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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
97.8 mg/m³
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA and ECETOC
Overall assessment factor (AF):
18
Modified dose descriptor starting point:
NOAEC
Value:
1 760 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 is a paste with a very 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:
1
Justification:
According to the ECHA guidance document Chapter R8, the default assessment factor is 1 when the starting point for the DNEL calculation is a NOAEL. In this particular case, the starting point used is a NOAEL > 1000 mg/kg bw, since no adverse effects was observed in the tests. Based on the low toxicity of the substance, it is not considered relevant to use a larger assessment factor, although the dose-response curve cannot be evaluated.
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 NOAEL to the equivalent human inhalation NOAEC.
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:
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:
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 Sodium N-(2-carboxyethyl)-N-(2-ethylhexyl)-β-alaninate, CAS No 94441-92-6, in a Klimisch 1 validity 28-day oral toxicity study performed according to GLP. Based on the quality of the available data and the low toxicity of the substance 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:
13.9 mg/kg bw/day
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA and ECETOC
Overall assessment factor (AF):
72
Modified dose descriptor starting point:
NOAEL
Value:
1 000 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:
According to the ECHA guidance document Chapter R8, the default assessment factor is 1 when the starting point for the DNEL calculation is a NOAEL. In this particular case, the starting point used is a NOAEL > 1000 mg/kg bw, since no adverse effects was observed in the tests. Based on the low toxicity of the substance, it is not considered relevant to use a larger assessment factor, although the dose-response curve cannot be evaluated.
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:
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:
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 Sodium N-(2-carboxyethyl)-N-(2-ethylhexyl)-β-alaninate, CAS No 94441-92-6, in a Klimisch 1 validity 28-day oral toxicity study performed according to GLP. Based on the quality of the available data and the low toxicity of the substance 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)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

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

ECHA (2010) has produced guidance on the assessment factors to use to derive a DNEL for human exposure based on 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 also confirmed in the ECETOC (2010) guidance. 

 

After reviewing these guidance documents, 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). For consumers we have taken the ECETOC recommended factor of 5. 

 

References:

 

ECHA, 2010Guidance 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:
DNEL (Derived No Effect Level)
Value:
29 mg/m³
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA and ECETOC
Overall assessment factor (AF):
30
Modified dose descriptor starting point:
NOAEC
Value:
870 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 is a paste with a very 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:
1
Justification:
According to the ECHA guidance document Chapter R8, the default assessment factor is 1 when the starting point for the DNEL calculation is a NOAEL. In this particular case, the starting point used is a NOAEL > 1000 mg/kg bw, since no adverse effects was observed in the tests. Based on the low toxicity of the substance, it is not considered relevant to use a larger assessment factor, although the dose-response curve cannot be evaluated.
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 NOAEL to the equivalent human inhalation NOAEC.
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 general public is 5 and not 10 as ECHA proposed, 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 Sodium N-(2-carboxyethyl)-N-(2-ethylhexyl)-β-alaninate, CAS No 94441-92-6, in a Klimisch 1 validity 28-day oral toxicity study performed according to GLP. Based on the quality of the available data and the low toxicity of the substance 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

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.3 mg/kg bw/day
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA and ECETOC
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
Value:
1 000 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:
According to the ECHA guidance document Chapter R8, the default assessment factor is 1 when the starting point for the DNEL calculation is a NOAEL. In this particular case, the starting point used is a NOAEL > 1000 mg/kg bw, since no adverse effects was observed in the tests. Based on the low toxicity of the substance, it is not considered relevant to use a larger assessment factor, although the dose-response curve cannot be evaluated.
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 general public is 5 and not 10 as ECHA proposed, 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 Sodium N-(2-carboxyethyl)-N-(2-ethylhexyl)-β-alaninate, CAS No 94441-92-6, in a Klimisch 1 validity 28-day oral toxicity study performed according to GLP. Based on the quality of the available data and the low toxicity of the substance 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:
hazard unknown (no further information necessary)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.3 mg/kg bw/day
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The DNEL is derived from a NOAEL in a 28 day oral study, so no route to route extrapolation is needed.

AF for dose response relationship:
1
Justification:
According to the ECHA guidance document Chapter R8, the default assessment factor is 1 when the starting point for the DNEL calculation is a NOAEL. In this particular case, the starting point used is a NOAEL > 1000 mg/kg bw, since no adverse effects was observed in the tests. Based on the low toxicity of the substance, it is not considered relevant to use a larger assessment factor, although the dose-response curve cannot be evaluated.
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 general public is 5 and not 10 as ECHA proposed, 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 Sodium N-(2-carboxyethyl)-N-(2-ethylhexyl)-β-alaninate, CAS No 94441-92-6, in a Klimisch 1 validity 28-day oral toxicity study performed according to GLP. Based on the quality of the available data and the low toxicity of the substance 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

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low 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 (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 also 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). For consumers we have taken the ECETOC recommended factor of 5. 

 

References:

 

ECHA, 2010Guidance 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