Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
106 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: See justification and comments.
Overall assessment factor (AF):
6
Dose descriptor starting point:
NOAEC
DNEL value:
1 266 mg/m³
Modified dose descriptor starting point:
NOAEC
DNEL value:
636 mg/m³
Explanation for the modification of the dose descriptor starting point:

The NOAEL is corrected for exposure duration and breathing rate as recommened in the guidance.

The correction is 1266 * 6/8 (hrs exposure in study versus duration of working day) * 6.7/10 (breathing rate at rest versus breathing rate at work) = 636 mg/m3

AF for dose response relationship:
1
Justification:
Based on a NOAEL.
AF for differences in duration of exposure:
2
Justification:
Sub-chronic to chronic default factor.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling not required for inhalation route of exposure.
AF for other interspecies differences:
1
Justification:
No additional factor deemed necessary. See detailed justification in document attached to this record.
AF for intraspecies differences:
3
Justification:
Proposed factor for workers. See detailed justification in document attached to this record.
AF for the quality of the whole database:
1
Justification:
Default
AF for remaining uncertainties:
1
Justification:
Default
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
500 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: See justification and comments.
Overall assessment factor (AF):
3
DNEL extrapolated from long term DNEL
Modified dose descriptor starting point:
NOAEC
DNEL value:
1 500 mg/m³
AF for dose response relationship:
1
Justification:
Based on a NOAEL
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling not required for inhalation route of exposure.
AF for other interspecies differences:
1
Justification:
No additional factor deemed necessary. See detailed justification in document attached to this record. Narcosis effects not likely to differ between species.
AF for intraspecies differences:
3
Justification:
Proposed factor for workers. See detailed justification in document attached to this record
AF for the quality of the whole database:
1
Justification:
Default
AF for remaining uncertainties:
1
Justification:
Default

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:
74 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
other: See justification and comments.
Overall assessment factor (AF):
29
Modified dose descriptor starting point:
NOAEL
DNEL value:
2 126 mg/kg bw/day
AF for dose response relationship:
1
Justification:
Based on a NOAEL
AF for differences in duration of exposure:
2
Justification:
A factor of 2 is used to extrapolate from sub-chronic to chronic exposure.
AF for interspecies differences (allometric scaling):
2.4
Justification:
Rabbit to human extrapolation.
AF for other interspecies differences:
1
Justification:
No additional factor deemed necessary. See detailed justification in document attached to this record.
AF for intraspecies differences:
3
Justification:
Proposed factor for workers. See detailed justification in document attached to this record.
AF for the quality of the whole database:
2
Justification:
It is considered prudent to add a further factor of 2 to account for uncertainty of the database due to the age of the study.
AF for remaining uncertainties:
1
Justification:
Default
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:
medium hazard (no threshold derived)

Additional information - workers

The long term DNEL is in line with the revised German MAK value from 2018. A value of 31ppm was derived as an acceptable exposure level. This was rounded down to 20ppm under the 'preferred number' system.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
127 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: See justification and comments.
Overall assessment factor (AF):
10
Dose descriptor starting point:
NOAEC
DNEL value:
1 266 mg/m³
Modified dose descriptor starting point:
NOAEC
DNEL value:
1 266 mg/m³
Explanation for the modification of the dose descriptor starting point:

According to the guidance on the characterisation of dose response for human health, the NOAEC should be corrected for duration of exposure by a factor of 6/24. This would be appropriate when deriving a DNEL for continuous exposure. For shorter exposures, the guidance on consumer exposure assessment states that the DNEL can be corrected back but in this case using Haber's law rather than the same linear correction. This is a scientifically flawed argument. If a DNEL for short exposures is required, it should be derived directly with a single correction rather than the double correction as stated in the guidance that effectively ends up at the same starting place for exposure but with a lower NOAEC.

In this case therefore no correction is made to the starting point and the DNEL derived here is therefore valid for consumer exposures up to 6 hours per day. For durations less than this corrections can be made using the Haber rule as follows (DNEL increased or assessment factor applied:

3hrs: 1.25

2hrs: 1.45

1hr: 1.8

0.5hr: 2.3

For durations longer than this, the DNEL should be reduced linearly:

8hrs: *0.75

24hrs: *0.25 (used for continuous exposures as would be the case for indoor air and environmental background exposures)

For a DNEL for infrequent use, see the next section on acute systemic inhalation exposure.

AF for dose response relationship:
1
Justification:
Based on a NOAEL.
AF for differences in duration of exposure:
2
Justification:
Sub-chronic to chronic default factor.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling not required for inhalation route of exposure.
AF for other interspecies differences:
1
Justification:
No additional factor deemed necessary. See detailed justification in document attached to this record.
AF for intraspecies differences:
5
Justification:
Proposed factor for consumers. See detailed justification in document attached to this record.
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
default
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
300 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
other: See justification and comments below.
Overall assessment factor (AF):
5
DNEL extrapolated from long term DNEL
Modified dose descriptor starting point:
NOAEC
DNEL value:
1 500 mg/m³
AF for dose response relationship:
1
Justification:
Based on a NOAEL
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling not required for inhalation route of exposure.
AF for other interspecies differences:
1
Justification:
No additional factor deemed necessary. See detailed justification in document attached to this record. Narcosis effects not likely to differ between species.
AF for intraspecies differences:
5
Justification:
Proposed factor for consumers. See detailed justification in document attached to this record.
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
default

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:
44.3 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
other: See comments and justification.
Overall assessment factor (AF):
48
Modified dose descriptor starting point:
NOAEL
DNEL value:
2 126 mg/kg bw/day
AF for dose response relationship:
1
Justification:
Based on a NOAEL.
AF for differences in duration of exposure:
2
Justification:
Sub-chronic to chronic default factor.
AF for interspecies differences (allometric scaling):
2.4
Justification:
Rabbit to human extrapolation.
AF for other interspecies differences:
1
Justification:
No additional factor deemed necessary. See detailed justification in document attached to this record.
AF for intraspecies differences:
5
Justification:
Proposed factor for consumers. See detailed justification in document attached to this record.
AF for the quality of the whole database:
2
Justification:
it is considered prudent to add a further factor of 2 to account for uncertainty of the database due to the age of the study.
AF for remaining uncertainties:
1
Justification:
default
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:
14 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: See justification and comments.
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
Explanation for the modification of the dose descriptor starting point:

See justification and comments below

Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population