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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.164 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):
75
Dose descriptor starting point:
NOAEL
Value:
5 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
12.3 mg/m³
Explanation for the modification of the dose descriptor starting point:

Kinetics (metabolism, distribution and excretion) are considered to be similar for oral and inhalation intake in the absence of evidence of the opposite.


Starting point:


NOAEL of 5 mg/kg bw/day in a 28-day repeated dose toxicity study in rat.


An additional factor of 1.4 was included in the modification calculation to take into account correction for differences between human and experimental exposure conditions. When correcting an oral NOAEL to inhalation NOAEC the correction factor for worker population would be: 7 day/week (experimental animal exposure, check study) / 5 days/week (worker exposure conditions) = 1.4. This additional factor is also provided by the IUCLID DNEL calculator tool.


 


Conversion of an oral NOAEL into a corrected NOAEC:


For workers (8h exposure/day), the corrected inhalatory NOAEC = oral NOAEL * 1/sRVrat * ABSoral-rat /ABSinhal-human * sRVhuman/wRV


= 5 * 1/0.38 m3/kg/8h * ABSoral-rat /ABSinhal-human * 6.7 m3


(8h)/10 m3 (8h) *1.4 


= 5 * 1/0.38 m3/kg/8h * 1 * 6.7 m3 (8h)/10 m3 (8h) *1.4


= 5 /0.38 * 1* (6.7/10) * 1.4 = 12.3 mg/m3


 


With ABS: Absorption, sRV: Standard Respiratory Volume; wRV: Worker Respiratory Volume;


ABSoral-rat /ABSinhal-human= 100/100= 1, assuming no differences in inhalation absorption between rats and humans.

AF for dose response relationship:
1
Justification:
Based on NOAEL
AF for differences in duration of exposure:
6
Justification:
Extrapolation from subacute study to chronic exposure worker
AF for interspecies differences (allometric scaling):
1
Justification:
No correction for caloric demand for inhalation; is included in dose descriptor starting point
AF for other interspecies differences:
2.5
Justification:
Factor to correct for toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part). No substance-specific information is available to address this aspect more specifically.
AF for intraspecies differences:
5
Justification:
Difference in sensitivity among workers
AF for the quality of the whole database:
1
Justification:
Reliable studies
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
33.33 µg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
300
Dose descriptor starting point:
NOAEL
Value:
10 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No modification needed, repeated dose study via the dermal route is available

AF for dose response relationship:
1
Justification:
Value is NOAEL
AF for differences in duration of exposure:
6
Justification:
Extrapolation from subacute study to chronic exposure worker
AF for interspecies differences (allometric scaling):
4
Justification:
Correction for caloric demand from rat to human
AF for other interspecies differences:
2.5
Justification:
Factor to correct for toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part). No substance-specific information is available to address this aspect more specifically.
AF for intraspecies differences:
5
Justification:
Difference in sensitivity among workers
AF for the quality of the whole database:
1
Justification:
Reliable studies used
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.75 µg/cm²
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
5
Dose descriptor:
other: NOAEL
AF for dose response relationship:
1
Justification:
Value is NOAEL
AF for differences in duration of exposure:
1
Justification:
Local effects are not dependent on exposure duration
AF for interspecies differences (allometric scaling):
1
Justification:
No correction for caloric demand needed for local effects
AF for other interspecies differences:
1
Justification:
For effects on the skin, eye or GI tract, where the mechanism of effect is direct chemical/pH reactivity, no further kinetic considerations apply and no safety factor needs to be included. Where tissue metabolism is a factor, the same kinetic and dynamic considerations (i.e. a chemical specific remaining uncertainties factor or the default factor of 2.5) should apply
AF for intraspecies differences:
5
Justification:
Difference in sensitivity among workers
AF for the quality of the whole database:
1
Justification:
Reliable studies used
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high 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:
0.029 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):
150
Dose descriptor starting point:
NOAEL
Value:
5 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
4.35 mg/m³
Explanation for the modification of the dose descriptor starting point:

Kinetics (metabolism, distribution and excretion) are considered to be similar for oral and inhalation intake in the absence of evidence of the opposite.


For the general population (24h exposure/day), the corrected inhalatory NOAEC = oral NOAEL * 1/sRVrat * ABSoral-rat /ABSinhal-human


= 5 * 1/1.15 m3/kg * ABSoral-rat /ABSinhal-human


= 5 * 1/1.15 m3/kg  * 1 =  4.35 mg/m3


 


With ABS: Absorption, sRV: Standard Respiratory Volume;


ABSoral-rat /ABSinhal-human= 100/100= 1, assuming no differences in inhalation absorption between rats and humans.

AF for dose response relationship:
1
Justification:
Value is NOAEL
AF for differences in duration of exposure:
6
Justification:
Extrapolation from subacute study to chronic exposure
AF for interspecies differences (allometric scaling):
1
Justification:
No correction for caloric demand for inhalation; is included in dose descriptor starting point
AF for other interspecies differences:
2.5
Justification:
Factor to correct for toxicokinetic differences not related to metabolic
rate (small part) and toxicodynamic differences (larger part). No substance-specific information is available to address this aspect more specifically. In case substance-specific information shows specific susceptibility differences between species, which are not related to differences in basal metabolic rate, the additional factor of 2.5 for ‘remaining differences’ should be modified accordingly.
AF for intraspecies differences:
10
Justification:
Difference in sensitivity within general population
AF for the quality of the whole database:
1
Justification:
Reliable studies used
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
16.67 µg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
600
Dose descriptor starting point:
NOAEL
Value:
10 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No modification needed, repeated dose study via the dermal route is available

AF for dose response relationship:
1
Justification:
Value is NOAEL
AF for differences in duration of exposure:
6
Justification:
Extrapolation from subacute study to chronic exposure
AF for interspecies differences (allometric scaling):
4
Justification:
Correction for caloric demand from rat to human
AF for other interspecies differences:
2.5
Justification:
Factor to correct for toxicokinetic differences not related to metabolic
rate (small part) and toxicodynamic differences (larger part). No substance-specific information is available to address this aspect more specifically.
AF for intraspecies differences:
10
Justification:
Difference in sensitivity within general population
AF for the quality of the whole database:
1
Justification:
Reliable studies used
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.875 µg/cm²
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
10
Dose descriptor:
other: NOAEL
AF for dose response relationship:
1
Justification:
Value is NOAEL
AF for differences in duration of exposure:
1
Justification:
Local effects are not dependent on exposure duration
AF for interspecies differences (allometric scaling):
1
Justification:
No correction for caloric demand needed for local effects
AF for other interspecies differences:
1
Justification:
For effects on the skin, eye or GI tract, where the mechanism of effect is direct chemical/pH reactivity, no further kinetic considerations apply and no safety factor needs to be included. Where tissue metabolism is a factor, the same kinetic and dynamic considerations (i.e. a chemical specific remaining uncertainties factor or the default factor of 2.5) should apply
AF for intraspecies differences:
10
Justification:
Difference in sensitivity within general population
AF for the quality of the whole database:
1
Justification:
Reliable studies used
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.33 µg/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):
600
Dose descriptor starting point:
NOAEL
Value:
5 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No modification needed, repeated dose study via the oral route is available

AF for dose response relationship:
1
Justification:
Value is NOAEL
AF for differences in duration of exposure:
6
Justification:
Extrapolation from subacute study to chronic exposure
AF for interspecies differences (allometric scaling):
4
Justification:
Correction for caloric demand from rat to human
AF for other interspecies differences:
2.5
Justification:
Factor to correct for toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part). No substance-specific information is available to address this aspect more specifically.
AF for intraspecies differences:
10
Justification:
Difference in sensitivity among general population
AF for the quality of the whole database:
1
Justification:
Reliable studies used
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - General Population