Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.07 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC
Overall assessment factor (AF):
90
Modified dose descriptor starting point:
LOAEC
Value:
6.2 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 additional assessment factor is not considered relevant in this particular case, since the substance has low vapour pressures and inhalation is therefore unlikely. 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:
3
Justification:
According to the ECHA guidance document Chapter R8, the recommended assessment factor is 3 when the starting point for the DNEL calculation is a LOAEL. In this particular case, the starting point used is a LOAEL which is considered to be close to the end of the dose response curve with only minimal and mild effects.
AF for differences in duration of exposure:
6
Justification:
Default assessment factor going from subacute to chronic, according to ECHA guidance document Chapter R8, in Table R. 8-5 Assessment factors for duration extrapolation.
AF for interspecies differences (allometric scaling):
1
Justification:
No additional factor as already included in the route to route extrapolation from the rat oral LOAEL to the equivalent human inhalation LOAEC.
AF for other interspecies differences:
1
Justification:
ECETOC reported in 2010 after an extensive scientific 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 fact 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:
According to ECHA guidance document Chapter R8, the default assessment factor to be applied for good/standard quality of the database, taking into account completeness, consistency and the standard information requirements, is 1. Data used is based on testing of C16-22-(even numbered)alkylamines (CAS no 68037-92-3) in a Klimisch 1 validity 28-day oral toxicity study performed according to GLP. Based on the quality of the available data an assessment factor of 1 is considered justified.
AF for remaining uncertainties:
1
Justification:
Possible uncertainties are already included in the assessment factors above, 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)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.01 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC
Overall assessment factor (AF):
360
Modified dose descriptor starting point:
LOAEL
Value:
3.5 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:
3
Justification:
According to the ECHA guidance document Chapter R8, the recommended assessment factor is 3 when the starting point for the DNEL calculation is a LOAEL. In this particular case, the starting point used is a LOAEL which is considered to be close to the end of the dose response curve with only minimal and mild effects.
AF for differences in duration of exposure:
6
Justification:
Default assessment factor going from subacute to chronic, according to ECHA guidance document Chapter R8, in Table R. 8-5 Assessment factors for duration extrapolation.
AF for interspecies differences (allometric scaling):
4
Justification:
Default assessment factor for allometric scaling between rat to human, according to ECHA guidance document Chapter R8, Table R. 8-3 Allometric scaling factors for different species as compared to humans.
AF for other interspecies differences:
1
Justification:
ECETOC reported in 2010 after an extensive scientific 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 fact 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:
According to ECHA guidance document Chapter R8, the default assessment factor to be applied for good/standard quality of the database, taking into account completeness, consistency and the standard information requirements, is 1. Data used is based on testing of C16-22-(even numbered)alkylamines (CAS no 68037-92-3) in a Klimisch 1 validity 28-day oral toxicity study performed according to GLP. Based on the quality of the available data an assessment factor of 1 is considered justified.
AF for remaining uncertainties:
1
Justification:
Possible uncertainties are already included in the assessment factors above, 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
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)

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, this is based on an assumption that absorption in the lungs will be 100% compared to 50% by the oral route. 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 as exposure will be via ingestion with absorption in the stomach and gastrointestinal tract rather than absorption in the lungs, an assessment factor of 1 will be applied rather than the default of 2 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 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. A similar concept was developed for the German Auschuss für Gefahrstoffe - AGS (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 intra species variation in response, then these factor may be increased for example as suggested by the German Auschuss für Gefahrstoffe 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.

 

In this case to ensure 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. For Consumers we have taken the ECETOC recommended factor of 5 and again added an additional 2 to give a factor of 7 to cover any additional variability.

 

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 a DNEL,Technical Report No.110,ISSN-0773-8072-110 (print),ISSN-2079-1562-110 (online), October 2010

 

German Auschuss für Gefahrstoffe(AGS) 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:
0.02 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC
Overall assessment factor (AF):
126
Modified dose descriptor starting point:
LOAEC
Value:
3.05 mg/m³
Explanation for the modification of the dose descriptor starting point:
Justification for route to route extrapolation: 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 additional assessment factor is not considered relevant in this particular case, since the substance has low vapour pressures and inhalation is therefore unlikely. 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:
3
Justification:
According to the ECHA guidance document Chapter R8, the recommended assessment factor is 3 when the starting point for the DNEL calculation is a LOAEL. In this particular case, the starting point used is a LOAEL which is considered to be close to the end of the dose response curve with only minimal and mild effects.
AF for differences in duration of exposure:
6
Justification:
Default assessment factor going from subacute to chronic, according to ECHA guidance document Chapter R8, in Table R. 8-5 Assessment factors for duration extrapolation.
AF for interspecies differences (allometric scaling):
1
Justification:
No additional factor as already included in the route to route extrapolation from the rat oral LOAEL to the equivalent human inhalation LOAEC.
AF for other interspecies differences:
1
Justification:
ECETOC reported in 2010 after an extensive scientific 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:
According to ECHA guidance document Chapter R8, the default assessment factor to be applied for good/standard quality of the database, taking into account completeness, consistency and the standard information requirements, is 1. Data used is based on testing of C16-22-(even numbered)alkylamines (CAS no 68037-92-3) in a Klimisch 1 validity 28-day oral toxicity study performed according to GLP. Based on the quality of the available data an assessment factor of 1 is considered justified.
AF for remaining uncertainties:
1
Justification:
Possible uncertainties are already included in the assessment factors above, so a factor of 1 is applied.
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.007 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC
Overall assessment factor (AF):
504
Modified dose descriptor starting point:
LOAEL
Value:
3.5 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:
3
Justification:
According to the ECHA guidance document Chapter R8, the recommended assessment factor is 3 when the starting point for the DNEL calculation is a LOAEL. In this particular case, the starting point used is a LOAEL which is considered to be close to the end of the dose response curve with only minimal and mild effects.
AF for differences in duration of exposure:
6
Justification:
Default assessment factor going from subacute to chronic, according to ECHA guidance document Chapter R8, in Table R. 8-5 Assessment factors for duration extrapolation.
AF for interspecies differences (allometric scaling):
4
Justification:
Default assessment factor for allometric scaling between rat to human, according to ECHA guidance document Chapter R8, Table R. 8-3 Allometric scaling factors for different species as compared to humans.
AF for other interspecies differences:
1
Justification:
ECETOC reported in 2010 after an extensive scientific 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:
According to ECHA guidance document Chapter R8, the default assessment factor to be applied for good/standard quality of the database, taking into account completeness, consistency and the standard information requirements, is 1. Data used is based on testing of C16-22-(even numbered)alkylamines (CAS no 68037-92-3) in a Klimisch 1 validity 28-day oral toxicity study performed according to GLP. Based on the quality of the available data an assessment factor of 1 is considered justified.
AF for remaining uncertainties:
1
Justification:
Possible uncertainties are already included in the assessment factors above, so a factor of 1 is applied.
Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.007 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC
Overall assessment factor (AF):
504
Modified dose descriptor starting point:
LOAEL
Value:
3.5 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
The DNEL is derived from a LOAEL in a 28 day oral study, so therefore no route to route extrapolation is needed.
AF for dose response relationship:
3
Justification:
According to the ECHA guidance document Chapter R8, the recommended assessment factor is 3 when the starting point for the DNEL calculation is a LOAEL. In this particular case, the starting point used is a LOAEL which is considered to be close to the end of the dose response curve with only minimal and mild effects.
AF for differences in duration of exposure:
6
Justification:
Default assessment factor going from subacute to chronic, according to ECHA guidance document Chapter R8, in Table R. 8-5 Assessment factors for duration extrapolation.
AF for interspecies differences (allometric scaling):
4
Justification:
Default assessment factor for allometric scaling between rat to human, according to ECHA guidance document Chapter R8, Table R. 8-3 Allometric scaling factors for different species as compared to humans.
AF for other interspecies differences:
1
Justification:
ECETOC reported in 2010 after an extensive scientific 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:
According to ECHA guidance document Chapter R8, the default assessment factor to be applied for good/standard quality of the database, taking into account completeness, consistency and the standard information requirements, is 1. Data used is based on testing of C16-22-(even numbered)alkylamines (CAS no 68037-92-3) in a Klimisch 1 validity 28-day oral toxicity study performed according to GLP. Based on the quality of the available data an assessment factor of 1 is considered justified.
AF for remaining uncertainties:
1
Justification:
Possible uncertainties are already included in the assessment factors above, so a factor of 1 is applied.
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

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, this is based on an assumption that absorption in the lungs will be 100% compared to 50% by the oral route. 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 as exposure will be via ingestion with absorption in the stomach and gastrointestinal tract rather than absorption in the lungs, an assessment factor of 1 will be applied rather than the default of 2 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 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. A similar concept was developed for the German Auschuss für Gefahrstoffe - AGS (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 intra species variation in response, then these factor may be increased for example as suggested by the German Auschuss für Gefahrstoffe 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.

 

In this case to ensure 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. For Consumers we have taken the ECETOC recommended factor of 5 and again added an additional 2 to give a factor of 7 to cover any additional variability.

 

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 a DNEL,Technical Report No.110,ISSN-0773-8072-110 (print),ISSN-2079-1562-110 (online), October 2010

 

German Auschuss für Gefahrstoffe(AGS) 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