
AF for differences in duration of exposure:
2
Justification:
DNEL is based on a subchronic study (90-day).
AF for interspecies differences (allometric scaling):
1
Justification:
AF not used for inhalation. Allometric scaling is implicitly taken into account in the factor for remaining differences.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 is applied for remaining differences
AF for intraspecies differences:
10
Justification:
A factor of 10 is applied for the general population DNELs.
AF for the quality of the whole database:
1
Justification:
The key study chosen for DNEL calculation is considered as a reliable study.
AF for remaining uncertainties:
1
Justification:
No other assessment factor is applied.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
irritation (respiratory tract)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
irritation (respiratory tract)
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):
100
Dose descriptor starting point:
NOAEL
Value:
25 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
250 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Dermal DNEL derivation is based on the oral extended one generation reproduction toxicity study (OECD 443, CRL 2021) because the extrapolation between oral and dermal routes is more relevant that the dermal and inhalation routes based on the toxicokinetics.


The starting dose for the dermal DNEL calculation is an oral NOAEL of 25 mg/kg/day. 


Based on the TK assessment, a dermal absorption of 10% and an oral absorption of 100% were used.


Dermal NOAEL = oral NOAEL x 100/10 = 25 x 100/10 = 250 mg/kg bw/day

AF for dose response relationship:
1
Justification:
This factor is applied because the dose-descriptor starting point is a NOAEL.
AF for differences in duration of exposure:
2
Justification:
DNEL is based on a subchronic study : in the EOGRTS, males and females were exposed at least 16 weeks
AF for interspecies differences (allometric scaling):
4
Justification:
An allometric scaling factor of 4 must be applied because the key study was performed on rats.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 is applied for remaining differences.
AF for intraspecies differences:
5
Justification:
A factor of 5 is applied for worker DNELs.
AF for the quality of the whole database:
1
Justification:
The key study chosen for DNEL calculation is considered as a reliable study.
AF for remaining uncertainties:
1
Justification:
No other assessment factor is applied.
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:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
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:
0.25 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:
25 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
25 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Oral DNEL derivation is based on the oral extended one generation reproduction toxicity study (OECD 443, CRL 2021), the most longer oral exposure study.


No difference between the oral absorption in rat and human is expected.

AF for dose response relationship:
1
Justification:
This factor is applied because the dose-descriptor starting point is a NOAEL
AF for differences in duration of exposure:
2
Justification:
DNEL is based on a subchronic study : in the EOGRTS, males and females were exposed at least 16 weeks
AF for interspecies differences (allometric scaling):
4
Justification:
An allometric scaling factor of 4 must be applied because the key study was performed on rats.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 is applied for remaining differences.
AF for intraspecies differences:
10
Justification:
A factor of 10 is applied for the general population DNELs.
AF for the quality of the whole database:
1
Justification:
The key study chosen for DNEL calculation is considered as a reliable study.
AF for remaining uncertainties:
1
Justification:
No other assessment factor is applied.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population