1-methylpiperazine

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.08 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Dose descriptor starting point:

NOAEC

Value:

53.5 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

26.88 mg/m³

Explanation for the modification of the dose descriptor starting point:

Key toxic endpoint was in the rabbit OECD414 study, the NOAEL was 75mg/kg bodyweight.

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

75 /2 (extrapolation from oral to inhalation) /2.4 (adjustment for allometic scaling for a rabbit) *70 kg/10m3 (converting from NOEAL in rats to NOAEC in workers) *7/5 to convert from 7 day a week exposure in rabbits to 5 days a week for workers) = NOAEC of 153.125 mg/m3 this is then divided by the assessment factors 1* (interspecies already included) 2.5* (other interspecies) 5*intraspecies 1 (exposure duration as OECD414) *1 (quality of data base) = 12.5 so DNEL = 153.125/12.5 = 12.25

Alternatively, the Long-term Inhalation DNEL for workers could be based on NOAEL for systemic effects in the 90-day inhalation study for the read across substance Aminoethyl piperazine of 53.5 mg/m3

The NOAEC for workers is calculated taking into account that exposure in the 90-day study was 6 hours a day 5 days a week. 53.5 * 6h/8h = 40.125* 6.7m3/10m3 = 26.88 mg/m3

This is then divided by the assessment factors:

1 (interspecies already included) * 2.5 (other interspecies) * 5 (intraspecies) *2 (duration 90 day) * 1 (dose response) *1 (data quality) = 25 so DNEL = 26.88/25 = 1.08 mg/m3

As this gives a more protective lower DNEL this was the approach used.

AF for dose response relationship:

1

Justification:

Effects show a clear dose response so factor of 1 used.

AF for differences in duration of exposure:

5

Justification:

ECHA guidance document Chapter R8, in Appendix R.8-12, indicates that DNELS derived using a NOAEC from a 90 day study are derived using an assessment factor of 2. The NOAEC used as a point of departure is from a modern 90 inhalation study therfore a factor of 2 was used.

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling is already included in the route to route extrapolation from the rat inhalation NOEC to the equivalent human inhalation NOAEC.

AF for other interspecies differences:

2.5

Justification:

ECHA guidelines require a factor of 2.5 for other interspecies differences

AF for intraspecies differences:

5

Justification:

ECHA guidance requires a factor of 5 for intraspecies differnces bewteen workers.

AF for the quality of the whole database:

1

Justification:

This DNEL is based on a NOAEC from a high quality modern 90-day inhalation study with the read across substance Aminoethyl piperazine.so a a factor of 1 was used. While the DNEL is based on read across to aminoethyl piperazine, as the effects seen are local irritation resulting from the corrosive properties of the test substance, as n-methyl piperazine is also corrosive the database is considered high quality no additional factor for read across is considered necessary.

AF for remaining uncertainties:

1

Justification:

All uncertainties are already included so a factor of 1 is applied.

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

15 µg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

10

Dose descriptor:

NOAEC

Value:

0.15 mg/m³

AF for dose response relationship:

1

Justification:

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

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 study to long term exposure.

AF for interspecies differences (allometric scaling):

1

Justification:

No assessment factor is required when extrapolating local concentration dependent effects in the respiratory tract in an inhalation study from rats to humans.

AF for other interspecies differences:

1

Justification:

As the effects were local irritation in the nasal passages and the substance is corrosive a factor of 1 is selected for remaining interspecies differences.

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:

While the DNEL is based on read across to aminoethyl piperazine, as the effects seen are local irritation resulting from the corrosive properties of the test substance, as n-methyl piperazine is also corrosive the database is considered high quality and a factor of 1 is applied as no additional factor for read across is considered necessary.

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:

DNEL (Derived No Effect Level)

Value:

80 µg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

5

Dose descriptor starting point:

NOAEC

Value:

0.4 mg/m³

AF for dose response relationship:

1

Justification:

There is a clear dose response in the 14-day inhalation probe study.

AF for interspecies differences (allometric scaling):

1

Justification:

There is no ECHA assessment for duration for short term local exposure effects in the 14-day (2-week) inhalation probe study so a factor of 1 is used.

AF for other interspecies differences:

1

Justification:

As the effects were local irritation in the nasal passages and the substance is corrosive a factor of 1 is selected for remaining interspecies differences

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:

While the DNEL is based on read across to aminoethyl piperazine, as the effects seen are local irritation resulting from the corrosive properties of the test substance, as n-methyl piperazine is also corrosive the database is considered high quality and a factor of 1 is applied as no additional factor for read across is considered necessary.

AF for remaining uncertainties:

1

Justification:

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

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.89 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):

300

Dose descriptor starting point:

NOAEL

Value:

190 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

266 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There are two possible ways to derive a long-term Dermal DNEL for workers.

Based on Rabbit OECD 414 NOAEL 75mg/kg bw/day which is modified to give the Point of Departure by a correction from the 7 day a week dosing in rabbits to the 5 days a week exposure for workers, Modified dose descriptor NOAEL = NOAEL OECD414 rabbit oral *7/5 = 75 mg/kg *7/5 = 105 mg/kg bw/day.

This is divided by the assessment factors. Allometric scaling for rabbits 2.4 x additional inter species factor 2.5 x intraspecies factor for workers of 5 x exposure duration 1 for an OECD414 study x 1 as there is clear dose response x data base quality of 1 = 30

This gives a Long-term DNEL of 105/30 = 3.5 mg/kg bw/day

If the DNEL is calculated based on the OECD422 study for N-methyl piperazine the NOAEL was 2500 ppm, which represented 190 mg/kg in the males.  This is the lowest dose level for the 2500ppm in the drinking water. To give a point of departure a correction from the 7 day a week dosing in rats to the 5 days a week exposure for workers. Modified dose descriptor NOAEL = NOAEL OECD422 males oral *7/5 = 190 *7/5 = 266 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 6 for an OECD422 study x 1 as there is clear dose response x data base quality of 1 = 300.

This gives a long-term Dermal DNEL of 266/300 = 0.89 mg/kg bw/day

Based on the two alternatives the DNEL will be calculated based on the NOAEL in males in the OECD422 study as this gives the lowest of the two possible DNELs.

AF for dose response relationship:

1

Justification:

Effects show a clear dose response so factor of 1 used.

AF for differences in duration of exposure:

6

Justification:

ECHA guidance document Chapter R8, in Appendix R.8-12, indicates that DNELS derived using a NOAEL from a 28 day study are derived using an assessment factor of 6 and with a 90 day study using an assessment factor of 2 for extrapolation of the study duration to chronic exposure. This OECD422 study was 43 days for males and at least 43 days for females, therefore a factor of 6 has been selected.

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:

2.5

Justification:

A factor of 2.5 is applied based on ECHA guidance for the assessment factor for other inter species differences.

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:

This DNEL is based on a NOAEL from a high quality modern OECD422 study on 1-methyl piperazine, therefore we have used a factor of 1.

AF for remaining uncertainties:

1

Justification:

All uncertainties are already included so a factor of 1 is applied.

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

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:

0.268 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Dose descriptor starting point:

NOAEC

Value:

53.5 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

13.375 mg/m³

Explanation for the modification of the dose descriptor starting point:

The Key toxic endpoint for the aminoethyl piperazine the read across source was in the rabbit OECD414 study, the NOAEL was 75mg/kg bodyweight.

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

75 *50/100 (extrapolation from oral to inhalation) /2.4 (allometric scaling converting from NOAEL in rabbits to NOAEC in the general population Exposure in rabbits was 7 days a week as would be the exposure of the general population via the environment = NOAEC of 46.875 mg/m3 this is then divided by the assessment factors 1* (interspecies already included) 2.5* (other interspecies) 10*intraspecies *1 (exposure duration as OECD414) *1 (quality of data base) = 25 so DNEL = 46.875/25 = 1.875 mg/m3

Alternatively, the Long-term Inhalation DNEL for workers could be based on NOAEL for systemic effects in the 90-day inhalation study for the read across substance Aminoethyl piperazine of 53.5 mg/m3

The NOAEC for the general population is calculated taking into account that exposure in the 90-day study was 6 hours a day, 5 days a week. 53.5 * 6h/24h = 13.375 mg/m3

This is then divided by the assessment factors:

1 (interspecies already included) * 2.5 (other interspecies) * 10 (intraspecies) *2 (duration 90 day) * 1 (dose response) *1 (data quality) = 50 so DNEL = 13.375/50 = 0.268 mg/m3

As this gives a more protective lower DNEL this was the approach used.

The basis for the DNEL calculation was selected as it gave the lowest DNEL based on the 90-day inhalation study which would also protect from the developmental toxicity seen in rabbits.

AF for dose response relationship:

1

Justification:

There is a clear dose response in the 90-day inhalation study.

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 study to long term exposure.

AF for interspecies differences (allometric scaling):

1

Justification:

No assessment factor is required when extrapolating from inhalation NOECs in rats to NOECs in humans and the different breathing volume already takes allometric scaling into account.

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:

While the DNEL is based on read across to aminoethyl piperazine, as the effects seen are local irritation resulting from the corrosive properties of the test substance, as n-methyl piperazine is also corrosive the database is considered high quality and a factor of 1 is applied as no additional factor for read across is considered necessary.

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:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

medium 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:

0.317 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:

190 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

190 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There are two possible ways to derive a long-term Dermal DNEL for the general population.

Based on Rabbit OECD 414 oral NOAEL 75mg/kg bw/day which does not need to be modified to give the Point of Departure as both the rabbits and the general population were exposed 7 day as a week unlike workers. This is divided by the assessment factors. Allometric scaling for rabbits 2.4 x additional inter species factor 2.5 x intraspecies factor for the general population of 10 x exposure duration 1 for an OECD414 study x 1 as there is clear dose response x 1 for data base quality = 60

This gives a Long-term DNEL of 75/60 = 1.25 mg/kg bw/day

If the DNEL is calculated based on the oral OECD422 study for 1-methyl piperazine the NOAEL was 2500 ppm, which represented 190 mg/kg in the males. This is the lowest dose level for the 2500ppm in the drinking water. 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 190 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 6 for an OECD422 study x 1 as there is clear dose response x 1 for the data base quality = 600.

This gives a long-term Dermal DNEL of 190/600 = 0.317 mg/kg bw/day

Based on the two alternatives the DNEL will be calculated based on the NOAEL in males in the OECD422 study as this gives the lowest of the two possible DNELs which would also protect from the developmental effects seen in the rabbit study.

AF for dose response relationship:

1

Justification:

There is a clear dose response in the OECD442 study.

AF for differences in duration of exposure:

6

Justification:

The ECHA guidelines provide a default assessment factor of 6 when extrapolating from an 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 OECD422 study on the 1-methyl piperazine. 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:

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:

0.317 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:

190 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

190 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There are two possible ways to derive a long-term oral DNEL for the general population.

Based on Rabbit OECD 414 oral NOAEL 75mg/kg bw/day which does not need to be modified to give the Point of Departure as both the rabbits and the general population were exposed 7 days as a week unlike workers. This is divided by the assessment factors. Allometric scaling for rabbits 2.4 x additional inter species factor 2.5 x intraspecies factor for the general population of 10 x exposure duration 1 for an OECD414 study x 1 as there is clear dose response x 1 for data base quality = 60

This gives a Long-term DNEL of 75/60 = 1.25 mg/kg bw/day

If the DNEL is calculated based on the OECD422 study for N-methyl piperazine the NOAEL was 2500 ppm, which represented 190 mg/kg in the males.  This is the lowest dose level for the 2500ppm in the drinking water.

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 190 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 6 for an OECD422 study x 1 as there is clear dose response x 1 for the data base quality = 600.

This gives a long-term Oral DNEL of 190/600 = 0.317 mg/kg bw/day

Based on the two alternatives the DNEL will be calculated based on the NOAEL in males in the OECD422 study as this gives the lowest of the two possible DNELs which would also protect from the developmental effects seen in the rabbit study.

AF for dose response relationship:

1

Justification:

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

AF for differences in duration of exposure:

6

Justification:

The ECHA guidelines provide a default assessment factor of 6 when extrapolating from an 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.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 on the 1-methyl piperazine. Therefore, the database is considered high quality and a factor of 1 is applied.

AF for remaining uncertainties:

1

Justification:

All uncertainties are already included so a factor of 1 is applied.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

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