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EC number: 290-058-5 | CAS number: 90063-97-1 Extractives and their physically modified derivatives such as tinctures, concretes, absolutes, essential oils, oleoresins, terpenes, terpene-free fractions, distillates, residues, etc., obtained from Mentha arvensis, Labiatae.
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Link to relevant study record(s)
- 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.
- 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.
- 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
- 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.
- 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%).
- 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
- 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.
- 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.
- 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
- 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.
- 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.
- 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%).
- 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
- 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.
Referenceopen allclose all
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.
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.) |
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.
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.) |
Description of key information
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.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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