Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.11 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA and ECETOC assessment factors with minor modifications
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
DNEL value:
52.8 mg/m³
Explanation for the modification of the dose descriptor starting point:

ECHA guidance recommends that a factor of 2 be applied when doing route to route extrapolation for oral to inhalation exposure, recognizing higher absorption via the lungs. This substance is a liquid with a very low vapour pressures and inhalation would have to be to an aerosol (of large particles). Droplets will deposit mainly on upper airways, and will be subsequently swallowed following mucociliary transportation to pharynx. This results to no principal difference in absorption compared to the oral route of administration. Allometric scaling is applied by taking account for the different breathing rates between rats and humans, as described in ECHA technical guidance the oral NOAEL in the rat mg/kg/day *1/0.38 * 6.7/10 = mg/m3 inhalation NOAEC for workers.

AF for dose response relationship:
1
Justification:
Effects show a clear dose response
AF for differences in duration of exposure:
1
Justification:
End point for NOAEC is developmental therefore no factor for study duration is required
AF for interspecies differences (allometric scaling):
1
Justification:
No additional factor as 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:
5
Justification:
ECETOC reported in 2010 after an extensive scientific review that the appropriate factor for intraspecies differences for workers is 3 and not 5 as ECHA proposed. It has been suggested that adding 2 to cover all remaining differences is advisable giving the factor of 5 used. See discussion for detailed justification
AF for the quality of the whole database:
1
Justification:
Data used is based on testing of 2, 2’-(C12-18 evennumbered alkyl imino) diethanol CAS No 71786-60-2 in a Klimisch 1 validity OECD422 Repeat dose and developmental toxicity screening study. This is a read across to a worst case (lower carbon chain length) related substance so no additional factor is added for read across. All other uncertainties are included in the assessment factor for remaining uncertainties.
AF for remaining uncertainties:
5
Justification:
ECHA guidance document Chapter R8, in Appendix R.8-12, indicates that DNELs from fertility and developmental effects from an OECD422 study either negative or positive can be derived using assessment factors of 2-5. Therefore based on the clear no effect level for developmental toxicity in the OECD422 due to it being a screen study a factor 5 has been selected as a conservative value, taking into account the lower sensitivity of this screening study.
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
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:
0.3 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA and ECETOC assessment factors with minor modifications
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
DNEL value:
30 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
AF for differences in duration of exposure:
1
Justification:
End point for NOAEL is developmental therfore no factor for study duration is required
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:
5
Justification:
ECETOC reported in 2010 after an extensive scientific review that the appropriate factor for intraspecies differences for workers is 3 and not 5 as ECHA proposed. It has been suggested that adding 2 to cover all remaining differences is advisable giving the factor of 5 used. See discussion for detailed justification.
AF for the quality of the whole database:
1
Justification:
Data used is based on testing of 2, 2’-(C12-18 evennumbered alkyl imino) diethanol CAS No 71786-60-2 in a Klimisch 1 validity OECD422 Repeat dose and developmental toxicity screening study. This is a read across to a worst case (lower carbon chain length) related substance so no additional factor is added for read across. All other uncertainties are included in the assessment factor for remaining uncertainties
AF for remaining uncertainties:
5
Justification:
ECHA guidance document Chapter R8, in Appendix R.8-12, indicates that DNELs from fertility and developmental effects from an OECD422 study either negative or positive can be derived using assessment factors of 2-5. Therefore based on the clear no effect level for developmental toxicity in the OECD422 due to it being a screen study a factor 5 has been selected as a conservative value, taking into account the lower sensitivity of this screening study.
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term
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:
medium hazard (no threshold derived)

Additional information - workers

Selection of Assessment factors for Intra – Inter species variation for workers and the general population (consumers)

ECHA (2012) 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 guidance proposes that an assessment factor of 2 to be applied when extrapolating from an oral NOAEL to an inhalation DNEL. However in the case of fatty nitriles and the related derivatives, their low vapour pressure minimises the potential for generating vapour, and thus the risk of inhaling these materials in general. In the unlikely event that particulates are inhaled the relatively large particle size compared to inhalation of a vapour, would be expected to impinge on the nasal passages and the upper respiratory tract. This would result in the particulates being ingested rather than being absorbed after entering the deep lung. Therefore, based on the physico-chemical properties of these chemicals, an assessment factor of 1 will be applied when extrapolating from oral NOAEL values to inhalation DNELS.

The ECHA guidance proposes an assessment factor of 4 for the allometric scaling from rats to humans when calculating 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 DNELs(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 intraspecies 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 intraspecies assessment factors, which ECHA proposed as 5 for workers and 10 for the general population. ECETOC 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 intraspecies variability, which includes the remaining differences factor of 2.5. A similar concept was developed for the German Auschuss für Gefahrstoffe -(2006), although arriving at a different factor. Apart from allometric scaling, taking interspecies differences for metabolism and toxicokinetics into account, a separate factor for overall (inter- and intra-species) variability for the workplace of 5 is taken. AGS explicitly did not differentiate between inter- and intra-species variability. They did not specifically propose an assessment factor for the general population. However, following the same principle that the AGS applied for workers, increasing the factor of 5 proposed by ECETOC for the general population also by 2 gives a factor of 7.

 

After reviewing the three proposals, we have adopted the proposal from ECETOC as our default assessment factors. Where we have limited information or consider there to be the likelihood of addition intraspecies variation in response, then these factor may be increased for example as suggested by the German Auschuss für Gefahrstoffe (AGS) of an assessment factor of 5 for workers. Scientifically justified alternative factors for the general public will be selected on a case by case basis, with appropriate modification to the factor of 5 recommended by ECETOC, Examples of modified factors for the general public could be for example a factor of 7 following the approach of the AGS or 10 following the ECHA guidance. This is considered a scientifically justified but still conservative approach, although the additional factor of 2.5 for remaining inter species differences as proposed by the ECHA guidance will not be used.

 

To ensure any additional intra species variability is included the ECETOC assessment factor of 3 for workers will be increased by 2 to give a factor of 5, as described above following the approach of the AGS.

 

References:

ECHA, 2012 Guidance on information requirements and chemical safety assessment

Chapter R.8: Characterisation of dose [concentration]-response for human health. November 2012

 

ECETOC, 2010Guidance on Assessment Factors to Derive DNELs,Technical Report110,ISSN-0773 -8072 -110, October 2010

GermanAuschuss für Gefahrstoff 2006. Technische Regeln für Gefahrstoffe. Begründungen und Erläuterungen zu Grenzwerten in der Luft am Arbeitsplatz. Ausschuss für gefahrstoffe. TRGS 901, BArbBl. Heft 1/2006.www.baua.de

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.745 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA and ECETOC assessment factor with minor modification see discussion.
Overall assessment factor (AF):
35
Modified dose descriptor starting point:
NOAEC
DNEL value:
26.09 mg/m³
Explanation for the modification of the dose descriptor starting point:

ECHA guidance recommends that a factor of 2 be applied when doing route to route extrapolation for oral to inhalation exposure, recognizing higher absorption via the lungs. This substance is a waxy solid with a very low vapour pressures and inhalation would have to be to an aerosol (of large particles). Droplets will deposit mainly on upper airways, and will be subsequently swallowed following mucociliary transportation to pharynx. This will result in no principal difference in absorption compared to the oral route of administration. Allometric scaling is applied by taking account for the different breathing rates between rats and humans as described in ECHA technical guidance the oral NOAEL in the rat mg/kg/day *1/1.15 mg/m3 inhalation NOAEC for consumers.

AF for dose response relationship:
1
Justification:
Effects show a clear dose response
AF for differences in duration of exposure:
1
Justification:
End point for NOAEC is developmental therefore no factor for study duration is required
AF for interspecies differences (allometric scaling):
1
Justification:
No additional factor as already included in the route to route extrapolation from the rat oral NOAEL to the equivalent human inhalation NOAEL.
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:
7
Justification:
ECETOC reported in 2010 after an extensive scientific review that the appropriate fact for intraspecies differences for the general population is 5 and not 10 as ECHA proposed. It has been suggested that adding 2 to cover all remaining differences is advisable giving the factor of 7 used. See discussion for detailed justification.
AF for the quality of the whole database:
1
Justification:
Data used is based on testing of 2, 2’-(C12-18 evennumbered alkyl imino) diethanol CAS No 71786-60-2 in a Klimisch 1 validity OECD422 Repeat dose and developmental toxicity screening study. This is a read across to a worst case (lower carbon chain length) related substance so no additional factor is added for read across. All other uncertainties are included in the assessment factor for remaining uncertainties.
AF for remaining uncertainties:
5
Justification:
ECHA guidance document Chapter R8, in Appendix R.8-12, indicates that DNELs from fertility and developmental effects from an OECD422 study either negative or positive can be derived using assessment factors of 2-5. Therefore based on the clear no effect level for developmental toxicity in the OECD4422 due to it being a screen study a factor 5 has been selected as a conservative value, taking into account the lower sensitivity of this screening study.
Acute/short term exposure
Hazard assessment conclusion:
medium 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)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.214 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other:
Overall assessment factor (AF):
140
Modified dose descriptor starting point:
NOAEL
DNEL value:
30 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
AF for differences in duration of exposure:
1
Justification:
End point for NOAEL is developmental therefore no factor for study duration is required
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:
7
Justification:
ECETOC reported in 2010 after an extensive scientific review that the appropriate factor for intraspecies differences for the general population 5 and not 10 as ECHA proposed. It has been suggested that adding 2 to cover all remaining differences is advisable giving the factor of 7 used. See discussion for detailed justification
AF for the quality of the whole database:
1
Justification:
Data used is based on testing of 2, 2’-(C12-18 evennumbered alkyl imino) diethanol CAS No 71786-60-2 in a Klimisch 1 validity OECD422 Repeat dose and developmental toxicity screening study. This is a read across to a worst case (lower carbon chain length) related substance so no additional factor is added for read across. All other uncertainties are included in the assessment factor for remaining uncertainties.
AF for remaining uncertainties:
5
Justification:
ECHA guidance document Chapter R8, in Appendix R.8-12, indicates that DNELs from fertility and developmental effects from an OECD422 study either negative or positive can be derived using assessment factors of 2-5. Therefore based on the clear no effect level for developmental toxicity in the OECD422 due to it being a screen study a factor 5 has been selected as a conservative value, taking into account the lower sensitivity of this screening study.
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term
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)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.214 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA and ECETOC assessment factors with minor modification see discussion
Overall assessment factor (AF):
140
Modified dose descriptor starting point:
NOAEL
DNEL value:
30 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Test data in rats is for the same oral route of exposure as the general population.

AF for dose response relationship:
1
Justification:
Effects show a clear dose response
AF for differences in duration of exposure:
1
Justification:
End point for NOAEL is developmental therefore no factor for study duration is required
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:
7
Justification:
ECETOC reported in 2010 after an extensive scientific review that the appropriate factor for intraspecies differences for the general population 5 and not 10 as ECHA proposed. It has been suggested that adding 2 to cover all remaining differences is advisable giving the factor of 7 used. See discussion for detailed justification.
AF for the quality of the whole database:
1
Justification:
Data used is based on testing of 2, 2’-(C12-18 evennumbered alkyl imino) diethanol CAS No 71786-60-2 in a Klimisch 1 validity OECD422 Repeat dose and developmental toxicity screening study. This is a read across to a worst case (lower carbon chain length) related substance so no additional factor is added for read across. All other uncertainties are included in the assessment factor for remaining uncertainties.
AF for remaining uncertainties:
5
Justification:
ECHA guidance document Chapter R8, in Appendix R.8-12, indicates that DNELs from fertility and developmental effects from an OECD422 study either negative or positive can be derived using assessment factors of 2-5. Therefore based on the clear no effect level for developmental toxicity in the OECD422 due to it being a screen study a factor 5 has been selected as a conservative value, taking into account the lower sensitivity of this screening study.
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

Selection of Assessment factors for Intra – Inter species variation for workers and the general population (consumers)

ECHA (2012) 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 guidance proposes that an assessment factor of 2 to be applied when extrapolating from an oral NOAEL to an inhalation DNEL. However in the case of fatty nitriles and the related derivatives, their low vapour pressure minimises the potential for generating vapour, and thus the risk of inhaling these materials in general. In the unlikely event that particulates are inhaled the relatively large particle size compared to inhalation of a vapour, would be expected to impinge on the nasal passages and the upper respiratory tract. This would result in the particulates being ingested rather than being absorbed after entering the deep lung. Therefore, based on the physico-chemical properties of these chemicals, an assessment factor of 1 will be applied when extrapolating from oral NOAEL values to inhalation DNELS.

The ECHA guidance proposes an assessment factor of 4 for the allometric scaling from rats to humans when calculating 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 DNELs(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 intraspecies 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 intraspecies assessment factors, which ECHA proposed as 5 for workers and 10 for the general population. ECETOC 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 intraspecies variability, which includes the remaining differences factor of 2.5. A similar concept was developed for the German Auschuss für Gefahrstoffe -(2006), although arriving at a different factor. Apart from allometric scaling, taking interspecies differences for metabolism and toxicokinetics into account, a separate factor for overall (inter- and intra-species) variability for the workplace of 5 is taken. AGS explicitly did not differentiate between inter- and intra-species variability. They did not specifically propose an assessment factor for the general population. However, following the same principle that the AGS applied for workers, increasing the factor of 5 proposed by ECETOC for the general population also by 2 gives a factor of 7.

 

After reviewing the three proposals, we have adopted the proposal from ECETOC as our default assessment factors. Where we have limited information or consider there to be the likelihood of addition intraspecies variation in response, then these factor may be increased for example as suggested by the German Auschuss für Gefahrstoffe (AGS) of an assessment factor of 5 for workers. Scientifically justified alternative factors for the general public will be selected on a case by case basis, with appropriate modification to the factor of 5 recommended by ECETOC, Examples of modified factors for the general public could be for example a factor of 7 following the approach of the AGS or 10 following the ECHA guidance. This is considered a scientifically justified but still conservative approach, although the additional factor of 2.5 for remaining inter species differences as proposed by the ECHA guidance will not be used.

To ensure any additional intra species variability is included the ECETOC assessment factor of 5 for the ge

neral population will be increased by 2 to give a value of 7, as described above applying the same principle as the AGS did for workers

 

References:

ECHA, 2012 Guidance on information requirements and chemical safety assessment

Chapter R.8: Characterisation of dose [concentration]-response for human health. November 2012

 

ECETOC, 2010  Guidance on Assessment Factors to Derive DNELs,Technical Report 110,ISSN-0773 -8072 -110, October 2010

GermanAuschuss für Gefahrstoff 2006 Technische Regeln für Gefahrstoffe. Begründungen und Erläuterungen zu Grenzwerten in der Luft am Arbeitsplatz. Ausschuss für gefahrstoffe. TRGS 901, BArbBl. Heft 1/2006.www.baua.de