Mentha arvensis, ext.

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Read across from peppermint oil. Study design and results were reported clearly and considered acceptable basic data

Objective of study:

toxicokinetics

Qualifier:

no guideline followed

Principles of method if other than guideline:

Four male volunteers were administered 180 mg of Peppermint oil in an enteric-coated capsule following a 16 hours fasting period. Urine was collected every 2 hours for up to 14 hours, volume was measured. Menthol and menthol glucuronide concentrations were determined in urine by gas chromatography using an enzme-sensitive internal standard and flame ionization detection..

GLP compliance:

no

Radiolabelling:

no

Species:

human

Strain:

other: N/A

Sex:

male

Details on test animals or test system and environmental conditions:

No data

Route of administration:

oral: capsule

Vehicle:

unchanged (no vehicle)

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
180 mg of Peppermint oil was administered in an enteric-coated capsule.

Duration and frequency of treatment / exposure:

One time administration

Remarks:

Doses / Concentrations:
180 mg peppermint oil

No. of animals per sex per dose / concentration:

4 male volunteers

Control animals:

no

Positive control reference chemical:

Not included

Details on study design:

- Dose selection rationale: No data

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine
- Time and frequency of sampling: every 2 hours after administration for up to 14 hours

Statistics:

Not performed

Preliminary studies:

Not performed

Type:

excretion

Results:

Between 37 and 116 mg menthol recovered in urine within 14 hours of administration of Peppermint oil

Details on absorption:

Not studied

Details on distribution in tissues:

Not studied

Details on excretion:

A significant amount of variation among each individual was observed in the urinary excretion profile over 14 hours (see attached illustration/graph). AUC analysis indicated that 37-116 mg of menthol was excreted. As no concentration of menthol in the administered peppermint oil was determined, it is not possible to calculate the percentage of recovery.

Metabolites identified:

no

Details on metabolites:

Menthol glucuronide is determined in urine (metabolite of menthol), which indicates the amount of Peppermint oil that is orally absorbed.

Conclusions:

Interpretation of results (migrated information): other: oral absorption and urinary excretion apparent
Under the condtions of this study, menthol was recovered in urine after peppermint oil administration. However, no percentage of recovery could be calculated as the menthol concentration in the administered peppermint oil was not determined.

Executive summary:

Four male volunteers were administered 180 mg of Peppermint oil in an enteric-coated capsule following a 16 hours fasting period. Urine was collected every 2 hours for up to 14 hours, volume was measured and analysed by gas chromatography.

A significant amount of variation among each individual was observed in the urinary excretion profile over 14 hours. AUC analysis indicated that 37-116 mg of menthol was excreted. As the menthol concentration in the administered peppermint oil was not determined, no percentage of recovery could be determined.

Reference 2

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

No data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Read across from peppermint oil. Study design and results were reported clearly and considered acceptable basic data

Objective of study:

metabolism

Qualifier:

no guideline followed

Principles of method if other than guideline:

Peppermint oil induced inhibition of in vitro CYP3A4 activity was studied. Microsomes from human liver samples were used and incubated with 0, 20, 50, 100 and 200 ug/ml Peppermint oil and different concentrations of nifedipine (substrate). NADPH was added for starting the metabolic reactions. The sample was analysed for nifedipine and its oxidation product by chromatography. A reversible and irreversible inhibition study was performed. All experiments were performed in triplicate.

GLP compliance:

no

Radiolabelling:

no

Species:

other: human liver samples

Strain:

other: N/A

Details on test animals or test system and environmental conditions:

Not relevant

Route of administration:

other: N/A

Vehicle:

other: acetonitrile, methanol or water

Details on exposure:

Human liver microsomes are incubated with substrate and Peppermint oil.

Duration and frequency of treatment / exposure:

N/A

Remarks:

Doses / Concentrations:
0, 20, 50, 100 and 200 ug/ml

No. of animals per sex per dose / concentration:

N/A

Control animals:

yes, concurrent vehicle

Positive control reference chemical:

Not included

Details on study design:

Assay of CYP3A4 activity (5x5 matrix)
- Human liver microsome homogenate
- 5, 10, 20, 50 or 100 umol/l nifedipine (substrate)
- 0, 20, 50, 100 or 200 ug/ml peppermint oil
- Diethylenetriaminepenta-acetic acid in phosphate buffer
- Incubation for 5 minutes at 37 degrees Celsius
- NADPH added to start metabolic reaction
- Reaction stopped with acetonitrile/glacial acetic acid containing diclofenac (internal standard)
- Protein precipitated by centrifugation
- Supernatant analysed for nifedipine and its oxidation product using HPLC

Details on dosing and sampling:

N/A

Statistics:

Data was fit to Michaelis-Menten models by means of weighted nonlinear regression analysis

Preliminary studies:

Not performed

Type:

metabolism

Results:

reversible inhibition: CYP3A4 residual activity was lower in presence of higher concentrations of peppermint oil. This effect was observd in presence and absence of NADPH.

Details on absorption:

N/A

Details on distribution in tissues:

N/A

Details on excretion:

N/A

Metabolites identified:

no

Details on metabolites:

N/A

Conclusions:

Interpretation of results (migrated information): other: N/A
Under the conditions of this study, Peppermint oil was found to be a reversible, partially mixed inhibitor of nifedipine metabolism in vitro.

Executive summary:

Peppermint oil induced inhibition of in vitro CYP3A4 activity was studied. Microsomes from human liver samples were used and incubated with 0, 20, 50, 100 and 200 ug/ml Peppermint oil and different concentrations of nifedipine (substrate). NADPH was added for starting the metabolic reactions. The sample was analysed for nifedipine and its oxidation product by chromatography. A reversible and irreversible inhibition study was performed. All experiments were performed in triplicate.

CYP3A4 residual activity was lower in presence of higher concentrations of peppermint oil. This effect was observed in presence and absence of NADPH. Under the conditions of this study, Peppermint oil was found to be a reversible, partially mixed inhibitor of nifedipine metabolism in vitro.

Reference 3

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

No data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Read across from peppermint oil. Study design and results were reported clearly and considered acceptable basic data

Objective of study:

metabolism

Qualifier:

no guideline followed

Principles of method if other than guideline:

Twelve healthy volunteers (9 males, 3 females) were used for this study, none were smokers or routinely using drugs. All subjects received racemic felodipine (10 mg) with (1) white grapefruit juice, (2) water plus peppermint oil (600 mg), (3) water plus ascorbyl palmitate (500 mg), or (4) water. The study was a single-dose, balanced, randomized, and 4-way cross-over study. Blood was sampled just before dosing and at several intervals up until 8 hours after dosing. Plasma concentrations of felodipine and dehydrofelodipine were determined by GC, which is an indication of the metabolic activity of CYP3A4.

GLP compliance:

no

Radiolabelling:

no

Species:

human

Strain:

other: N/A

Sex:

male/female

Details on test animals or test system and environmental conditions:

VOLUNTEERS
- Number: 12
- Sex: 9 males, 3 females
- Age at study initiation:
M: 18-43 years
F: 26-29 years
- Health state: Normal findings on physical examination and laboratory testing (incl. hematologic and serum chemical studies), non-smoking or non-drug using

Route of administration:

oral: capsule

Vehicle:

unchanged (no vehicle)

Remarks:

acetonitrile, methanol or water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Test substance was given in 2 opaque gelatin capsules (containing 330 uL Peppermint oil)

Duration and frequency of treatment / exposure:

One time administration

Remarks:

Doses / Concentrations:
600 mg Peppermint oil

No. of animals per sex per dose / concentration:

9 male and 3 female subjects

Control animals:

yes, concurrent no treatment

Positive control reference chemical:

Yes, adminstered white grapefruit juice (known inhibitor of CYP3A4 activity)

Details on study design:

- Dose selection rationale: No data

Details on dosing and sampling:

METABOLITE CHARACTERISATION STUDIES (for determination of plasma felodipine and metabolite dehydrofelodipine)
- Tissues and body fluids sampled: blood
- Time and frequency of sampling: before dosing and 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0 and 8.0 hours after dosing
- From how many volunteers: 12
- Method type(s) for identification: GC
- Limits of detection: <0.5 nmol/L
- Objective: Dehydrofelodipine was determined as metabolite of felodipine, to study the activity of CYP3A4

Statistics:

- A noncompartmental method was used to analyse the concentrations
- Log-linear regression
- ANOVA

Preliminary studies:

Not performed

Details on absorption:

N/A

Details on distribution in tissues:

N/A

Details on excretion:

N/A

Metabolites identified:

no

Details on metabolites:

N/A

Administration of peppermint oil increased concentration of felodipine, AUCs and Cmax values in blood, compared to control values (water). Concentrations of the major metabolite of felodipine, dehydrofelodipine, also increased, as well as AUCs and Cmax values. The ratio between dehydrofelodipine/felodipine was not altered.

Conclusions:

Interpretation of results (migrated information): other: peppermint oil can inhibit CYP3A4 activity
Under the conditions of this study, Peppermint oil was found to be a reversible, partially mixed inhibitor of felodipine metabolism in vivo, indicating inhibition of CYP3A4.

Executive summary:

Peppermint oil induced inhibition of in vivo CYP3A4 activity was studied in healthy human volunteers. All subjects received racemic felodipine with white grapefruit juice, water plus peppermint oil, water plus ascorbyl palmitate, or water. Blood was sampled just before dosing and at several intervals up until 8 hours after dosing. Plasma concentrations of felodipine and dehydrofelodipine were determined by GC, which is an indication of the metabolic activity of CYP3A4.

Administration of peppermint oil increased concentration of felodipine, AUCs and Cmax values in blood, compared to control values (water). Concentrations of the major metabolite of felodipine, dehydrofelodipine, also increased, as well as AUCs and Cmax values. The ratio between dehydrofelodipine/felodipine was not altered.

Under the conditions of this study, Peppermint oil was found to be a reversible, partially mixed inhibitor of felodipine metabolism in vivo, indicating inhibition of CYP3A4.

Reference 4

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

No data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Read across from peppermint oil. Study design and results were reported clearly and considered acceptable basic data

Objective of study:

toxicokinetics

Qualifier:

no guideline followed

Principles of method if other than guideline:

The purpose of the study was to investigate the effectiveness of two different delayed release capsules containing peppermint oil. Six healthy volunteers received Peppermint oil (Colpermin capsule or gelatine capsule). Subsequently, urine was collected for 24 hours (2 hourly in the first 14 hours) and the amount of menthol (major constituent) was determined (as menthol glucuronide). The experiment was repeated with 6 patients with an ileostomy, in which urine was only collected at the 24 hour timepoint.

GLP compliance:

no

Radiolabelling:

no

Species:

human

Strain:

other: N/A

Sex:

male/female

Details on test animals or test system and environmental conditions:

VOLUNTEERS

Experiment 1 - healthy volunteers
- Age at study initiation: 17-37 years
- Fasting period before study: Yes

Experiment 2 - patients with an ileostomy
- Age at study initiation: 22-49 years
- Fasting period before study: Yes

Route of administration:

oral: capsule

Vehicle:

unchanged (no vehicle)

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
0.4 ml of peppermint oil (91-97 mg menthol/capsule) was administered as two Colpermin capsules or as two soft gelatine capsules without enteric coating and known to dissolve in the stomach

Duration and frequency of treatment / exposure:

One time administration

Remarks:

Doses / Concentrations:
0.4 ml peppermint oil by capsule/volunteer

No. of animals per sex per dose / concentration:

Experiment 1: 4 male, 2 female
Experiment 2: 3 male, 3 female

Control animals:

no

Positive control reference chemical:

N/A

Details on study design:

- Dose selection rationale: No data

Details on dosing and sampling:

PHARMACOKINETIC STUDY (excretion only)
- Tissues and body fluids sampled: urine
- Time and frequency of sampling: for 24 hours after exposure, in 2 hourly aliquots for the first 14 hours

Statistics:

Not performed

Preliminary studies:

Not included

Type:

excretion

Results:

35% and 40% (two different capsules) of menthol (as menthol glucuronide) was recovered after 24 hours in healthy individuals.

Type:

excretion

Results:

17% and 29% (two different capsules) of menthol (as menthol glucuronide) was recovered after 24 hours in ileostomy patients.

Details on absorption:

Not determined

Details on distribution in tissues:

Not determined

Details on excretion:

The peak in excretion of menthol in the urine of healthy volunteers was observed after 2 hours for the gelatin capsule, and after 4 hours for the Colpermin capsule (see attached illustration/graph). This information is not available for the ileostomy patients.

The total amount of menthol excreted in urine was measured as menthol glucuronide:

Experiment 1 - Healthy volunteers
- Gelatine capsule: 74 (46-91) mg menthol = 40% of total
- Colpermin capsule: 64 (45-75) mg menthol = 35% of total

Experiment 2 - Ileostomy patients
- Gelatine capsule: 55 (41-72) mg menthol = 29% of total
- Colpermin capsule: 31 (2-44) mg menthol = 17% of total

Metabolites identified:

no

Details on metabolites:

Menthol glucuronide is a known metabolite of menthol, and was measured in urine to determine the amount of Peppermint oil (and thus menthol) absorbed after oral administration.

Conclusions:

Interpretation of results (migrated information): other: oral absorption and excretion in urine apparent
Under the conditions of this study, 35% and 40% (two different capsules) of menthol (as menthol glucuronide) administered as Peppermint oil was recovered in urine within 24 hours in healthy volunteers. This indicates that oral absorption of Peppermint oil and subsequent excretion in urine occurs. The peak concentration in urine after oral administration in the gelatin capsule is observed after 2 hours.

Executive summary:

Six healthy volunteers received Peppermint oil (Colpermin capsule or gelatine capsule). Subsequently, urine was collected for 24 hours (2 hourly in the first 14 hours) and the amount of menthol (major constituent) was determined (as methol glucuronide). The experiment was repeated with 6 patients with an ileostomy, in which urine was only collected at the 24 hour timepoint.

Under the conditions of this study, 35% and 40% (two different capsules) of menthol (as menthol glucuronide) administered as Peppermint oil was recovered in urine within 24 hours in healthy volunteers. This indicates that oral absorption of Peppermint oil and subsequent excretion in urine occurs. The peak concentration in urine after oral administration in the gelatin capsule is observed after 2 hours. Excretion in urine of ileostomy patients was lower (17% and 29%).

Reference 5

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

No data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Read across from peppermint oil. Study design and results were reported clearly and considered acceptable basic data

Objective of study:

excretion

Qualifier:

no guideline available

Principles of method if other than guideline:

The pharmacokinetic profile of peppermint oil given in two different delayed-release preparations was investigated in human volunteers. Urine was collected at 2 hr intervals for 14 hr, and at 24 hr. Menthol and its glucuronide metabolites were analysed in urine using gas chromatography.

GLP compliance:

not specified

Radiolabelling:

no

Species:

human

Strain:

other: not relevant

Sex:

male/female

Details on test animals or test system and environmental conditions:

HUMAN VOLUNTEERS
- Mean age: 35 years (range 18-70)
- Mean weight: 67.5 kg (47-76)
- Fasting period before study: overnight
- Diet: 2 hr after ingestion of the capsules, subjects were permitted to eat normally. Subjects were asked not to ingest any menthol-containing sweets, cough pastilles, toothpaste etc. at least 24 hr before and during the study
- Water: Subjects were encouraged to drink liberal amounts of non-alcoholic fluids throughout the study to make sure urinary production was adequate

Route of administration:

oral: capsule

Vehicle:

not specified

Details on exposure:

Subjects took peppermint oil as capsules of Colpermin or Mintec (in random order)

Duration and frequency of treatment / exposure:

single exposure

Remarks:

Doses / Concentrations:
0.6 ml of peppermint oil:
test 1: Colpermin Icontaining 110 ± 5 mg menthol)
test 2: Mintec (containing 117 ± 5 mg menthol)

No. of animals per sex per dose / concentration:

6 males and 5 females

Control animals:

no

Positive control reference chemical:

not applicable

Details on study design:

not applicable

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled (delete / add / specify): urine
- Time and frequency of sampling: 2 hr intervals for 14 hr, and at 24 hr

Statistics:

Data were analysed using a microcomputer-based pharmacokinetic programm (MAC-LSNR) using two- or three-compartment models.

Preliminary studies:

not relevant

Details on absorption:

not relevant

Details on distribution in tissues:

not relevant

Details on excretion:

Peak urinary excretion after Colpermin administration occurred over a sustained period from 3 to 9 hr. After administration of Mintec, peak urinary excretion occurred at 3 hr post-dosing.

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: 3.6 ± 0.8 h (terminal elimination)

Test no.:

#1

Toxicokinetic parameters:

AUC: 84.0 ± 42.9 mg

Test no.:

#1

Toxicokinetic parameters:

Tmax: 5 ± 2 h

Test no.:

#2

Toxicokinetic parameters:

half-life 1st: 3.8 ± 2.4 (terminal elimination)

Test no.:

#2

Toxicokinetic parameters:

AUC: 127.2 ± 56.7 mg

Test no.:

#2

Toxicokinetic parameters:

Tmax: 2.8 ± 0.6 h

Details on metabolites:

not relevant

The table below shows the total recovery of menthol and metabolites following administration of Colpermin and Mintec.

subject	sex	age	weight (kg)	menthol recovered (mg)
				Colpermin	Mintec
1	F	30	56	110.6	137.5
2	F	40	67	100.5	99.3
3	M	38	86	83.0	158.0
4	F	45	67	77.7	171.2
5	F	18	52	68.3	112.7
6	F	18	47	71.6	229.9
7	M	46	73	82.8	199.4
8	M	40	72	147.1	133.3
9	M	42	91	95.5	91.1
10	M	18	64	60.8	74.6
11	M	19	67	18.8	81.1
12	F	30	59	275.5	117.6
13	F	70	76	49.5	95.5
Mean		34.9	67.5	95.5	130.9
S.D.		± 15.1	± 12.6	± 62.2	± 47.3
Paired t-test				P=0.123 (n.s.)

Conclusions:

Interpretation of results (migrated information): no data
The pharmacokinetic profile of peppermint oil given in two different delayed-release preparations was investigated in human volunteers. Urine was collected at 2 hr intervals for 14 hr, and at 24 hr. Menthol and its glucuronide metabolites were analysed in urine using gas chromatography. Peak urinary excretion after Colpermin administration occurred over a sustained period from 3 to 9 hr. After administration of Mintec, peak urinary excretion occurred at 3 hr post-dosing. Recovery of menthol in urine was 87% for Colpermint and 112% for Mintec.

Executive summary:

The pharmacokinetic profile of peppermint oil given in two different delayed-release preparations was investigated in human volunteers. Urine was collected at 2 hr intervals for 14 hr, and at 24 hr. Menthol and its glucuronide metabolites were analysed in urine using gas chromatography.

Peak urinary excretion after Colpermin administration occurred over a sustained period from 3 to 9 hr. After administration of Mintec, peak urinary excretion occurred at 3 hr post-dosing. Recovery of menthol in urine was 87% for Colpermint and 112% for Mintec.

Reference 6

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

The read across justification is presented in the document attached to this record.

Reason / purpose for cross-reference:

read-across source

Positive control reference chemical:

Not included

Preliminary studies:

Not performed

Type:

excretion

Results:

Between 37 and 116 mg menthol recovered in urine within 14 hours of administration of Peppermint oil

Details on absorption:

Not studied

Details on distribution in tissues:

Not studied

Details on excretion:

A significant amount of variation among each individual was observed in the urinary excretion profile over 14 hours (see attached illustration/graph). AUC analysis indicated that 37-116 mg of menthol was excreted. As no concentration of menthol in the administered peppermint oil was determined, it is not possible to calculate the percentage of recovery.

Metabolites identified:

no

Details on metabolites:

Menthol glucuronide is determined in urine (metabolite of menthol), which indicates the amount of Peppermint oil that is orally absorbed.

Conclusions:

The toxicokinetic properties of cornmint oil were assessed using read across from the source substance peppermint oil.
Under the condtions of this study, menthol was recovered in urine after peppermint oil administration. However, no percentage of recovery could be calculated as the menthol concentration in the administered peppermint oil was not determined.

Executive summary:

The toxicokinetic properties of cornmint oil were assessed using read across from the source substance peppermint oil. Four male volunteers were administered 180 mg of Peppermint oil in an enteric-coated capsule following a 16 hours fasting period. Urine was collected every 2 hours for up to 14 hours, volume was measured and analysed by gas chromatography.

A significant amount of variation among each individual was observed in the urinary excretion profile over 14 hours. AUC analysis indicated that 37-116 mg of menthol was excreted. As the menthol concentration in the administered peppermint oil was not determined, no percentage of recovery could be determined.

Reference 7

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

The read across justification is presented in the document attached to this record.

Reason / purpose for cross-reference:

read-across source

GLP compliance:

no

Preliminary studies:

Not performed

Details on absorption:

N/A

Details on distribution in tissues:

N/A

Details on excretion:

N/A

Metabolites identified:

no

Details on metabolites:

N/A

Administration of peppermint oil increased concentration of felodipine, AUCs and Cmax values in blood, compared to control values (water). Concentrations of the major metabolite of felodipine, dehydrofelodipine, also increased, as well as AUCs and Cmax values. The ratio between dehydrofelodipine/felodipine was not altered.

Conclusions:

The toxicokinetic properties of cornmint oil were assessed using read across from the source substance peppermint oil.
Under the conditions of this study, Peppermint oil was found to be a reversible, partially mixed inhibitor of felodipine metabolism in vivo, indicating inhibition of CYP3A4.

Executive summary:

The toxicokinetic properties of cornmint oil were assessed using read across from the source substance peppermint oil.

Peppermint oil induced inhibition of in vivo CYP3A4 activity was studied in healthy human volunteers. All subjects received racemic felodipine with white grapefruit juice, water plus peppermint oil, water plus ascorbyl palmitate, or water. Blood was sampled just before dosing and at several intervals up until 8 hours after dosing. Plasma concentrations of felodipine and dehydrofelodipine were determined by GC, which is an indication of the metabolic activity of CYP3A4.

Administration of peppermint oil increased concentration of felodipine, AUCs and Cmax values in blood, compared to control values (water). Concentrations of the major metabolite of felodipine, dehydrofelodipine, also increased, as well as AUCs and Cmax values. The ratio between dehydrofelodipine/felodipine was not altered.

Under the conditions of this study, Peppermint oil was found to be a reversible, partially mixed inhibitor of felodipine metabolism in vivo, indicating inhibition of CYP3A4.

Reference 8

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

The read across justification is presented in the document attached to this record.

Reason / purpose for cross-reference:

read-across source

Preliminary studies:

Not performed

Type:

metabolism

Results:

reversible inhibition: CYP3A4 residual activity was lower in presence of higher concentrations of peppermint oil. This effect was observd in presence and absence of NADPH.

Details on absorption:

N/A

Details on distribution in tissues:

N/A

Details on excretion:

N/A

Metabolites identified:

no

Details on metabolites:

N/A

Conclusions:

The toxicokinetic properties of cornmint oil were assessed using read across from the source substance peppermint oil.
Under the conditions of this study, Peppermint oil was found to be a reversible, partially mixed inhibitor of nifedipine metabolism in vitro.

Executive summary:

The toxicokinetic properties of cornmint oil were assessed using read across from the source substance peppermint oil. Peppermint oil induced inhibition of in vitro CYP3A4 activity was studied. Microsomes from human liver samples were used and incubated with 0, 20, 50, 100 and 200 ug/ml Peppermint oil and different concentrations of nifedipine (substrate). NADPH was added for starting the metabolic reactions. The sample was analysed for nifedipine and its oxidation product by chromatography. A reversible and irreversible inhibition study was performed. All experiments were performed in triplicate.

CYP3A4 residual activity was lower in presence of higher concentrations of peppermint oil. This effect was observed in presence and absence of NADPH. Under the conditions of this study, Peppermint oil was found to be a reversible, partially mixed inhibitor of nifedipine metabolism in vitro.

Reference 9

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

The read across justification is presented in the document attached to this record.

Reason / purpose for cross-reference:

read-across source

Preliminary studies:

Not included

Type:

excretion

Results:

35% and 40% (two different capsules) of menthol (as menthol glucuronide) was recovered after 24 hours in healthy individuals.

Type:

excretion

Results:

17% and 29% (two different capsules) of menthol (as menthol glucuronide) was recovered after 24 hours in ileostomy patients.

Details on absorption:

Not determined

Details on distribution in tissues:

Not determined

Details on excretion:

The peak in excretion of menthol in the urine of healthy volunteers was observed after 2 hours for the gelatin capsule, and after 4 hours for the Colpermin capsule (see attached illustration/graph). This information is not available for the ileostomy patients.

The total amount of menthol excreted in urine was measured as menthol glucuronide:

Experiment 1 - Healthy volunteers
- Gelatine capsule: 74 (46-91) mg menthol = 40% of total
- Colpermin capsule: 64 (45-75) mg menthol = 35% of total

Experiment 2 - Ileostomy patients
- Gelatine capsule: 55 (41-72) mg menthol = 29% of total
- Colpermin capsule: 31 (2-44) mg menthol = 17% of total

Metabolites identified:

no

Details on metabolites:

Menthol glucuronide is a known metabolite of menthol, and was measured in urine to determine the amount of Peppermint oil (and thus menthol) absorbed after oral administration.

Conclusions:

The toxicokinetic properties of cornmint oil were assessed using read across from the source substance peppermint oil.
Under the conditions of this study, 35% and 40% (two different capsules) of menthol (as menthol glucuronide) administered as Peppermint oil was recovered in urine within 24 hours in healthy volunteers. This indicates that oral absorption of Peppermint oil and subsequent excretion in urine occurs. The peak concentration in urine after oral administration in the gelatin capsule is observed after 2 hours.

Interpretation of results: oral absorption and excretion in urine apparent

Executive summary:

The toxicokinetic properties of cornmint oil were assessed using read across from the source substance peppermint oil. Six healthy volunteers received Peppermint oil (Colpermin capsule or gelatine capsule). Subsequently, urine was collected for 24 hours (2 hourly in the first 14 hours) and the amount of menthol (major constituent) was determined (as methol glucuronide). The experiment was repeated with 6 patients with an ileostomy, in which urine was only collected at the 24 hour timepoint.

Under the conditions of this study, 35% and 40% (two different capsules) of menthol (as menthol glucuronide) administered as Peppermint oil was recovered in urine within 24 hours in healthy volunteers. This indicates that oral absorption of Peppermint oil and subsequent excretion in urine occurs. The peak concentration in urine after oral administration in the gelatin capsule is observed after 2 hours. Excretion in urine of ileostomy patients was lower (17% and 29%).

Reference 10

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

The read across justification is presented in the document attached to this record.

Preliminary studies:

not relevant

Details on absorption:

not relevant

Details on distribution in tissues:

not relevant

Details on excretion:

Peak urinary excretion after Colpermin administration occurred over a sustained period from 3 to 9 hr. After administration of Mintec, peak urinary excretion occurred at 3 hr post-dosing.

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: 3.6 ± 0.8 h (terminal elimination)

Test no.:

#1

Toxicokinetic parameters:

AUC: 84.0 ± 42.9 mg

Test no.:

#1

Toxicokinetic parameters:

Tmax: 5 ± 2 h

Test no.:

#2

Toxicokinetic parameters:

half-life 1st: 3.8 ± 2.4 (terminal elimination)

Test no.:

#2

Toxicokinetic parameters:

AUC: 127.2 ± 56.7 mg

Test no.:

#2

Toxicokinetic parameters:

Tmax: 2.8 ± 0.6 h

Details on metabolites:

not relevant

The table below shows the total recovery of menthol and metabolites following administration of Colpermin and Mintec.

subject	sex	age	weight (kg)	menthol recovered (mg)
				Colpermin	Mintec
1	F	30	56	110.6	137.5
2	F	40	67	100.5	99.3
3	M	38	86	83.0	158.0
4	F	45	67	77.7	171.2
5	F	18	52	68.3	112.7
6	F	18	47	71.6	229.9
7	M	46	73	82.8	199.4
8	M	40	72	147.1	133.3
9	M	42	91	95.5	91.1
10	M	18	64	60.8	74.6
11	M	19	67	18.8	81.1
12	F	30	59	275.5	117.6
13	F	70	76	49.5	95.5
Mean		34.9	67.5	95.5	130.9
S.D.		± 15.1	± 12.6	± 62.2	± 47.3
Paired t-test				P=0.123 (n.s.)

Conclusions:

The toxicokinetic properties of cornmint oil were assessed using read across from the source substance peppermint oil.
The pharmacokinetic profile of peppermint oil given in two different delayed-release preparations was investigated in human volunteers. Urine was collected at 2 hr intervals for 14 hr, and at 24 hr. Menthol and its glucuronide metabolites were analysed in urine using gas chromatography. Peak urinary excretion after Colpermin administration occurred over a sustained period from 3 to 9 hr. After administration of Mintec, peak urinary excretion occurred at 3 hr post-dosing. Recovery of menthol in urine was 87% for Colpermint and 112% for Mintec.

Executive summary:

The toxicokinetic properties of cornmint oil were assessed using read across from the source substance peppermint oil. The pharmacokinetic profile of peppermint oil given in two different delayed-release preparations was investigated in human volunteers. Urine was collected at 2 hr intervals for 14 hr, and at 24 hr. Menthol and its glucuronide metabolites were analysed in urine using gas chromatography.

Peak urinary excretion after Colpermin administration occurred over a sustained period from 3 to 9 hr. After administration of Mintec, peak urinary excretion occurred at 3 hr post-dosing. Recovery of menthol in urine was 87% for Colpermint and 112% for Mintec.

Key value for chemical safety assessment

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100

Additional information

Background

Cornmint oil is a substance of Unknown or Variable composition, Complex reaction products or Biological material (UVCB substances), or more specifically an NCS (Natural Complex Substance). As such, cornmint oil is part of the particular category of essential oils, extracts, fractions and distillation products of the mint species of chapter 1.2, which are all variants of the botanical Lamiaceae family, genus Mentha. A justification for read across within this category can be found in the “Reporting format for Natural Complex Substances of the Mint essential oils of the Lamiaceae family, genus Mentha”. The other member of this category is peppermint oil. The category is based on the part of the plant from which the NCSs are produced (fresh, above ground parts of the flowering plants), the common methods of production, the same dominant constituent (L-menthol and Menthone (in combination >60%)), and the same and/or similar constituents.

For cornmint oil, no information on toxicokinetics properties was retrieved. However, several publications concerning the toxicokinetics of the other member of the mint category, peppermint oil, are available in the dossier. Furthermore, the physical/chemical parameters of the constituents of cornmint oil will be taken into account.

 

Information from experimental studies with peppermint oil

The toxicokinetics properties of peppermint oil were examined in several in vivo human studies, as well as in vitro studies with human liver microsomes. In the in vivo studies, human volunteers were exposed to different forms of delayed-release capsules containing peppermint oil, for its use to treat irritable bowel/spastic colon syndrome.

The excretion of menthol in the urine was measured after a single dose of peppermint oil to human volunteers in three different experiments. Results show a recovery of 35-40% in urine as menthol or mentholglucuronide after 24hr (Somerville et al., 1984), while in another experiment 87 -112% was recovered as urine (White, 1987). In the third study menthol was also determined in urine, however, percentage recovery could not be determined (Kaffenberger, 1990). These studies indicate that peppermint oil is absorbed after oral exposure.

In vitro and in vivo experiments examining effects of peppermint oil on the metabolism of two different calcium channel blockers (nifedipine and felodipine), show that peppermint oil is a reversible, partially mixed inhibitor of metabolism of these substances both in vitro and in vivo, indicating inhibition of CYP3A4. (Dresser et al., 2002) This study indicates that metabolism of peppermint oil is expected in the human body.

No information could be retrieved concerning dermal and inhalation absorption.

 

Other constituents

Physical/chemical parameters indicating whether absorption via the oral, inhalation and dermal route is expected, are for example molecular weight, water solubility, log Kow, and vapour pressure. Please find below a table containing these parameters for the constituents of cornmint oil.

 

Constituent	Molecular weight	Water solubility (mg/l at 25°C)	Log Kow	Vapour pressure (Pa at 25°C)
L-menthol	156.27	941.74	3.38	1.02
Menthone	154.25	895.86	2.87	49.4
limonene	136.24	44.388	4.83	193
alpha pinene	136.24	3.4834	4.27	536
betapinene	136.24	2.6192	4.35	334
Iso-menthone	154.25	895.86	2.87	49.4
neo-menthol	156.27	941.74	3.38	1.02
Menthyl Acetate	198.31	53.781	4.39	12.2
Piperitone	152.24	135.01	3.07	13.8
Pulegone	152.24	212.83	3.2	21.6
Iso-Pulegol	154.25	943.2	3.37	0.662
Germacrene-D	204.36	0.81945	6.99	3.04
Neo-iso pulegol	154.25	943.2	3.37	0.662
1,8-cineole	154,25	551.66	3,13	208
octan-3-ol	130.23	1285.3	2.73	13.3
sabinene	136.24	2.6192	4.69	981
Myrcene	136.24	17.814	4.88	320
Neo-iso menthol	156.27	941.74	3.38	1.02
Beta-caryophyllene	204.36	0.54268	6.3	4.16

 

Although, based on vapour pressure, most constituents have a low volatility (<0.5 KPa), exposure via inhalation is included based on the use of cornmint oil as a fragrance. Oral absorption and absorption via inhalation is expected for most substances, as they have a molecular weight <500, moderate to high water solubility, and log Kow between 1-4. Substances with a log Kow>4 and with a low water solubility, such as betapinene, alpha-pinene, germacrene-D, sabinene, beta-caryophyllene, may be less well absorbed orally due to their log Kow >4 and relatively low water solubility.

Dermal absorption is not favoured based on the molecular weights of the substances, neither can it be ruled out. For the substances which have a log Kow <4 combined with a relatively high water solubility, dermal absorption is expected. For betapinene, alpha-pinene, germacrene-D, sabinene, beta-caryophyllene, which have a log Kow >4 and relatively low water solubility, dermal absorption is expected to be low to moderate.

 

Conclusion

Based on toxicokinetic studies with peppermint oil, cornmint oil is expected to be orally absorbed and metabolized. Based on physical properties of the constituents, absorption via the oral, inhalation and dermal route is expected to be moderate to high. For risk assessment, a default absorption of 100% is assumed.