Registration Dossier

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
55.7 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:
1 129 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
1 393 mg/m³
Explanation for the modification of the dose descriptor starting point:

Route to route extrapolation required for oral to inhalation route as no long term inhalation study available.

The dose starting point was the NOAEL result of 1129 mg/kg bw/day (female rats) obtained from the 90-day oral repeated dose toxicity study.

A modification of the dose descriptor starting point (oral to inhalation) was conducted. It is assumed as a worst case assumption that the oral absorption rate is 50% of that of the inhalation absorption.

The corrected dose descriptor (NOAEC) for inhalation was calculated in accordance with the ECHA Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health.

The conversion of an oral rat NOAEL into a corrected inhalatory NOAEC to assess human inhalatory exposure was performed using the modification of starting point equation as given in Figure R. 8-3 (see below) for workers (in the case of 8 hour exposure/day).

Default parameters for rats and humans (for 8 hour exposure) were used for the modification of starting point under the allometric scaling principle as given in Table R. 8-2 of the above ECHA guidance.

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 NOEAL to inhaltion NOEAC the correction factor for worker population would be : 7 day/week (experimental animal exposure) / 5 days/week (worker exposure conditions) = 1.4. This additional factor is also provided by the IUCLID DNEL calculator tool (for dose-dependent effects).

Conversion of an oral rate N(L)OAEL into a correct inhalatory N(L)OAEC to assess human inhalatory exposure:

For workers (in case of 8h exposure/day):

Corrected inhalatory N(L)OAEC = oral N(L)OAEL x (1 / sRVrat) x (ABSoral-rat / ABSinh-human) x (sRVhuman / wRV) x 1.4

Corrected inhalatory N(L)OAEC= 1129 mg/kg bw/day x (1 / 0.38 m3/kg/d) x (0.5) x (6.7 m3(8h) / 10 m3(8h)) x 1.4 = 1393 mg/m3

Where:

ABS: Absorption

sRV: standard Respiratory Volume

wRV: worker Respiratory Volume (light activity)

Default parametrs:

sRVrat (8 h): 0.38m3/kg bw

sRVhuman (8 h): 6.7 m3/ person

wRV (8 h): 10 m3/ person

AF for dose response relationship:
1
Justification:
When the starting point for the DNEL calculation is a NOAEL an assessment factor of 1 is appropriate
AF for differences in duration of exposure:
2
Justification:
Default AF for subchronic (90 day) to chronic studies
AF for interspecies differences (allometric scaling):
1
Justification:
AF for allometric scaling not required as the differences in allometry (respiration rate and rat to human body sizes) were considered in the conversion from oral to inhalation starting point.
AF for other interspecies differences:
2.5
Justification:
Default AF for remaining interspecies differences
AF for intraspecies differences:
5
Justification:
Default AF for worker population
AF for the quality of the whole database:
1
Justification:
Relevant studies conducted to GLP and considered to be of reliability 1.
AF for remaining uncertainties:
1
Justification:
None considered applicable.
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:
15.8 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:
1 129 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 580.6 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Route to route extrapolation required for oral to dermal route as no long term dermal study available.

The dose starting point was the NOAEL result of 1129 mg/kg bw/day (female rats), obtained from the 90 day oral repeated dose toxicity study.

Modification of this oral result into a dermal starting point was performed.

It is considered that dermal absorption will not be higher than oral absorption, therefore no default factor (i.e. factor 1) should be introduced when performing oral-to dermal extrapolation.

An addition 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 NOEAL to dermal NOEAL the correction factor for worker population would be : 7 day/week (experimental animal exposure) / 5 days/week (worker exposure conditions) = 1.4.

This additional factor is also provided by the IUCLID DNEL calculator tool (for dose-dependent effects).

AF for dose response relationship:
1
Justification:
When the starting point for the DNEL calculation is a NOAEL an assessment factor of 1 is appropriate
AF for differences in duration of exposure:
2
Justification:
Default AF for subchronic (90 day) to chronic studies
AF for interspecies differences (allometric scaling):
4
Justification:
Default AF for allometric scaling based on rats
AF for other interspecies differences:
2.5
Justification:
Default AF for remaining interspecies differences
AF for intraspecies differences:
5
Justification:
Default AF for worker population
AF for the quality of the whole database:
1
Justification:
Relevant studies conducted to GLP and considered to be of reliability 1.
AF for remaining uncertainties:
1
Justification:
None considered applicable.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
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:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low 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:
9.82 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:
1 129 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
490.9 mg/m³
Explanation for the modification of the dose descriptor starting point:

Route to route extrapolation required for oral to inhalation route as no long term inhalation study available.

The dose starting point was the NOAEL result of 1129 mg/kg bw/day (female rats), obtained from the 90 day oral repeated dose toxicity study.

A modification of the dose descriptor starting point (oral to inhalation) was conducted. It is assumed as a worst case assumption that the oral absorption rate is 50% of that of the inhalation absorption.

The corrected dose descriptor (NOAEC) for inhalation was calculated in accordance with the ECHA Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health.

Conversion of an oral rate N(L)OAEL into a correct inhalatory N(L)OAEC to assess human inhalatory exposure:

For general population (in case of 24 h exposure/day):

Corrected inhalatory N(L)OAEC = oral N(L)OAEL x (1 / sRVrat) x (ABSoral-rat / ABSinh-human)

Corrected inhalatory N(L)OAEC= 1129 mg/kg bw/day x (1 / 1.15 m3/kg/d) x (0.5) = 490.9 mg/m3

Where:

ABS: Absorption

sRV: standard Respiratory Volume

Default parametrs:

sRVrat (24 h): 1.15 m3/kg bw

AF for dose response relationship:
1
Justification:
When the starting point for the DNEL calculation is a NOAEL an assessment factor of 1 is appropriate
AF for differences in duration of exposure:
2
Justification:
Default AF for subchronic (90 day) to chronic studies
AF for interspecies differences (allometric scaling):
1
Justification:
AF for allometric scaling not required as the differences in allometry (respiration rate and rat to human body sizes) were considered in the conversion from oral to inhalation starting point.
AF for other interspecies differences:
2.5
Justification:
Default AF for remaining interspecies differences
AF for intraspecies differences:
10
Justification:
Default for general population
AF for the quality of the whole database:
1
Justification:
None considered applicable.
AF for remaining uncertainties:
1
Justification:
None considered applicable.
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:
5.65 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:
1 129 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 129 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Route to route extrapolation required for oral to dermal route as no long term dermal study available.

The dose starting point was the NOAEL result of 1129 mg/kg bw/day (female rats) obtained from the 90 day oral repeated dose toxicity study.

Modification of this oral result into a dermal starting point was performed.

It is considered that dermal absorption will not be higher than oral absorption, therefore no default factor (i.e. factor 1) should be introduced when performing oral-to dermal extrapolation.

AF for dose response relationship:
1
Justification:
When the starting point for the DNEL calculation is a NOAEL an assessment factor of 1 is appropriate
AF for differences in duration of exposure:
2
Justification:
Default AF for subchronic (90 day) to chronic studies
AF for interspecies differences (allometric scaling):
4
Justification:
Default for rat
AF for other interspecies differences:
2.5
Justification:
Default AF for remaining interspecies differences
AF for intraspecies differences:
10
Justification:
Default for general population
AF for the quality of the whole database:
1
Justification:
None considered applicable
AF for remaining uncertainties:
1
Justification:
None considered applicable
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.65 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:
1 129 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Not required as starting point is based on repeat dose oral study.

AF for dose response relationship:
1
Justification:
When the starting point for the DNEL calculation is a NOAEL an assessment factor of 1 is appropriate
AF for differences in duration of exposure:
2
Justification:
Default AF for subchronic (90 day) to chronic studies
AF for interspecies differences (allometric scaling):
4
Justification:
Default AF for allometric scaling based on rats
AF for other interspecies differences:
2.5
Justification:
Default AF for remaining interspecies differences
AF for intraspecies differences:
10
Justification:
Default AF for general population
AF for the quality of the whole database:
1
Justification:
Relevant studies conducted to GLP and considered to be of reliability 1.
AF for remaining uncertainties:
1
Justification:
None considered applicable.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population