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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.175 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:
50 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
88.1 mg/m³
Explanation for the modification of the dose descriptor starting point:

The dose descriptor start point is modified from a NOAEL by oral administration in rats (mg/kg/day) to a No Observed Adverse Effect Concentration (NOAEC) in humans by inhalation exposure (mg/m3) before Adjustment Factors (AFs) can be applied to determine the DNEL. The conversion in accordance with ECHA Guidance on Information Requirements and Chemical Safety Assessment Chapter R8 is as follows (in case of Workers exposed 8 hours/day):

NOAEC = oral NOAEL x 1/sRVratx ABSoral rat/ABSinh humanx sRVhuman/wRV

Where:            sRV = Standard Respiratory Volume (0.38 m3rat and 6.7 m3human)
                       ABS = Absorption
                       wRV = Worker Respiratory Volume (10 m3)

NOAEC = 50 x 1/0.38 x 1/1 x 6.7/10 where worst-case absorption scenario is assumed
NOAEC = 88.1 mg/m3

AF for dose response relationship:
1
Justification:
NOAEL taken s PoD for modification
AF for differences in duration of exposure:
6
Justification:
Subacute to hronic duration
AF for interspecies differences (allometric scaling):
1
Justification:
Not required since modificatin of oral NOAEL to inhalation NOAEC has been made
AF for other interspecies differences:
2.5
Justification:
Default factor for toxicokinetic and toxicodynamic differences
AF for intraspecies differences:
5
Justification:
Default factor for Workers as does not include the very old, the young or very ill individuals
AF for the quality of the whole database:
1
Justification:
Starting dose level taken from a GLP Guideline study
AF for remaining uncertainties:
1
Justification:
No other uncertainties
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Value:
722 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL
Dose descriptor starting point:
other: Systemic long term DNEL
Value:
1.175 mg/m³

Local effects

Long term exposure
Hazard assessment conclusion:
insufficient hazard data available (further information necessary)
Value:
722 mg/m³
Most sensitive endpoint:
acute toxicity
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Value:
722 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.5 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):
300
Dose descriptor starting point:
LOAEL
Value:
150 mg/kg bw/day
Modified dose descriptor starting point:
other: The LOAEL from the repeat dose oral toxicity study was taken as a NOAEL by dermal application based on the absence of toxicity in a dermal acute toxicity study
Value:
150 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No dermal hazard has been identified in an acute toxicity study in rats by the dermal route at the limit dose of 2000 mg/kg bw, and the substance has been classified as non-irritant and non-corrosive to the skin. There are no data available indicating any potential differences in absorption of the test substance between oral and dermal routes of exposure or between rats and humans. Consequently, selection of the acute NOAEL dose level of 2000 mg/kg bw was taken as indicative of lack of toxicological activity by this route and the high dose level in the repeat dose oral study, 150 mg/kg/day, was taken as the Point of Departure with no further modification other than the application of the AFs based upon the oral repeat dose LOAEL taken as a dermal NOAEL.

AF for dose response relationship:
1
Justification:
A predicted NOAEL taken as the start point
AF for differences in duration of exposure:
6
Justification:
Subacute to chronic extrapolation
AF for interspecies differences (allometric scaling):
4
Justification:
Default conversion from rat to human
AF for other interspecies differences:
2.5
Justification:
Default to allow for possible differences in metabolic parameters
AF for intraspecies differences:
5
Justification:
Default Worker AF which does not include the very old, very young or very ill.
AF for the quality of the whole database:
1
Justification:
Both the acute toxicity study and the repeated dose toxicity study were GLP and/or Guideline studies
AF for remaining uncertainties:
1
Justification:
There were no further uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Value:
2 000 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information
DNEL extrapolated from long term DNEL
Value:
0.5 mg/kg bw/day

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:
no hazard identified
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:
0.29 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:
50 mg/kg bw/day
Value:
43.5 mg/m³
Explanation for the modification of the dose descriptor starting point:

The dose descriptor start point is modified from a NOAEL by oral administration in rats (mg/kg/day) to a No Observed Adverse Effect Concentration (NOAEC) in humans by inhalation exposure (mg/m3) before Adjustment Factors (AFs) can be applied to determine the DNEL. The conversion in accordance with ECHA Guidance on Information Requirements and Chemical Safety Assessment Chapter R8 is as follows (in case of the General Population exposed 24 hours/day):

NOAEC = oral NOAEL x 1/sRVratx ABSoral rat/ABSinh human

Where:            sRV = Standard Respiratory Volume (1.15 m3/kg/day)
                       ABS = Absorption

NOAEC = 50 x 1/1.15 x 1/1 where worst-case absorption scenario is assumed
NOAEC = 43.5 mg/m3

AF for dose response relationship:
1
Justification:
NOAEL taken as PoD for modification
AF for differences in duration of exposure:
6
Justification:
Subacute to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Not required since modification of oral NOAEL to inhalation NOAEC has been made
AF for other interspecies differences:
2.5
Justification:
Default factor for toxicokinetic and toxicodynamic differences
AF for intraspecies differences:
10
Justification:
Default factor for General Population
AF for the quality of the whole database:
1
Justification:
Starting dose level taken from a GLP Guideline study
AF for remaining uncertainties:
1
Justification:
No further uncertainties
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Value:
722 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL
Dose descriptor starting point:
other: Modification of systemic long term DNEL
Value:
1.31 mg/m³

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard via dermal 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):
600
Dose descriptor starting point:
LOAEL
Value:
150 mg/kg bw/day
Modified dose descriptor starting point:
other: The LOAEL from the repeat dose oral toxicity study was taken as a NOAEL by dermal application based on the absence of toxicity in a dermal acute toxicity study
Value:
150 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No dermal hazard has been identified in an acute toxicity study in rats by the dermal route at the limit dose of 2000 mg/kg bw, and the substance has been classified as non-irritant and non-corrosive to the skin. There are no data available indicating any potential differences in absorption of the test substance between oral and dermal routes of exposure or between rats and humans. Consequently, selection of the acute NOAEL dose level of 2000 mg/kg bw was taken as indicative of lack of toxicological activity by this route and the high dose level in the repeat dose oral study, 150 mg/kg bw/day, was taken as the Point of Departure with no further modification other than the application of the AFs based upon the oral repeat dose LOAEL taken as a dermal NOAEL.

AF for dose response relationship:
1
Justification:
A predicted NOAEL taken as the start point
AF for differences in duration of exposure:
6
Justification:
Subacute to chronic extrapolation
AF for interspecies differences (allometric scaling):
4
Justification:
Default conversion from rat to human
AF for other interspecies differences:
2.5
Justification:
Default to allow for possible differences in metabolic parameters
AF for intraspecies differences:
10
Justification:
Default factor for General Population
AF for the quality of the whole database:
1
Justification:
Both the acute toxicity study and the repeated dose toxicity study were GLP and/or Guideline studies
AF for remaining uncertainties:
1
Justification:
No other uncertainties
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
83.3 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:
50 mg/kg bw/day
Value:
50 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Relevant dose descriptor is taken from a rat study by the same route of exposure and similar bioavailability is assumed by this route by rats and humans.

AF for dose response relationship:
1
Justification:
NOAEL taken as the start point
AF for differences in duration of exposure:
6
Justification:
Subacute to chronic extrapolation
AF for interspecies differences (allometric scaling):
4
Justification:
Default conversion from rat to human
AF for other interspecies differences:
2.5
Justification:
Default to allow for possible differences in metabolic parameters
AF for intraspecies differences:
10
Justification:
Default factor for General Population
AF for the quality of the whole database:
1
Justification:
Starting dose level taken from a GLP Guideline study
AF for remaining uncertainties:
1
Justification:
No other uncertainties
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population

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