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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
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.

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:
1976
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
Name:
Unnamed
Type:
Constituent
Details on test material:
- Locations of the label (if radiolabelling): on the 9 position
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:
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 (migrated information): 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.