Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.73 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA Guidance and ECETOC TR no110
Overall assessment factor (AF):
18
Modified dose descriptor starting point:
NOAEC
DNEL value:
13.22 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= NOAEL(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)= 15 mg/kg bw/day* (1/0.38 m3/kg/d)*(50%/100%)* 6.7m3 (8hr)/ 10m3(8hr) NOAEC(corrected)= 13.22 mg/m3
AF for dose response relationship:
1
Justification:
Effects show a clear dose response 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:
Allometric scaling is already included in the route to route extrapolation from the rat oral NOAEL to the equivalent human inhalation NOAEC.
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:
All uncertainties are already included so a factor of 1 is applied.
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
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)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.21 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA Guidance and ECETOC TR no110
Overall assessment factor (AF):
72
Modified dose descriptor starting point:
NOAEL
DNEL value:
15 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
ECHA guidance assumes that absorption for dermal exposure is the same as for oral exposure, which is a worst case assumption.
AF for dose response relationship:
1
Justification:
Effects show a clear dose response 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 factor of 4 is applied based on ECHA guidance for allometric scaling of data from rats to humans.
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:
All uncertainties are already included so a factor of 1 is applied.
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
38.94 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
other: ECHA Guidance and ECETOC TR no110
Overall assessment factor (AF):
90
Dose descriptor:
other: LOAEL
AF for dose response relationship:
3
Justification:
default AF for the extrapolation of the LOAEL to the NOAEL
AF for differences in duration of exposure:
1
Justification:
Sensitisation induction can be considered to be a single exposure event, therefore no AF for duration of exposure is required.
AF for interspecies differences (allometric scaling):
10
Justification:
ECHA guidance document Chapter R8, Appendix R.8-10 indicates that a default AF of 10 for interspecies variaiton is applied
AF for other interspecies differences:
1
Justification:
included in the above AF
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:
The Point of departure has been interpolated from the existing data points of a reliable study- no further AF required
AF for remaining uncertainties:
1
Justification:
All uncertainties are already included so a factor of 1 is applied.
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - workers

Selection of Assessment factors for Intra – Inter species variation for workers

ECHA (2010) has produced guidance on the assessment factors to use to derive a DNEL for human exposure based the application of assessment factors (safety factors) to an NOAEL or LOAEL in animal studies.

 

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 itsGuidance 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

No DNELs have been derived for exposure of the general public since the substance BMS 587319-03 EC 619-496-0 CAS 960404-59-5 is a pharmaceutical intermediate and no exposure of the General Population is anticipated.