Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
48.97 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
18
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
881.57 mg/m³
Explanation for the modification of the dose descriptor starting point:

The DNEL for inhalation exposure for workers is given by the formula:

corrected inhalation NOAEC = LOAEL(oral-rat) * 1/sRVrat * (Absorption (oral-rat) / Absorption(inhal-human)) * (sRVhuman/wRV)

Where SRV is the standard Respiratory Volume and wRV is the worker Respiratory Volume. The default values assumed for these factors are as follows:

·        Absorption(oral-rat) =50%;

·        Absorption(inhal-human) =100%;

·        sRVrat=0.38 m3/kg/d;

·        sRVhuman= 6.7m3 (8hr);

·        wRV=10m3(8hr).

NOAEC(corrected)= 1000 mg/kg bw/day* (1/0.38 m3/kg/d)*(50%/100%)* 6.7m3 (8hr)/ 10m3(8hr) NOAEC(corrected)= 881.57 mg/m3

AF for dose response relationship:
1
Justification:
A NOAEL of 1000mg/kg derived from the toxicity to reproduction study with no effects seen on parental toxicity or reproductive and development endpoint up to the highest dose tested. This value has been selected as the point of departure so factor of 1 used.
AF for differences in duration of exposure:
6
Justification:
ECHA guidance document Chapter R8, in Appendix R.8-12, indicates that DNELS derived using a NOAEL from a 28 day study are derived using an assessment factor of 6 for extrapolation of the study duration to chronic exposure
AF for interspecies differences (allometric scaling):
1
Justification:
This is already accounted for in the modification of the dose descriptor starting point.
AF for other interspecies differences:
1
Justification:
ECETOC reported in 2010 after an extensive review (see discussion) that there is no justification for the suggested additional factor of 2.5 for this, therefore a factor of 1 has been applied
AF for intraspecies differences:
3
Justification:
ECETOC reported in 2010 after an extensive scientific review that the appropriate fact for intraspecies differences for workers is 3 and not 5 as ECHA proposed. See discussion for detailed justification.
AF for the quality of the whole database:
1
Justification:
A full Annex VIII dataset is available for this substance, including a combined 28 day/reproductive screening study
AF for remaining uncertainties:
1
Justification:
uncertainties are already included so a factor of 1 is applied
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
69.44 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
72
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
5 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Based on the ECHA guidance R8 Dermal exposure derived from a Oral NOAEL can be derived from the calculation Oral (N/LOAEL)*ABSoral-rat/ABSderm-human. Guidance proposes that 50% ABS from oral to dermal and based on the phy/chem and toxicokinetics profile of the substance we can apply a ABS of 10% for the human dermal absorption therefore there is 5 fold factor applied to the starting value

AF for dose response relationship:
1
Justification:
A NOAEL of 1000 mg/kg derived from the toxicity to reproduction study with no effects seen on parental toxicity or reproductive and development endpoint up to the highest dose tested. This value has been selected as the point of departure so factor of 1 used.
AF for differences in duration of exposure:
6
Justification:
ECHA guidance document Chapter R8, in Appendix R.8-12, indicates that DNELS derived using a NOAEL from a 28 day study are derived using an assessment factor of 6 for extrapolation of the study duration to chronic exposure
AF for interspecies differences (allometric scaling):
4
Justification:
A default allometric scaling factor of 4 between rats and humans is applied as per the ECHA guidance R8
AF for other interspecies differences:
1
Justification:
ECETOC reported in 2010 after an extensive review (see discussion) that there is no justification for the suggested additional factor of 2.5 for this, therefore a factor of 1 has been applied
AF for intraspecies differences:
3
Justification:
ECETOC reported in 2010 after an extensive scientific review that the appropriate fact for intraspecies differences for workers is 3 and not 5 as ECHA proposed. See discussion for detailed justification
AF for the quality of the whole database:
1
Justification:
A full Annex VIII dataset is available for this substance, including a combined 28 day/reproductive screening study
AF for remaining uncertainties:
1
Justification:
uncertainties are already included so a factor of 1 is applied
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

The ECHA guidance proposes an assessment factor of 4 for the allometric scaling from rats to humans when calculating oral and dermal DNELs. However, it then proposes an additional factor of 2.5 to cover remaining differences (uncertainties). There is no clear scientific justification for this additional factor. ECETOC in its Guidance on Assessment Factors to Derive a DNEL (2010) reviewed the scientific evidence and concluded that the factor of 4 for rats was sufficient to cover the allometric scaling from rats to humans and any remaining differences are of intra-species rather than interspecies variability. Based on this, the additional assessment factor of 2.5 for inter-species variability will not be used.

This ECETOC guidance also reviewed the intra-species assessment factors, which ECHA proposed as 5 for workers and 10 for the general population. ECETOC originally proposed in 2003, based on the scientific evidence, that assessment factors of 3 for workers and 5 for the general population are sufficient for covering any intra-species variability, which includes the remaining differences factor of 2.5. 

 This was confirmed in the ECETOC (2010) Guidance.

 After reviewing these proposals, we have adopted the proposal from ECETOC as our default assessment factors but consider possible additional factors on a case by case basis.

 In this case we have decided to use an assessment factor of 3 for workers based on the ECETOC Guidance (ECETOC 2010).

 References:

 ECHA, 2010 Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health. Version 2 December 2010

 ECETOC, 2010Guidance on Assessment Factors to Derive a DNEL, Technical Report No.110,ISSN-0773-8072-110 (print),ISSN-2079-1562-110 (online), October 2010

General Population - Hazard via inhalation 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
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:
no hazard identified
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