Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.31 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: See explanation for hazard conclusion below
Overall assessment factor (AF):
12.5
Dose descriptor starting point:
NOAEC
DNEL value:
9.5 mg/m³
Modified dose descriptor starting point:
NOAEC
DNEL value:
3.82 mg/m³
Explanation for the modification of the dose descriptor starting point:

Correction for exposure to workers

corrNOAEC =inhalNOAEC*6h/day/8h/day*6.7 m3(8h)/10 m3(8h)

corrNOAEC = 9.5 mg/m3*6h/day/8h/day*6.7 m3(8h)/10 m3(8h)

corrNOAEC = 4.8 mg/m3

Starting point is the Hanley rabbit developmental toxicity study.

The guidance states that ‘in case the inhalation route is involved one should also keep the principle of allometric scaling in mind when using inhalation volumes for animals and humans. This implies that standard respiratory volumes (in l/min/kg bw) for rats and humans differ by a factor of 4’ The factor of 4 comes from the difference of respiratory volume of 0.2l/min/kgbw for humans versus 0.8l/min/kgbw for rats, as shown in table 8-2 of the guidance. No figure is quoted for rabbits but a figure of 0.25L/min/kg is available elsewhere*. This leads to a factor of 1.25 for rabbits to humans.

The corrected NOAEL for starting the DNEL derivation is 4.8/1.25 = 3.82mg/m3

AF for dose response relationship:
1
Justification:
Default. There is little change in outcome for 3x the exposure of the NOAEL
AF for differences in duration of exposure:
1
Justification:
No correction required as the study is a developmental toxicity study.
AF for interspecies differences (allometric scaling):
1
Justification:
The guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health quite clearly states in table 8-4 that a correction is not required for the inhalation route. Any correction required is already accounted for in the correction for respiratory volumes.
AF for other interspecies differences:
2.5
Justification:
Default
AF for intraspecies differences:
5
Justification:
Default for workers
AF for the quality of the whole database:
1
Justification:
Default. Large database of information available in mulitple specie
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
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.22 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Dose descriptor starting point:
NOAEL
DNEL value:
11 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
11 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

For dermal effects, there is no adequate study, thefore route to route extrapolation is used from the oral data. The lowest figure is that from the fertility studies in rats. According to the guidance, it should be assumed as a worse case that oral uptake is 50% and dermal uptake 100%, which would mean dermal toxicity would be higher than oral toxicity. This is not the case. There is limited data available in the same species across multiple routes, but for the rabbit, the oral LD50 is actually lower than the dermal LD50. For rats, there is also data from repeat dose toxicity studies that show no evidence of the dermal route being more toxic. Therefore, no factor is required to extrapolate between the two routes. Absorption is assumed to be 100% in both cases.

AF for dose response relationship:
1
Justification:
Default for NOAEL as starting point.
AF for differences in duration of exposure:
1
Justification:
No correction for duration is required since this is a fertility study for an end point that is concentration rather than cumulative dose influenced.
AF for interspecies differences (allometric scaling):
4
Justification:
Rat to human default extrapolation factor
AF for other interspecies differences:
2.5
Justification:
Default factor
AF for intraspecies differences:
5
Justification:
Default factor
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:
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

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
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:
high hazard (no threshold derived)
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:
0.11 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Dose descriptor starting point:
NOAEL
DNEL value:
11 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
11 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No correction required.

AF for dose response relationship:
1
Justification:
Default for NOAEL as starting point
AF for differences in duration of exposure:
1
Justification:
No correction for duration is required since this is a fertility study for an end point that is concentration rather than cumulative dose influenced
AF for interspecies differences (allometric scaling):
4
Justification:
Rat to human extrapolation
AF for other interspecies differences:
2.5
Justification:
Default
AF for intraspecies differences:
10
Justification:
Proposed factor for general population. See detailed justification in document attached to this record.
AF for the quality of the whole database:
1
Justification:
Defaullt
AF for remaining uncertainties:
1
Justification:
Default
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

This substance is classified as a category 1B reprotoxic. As such it is not permitted in consumer products and no consumer uses are identified. The substance has very low bioaccumulation potential (low logKow, readily biodegradable) and has no wide dispersive uses, indirect exposure via the environment can be disregarded. Consumer DNELS are therefore not needed for risk characterisation. However, a figure is derived for systemic long term oral consumption to be used for risk characterisation for chronic exposure via the environment. For use in this way, a further factor of 3 should be applied to account for 24hr/day exposure rather than the 8hr exposure assumed in the DNEL.