Bis(2-ethylhexyl)amine

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.76 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):

75

Dose descriptor starting point:

NOAEL

Value:

75 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

132.24 mg/m³

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by inhalation.

For DNEL derivation, a NOAEL from an oral OECD 422 study was used. The NOAEL is 75 mg/kg bw/d.

(75 mg/kg bw/d / 0.38 m³/kg bw/d) * 0.67 = 132.24 mg/m³

The recommended approach assuming 50% absorption for oral and 100% absorption for inhalation exposure was not taken into account, because of the physico-chemical properties of the substance.

log Pow is 7.3

water solubility is 14 mg/l

Thus, the substance is highly lipophilic and poorly water soluble. According to ECHA guidance document R.7c (v3.0, June 2017), any lipophilic compound may be taken up by micellular solubilisation but this mechanism may be of particular importance for highly lipophilic compounds (log P >4), particularly those that are poorly soluble in water (0.001 mg/l or less) that would otherwise be poorly absorbed. This applies to both exposure routes, oral as well as inhalation. That is why a similar absorption for both exposure routes is assumed and no additional correction factor is used.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

Default value for time extrapolation from subacute to chronic study.

AF for interspecies differences (allometric scaling):

1

Justification:

Respiratory interspecies differences are fully covered by the factors (respiratory volumina) used for route to route extrapolation.

AF for other interspecies differences:

2.5

Justification:

Default value.

AF for intraspecies differences:

5

Justification:

The default value for "worker" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical (GLP Guideline study).

AF for remaining uncertainties:

1

Justification:

Default value.

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

acute toxicity

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.25 mg/kg bw/day

Most sensitive endpoint:

skin irritation/corrosion

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

300

Dose descriptor starting point:

NOAEL

Value:

75 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

75 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

According to ECHA Guidance R.8 (v.2.1, Nov 2012), on the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral-to-dermal extrapolation.

For Bis(2-ethylhexyl)amine the following should be noted:

- Data on toxicokinetics are not available.

- The substance is highly lipophilic (log Pow 7.3). According to ECHA guidance document R.7c (v3.0, June 2017), at logPow above 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. Uptake into the stratum corneum itself may be slow.

- The substance is poorly water soluble (14 mg/L). According to ECHA guidance document R.7c (v3.0, June 2017), if the water solubility is between 1-100 mg/L dermal absorption is anticipated to be low to moderate.

- The substance is classified as skin corrosive category 1B. According to ECHA guidance document R.7c (v3.0, June 2017), if the substance is skin corrosive, damage to the skin surface may enhance penetration.

 

Overall, according to ECHA Guidance R.8 (v.2.1, Nov 2012), and considering the physio-chemical properties of the substance (which might favour or not absorptive processes), a modification of the starting point was not reasonable.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

Default value for time extrapolation from subacute to chronic study.

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is applied.

AF for other interspecies differences:

2.5

Justification:

The recommended AF for other interspecies differences is applied.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

acute toxicity

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium 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

Worker:

Inhalation long-term exposure – systemic effects:

The NOAEL from an oral combined repeated dose toxicity study with the reproduction / developmental toxicity screening test in rats conducted according to OECD 422 (BASF SE 2013) was identified as the appropriate starting point for DNEL derivation for long-term exposure following inhalation. The NOAEL for general, systemic toxicity of the test substance was 75 mg/kg bw/day for rats which was the highest dose tested.

This point of departure was modified to get the corrected starting point for DNEL derivation. As a first step, route-to-route extrapolation was performed as recommended in the "Guidance on information requirements and chemical safety assessment, Chapter R.8, v 2.1, Nov. 2012":

The oral rat NOAEL was converted into the inhalative human NOAEC corrected for differences between the 8-hour standard inhalation volume of rats versus humans, and for differences between the 8-hour inhalation volume of workers in rest versus workers in light activity, by multiplying with the corresponding factors (x 1/0.38 m³/kg/d x 6.7 m³/10 m³). The resulting corrected starting point for inhalation DNEL derivation for workers is equal to 132.24 mg/m³.

The calculated long-term DNEL for inhalative systemic effects is lower than known MAK values for other secondary amines like dimetyhlamine (3.7 mg/m3) or diethylamine (6.1 mg/m3) which cover local but also systemic effects.

DNELlong-term, systemic, inhalative	1,76 mg/m^3	Calculated according to ECHA R.8
MAK value	6.1 mg/m^3	MAK Commission, Diethylamine (CAS 109-89-7)
MAK value	3.7 mg/m^3	MAK Commission, Dimethylamine (CAS 124-40-3)

 

Corrosive effects and local irritation including effects on the eyes were not quantifiable and therefore assessed via a qualitative approach. As these corrosive properties are the primary mode of action no further DNELs are calculated.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.435 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):

150

Dose descriptor starting point:

NOAEL

Value:

75 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

65.22 mg/m³

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by inhalation.

For DNEL derivation, a NOAEL from an oral OECD 422 study was used. The NOAEL is 75 mg/kg bw/d.

(75 mg/kg bw/d / 1.15 m³/kg bw/d) = 65.22 mg/m³

The recommended approach assuming 50% absorption for oral and 100% absorption for inhalation exposure was not taken into account, because of the physico-chemical properties of the substance.

log Pow is 7.3

water solubility is 14 mg/l

Thus, the substance is highly lipophilic and poorly water soluble. According to ECHA guidance document R.7c (v3.0, June 2017), any lipophilic compound may be taken up by micellular solubilisation but this

mechanism may be of particular importance for highly lipophilic compounds (log P >4), particularly those that are poorly soluble in water (0.001 mg/l or less) that would otherwise be poorly absorbed. This applies

to both exposure routes, oral as well as inhalation. That is why a similar absorption for both exposure routes is assumed and no additional correction factor is used.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

Default value for time extrapolation from subacute to chronic study.

AF for interspecies differences (allometric scaling):

1

Justification:

Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.

AF for other interspecies differences:

2.5

Justification:

Default value.

AF for intraspecies differences:

10

Justification:

The default value for "consumer" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical (GLP Guideline study).

AF for remaining uncertainties:

1

Justification:

Default value.

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

acute toxicity

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.125 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):

600

Dose descriptor starting point:

NOAEL

Value:

75 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

75 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

According to ECHA Guidance R.8 (v.2.1, Nov 2012), on the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral-to-dermal extrapolation.

For Bis(2-ethylhexyl)amine the following should be noted:

- Data on toxicokinetics are not available.

- The substance is highly lipophilic (log Pow 7.3). According to ECHA guidance document R.7c (v3.0, June 2017), at logPow above 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. Uptake into the stratum corneum itself may be slow.

- The substance is poorly water soluble (14 mg/L). According to ECHA guidance document R.7c (v3.0, June 2017), if the water solubility is between 1-100 mg/L dermal absorption is anticipated to be low to moderate.

- The substance is classified as skin corrosive category 1B. According to ECHA guidance document R.7c (v3.0, June 2017), if the substance is skin corrosive, damage to the skin surface may enhance penetration.

Overall, according to ECHA Guidance R.8 (v.2.1, Nov 2012), and considering the physio-chemical properties of the substance (which might favour or not absorptive processes), a modification of the starting point was not reasonable.

AF for dose response relationship:

1

Justification:

Default value. The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

Default value for time extrapolation from subacute to chronic study.

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is applied.

AF for other interspecies differences:

2.5

Justification:

The recommended AF for other interspecies differences is applied.

AF for intraspecies differences:

10

Justification:

The default value for "consumer" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical (GLP Guideline study).

AF for remaining uncertainties:

1

Justification:

Default value for remaining uncertainties. The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

acute toxicity

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium 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

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.125 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):

600

Dose descriptor starting point:

NOAEL

Value:

75 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

75 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Experimental data on repeated oral exposure were available (OECD 422) and chosen for calculation of a systemic oral DNEL.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

Default value for time extrapolation from subacute to chronic study.

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is applied.

AF for other interspecies differences:

2.5

Justification:

The recommended AF for other interspecies differences is applied.

AF for intraspecies differences:

10

Justification:

The default value for "consumer" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical (GLP Guideline study).

AF for remaining uncertainties:

1

Justification:

Default value for remaining uncertainties. The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

Consumer:

Inhalation long-term exposure – systemic effects:

The NOAEL from an oral combined repeated dose toxicity study with the reproduction/ developmental toxicity screening test in rats conducted according to OECD 422 (BASF SE, 2013) was identified as the appropriate starting point for DNEL derivation for long-term exposure following inhalation. The NOAEL for general, systemic toxicity of the test substance was 75 mg/kg bw/day for rats which was the highest dose tested.

This point of departure was modified to get the correct starting point for DNEL derivation. As a first step, route-to-route extrapolation was performed as recommended in the "Guidance on information requirements and chemical safety assessment, Chapter R.8, v 2.1, Nov. 2012":

The oral rat NOAEL was converted into the inhalation human NOAEC corrected for differences between the 24-hour standard inhalation volume of rats versus humans by multiplying with the corresponding factor (x 1/1.15 m³/kg/d).

Furthermore, it is proposed, thus, in the absence of route-specific information on the starting route, to include a default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route) in the case of oral-to-inhalation extrapolation. However, this recommended approach assuming 50% absorption for oral and 100% absorption for inhalation exposure was not taken into account in the current case of Bis(2-ethylhexyl)amine, because of the physico-chemical properties of the substance.

log Pow is 7.3

water solubility is 14 mg/l

Thus, the substance is highly lipophilic and poorly water soluble. According to ECHA guidance document R.7c (v3.0, June 2017), any lipophilic compound may be taken up by micellular solubilisation but this mechanism may be of particular importance for highly lipophilic compounds (log P >4), particularly those that are poorly soluble in water (0.001 mg/l or less) that would otherwise be poorly absorbed. This applies to both exposure routes, oral as well as inhalation. That is why a similar absorption for both exposure routes is assumed and no additional correction factor is used.

The resulting corrected starting point for inhalation DNEL derivation for the general population is equal to 65.22 mg/m³.

Dermal long-term exposure – systemic effects:

The NOAEL from an oral combined repeated dose toxicity study with the reproduction/ developmental toxicity screening test in rats conducted according to OECD 422 (BASF SE, 2013) was identified as the appropriate starting point for DNEL derivation for long-term exposure following dermal application. The NOAEL for general, systemic toxicity of the test substance was 75 mg/kg bw/day for rats which was the highest dose tested. 

This point of departure was also taken as starting point for DNEL derivation as the same absorption rate for the oral and dermal route was assumed. Therefore, a route-to-route (oral -> dermal) extrapolation factor of 1 was used which resulted in a starting point of 75 mg/kg bw/day.

Oral long-term exposure – systemic effects:

DNEL for oral long-term exposure was derived from the NOAEL obtained from an oral Combined repeated dose toxicity study with the reproduction/ developmental toxicity screening test in rats according to OECD 422 (BASF SE, 2013). The NOAEL for general, systemic toxicity of the test substance was 75 mg/kg bw/d for rats which was the highest dose tested. 

A correction of the starting point is not necessary since an oral study is available. Therefore, a starting point of 75 mg/kg bw/day was taken for DNEL derivation.