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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:
21.16 mg/m³
Most sensitive endpoint:
repeated dose toxicity
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):
25
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
529 mg/m³
Explanation for the modification of the dose descriptor starting point:

Starting point is OECD 422 study by oral dosing in rats, resulting to a NOAEL of 300 mg/kg bw/day. 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 of 300 mg/kg/day *1/0.38 * 6.7/10 = 529 mg/m3 inhalation NOAEC for workers. As described at toxicokinetics information, absorption via inhalation is considered to be complete (100%). In view of the very low vapour pressure is exposure via inhalation in principle only possible via aerosol of dust. In both cases most is expected to be deposited in the nose, throat and upper airways and will be subsequently swallowed following mucociliary transportation to pharynx. This results to no principal difference in absorption compared oral route. Consequently, no additional factor 2 is applied.

AF for dose response relationship:
1
Justification:
No specific concerns; starting point is NOAEL and the effects show a clear dose response.
AF for differences in duration of exposure:
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.
AF for interspecies differences (allometric scaling):
1
Justification:
Already included in NOAEC calculation
AF for other interspecies differences:
1
Justification:
ECETOC reported in 2010 after an extensive review that there is no justification for the suggested additional factor of 2.5 for this, therefore a factor of 1 has been applied. As effects are interpreted as being local and related to the route of exposure (see comments), the already applied allometric scaling already represents a worst case.
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:
Available data are derived from recent, high quality and valid studies showing consistent results.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties. To this can be remarked that toxicity is mainly driven by local effects rather than systemic toxicity. The use of the resulting NOAEL therefore adds to additional conservatism.
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
other: According to H. Messinger (2014), applyinmg a generic cut-off value for local respiratory tract irritation by irritating or corrosive substances
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
other: According to H. Messinger (2014), applyinmg a generic cut-off value for local respiratory tract irritation by irritating or corrosive substances

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
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):
100
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
300 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. Starting point is OECD 422 study by oral dosing in rats, resulting to a NOAEL of 300 mg/kdbw/day based on the histopathological findings in the stomach above this level.

At this stage no data are available on dermal absorption. ANS is not expected to easily pass the skin in view of its ionised form at physiological conditions. However, as this is not quantitatively evaluated, 100% dermal absorption is considered as worst case assumption.
AF for dose response relationship:
1
Justification:
No specific concerns; starting point is NOAEL and the effects show a clear dose response.
AF for differences in duration of exposure:
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.
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 that there is no justification for the suggested additional factor of 2.5 for this, therefore a factor of 1 has been applied. As effects are interpreted as being local related to the route of exposure, the applied allometric scaling already represents a worst case.
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:
Available data are derived from recent, hight quality and valid study.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties. To this can be remarked that toxicity is mainly driven by local effects rather than systemic toxicity. The use of the resulting NOAEL therefore adds to additional conservatism.
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)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

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 (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 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.

References:

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

 

GermanAuschuss 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:
7.46 mg/m³
Most sensitive endpoint:
repeated dose toxicity
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):
35
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
261 mg/m³
Explanation for the modification of the dose descriptor starting point:

Starting point is OECD 422 study by oral dosing in rats, resulting to a NOAEL of 300 mg/kg bw/day. 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 of 300 mg/kg/day *1/1.15 mg/m3 = 261 mg/m3 inhalation NOAEC for consumers. As described at toxicokinetics information, absorption via inhalation is considered to be complete (100%). In view of the very low vapour pressure is exposure via inhalation in principle only possible via aerosol of dust. In both cases most is expected to be deposited in the nose, throat and upper airways and will be subsequently swallowed following mucociliary transportation to pharynx. This results to no principal difference in absorption compared oral route. Consequently, no additional factor 2 is applied.

AF for dose response relationship:
1
Justification:
No specific concerns; starting point is NOAEL and the effects show a clear dose response.
AF for differences in duration of exposure:
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.
AF for interspecies differences (allometric scaling):
1
Justification:
Already included in NOAEC calculation
AF for other interspecies differences:
1
Justification:
ECETOC reported in 2010 after an extensive review that there is no justification for the suggested additional factor of 2.5 for this, therefore a factor of 1 has been applied. As effects are interpreted as being local and related to the route of exposure (see comments), the already applied allometric scaling already represents a worst case.
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:
Available data are derived from recent, high quality and valid studies showing consistent results.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties. To this can be remarked that toxicity is mainly driven by local effects rather than systemic toxicity. The use of the resulting NOAEL therefore adds to additional conservatism.
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:
DNEL (Derived No Effect Level)
Value:
2.143 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
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
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
300 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. Starting point is OECD 422 study by oral dosing in rats, resulting to a NOAEL of 300 mg/kdbw/day based on the histopathological findings in the stomach above this level. At this stage no data are available on dermal absorption. ANS is not expected to easily pass the skin in view of its ionised form at physiological conditions. However, as this is not quantitatively evaluated, 100% dermal absorption is considered as worst case assumption.

AF for dose response relationship:
1
Justification:
No specific concerns; starting point is NOAEL and the effects show a clear dose response.
AF for differences in duration of exposure:
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 OECD 422 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.
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 that there is no justification for the suggested additional factor of 2.5 for this, therefore a factor of 1 has been applied. As effects are interpreted as being local related to the route of exposure, the applied allometric scaling already represents a worst case.
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 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:
Available data are derived from recent, high quality and valid study
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties. To this can be remarked that toxicity is mainly driven by local effects rather than systemic toxicity. The use of the resulting NOAEL therefore adds to additional conservatism.
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:
DNEL (Derived No Effect Level)
Value:
2.143 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
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):
140
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Starting point is OECD 422 study by oral dosing in rats, resulting to a NOAEL of 300 mg/kdbw/day based on the histopathological findings in the stomach above this level. No route-to-route extrapolation is needed.

AF for dose response relationship:
1
Justification:
No specific concerns; starting point is NOAEL.
AF for differences in duration of exposure:
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.
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 that there is no justification for the suggested additional factor of 2.5 for this, therefore a factor of 1 has been applied. As effects are interpreted as being local related to the route of exposure, the applied allometric scaling already represents a worst case.
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 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:
Available data are derived from recent, high quality and valid study.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties. To this can be remarked that toxicity is mainly driven by local effects rather than systemic toxicity. The use of the resulting NOAEL therefore adds to additional conservatism.
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

ANS is only used in industrially and professional settings; no consumers uses have been identified. However, in order to be able to evaluate possible secondary exposures via environment, additionally long-term systemic DNELs for general population have been derived.

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 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.

References:

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

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