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EC number: 297-672-2 | CAS number: 93686-22-7 Extractives and their physically modified derivatives such as tinctures, concretes, absolutes, essential oils, oleoresins, terpenes, terpene-free fractions, distillates, residues, etc., obtained from Citrus reticulata, x C. sinensis, Rutaceae.
- 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
Basic toxicokinetics
Administrative data
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- not reported
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: see 'Remark'
- Remarks:
- Old study but a lot of details available. Due to the read-across purpose it was given a Klimisch 2 rating, in accordance with the ECHA Practical guide #6 on the reporting of read-across in IUCLID. The justification for read across is provided in the attached background material of the chapter summary.
Cross-reference
- Reason / purpose for cross-reference:
- read-across: supporting information
Reference
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: see 'Remark'
- Remarks:
- Old study but a lot of details available. Due to the read-across purpose it was given a Klimisch 2 rating, in accordance with the ECHA Practical guide #6 on the reporting of read-across in IUCLID. The justification for read across is provided in the attached background material of the chapter summary.
- Justification for type of information:
- The read across is primarily based on limonene (> 25%), and to a lesser extent also on β-pinene, γ-terpinene and citral (all max 35%). There are no other major constituents ≥ 10% (with the exception of some qualities of lime oil where maximum values may be up to 22%). Although this threshold for limonene and the other constituents can be considered arbitrary, it is clear that the lower the limonene content, the more difficult read across for some endpoints is. In this category, read across was feasible because 1) the citrus NCSs did not only share limonene as a major constituent in a percentage >25%, but 2) citrus NCSs with a lower content of limonene also share β-pinene and/or γ-terpinene and or citral in the same range (max 35%%) and 3) there were no other major constituents ≥ 10% (except for lime oil). The latter criterion is also important because it excludes the addition of constituents which are uncommon to this citrus category and may hamper read across. For Lime oil some constituents are > 10%, but they do not alter the C&L and therefore can also be considered not hampering read across.
Based on the fact that the citrus NCSs share the same constituents and all contain one major constituent (D-limonene) and since physico-chemical properties are similar, there is no reason to expect any differences in toxicokinetic behaviour among the category members.
See also the attached justification - Reason / purpose for cross-reference:
- read-across source
- Preliminary studies:
- In Igimi H. and Nishimura M. (1974) Studies on the metabolism of d-limonene (p-mentha-1,8-diene) I. The absorption, distribution and excretion of d-limonene in rats, Xenobiotica, vol 4(2), 77-84: the absorption, distribution and excretion of d-limonene were investigated in rats. About 60% of administered radioactivity was recovered in urine, 5% from faeces and 2% from expired CO2 within 48h. In bile duct cannulated rats, about 25% of the dose was escreted in bile within 24h.
In Kodama R., Noda K. and Ide H. (1974) Studies on the metabolism of d-limonene (p-mentha-1,8-diene) II. The metabolic fate of d-limonene in rabbits, Xenobiotica, Vol 4 (2), 85-95: following oral administration to 3 male rabbits, about 72% and 7% of the dose was excreted in urine and faeces during 72 hours respectively. - Type:
- excretion
- Type:
- metabolism
- Details on absorption:
- rapid and almost complete on the basis of the urinary excretion level, with most excretion occuring within the first 24 hours.
In the case of man, absorption may also be rapid and complete as the urinary excretion was about 85% during 48 hours (about 80% within 24 hours) in subject 1 (relatively low urinary excretion in subject 2 might be due to diarrhoea which occurred at 2 hours after administration). - Details on excretion:
- The main route of excretion of d-limonene was via urine, 75-95% of administered radioactivity being excreted in the urine during 2-3 days.
Faecal excretion amounted to less than 10% in animals during 2-3 days. - Metabolites identified:
- yes
- Details on metabolites:
- The reactions in the d-limonene biotransformation include the oxidation of methyl groups to hydroxyl and further to carboxylic acid derivatives, hydroxylation at the C-6 position, oxidation at the 8,9-double bond, and glycine and glucuronide conjugation. Hydroxylation at the C-6 position leads to the formation of p-mentha-1,8-dien-6-ol (M-X).
The 8,9-diol metabolites such as M-II and M-IV are likely to be derived through the epoxide intermediate. The structure of 2-hydroxy-p-menth-8-en-7-oic acid (M-VII) can be derived by hydration of the 1,2-double bond of perillic acid (M-III).
The major metabolite of d-limonene in the urine was M-IV in rat and rabbit, M-IX in hamster, M-II in dog and M-VI in guinea pig and man. - Conclusions:
- Interpretation of results: no bioaccumulation potential based on study results
The rate and amount of urinary excretion in rat, rabbit, hamster, guinea pig, dog and man suggest rapid elimination with no significant accumulation of compounds related to d-limonene in these species. - Executive summary:
The excretion and metabolism of d-limonene was studied in various species (rat, rabbit, hamster, guinea pig, dog and human after one oral administration (gavage or capsule according to species). Excretion was measured in urine and/or faeces during 2 to 3 days after administration.
Up to 11 metabolites were isolated and characterized.
The main route of elimination of d-limonene administered orally was via the urine in animals and man, 75 -95% of the administered radioactivity being excreted in the urine during 2 -3 days. Faecal excretion accounted for less than 10% of the dose in animals during 2 -3 days.
List of the metabolites of d-limonene:
M-I: p-mentha1,8 -dien-10 -ol
M-II: p-menth-1-ene-8,9 -diol
M-III: perillic acid
M-IV: perillic acid-8,9 -diol
M-V: p-mentha-1,8 -dien-10 -yl-beta-D-glucopyranosiduronic acid
M-VI: 8 -hydroxy-p-menth-1 -en-9 -yl-beta-D-glucopyranosiduronic acid
M-VII: 2 -hydroxy-p-menth-8 -en-7 -oic acid
M-VIII: perillylglycine
M-IX: perillyl-beta-D-glucopyranosiduronic acid
M-X: p-mentha-1,8 -dien-6 -ol
M-XI: p-menth-1 -ene-6,8,9 -triol
Data source
Reference
- Reference Type:
- publication
- Title:
- Studies on the metabolism of d-limonene (p-mentha-1, 8-diene). IV Isolation and characterisation of new metabolites and species differences in metabolism
- Author:
- Kodama R, Yano T, Furukawa K, Noda K and Ide H
- Year:
- 1 976
- Bibliographic source:
- Xenobiotica, vol. 6(6), 377-389
Materials and methods
- Objective of study:
- other: excretion and metabolism
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- The metabolism of d-limonene was investigated in various animal species. Isolation and characterisation of several metabolites was done.
- GLP compliance:
- no
Test material
- Reference substance name:
- p-mentha-1,8-diene
- IUPAC Name:
- p-mentha-1,8-diene
- Details on test material:
- - Locations of the label (if radiolabelling): on the 9 position
Constituent 1
- Radiolabelling:
- yes
Test animals
- Species:
- other: rat, hamster, guinea-pig, rabbit, dog
- Strain:
- other: Wistar, Syrian, Hartley, albino, mongrel
- Sex:
- male
Administration / exposure
- Route of administration:
- other: oral gavage for rat, rabbit, hamster and guinea pig; oral capsule for dog and human
- Duration and frequency of treatment / exposure:
- one administration only
Doses / concentrations
- Remarks:
- Doses / Concentrations:
800 mg/kg bw: rat, guinea pig, hamster and rabbit
400 mg/kg bw: dog
1.6 g: human (57 and 60 kg bw)
- No. of animals per sex per dose / concentration:
- 3 rats, 3 guinea pigs, 4 hamsters, 3 rabbits, 2 dogs and 2 human beings
- Control animals:
- no
- Details on dosing and sampling:
- For the excretion study and quantitative determination of acidic urine metabolites, [14C]d-limonene was administered orally.
For quantitative determination of neutral urine metabolites, non-labelled d-limonene was administered to another group of animals.
Animals were placed in metabolism cages, and urine and faeces were collected separately during 2 to 3 days.
Humans took the compound in hard gelatin capsules with water, and urine only was collected during 2 days.
Results and discussion
- Preliminary studies:
- In Igimi H. and Nishimura M. (1974) Studies on the metabolism of d-limonene (p-mentha-1,8-diene) I. The absorption, distribution and excretion of d-limonene in rats, Xenobiotica, vol 4(2), 77-84: the absorption, distribution and excretion of d-limonene were investigated in rats. About 60% of administered radioactivity was recovered in urine, 5% from faeces and 2% from expired CO2 within 48h. In bile duct cannulated rats, about 25% of the dose was escreted in bile within 24h.
In Kodama R., Noda K. and Ide H. (1974) Studies on the metabolism of d-limonene (p-mentha-1,8-diene) II. The metabolic fate of d-limonene in rabbits, Xenobiotica, Vol 4 (2), 85-95: following oral administration to 3 male rabbits, about 72% and 7% of the dose was excreted in urine and faeces during 72 hours respectively.
Main ADME resultsopen allclose all
- Type:
- excretion
- Type:
- metabolism
Toxicokinetic / pharmacokinetic studies
- Details on absorption:
- rapid and almost complete on the basis of the urinary excretion level, with most excretion occuring within the first 24 hours.
In the case of man, absorption may also be rapid and complete as the urinary excretion was about 85% during 48 hours (about 80% within 24 hours) in subject 1 (relatively low urinary excretion in subject 2 might be due to diarrhoea which occurred at 2 hours after administration).
- Details on excretion:
- The main route of excretion of d-limonene was via urine, 75-95% of administered radioactivity being excreted in the urine during 2-3 days.
Faecal excretion amounted to less than 10% in animals during 2-3 days.
Metabolite characterisation studies
- Metabolites identified:
- yes
- Details on metabolites:
- The reactions in the d-limonene biotransformation include the oxidation of methyl groups to hydroxyl and further to carboxylic acid derivatives, hydroxylation at the C-6 position, oxidation at the 8,9-double bond, and glycine and glucuronide conjugation. Hydroxylation at the C-6 position leads to the formation of p-mentha-1,8-dien-6-ol (M-X).
The 8,9-diol metabolites such as M-II and M-IV are likely to be derived through the epoxide intermediate. The structure of 2-hydroxy-p-menth-8-en-7-oic acid (M-VII) can be derived by hydration of the 1,2-double bond of perillic acid (M-III).
The major metabolite of d-limonene in the urine was M-IV in rat and rabbit, M-IX in hamster, M-II in dog and M-VI in guinea pig and man.
Any other information on results incl. tables
List of the metabolites of d-limonene:
M-I: p-mentha1,8 -dien-10 -ol
M-II: p-menth-1-ene-8,9 -diol
M-III: perillic acid
M-IV: perillic acid-8,9 -diol
M-V: p-mentha-1,8 -dien-10 -yl-beta-D-glucopyranosiduronic acid
M-VI: 8 -hydroxy-p-menth-1 -en-9 -yl-beta-D-glucopyranosiduronic acid
M-VII: 2 -hydroxy-p-menth-8 -en-7 -oic acid
M-VIII: perillylglycine
M-IX: perillyl-beta-D-glucopyranosiduronic acid
M-X: p-mentha-1,8 -dien-6 -ol
M-XI: p-menth-1 -ene-6,8,9 -triol
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results: no bioaccumulation potential based on study results
The rate and amount of urinary excretion in rat, rabbit, hamster, guinea pig, dog and man suggest rapid elimination with no significant accumulation of compounds related to d-limonene in these species. - Executive summary:
The excretion and metabolism of d-limonene was studied in various species (rat, rabbit, hamster, guinea pig, dog and human after one oral administration (gavage or capsule according to species). Excretion was measured in urine and/or faeces during 2 to 3 days after administration.
Up to 11 metabolites were isolated and characterized.
The main route of elimination of d-limonene administered orally was via the urine in animals and man, 75 -95% of the administered radioactivity being excreted in the urine during 2 -3 days. Faecal excretion accounted for less than 10% of the dose in animals during 2 -3 days.
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