Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.391 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):
450
Modified dose descriptor starting point:
NOAEC
Value:
176 mg/m³
Explanation for the modification of the dose descriptor starting point:

Per REACH Guidance 8.4.2 (Example R. 8-2 Workers), the oral NOAEL of 100 mg/kg/day (rat 28-day study) was converted to an inhalation equivalent:

100 mg/kg/day ÷ 0.38 m3/kg bw (8 h exposure – rat) × 6.7 m3 (8 h exposure – human) ÷ 10 m3 (worker respiratory volume [wRV] - 8 h) = 176 mg/m3

AF for dose response relationship:
1
Justification:
When the starting point for the DNEL calculation is a NOAEL, the default assessment factor, as a standard procedure, is 1. Therefore, a default factor of 1 is appropriate per REACH Guidance R.8.4.3.1.
AF for differences in duration of exposure:
6
Justification:
A factor allowing for differences in the experimental exposure duration and the duration of exposure for the population and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. The NOAEL (an inhalation equivalent of 176 mg/kg/day) is based on a 28-day rat study (subacute) and a default factor of 6 (sub-acute to chronic exposure) is appropriate per REACH Guidance R.8.4.3.1.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling extrapolates doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight. Modification of the starting point (oral NOAEL to an inhalation equivalent) has already accounted for allometric scaling (animal to human). Therefore, a factor of 1 is appropriate.
AF for other interspecies differences:
2.5
Justification:
The standard procedure for threshold effects would be, as a default, to correct for differences in metabolic rate (allometric scaling) and to apply an additional factor of 2.5 for other interspecies differences. A default factor of 2.5 is appropriate per REACH Guidance R.8.4.3.1.
AF for intraspecies differences:
5
Justification:
For workers, as standard procedure for threshold effects a default assessment factor of 5 is to be used, based on the fact that this sub population does not cover the very young, the very old, and the very ill. A default factor of 5 is appropriate per REACH Guidance R.8.4.3.3.
AF for the quality of the whole database:
3
Justification:
An evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps. Lacking a screening test for reproductive/developmental toxicity test in rats, an assessment factor of 3 is applied per REACH Guidance R.8.4.3.1.
AF for remaining uncertainties:
2
Justification:
According to REACH Guidance (R.8.4.2), in the case of oral-to-inhalation extrapolation, and in the absence of route-specific information on the starting route, a default factor of 2 should be included (i.e. the absorption percentage for the starting route is half that of the end route). The inclusion of factor of 2 means that 50% (instead of 100%) absorption is assumed for oral absorption, and 100% for inhalation. A default factor of 2 is appropriate per REACH Guidance R.8.4.2.
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:
0.11 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):
900
Modified dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

This is the concentration where a no adverse effect (based on bodyweight along with other systemic effect indicators) was observed in the sub-acute (28-day) oral study in rats. A NOAEL is the highest dose level or concentration of the substance used in a test at which no statistically significant adverse effects were observed. A NOAEL of 100 mg/kg/day is appropriate per REACH Guidance R.8.2.

Assessment factor ─ Route to Route Extrapolation

Value: 1

Remark: On the assumption that, in general, dermal absorption will not be higher than oral absorption,

no default factor (ie. factor 1) should be introduced when performing oral-to-dermal extrapolation. A

default factor of 1 is appropriate per REACH Guidance R.8.4.2.

AF for dose response relationship:
1
Justification:
When the starting point for the DNEL calculation is a NOAEL, the default assessment factor, as a standard procedure, is 1. Therefore, a default factor of 1 is appropriate per REACH Guidance R.8.4.3.1.
AF for differences in duration of exposure:
6
Justification:
A factor allowing for differences in the experimental exposure duration and the duration of exposure for the population and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. The NOAEL (100 mg/kg/day) is based on a 28-day rat study (sub-acute) and a default factor of 6 (sub-acute to chronic exposure) is appropriate per REACH Guidance R.8.4.3.1.
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling extrapolates doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight. A default factor of 4 (rat to human) is appropriate per REACH Guidance R.8.4.3.1.
AF for other interspecies differences:
2.5
Justification:
The standard procedure for threshold effects would be, as a default, to correct for differences in metabolic rate (allometric scaling) and to apply an additional factor of 2.5 for other interspecies differences. A default factor of 2.5 is appropriate per REACH Guidance R.8.4.3.1.
AF for intraspecies differences:
5
Justification:
For workers, as standard procedure for threshold effects a default assessment factor of 5 is to be used, based on the fact that this sub population does not cover the very young, the very old, and the very ill. A default factor of 5 is appropriate per REACH Guidance R.8.4.3.3.
AF for the quality of the whole database:
3
Justification:
An evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps. Lacking a screening test for reproductive/developmental toxicity test in rats, an assessment factor of 3 is applied per REACH Guidance R.8.4.3.1.
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

The test substance is a solid at room temperature and potential worker exposure would primarily occur via the dermal route; exposure to the substance via inhalation is also possible but less likely given the test substance’s extremely low vapour pressure and large particle size. The substance is not classified for acute or repeated exposure toxicity, but at very high repeat (oral) exposures (1000 mg/kg/day) evidence of systemic toxicity was observed. A clear no observable adverse effect level (NOAEL) following daily oral dosing in rats was 100 mg/kg/day. This NOAEL is the principal dose descriptor for derivation of a DNEL for long-term systemic effects following dermal and inhalation exposure in workers. Systemic and local effects following acute exposure and long-term local effects were not observed. Therefore, a DNEL was not derived for these exposure patterns.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.097 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):
900
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
87 mg/m³
Explanation for the modification of the dose descriptor starting point:

Per REACH Guidance 8.4.2 (Example R. 8-1 General public), the oral NOAEL of 100 mg/kg/day (bodyweight effects in rat 28-day study) was converted to an inhalation equivalent:

100 mg/kg/day ÷ 1.15 m3/kg bw (24 h exposure – rat) = 87 mg/m3

AF for dose response relationship:
1
Justification:
When the starting point for the DNEL calculation is a NOAEL, the default assessment factor, as a standard procedure, is 1. Therefore, a default factor of 1 is appropriate per REACH Guidance R.8.4.3.1.
AF for differences in duration of exposure:
6
Justification:
A factor allowing for differences in the experimental exposure duration and the duration of exposure for the population and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. The NOAEL (an inhalation equivalent of 87 mg/m3) is based on a 28-day rat oral study (sub-acute) and a default factor of 6 (sub-acute to chronic exposure) is appropriate per REACH Guidance R.8.4.3.1.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling extrapolates doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight. Modification of the starting point (oral NOAEL to an inhalation equivalent) has already accounted for allometric scaling (rat to human). Therefore, a factor of 1 is appropriate.
AF for other interspecies differences:
2.5
Justification:
The standard procedure for threshold effects would be, as a default, to correct for differences in metabolic rate (allometric scaling) and to apply an additional factor of 2.5 for other interspecies differences. A default factor of 2.5 is appropriate per REACH Guidance R.8.4.3.1.
AF for intraspecies differences:
10
Justification:
A default assessment factor of 10 is sufficient to protect the larger part of the population, including children and the elderly. For threshold effects, this factor of 10 is the standard procedure, as a default, when assessing exposure to the general population. A default factor of 10 is appropriate per REACH Guidance R.8.4.3.1.
AF for the quality of the whole database:
3
Justification:
An evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps. Lacking a screening test for reproductive/developmental toxicity test in rats, an assessment factor of 3 is applied per REACH Guidance R.8.4.3.1.
AF for remaining uncertainties:
2
Justification:
Route to Route Extrapolation: According to REACH Guidance (R.8.4.2), in the case of oral-to-inhalation extrapolation, and in the absence of route-specific information on the starting route, a default factor of 2 should be included (i.e. the absorption percentage for the starting route is half that of the end route). The inclusion of factor of 2 means that 50% (instead of 100%) absorption is assumed for oral absorption, and 100% for inhalation.
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:
no hazard identified
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:
0.056 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):
1 800
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

This is the concentration where a no adverse effect (based on bodyweight along with other systemic effect indicators) was observed in the sub-acute (28-day) oral study in rats. A NOAEL is the highest dose level or concentration of the substance used in a test at which no statistically significant adverse effects were observed. A NOAEL of 100 mg/kg/day is appropriate per REACH Guidance R.8.2.

AF for dose response relationship:
1
Justification:
When the starting point for the DNEL calculation is a NOAEL, the default assessment factor, as a standard procedure, is 1. Therefore, a default factor of 1 is appropriate per REACH Guidance R.8.4.3.1.
AF for differences in duration of exposure:
6
Justification:
A factor allowing for differences in the experimental exposure duration and the duration of exposure for the population and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. The NOAEL (100 mg/kg/day) is based on a 28-day rat study (sub-acute) and a default factor of 6 (sub-acute to chronic exposure) is appropriate per REACH Guidance R.8.4.3.1.
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling extrapolates doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight. A default factor of 4 (rat to human) is appropriate per REACH Guidance R.8.4.3.1.
AF for other interspecies differences:
2.5
Justification:
The standard procedure for threshold effects would be, as a default, to correct for differences in metabolic rate (allometric scaling) and to apply an additional factor of 2.5 for other interspecies differences. A default factor of 2.5 is appropriate per REACH Guidance R.8.4.3.1.
AF for intraspecies differences:
10
Justification:
A default assessment factor of 10 is sufficient to protect the larger part of the population, including children and the elderly. For threshold effects, this factor of 10 is the standard procedure, as a default, when assessing exposure to the general population. A default factor of 10 is appropriate per REACH Guidance R.8.4.3.1.
AF for the quality of the whole database:
3
Justification:
An evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps. Lacking a screening test for reproductive/developmental toxicity test in rats, an assessment factor of 3 is applied per REACH Guidance R.8.4.3.1.
AF for remaining uncertainties:
1
Justification:
Route to Route Extrapolation: This is an oral-to-oral DNEL. A default factor of 1 is appropriate per REACH Guidance R.8.4.2.
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

The test substance is a cross-linking agent and is used to modify the viscosity of molten polymer (polycarbonate) to facilitate processing. The substance also enhances the clarity of the final polymer product and key performance properties such as adhesion, hardness, heat resistance and solvent resistance. Exposure to unreacted material in the final product is not expected. However, a DNEL was derived for the oral and inhalation exposure routes for the general population. The substance is not classified for acute or repeated exposure toxicity, but at very high repeat (oral) exposures (1000 mg/kg/day) some evidence of systemic toxicity was observed. A clear no observable adverse effect level (NOAEL) following daily oral dosing for 28 days in rats was 100 mg/kg/day. This NOAEL is the principal dose descriptor for derivation of a DNEL for long-term systemic effects following oral and inhalation exposure in the general population. Systemic and local effects following acute exposure and long-term local effects were not observed. Therefore, a DNEL was not derived for these exposure patterns.