N-[3-(dimethylamino)propyl] C6-9 alkyl amides

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.64 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

Dose descriptor starting point:

NOAEL

Value:

175 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

215.98 mg/m³

Explanation for the modification of the dose descriptor starting point:

Key toxic endpoint was in the rat extended duration 90 day / OECD422 rat study where, the NOAEL was 175mg/kg bodyweight. This applied to systemic toxicity and maternal and pup effects.

Based on this the Long-Term Inhalation DNEL for workers would be:

175 /2 (extrapolation from oral to inhalation) * 1/0.38 *6.7/10 (adjustment for allometric scaling for a rat converting from NOEAL in rats to NOAEC in workers) *7/5 to convert from 7 day a week dietary administration in rats to 5 days a week for workers) = NOAEC of 215.98 mg/m3

This worker NOEC is then divided by the assessment factors 1* (interspecies already included) 2.5* (other interspecies) 5*intraspecies 2 (exposure duration as 90-day OECD422) *1 (quality of data base) = 25 so DNEL = 215.95/25 = 8.6395 mg/m3

AF for dose response relationship:

1

Justification:

There is a clear dose response in the 90day / OECD442 study.

AF for differences in duration of exposure:

2

Justification:

The ECHA guidance recommend a factor of 2 when extrapolating from a 90-day study as in this case and long-term exposure.

AF for interspecies differences (allometric scaling):

1

Justification:

This is included in the conversion from a NOAEL in rats to a NOEC in workers

AF for other interspecies differences:

2.5

Justification:

ECHA guidance recommends a factor of 2.5 to cover any additional interspecies differences in addition to allometric scaling.

AF for intraspecies differences:

5

Justification:

The ECHA guideline give an assessment factor of 5 for intra species differences between workers.

AF for the quality of the whole database:

1

Justification:

The DNEL is based on the NOAEL from a modern GLP compliant guideline OECD422 study which was extended to include at least 90 days dietary administration, on N-[3-(dimethylamino)propyl] C6-9 alkyl amides Therefore, the database is considered high quality and a factor of 1 is applied.

AF for remaining uncertainties:

1

Justification:

A factor of 1 is selected as there are no remaining uncertainties.

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:

2.45 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

Dose descriptor starting point:

NOAEL

Value:

175 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

245 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

If the DNEL is calculated based on the OECD422 study forN-[3-(dimethylamino)propyl] C6-9 alkyl amides the NOAEL was 175 mg/kg.   To give a point of departure a correction from the 7 day a week dietary administration in rats to the 5 days a week exposure for workers. Modified dose descriptor NOAEL = NOAEL OECD422 males oral *7/5 = 175 *7/5 = 245 mg/kg bw/day.

This is divided by the assessment factors. Allometric scaling for rats 4 x additional inter species factor 2.5 x intraspecies factor for workers of 5 x exposure duration 2 for an OECD422 study x 1 as there is clear dose response x data base quality of 1 = 100.

This gives a long-term Dermal DNEL of 245/100 = 2.45 mg/kg bw/day

AF for dose response relationship:

1

Justification:

There is a clear dose response in the 90day / OECD442 study.

AF for differences in duration of exposure:

2

Justification:

The ECHA guidance recommend a factor of 2 when extrapolating from a 90-day study as in this case and long-term exposure.

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA guidelines recommend a factor of 4 for allometric scaling when extrapolating for rats to humans.

AF for other interspecies differences:

2.5

Justification:

ECHA guidance recommends a factor of 2.5 to cover any additional interspecies differences in addition to allometric scaling.

AF for intraspecies differences:

5

Justification:

The ECHA guideline give an assessment factor of 5 for intra species differences between workers.

AF for the quality of the whole database:

1

Justification:

The DNEL is based on the NOAEL from a modern GLP compliant guideline OECD422 study which was extended to include at least 90 days dietary administration, on N-[3-(dimethylamino)propyl] C6-9 alkyl amides Therefore, the database is considered high quality and a factor of 1 is applied.

AF for remaining uncertainties:

1

Justification:

A factor of 1 is selected as there are no remaining uncertainties.

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:

high hazard (no threshold derived)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.296 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):

50

Dose descriptor starting point:

NOAEL

Value:

175 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

64.815 mg/m³

Explanation for the modification of the dose descriptor starting point:

Based on the NOAEL in the 90 day / OECD422 study of 175 mg/kg, the Long-Term Inhalation DNEL for the general population would be:

175 /2 (extrapolation from oral to inhalation) *1/1.35 (allometric scaling from NOAEL in rats to NOAEC in the general population, dietary exposure in rats was 7 days a week as would be the exposure of the general population via the environment = NOAEC of 64.815 mg/m3

This is then divided by the assessment factors 1* (interspecies already included) 2.5* (other interspecies) 10*intraspecies *2 (exposure duration as OECD414) *1 (quality of data base) = 50 so DNEL = 64.815/50 = 1.296 mg/m3

AF for dose response relationship:

1

Justification:

There is a clear dose response in the 90day / OECD442 study.

AF for differences in duration of exposure:

2

Justification:

The ECHA guidance recommend a factor of 2 when extrapolating from a 90-day study as in this case and long-term exposure.

AF for interspecies differences (allometric scaling):

1

Justification:

This is included in the conversion from a NOAEL in rats to a NOEC in workers so a factor of 1 is used.

AF for other interspecies differences:

2.5

Justification:

ECHA guidance recommends a factor of 2.5 to cover any additional interspecies differences in addition to allometric scaling.

AF for intraspecies differences:

10

Justification:

The ECHA guideline give an assessment factor of 10 for intra species differences between the general population.

AF for the quality of the whole database:

1

Justification:

The DNEL is based on the NOAEL from a modern GLP compliant guideline OECD422 study which was extended t include at least 90 days dietary administration, on N-[3-(dimethylamino)propyl] C6-9 alkyl amides Therefore, the database is considered high quality and a factor of 1 is applied.

AF for remaining uncertainties:

1

Justification:

A factor of 1 is selected as there are no remaining uncertainties.

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:

0.875 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):

200

Dose descriptor starting point:

NOAEL

Value:

175 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

175 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The DNEL is calculated based on the OECD422 study forN-[3-(dimethylamino)propyl] C6-9 alkyl amides the NOAEL was 175mg/kg.  ECHA guidance indicates that oral NOAEL values can also be used for deriving dermal DNELs which is a conservative approach.

To give a point of departure no correction is needed for days of dosing as both the rats and general population are exposed 7 days a week.

The 175 mg/kg NOAEL is divided by the assessment factors. Allometric scaling for rats 4 x additional inter species factor 2.5 x intraspecies factor for the general population of 10 x exposure duration 2 for the 90-day extended OECD422 study x 1 as there is clear dose response x 1 for the data base quality = 200.

This gives a long-term Dermal DNEL of 175/200 = 0.875 mg/kg bw/day

AF for dose response relationship:

1

Justification:

There is a clear dose response in the 90day / OECD442 study.

AF for differences in duration of exposure:

2

Justification:

The ECHA guidance recommend a factor of 2 when extrapolating from a 90-day study as in this case and long-term exposure.

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA guidelines recommend a factor of 4 for allometric scaling when extrapolating for rats to humans.

AF for other interspecies differences:

2.5

Justification:

ECHA guidance recommends a factor of 2.5 to cover any additional interspecies differences in addition to allometric scaling.

AF for intraspecies differences:

10

Justification:

The ECHA guideline give an assessment factor of 10 for intra species differences between the general population.

AF for the quality of the whole database:

1

Justification:

The DNEL is based on the NOAEL from a modern GLP compliant guideline OECD422 study which was extended to include at least 90 days dietary administration, on N-[3-(dimethylamino)propyl] C6-9 alkyl amides Therefore, the database is considered high quality and a factor of 1 is applied.

AF for remaining uncertainties:

1

Justification:

A factor of 1 is selected as there are no remaining uncertainties.

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:

0.875 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):

200

Dose descriptor starting point:

NOAEL

Value:

175 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

175 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The DNEL is calculated based on the 90 day/OECD422 study forN-[3-(dimethylamino)propyl] C6-9 alkyl amides, where the NOAL was 175 mg/kg bw/day by dietary administration.

To give a point of departure no correction is needed for days of dosing as both the rats and general population are exposed 7 days a week.

The 175 mg/kg NOAEL is divided by the assessment factors. Allometric scaling for rats 4 x additional inter species factor 2.5 x intraspecies factor for the general population of 10 x exposure duration 2 for an 90 day/OECD422 study x 1 as there is clear dose response x 1 for the data base quality = 200.

This gives a long-term Oral DNEL of 175/200 = 0.875 mg/kg bw/day

AF for dose response relationship:

1

Justification:

There is a clear dose response in the 90 day / OECD442 study so factor of 1 used.

AF for differences in duration of exposure:

2

Justification:

The ECHA guidelines provide a default assessment factor of 2 when extrapolating from a 90 day / OECD422 study to long term exposure.

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA guidelines recommend a factor of 4 for allometric scaling when extrapolating for rats to humans.

AF for other interspecies differences:

2.5

Justification:

ECHA guidance recommends a factor of 2.5 to cover any additional interspecies differences in addition to allometric scaling.

AF for intraspecies differences:

10

Justification:

The ECHA guideline give an assessment factor of 10 for intra species differences between the general population.

AF for the quality of the whole database:

1

Justification:

The DNEL is based on the NOAEL from a modern GLP compliant guideline 90 day / OECD422 study on N-[3-(dimethylamino)propyl] C6-9 alkyl amides. Therefore, the database is considered high quality and a factor of 1 is applied.

AF for remaining uncertainties:

1

Justification:

A factor of 1 is selected as there are no remaining uncertainties.

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:

high hazard (no threshold derived)