Oleic acid, compound with (Z)-N-octadec-9-enylpropane-1,3-diamine (2:1)

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

98.4 µg/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

Dose descriptor starting point:

NOAEL

Value:

1 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

2.46 mg/m³

Explanation for the modification of the dose descriptor starting point:

Starting point is the NOAEL for Oleyl-diamine in Oleyl-diamine dioleate (see documents supporting the read-across) which is based upon cross-reading from the 90-day study on C12-14-Diamine resulting to a NOAEL of 0.4 mg/kgbw/d. The NOAEL of 0.4 mg/kgbw/d for C12-14-diamine is based on effects observed of foamy macrophages seen at higher dose levels of 1.5 and 6 mg/kg. The effects are comparable and evaluated similar as in all other studies involving primary amine structures, and are considered to be of a non-adverse and local nature. This NOAEL therefore represents a very conservative level. Furthermore, the NOAEL is not really influenced by the duration of the study, which supports the lack of bio-accumulating potential of the diamines. Despite this, and the results from a 28-day study on Oleyl diamine and Oleyl diamine dioleate showing a NOAEL of 1.25 and 5 mg/kg/day, respectively, the NOAEL from the 28 and 90-day study with C12/14-diamine of 0.4 mg/kg/day is taken as conservative value.

This is then converted to the corresponding value for the dioleate salt of Oleyl-diamine, resulting to a derived oral NOAEL for Oleyl-diamine dioleate of about 1 mg/kg bw/day. (mw oleyl-diamine = 324.7, mw oleyl-diamine dioleate = 889.5; 0.4 x 889.5/324.7 = 1.1)

The corrected 8 hr inhalation NOAEC for workers is NOAEL (1) * 1.76 *1.4 mg/m3 = 2.46 mg/m3.

- 1.76 : correction for differences in respiratory volume (workers) 

- 1.4 : correction for differences between human and experimental exposure condition (workers)

- The use of the factor 2 for route extrapolation from oral to inhalation would represent a conservative approach. Due to very low vp, exposure is only possible as aerosol or larger particles. If any inhalation does occur, this can only be in the form of larger droplets, as the use does not include fine spraying. 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.

AF for dose response relationship:

1

Justification:

Default (DNEL calculator). No specific concerns; starting point is NOAEL.

AF for differences in duration of exposure:

2

Justification:

Default (DNEL calculator). Default assessment factor for sub-chronic to chronic.

AF for interspecies differences (allometric scaling):

1

Justification:

Default (DNEL calculator). Already included in NOAEC calculation

AF for other interspecies differences:

2.5

Justification:

Default (DNEL calculator). Default assessment factor for remaining differences

AF for intraspecies differences:

5

Justification:

Default (DNEL calculator). Assessment factor of 5 for workers recommended by Reach guidance.

AF for the quality of the whole database:

1

Justification:

Default (DNEL calculator). Available data derived from valid studies showing consistent results.

AF for remaining uncertainties:

1

Justification:

Cross-reading to more studies on similar amine structures does not indicate additional concerns to be considered.

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:

14 µg/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

Dose descriptor starting point:

NOAEL

Value:

1 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1.4 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Starting point is the NOAEL for Oleyl-diamine in Oleyl-diamine dioleate (see discussion) which is based upon cross-reading from the 90-day study on C12-14-Diamine resulting to a NOAEL of 0.4 mg/kgbw/d. This is then converted to the corresponding value for the dioleate salt of Oleyl-diamine, resulting to a derived oral NOAEL for Oleyl-diamine dioleate of about 1 mg/kg bw/day. (mw oleyl-diamine = 324.7, mw oleyl-diamine dioleate = 889.5; 0.4 x 889.5/324.7 = 1.1) At this stage no data are available on dermal absorption. As this is not quantitatively evaluated, 100% dermal absorption is considered as worst case assumption.

The corrected dermal NOAEL for workers is NOAEL (1) * 1.4 = 1.4 mg/kg bw/day.

- 1.4 : correction for differences between human and experimental exposure condition (workers)

AF for dose response relationship:

1

Justification:

Default (DNEL Calculator); No specific concerns; starting point is NOAEL.

AF for differences in duration of exposure:

2

Justification:

Default (DNEL calculator). Default assessment factor for sub-chronic to chronic.

AF for interspecies differences (allometric scaling):

4

Justification:

Default (DNEL calculator).

AF for other interspecies differences:

2.5

Justification:

Default (DNEL calculator). Default assessment factor for remaining differences

AF for intraspecies differences:

5

Justification:

Default (DNEL calculator). Assessment factor of 5 for workers recommended by Reach guidance.

AF for the quality of the whole database:

1

Justification:

Default (DNEL calculator). Available data derived from valid studies showing consistent results.

AF for remaining uncertainties:

1

Justification:

Cross-reading to more studies on similar amine structures does not indicate additional concerns to be considered.

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)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

17.4 µg/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):

50

Dose descriptor starting point:

NOAEL

Value:

0.4 mg/kg bw/day

Value:

0.87 mg/m³

Explanation for the modification of the dose descriptor starting point:

Starting point is the NOAEL for Oleyl-diamine in Oleyl-diamine dioleate (see documents supporting the read-across) which is based upon cross-reading from the 90-day study on C12-14-Diamine resulting to a NOAEL of 0.4 mg/kgbw/d. The NOAEL of 0.4 mg/kgbw/d for C12-14-diamine is based on effects observed of foamy macrophages seen at higher dose levels of 1.5 and 6 mg/kg. The effects are comparable and evaluated similar as in all other studies involving primary amine structures, and are considered to be of a non-adverse and local nature. This NOAEL therefore represents a very conservative level. Furthermore, the NOAEL is not really influenced by the duration of the study, which supports the lack of bio-accumulating potential of the diamines. Despite this, and the results from a 28-day study on Oleyl diamine and Oleyl diamine dioleate showing a NOAEL of 1.25 and 5 mg/kg/day, respectively, the NOAEL from the 28 and 90-day study with C12/14-diamine of 0.4 mg/kg/day is taken as conservative value.

This is then converted to the corresponding value for the dioleate salt of Oleyl-diamine, resulting to a derived oral NOAEL for Oleyl-diamine dioleate of about 1 mg/kg bw/day. (mw oleyl-diamine = 324.7, mw oleyl-diamine dioleate = 889.5; 0.4 x 889.5/324.7 = 1.1)

The corrected 8 hr inhalation NOAEC for General population is NOAEL (1) * 1/1.15 mg/m3 = 0.87 mg/m3.

- 1.15 : correction for differences in respiratory volume (General Population) 

- The use of the factor 2 for route extrapolation from oral to inhalation would represent a conservative approach. Due to very low vp, exposure is only possible as aerosol or larger particles. If any inhalation does occur, this can only be in the form of larger droplets, as the use does not include fine spraying. 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.

AF for dose response relationship:

1

Justification:

Default (DNEL calculator). No specific concerns; starting point is NOAEL and the highest dose-level tested.

AF for differences in duration of exposure:

2

Justification:

Default (DNEL calculator). Default assessment factor for sub-chronic to chronic.

AF for interspecies differences (allometric scaling):

1

Justification:

Default (DNEL calculator). Already included in NOAEC calculation;

AF for other interspecies differences:

2.5

Justification:

Default (DNEL calculator). Default assessment factor for remaining differences

AF for intraspecies differences:

10

Justification:

Default (DNEL calculator). Assessment factor of 10 for General Population recommended by Reach guidance.

AF for the quality of the whole database:

1

Justification:

Default (DNEL calculator). Available data derived from valid studies showing consistent results.

AF for remaining uncertainties:

1

Justification:

Cross-reading to more studies on similar amine structures does not indicate additional concerns to be considered.

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:

5 µg/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):

200

Dose descriptor starting point:

NOAEL

Value:

1 mg/kg bw/day

Value:

1 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Starting point is the NOAEL for Oleyl-diamine in Oleyl-diamine dioleate (see discussion) which is based upon cross-reading from the 90-day study on C12-14-Diamine resulting to a NOAEL of 0.4 mg/kgbw/d. This is then converted to the corresponding value for the dioleate salt of Oleyl-diamine, resulting to a derived oral NOAEL for Oleyl-diamine dioleate of about 1 mg/kg bw/day. (mw oleyl-diamine = 324.7, mw oleyl-diamine dioleate = 889.5; 0.4 x 889.5/324.7 = 1.1) At this stage no data are available on dermal absorption. As this is not quantitatively evaluated, 100% dermal absorption is considered as worst case assumption.

AF for dose response relationship:

1

Justification:

Default (DNEL calculator). No specific concerns; starting point is NOAEL.

AF for differences in duration of exposure:

2

Justification:

Default (DNEL calculator). Default assessment factor for sub-chronic to chronic.

AF for interspecies differences (allometric scaling):

4

Justification:

Default (DNEL calculator).

AF for other interspecies differences:

2.5

Justification:

Default (DNEL calculator). Default assessment factor for remaining differences

AF for intraspecies differences:

10

Justification:

Default (DNEL calculator). Assessment factor of 10 for General Population recommended by Reach guidance.

AF for the quality of the whole database:

1

Justification:

Default (DNEL calculator). Available data derived from valid studies showing consistent results.

AF for remaining uncertainties:

1

Justification:

Cross-reading to more studies on similar amine structures does not indicate additional concerns to be considered.

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)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5 µg/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):

200

Dose descriptor starting point:

NOAEL

Value:

1 mg/kg bw/day

Value:

1 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Starting point is the NOAEL for Oleyl-diamine in Oleyl-diamine dioleate (see documents supporting the read-across) which is based upon cross-reading from the 90-day study on C12-14-Diamine resulting to a NOAEL of 0.4 mg/kgbw/d. This is then converted to the corresponding value for the dioleate salt of Oleyl-diamine, resulting to a derived oral NOAEL for Oleyl-diamine dioleate of about 1 mg/kg bw/day. (mw oleyl-diamine = 324.7, mw oleyl-diamine dioleate = 889.5; 0.4 x 889.5/324.7 = 1.1) At this stage no data are available on oral absorption. Oleyl-diamine is not expected to easily pass the intestinal wall from the dioleate salt form, however, as this is not quantitatively evaluated, 100% oral absorption is considered as worst case assumption.

AF for dose response relationship:

1

Justification:

Default (DNEL calculator). No specific concerns; starting point is NOAEL.

AF for differences in duration of exposure:

2

Justification:

Default (DNEL calculator). Default assessment factor for sub-chronic to chronic.

AF for interspecies differences (allometric scaling):

4

Justification:

Default (DNEL calculator). Already included in NOAEC calculation.

AF for other interspecies differences:

2.5

Justification:

Default (DNEL calculator). Default assessment factor for remaining differences.

AF for intraspecies differences:

10

Justification:

Default (DNEL calculator). Assessment factor of 10 for General Population recommended by Reach guidance

AF for the quality of the whole database:

1

Justification:

Default (DNEL calculator). Available data derived from valid studies showing consistent results.

AF for remaining uncertainties:

1

Justification:

Cross-reading to more studies on similar amine structures does not indicate additional concerns to be considered.

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)