Peppermint, ext.

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

35.3 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):

20

Modified dose descriptor starting point:

NOAEC

Value:

705.26 mg/m³

Explanation for the modification of the dose descriptor starting point:

The NOAEC for workers is calculated from the oral NOAEL by dividing by the respiratory volume of rats (8h: 0.38 m3/kg bw) followed by multiplication by the respiratory volume of human (6.7 m3/person) corrected for the respiratory volume for light activity to address the workers (10 m3/person), arriving at a NOAEC of 705.26 mg/m3. Although Guidance R.8 recommends to use a standard factor of 2 to correct for differences in inhalation absorption vs oral absorption, this assessment factor is debatable. In its “Guidance on Assessment Factors to Derive a DNEL” ECETOC recommends using a case-by-case approach. The standard factor is based on a worst-case approach, assuming that the absorption via the starting route is limited. ECETOC considers the general applicability of this AF inconsistent with an evaluation of the published EU risk assessment data (excluding metals and inorganic chemicals), in which from 55 substances, only 8 substances showed higher absorption after inhalation. None of these substances are structurally related to the constituents of cornmint and peppermint oil. In 44 cases, no differences were reported. In the case of peppermint and cornmint oil, information on oral absorption is limitedly available, as only absorption of menthol was measured. Recovery of menthol was high, 35-112% could be recovered in the first 24 hr (peppermint oil in delayed release capsule). Thus, a higher bioavailability for the inhalation route is considered unlikely. Two constituents have vapour pressures >0.5 kPa, i.e. alpha-pinene and sabinene. As these substances have high log Kow (>4) and low water solubility, they will be less well absorbed via the inhalation route. Based on the available information, it is not likely that the absorption via inhalation is different from the oral absorption. It is therefore considered appropriate that no extra AF for route-to-route extrapolation is needed.

AF for dose response relationship:

1

Justification:

Default assessment factor for dose response relationship

AF for differences in duration of exposure:

2

Justification:

Although the DNEL is based on a subacute study, sufficient information is available from sub-chronic and chronic studies with constituents. This information indicates a NOAEL of ≥375 mg/kg bw/d for the major constituents, and NOAELs of 170-600 mg/kg for minor constituents. Based on this supporting information, and taking into consideration that the NOAEL from the 28-day study was the highest dose tested, so that the real NOAEL was likely higher than the value used, it is expected that the NOAEL will be in the same range for cornmint oil and peppermint oil, and consequently an assessment factor of 2 is considered adequate to correct for exposure duration.

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling was taken into account in route to route extrapolation

AF for other interspecies differences:

1

Justification:

Peppermint oil and its constituents have been tested in several species, and the effects were either absent (peppermint oil, both in rat and dog), or unspecifc effects such as decreased bodyweight, clinical signs and increased liver/kidney weight were observed (constituents, rat and mice). Therefore, no AF for remaining interspecies differences is taken into account.

AF for intraspecies differences:

5

Justification:

Default assessment factor for intraspecies differences

AF for the quality of the whole database:

2

Justification:

An assessment factor of 2 is taken into account based on the use of subacute peppermint oil data combined with subchronic/chronic data on peppermint/cornmint oil constituents (71.1% of cornmint oil constituents and 70.6% of peppermint oil constituents). Taking into account the similarity in constituents between cornmint oil and peppermint oil, no additional factor for read across is deemed necessary.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties identified

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

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

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):

80

Modified dose descriptor starting point:

NOAEL

Value:

400 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Dermal absorption is considered to be similar to oral absorption, therefore route to route extrapolation results in a NOAEL of 400 mg/kg bw/day

AF for dose response relationship:

1

Justification:

Default assessment factor for dose response relationship

AF for differences in duration of exposure:

2

Justification:

Although the DNEL is based on a subacute study, sufficient information is available from sub-chronic and chronic studies with constituents. This information indicates a NOAEL of ≥375 mg/kg bw/d for the major constituents, and NOAELs of 170-600 mg/kg for minor constituents. Based on this supporting information, and taking into consideration that the NOAEL from the 28-day study was the highest dose tested, so that the real NOAEL was likely higher than the value used, it is expected that the NOAEL will be in the same range for cornmint oil and peppermint oil, and consequently an assessment factor of 2 is considered adequate to correct for exposure duration.

AF for interspecies differences (allometric scaling):

4

Justification:

Default assessment factor for allometric scaling

AF for other interspecies differences:

1

Justification:

Peppermint oil and its constituents have been tested in several species, and the effects were either absent (peppermint oil, both in rat and dog), or unspecifc effects such as decreased bodyweight, clinical signs and increased liver/kidney weight were observed (constituents, rat and mice). Therefore, no AF for remaining interspecies differences is taken into account.

AF for intraspecies differences:

5

Justification:

Default assessment factor for intraspecies differences

AF for the quality of the whole database:

2

Justification:

An assessment factor of 2 is taken into account based on the use of subacute peppermint oil data combined with subchronic/chronic data on peppermint/cornmint oil constituents (71.1% of cornmint oil constituents and 70.6% of peppermint oil constituents). Taking into account the similarity in constituents between cornmint oil and peppermint oil, no additional factor for read across is deemed necessary.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties were identified

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)

Most sensitive endpoint:

sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - workers

The DNEL should be based on the most relevant and critical NOAEL observed in the available studies with peppermint oil, which was read across to cornmint oil. As in all available and reliable studies, the NOAEL was the highest concentration tested (no effects observed in all studies), the DNEL was based on the most reliable study, the key study of Serota (1990). A NOAEL of 400 mg/kg bw/day was established in this study. Subchronic studies with the constituents of cornmint oil and peppermint oil. were included as supporting information.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.7 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):

40

Modified dose descriptor starting point:

NOAEC

Value:

347.83 mg/m³

Explanation for the modification of the dose descriptor starting point:

The NOAEC for the general population is calculated from the oral NOAEL by correcting for the respiratory volume of rats (24h: 1.15 m3/kg bw), arriving at a NOAEC of 347.83 mg/m3.

AF for dose response relationship:

1

Justification:

Default assessment for dose response relationship

AF for differences in duration of exposure:

2

Justification:

Although the DNEL is based on a subacute study, sufficient information is available from sub-chronic and chronic studies with constituents. This information indicates a NOAEL of ≥375 mg/kg bw/d for the major constituents, and NOAELs of 170-600 mg/kg for minor constituents. Based on this supporting information, and taking into consideration that the NOAEL from the 28-day study was the highest dose tested, so that the real NOAEL was likely higher than the value used, it is expected that the NOAEL will be in the same range for cornmint oil and peppermint oil, and consequently an assessment factor of 2 is considered adequate to correct for exposure duration.

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling taken into account in route to route extrapolation

AF for other interspecies differences:

1

Justification:

Peppermint oil and its constituents have been tested in several species, and the effects were either absent (peppermint oil, both in rat and dog), or unspecifc effects such as decreased bodyweight, clinical signs and increased liver/kidney weight were observed (constituents, rat and mice). Therefore, no AF for remaining interspecies differences is taken into account.

AF for intraspecies differences:

10

Justification:

Default assessment factor for intraspecies differences (general population)

AF for the quality of the whole database:

2

Justification:

An assessment factor of 2 is taken into account based on the use of subacute peppermint oil data combined with subchronic/chronic data on peppermint/cornmint oil constituents (71.1% of cornmint oil constituents and 70.6% of peppermint oil constituents). Taking into account the similarity in constituents between cornmint oil and peppermint oil, no additional factor for read across is deemed necessary.

AF for remaining uncertainties:

1

Justification:

No remaining differences identified

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:

2.5 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):

160

Modified dose descriptor starting point:

NOAEL

Value:

400 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Dermal absorption is considered to be similar to oral absorption, therefore route to route extrapolation results in a NOAEL of 400 mg/kg bw/day

AF for dose response relationship:

1

Justification:

Default assessment factor for dose response relationship

AF for differences in duration of exposure:

2

Justification:

Although the DNEL is based on a subacute study, sufficient information is available from sub-chronic and chronic studies with constituents. This information indicates a NOAEL of ≥375 mg/kg bw/d for the major constituents, and NOAELs of 170-600 mg/kg for minor constituents. Based on this supporting information, and taking into consideration that the NOAEL from the 28-day study was the highest dose tested, so that the real NOAEL was likely higher than the value used, it is expected that the NOAEL will be in the same range for cornmint oil and peppermint oil, and consequently an assessment factor of 2 is considered adequate to correct for exposure duration.

AF for interspecies differences (allometric scaling):

4

Justification:

Default assessmnet factor for allometric scaling

AF for other interspecies differences:

1

Justification:

Peppermint oil and its constituents have been tested in several species, and the effects were either absent (peppermint oil, both in rat and dog), or unspecifc effects such as decreased bodyweight, clinical signs and increased liver/kidney weight were observed (constituents, rat and mice). Therefore, no AF for remaining interspecies differences is taken into account.

AF for intraspecies differences:

10

Justification:

Default assessment factor for intraspecies differences (general population)

AF for the quality of the whole database:

2

Justification:

An assessment factor of 2 is taken into account based on the use of subacute peppermint oil data combined with subchronic/chronic data on peppermint/cornmint oil constituents (71.1% of cornmint oil constituents and 70.6% of peppermint oil constituents). Taking into account the similarity in constituents between cornmint oil and peppermint oil, no additional factor for read across is deemed necessary

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties were identified

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)

Most sensitive endpoint:

sensitisation (skin)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.5 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):

160

Explanation for the modification of the dose descriptor starting point:

Not applicable, study was via oral route.

AF for dose response relationship:

1

Justification:

Default assessment factor for dose response relationship

AF for differences in duration of exposure:

2

Justification:

Although the DNEL is based on a subacute study, sufficient information is available from sub-chronic and chronic studies with constituents. This information indicates a NOAEL of ≥375 mg/kg bw/d for the major constituents, and NOAELs of 170-600 mg/kg for minor constituents. Based on this supporting information, and taking into consideration that the NOAEL from the 28-day study was the highest dose tested, so that the real NOAEL was likely higher than the value used, it is expected that the NOAEL will be in the same range for cornmint oil and peppermint oil, and consequently an assessment factor of 2 is considered adequate to correct for exposure duration.

AF for interspecies differences (allometric scaling):

4

Justification:

Default assessment factor for allometric scaling

AF for other interspecies differences:

1

Justification:

Peppermint oil and its constituents have been tested in several species, and the effects were either absent (peppermint oil, both in rat and dog), or unspecifc effects such as decreased bodyweight, clinical signs and increased liver/kidney weight were observed (constituents, rat and mice). Therefore, no AF for remaining interspecies differences is taken into account.

AF for intraspecies differences:

10

Justification:

Default assessment factor for intraspecies differences (general population)

AF for the quality of the whole database:

2

Justification:

An assessment factor of 2 is taken into account based on the use of subacute peppermint oil data combined with subchronic/chronic data on peppermint/cornmint oil constituents (71.1% of cornmint oil constituents and 70.6% of peppermint oil constituents). Taking into account the similarity in constituents between cornmint oil and peppermint oil, no additional factor for read across is deemed necessary

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties were identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - General Population

The DNEL should be based on the most relevant and critical NOAEL observed in the available studies with peppermint oil, which was read across to cornmint oil. As in all available and reliable studies, the NOAEL was the highest concentration tested (no effects observed in all studies), the DNEL was based on the most reliable study, the key study of Serota (1990). A NOAEL of 400 mg/kg bw/day was established in this study. Subchronic studies with the constituents of cornmint oil and peppermint oil. were included as supporting information.