Amines, C36-alkylenedi-

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.5 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Modified dose descriptor starting point:

NOAEC

Value:

88 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 50 mg/kg bw/day. Allometric scaling is applied to account for the different breathing rates between rats and humans, as described in ECHA guidance. The recommends factor of 2 when doing route to route extrapolation for oral to inhalation exposure, recognizing higher absorption via the lungs has not been applied here. Due to low vp, exposure is only possible as aerosol (no fine spraying, only larger droplets). 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 oral route. ECHA technical guidance for route to route extrapolation: the oral NOAEL in the rat mg/kg/day *1/0.38 * 6.7/10 = 50 * 1.76 = 88 mg/m3 inhalation NOAEC for workers.

AF for dose response relationship:

1

Justification:

No specific concerns. Effects at LOAEL are not severe and probably only of local nature.

AF for differences in duration of exposure:

5

Justification:

The guidance indicates that for subacute to chronic a factor 6 should be applied. However, we know that the dose levels of the NOAEL for this effect of foamy macrophages in mesenteric lymph nodes is not influenced by the duration of the study. Besides, the females have been dosed for 43-57 days rather than 28 days (Males 28 days).

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, the already applied allometric scaling already represents a worst case.

AF for intraspecies differences:

5

Justification:

Default. Although ECETOC reported in 2010 after an extensive scientific review that the appropriate fact for intraspecies differences for workers is 3 and not 5, the factor 5 is used to accommodate for the possible high uncertainty between individuals as the effects for which the risk assessment is made possibly includes a local response.

AF for the quality of the whole database:

1

Justification:

It involves recent studies

AF for remaining uncertainties:

1

Justification:

A worst case cross-reading to the monomeric fatty amines does also not indicate additional concerns to be considered.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

17.6 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

5

DNEL extrapolated from long term DNEL

Modified dose descriptor starting point:

NOAEC

Value:

88 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 50 mg/kg bw/day. Allometric scaling is applied to account for the different breathing rates between rats and humans, as described in ECHA guidance. The recommends factor of 2 when doing route to route extrapolation for oral to inhalation exposure, recognizing higher absorption via the lungs has not been applied here. Due to low vp, exposure is only possible as aerosol (no fine spraying, only larger droplets). 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 oral route. ECHA technical guidance for route to route extrapolation: the oral NOAEL in the rat mg/kg/day *1/0.38 * 6.7/10 = mg/m3 inhalation NOAEL for workers.

AF for dose response relationship:

1

Justification:

No specific concerns. Effects at LOAEL are not severe and probably only of local nature.

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, the already applied allometric scaling already represents a worst case.

AF for intraspecies differences:

5

Justification:

Default. Although ECETOC reported in 2010 after an extensive scientific review that the appropriate fact for intraspecies differences for workers is 3 and not 5, the factor 5 is used to accommodate for the possible high uncertainty between individuals as the effects for which the risk assessment is made possibly includes a local response.

AF for the quality of the whole database:

1

Justification:

It involves recent studies

AF for remaining uncertainties:

1

Justification:

A worst case cross-reading to the monomeric fatty amines does also not indicate additional concerns to be considered

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

Value:

50 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 50 mg/kg bw/day. 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:

No specific concerns. Effects at LOAEL are not severe and probably only of local nature.

AF for differences in duration of exposure:

5

Justification:

The guidance indicates that for subacute to chronic a factor 6 should be applied. However, we know that the dose levels of the NOAEL for this effect of foamy macrophages in mesenteric lymph nodes is not influenced by the duration of the study. Besides, the females have been dosed for 43-57 days rather than 28 days (Males 28 days).

AF for interspecies differences (allometric scaling):

4

Justification:

Default factor for allometric scaling from rat to human.

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:

Default. Although ECETOC reported in 2010 after an extensive scientific review that the appropriate fact for intraspecies differences for workers is 3 and not 5, the factor 5 is used to accommodate for the possible high uncertainty between individuals as the effects for which the risk assessment is made possibly includes a local response.

AF for the quality of the whole database:

1

Justification:

It involves recent studies

AF for remaining uncertainties:

1

Justification:

A worst case cross-reading to the monomeric fatty amines does also not indicate additional concerns to be considered.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

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:

low 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)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.24 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

35

Modified dose descriptor starting point:

NOAEC

Value:

43.5 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 50 mg/kg bw/day. Allometric scaling is applied to account for the different breathing rates between rats and humans, as described in ECHA guidance. The recommends factor of 2 when doing route to route extrapolation for oral to inhalation exposure, recognizing higher absorption via the lungs has not been applied here. Due to low vp (2.2 x10-7 Pa @ 20°C), exposure is only possible as aerosol (no fine spraying, only larger droplets). 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 oral route. Besides, there is no direct use or exposure to the general public. ECHA technical guidance for route to route extrapolation: the oral NOAEL in the rat (= 50) mg/kg/day *1/0.38 * 6.7/10 = 43.5 mg/m3 inhalation

AF for dose response relationship:

1

Justification:

No specific concerns. Effects at LOAEL are not severe and probably only of local nature.

AF for differences in duration of exposure:

5

Justification:

The guidance indicates that for subacute to chronic a factor 6 should be applied. However, we know that the dose levels of the NOAEL for this effect of foamy macrophages in mesenteric lymph nodes is not influenced by the duration of the study. Besides, the females have been dosed for 43-57 days rather than 28 days (Males 28 days).

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, 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 general public is 5 and not 10, In this case the factor 7 is used to accommodate for the possible high uncertainty between individuals as the effects for which the risk assessment is made possibly includes a local response.

AF for the quality of the whole database:

1

Justification:

It involves recent studies

AF for remaining uncertainties:

1

Justification:

A worst case cross-reading to the monomeric fatty amines does also not indicate additional concerns to be considered.

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:

0.36 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

140

Modified dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Extrapolation from oral NOAEL represents a worst case situation, as dermal absorption is considered to be lower compared to oral absorption.

AF for dose response relationship:

1

Justification:

No specific concerns. Effects at LOAEL are not severe and probably only of local nature.

AF for differences in duration of exposure:

5

Justification:

The guidance indicates that for subacute to chronic a factor 6 should be applied. However, we know that the dose levels of the NOAEL for this effect of foamy macrophages in mesenteric lymph nodes is not influenced by the duration of the study. Besides, the females have been dosed for 43-57 days rather than 28 days (Males 28 days).

AF for interspecies differences (allometric scaling):

4

Justification:

Default factor for allometric scaling from rat to human.

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 general public is 5 and not 10, In this case the factor 7 is used to accommodate for the possible high uncertainty between individuals as the effects for which the risk assessment is made possibly includes a local response.

AF for the quality of the whole database:

1

Justification:

It involves recent studies

AF for remaining uncertainties:

1

Justification:

A worst case cross-reading to the monomeric fatty amines does also not indicate additional concerns to be considered

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:

0.36 mg/kg bw/day

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

140

Modified dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No route-to-route extrapolation needed

AF for dose response relationship:

1

Justification:

No specific concerns. Effects at LOAEL are not severe and probably only of local nature.

AF for differences in duration of exposure:

5

Justification:

The guidance indicates that for subacute to chronic a factor 6 should be applied. However, we know that the dose levels of the NOAEL for this effect of foamy macrophages in mesenteric lymph nodes is not influenced by the duration of the study. Besides, the females have been dosed for 43-57 days rather than 28 days (Males 28 days).

AF for interspecies differences (allometric scaling):

4

Justification:

Default factor for allometric scaling from rat to human.

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 general public is 5 and not 10, In this case the factor 7 is used to accommodate for the possible high uncertainty between individuals as the effects for which the risk assessment is made possibly includes a local response.

AF for the quality of the whole database:

1

Justification:

It involves recent studies

AF for remaining uncertainties:

1

Justification:

A worst case cross-reading to the monomeric fatty amines does also not indicate additional concerns to be considered.

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

Consumers will only be exposed to low residual amounts of the substance, since it is mainly used as an intermediate.