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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
other toxicological threshold
Value:
3 mg/m³
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:
83 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):
120
Modified dose descriptor starting point:
NOAEL
Value:
10 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by the dermal 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:
6
Justification:
The default extrapolation factor for exposure duration is used: subacute (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:
1
Justification:
There is no evidence for species differences in the general mode of action or kinetics.
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
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

Long-term exposure - systemic effects


Inhalation exposure


In the absence of an suitable inhalation toxicity study with repeated exposure, the worker-DNEL (long-term inhalation, systemic) was derived from the NOAEL obtained in the 28 -Day Oral Gavage Toxicity study in Wistar rats. A corrected inhalatory NOAEC (NOAECcorr) was calculated using a default respiratory volume for the rat and a correction for the difference between human respiratory rats under standard conditions and under conditions of light activity (under the assumption of no difference in absorption between rat and human, and between routes). Using this NOAECcorr and considering the appropriate modification and assessment factors, the worker-DNEL (long-term inhalation, systemic) was calculated to be 59 mg/m³ (see below).


 


Calculation of the NOAECcorr


- Standard dose descriptor (NOAEL): 1000 mg/kg bw/d


- 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)/ABSinhal-human): 1/1


- 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:


= NOAEL * (1/sRVrat) * (ABSoral-rat/ABSinhal-human) *(sRVhuman/wRV)


= 1000 mg/kg bw/d * (1/0.38 m³/kg bw/d)* (1/1) * (6.7m³/10 m³)


= 1762 mg/m³


 


Calculation of the worker-DNELlong-term for inhalation route-systemic


- Corrected inhalatory NOAEC for workers: 1762 mg/m³


- Assessment Factor for dose response relationship: 1


Justification: The dose response relationship is considered unremarkable, therefore no additional factor is used.


- Assessment Factor for differences in duration of exposure: 6


Justification: The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).


- Assessment Factor for interspecies differences (allometric scaling): 1


Justification: Allometric scaling is not applied, because the ventilation rate directly depends on the basal metabolic rate.


- Assessment Factor for other interspecies differences: 1


Justification: There is no evidence for species differences in the general mode of action or kinetics.


- Assessment Factor for intraspecies differences: 5


Justification: The default value for the relatively homogenous group "worker" is used.


- Assessment Factor for the quality of the whole database: 1


Justification: The quality of the whole data base is considered to be sufficient and uncritical.


- Assessment Factor for remaining uncertainties: 1


Justification: The approach used for DNEL derivation is conservative. No further assessment factors are required.


Worker DNEL (long-term inhalation exposure) 


= 1762 mg/m³/6*5 = 59 mg/m³


 


References


 


ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health.Version: 2.1, ECHA-2012 -G-19 -EN.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
other toxicological threshold
Value:
3 mg/m³
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:
42 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):
240
Modified dose descriptor starting point:
NOAEL
Value:
10 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on repeated exposure by the dermal 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:
6
Justification:
The default extrapolation factor for exposure duration is used: subacute (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:
1
Justification:
There is no evidence for species differences in the general mode of action or kinetics.
AF for intraspecies differences:
10
Justification:
The default value for the relatively homogenous 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

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:
4.2 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):
240
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
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:
6
Justification:
The default extrapolation factor for exposure duration is used: subacute (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:
1
Justification:
There is no evidence for species differences in the general mode of action or kinetics.
AF for intraspecies differences:
10
Justification:
The default value for the relatively homogenous 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

Long-term exposure - systemic effects

Inhalation exposure

In the absence of a suitable inhalation toxicity study with repeated exposure, the general population-DNEL (long-term inhalation, systemic) was derived from the NOAEL obtained in the 28 -Day Oral Gavage Toxicity study in Wistar rats. A corrected inhalatory NOAEC (NOAECcorr) was calculated using a default respiratory volume for the rat (under the assumption of no difference in absorption between rat and human, and between routes). Using this NOAECcorr and considering the appropriate modification and assessment factors, the general population-DNEL (long-term for inhalation route-systemic) was calculated to be 14.5 mg/m³ (see below).

 

Calculation of the NOAECcorr

- Standard dose descriptor (NOAEL): 1000 mg/kg bw

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

- Oral absorption of the rat/inhalation absorption of humans (ABSoral-rat)/ABSinhal-human): 1/1

Corrected inhalatory NOAEC for general population:

= NOAEL * (1/sRVrat) * (ABSoral-rat/ABSinhal-human)

= 1000 mg/kg bw/d * (1/1.15 m³/kg bw/d)* (1/1)

= 870 mg/m³

Calculation of the general population-DNEL long term for inhalation route-systemic

- Corrected inhalatory NOAEC for general population: 870 mg/m³

- Assessment Factor for dose response relationship: 1

Justification: The dose response relationship is considered unremarkable, therefore no additional factor is used.

- Assessment Factor for differences in duration of exposure: 6

Justification: The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).

- Assessment Factor for interspecies differences (allometric scaling): 1

Justification: Allometric scaling is not applied, because the ventilation rate directly depends on the basal metabolic rate.

- Assessment Factor for other interspecies differences: 1

Justification: There is no evidence for species differences in the general mode of action or kinetics.

- Assessment Factor for intraspecies differences: 10

Justification: The default value for the relatively homogenous group "general population" is used.

- Assessment Factor for the quality of the whole database: 1

Justification: The quality of the whole data base is considered to be sufficient and uncritical.

- Assessment Factor for remaining uncertainties: 1

Justification: The approach used for DNEL derivation is conservative. No further assessment factors are required.

General population DNEL (long-term inhalation exposure)

= 870 mg/m³/6*10 = 14.5 mg/m³

References

ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health.Version: 2.1, ECHA-2012 -G-19 -EN.