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Diss Factsheets
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EC number: 207-856-6 | CAS number: 498-15-7
- 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
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Basic toxicokinetics
Administrative data
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- No data
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Study well documented, meets generally accepted scientific principles, acceptable for assessment
Cross-referenceopen allclose all
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to other study
Data source
Reference
- Reference Type:
- publication
- Title:
- Human metabolism of Δ3-carene and renal elimination of Δ3-caren-10-carboxylic acid (chaminic acid) after oral administration.
- Author:
- Schmidt L, Belov VN and Göen T.
- Year:
- 2 015
- Bibliographic source:
- Arch Toxicol. 89(3):381-392.
Materials and methods
- Objective of study:
- metabolism
- Principles of method if other than guideline:
- Metabolism of Δ3-carene was studied in volunteers.
- GLP compliance:
- no
Test material
- Reference substance name:
- 3,7,7-trimethylbicyclo[4.1.0]hept-3-ene
- EC Number:
- 236-719-3
- EC Name:
- 3,7,7-trimethylbicyclo[4.1.0]hept-3-ene
- Cas Number:
- 13466-78-9
- Molecular formula:
- C10H16
- IUPAC Name:
- 3,7,7-trimethylbicyclo[4.1.0]hept-3-ene
- Test material form:
- liquid
Constituent 1
- Radiolabelling:
- no
Test animals
- Species:
- human
- Sex:
- male/female
Administration / exposure
- Route of administration:
- other: oral
- Duration and frequency of treatment / exposure:
- Single dose
Doses / concentrations
- Remarks:
- Doses / Concentrations:
10 mg
- No. of animals per sex per dose / concentration:
- Four healthy human volunteers
- Details on dosing and sampling:
- TEST ITEM ADMINISTRATION
- Four healthy human volunteers (3 men and 1 woman, mean age 33 ± 11 years, mean body weight 80 ± 8 kg) were orally exposed to ca 10 mg (ca 73 μmol, M = 136.23 mg/mmol) via spiked gelatin capsules.
- The volunteers ingested the capsules in the morning on an empty stomach, directly after the collection of one pre-exposure urine sample. After the exposure, they fasted for 1 h. During the remaining time of the experiment, they were allowed to eat and drink normally.
METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: Urine
- Time and frequency of sampling: Urine samples were collected by every volunteer throughout 24 h as often as possible. For every urine sample, the sampling time and the excretion volume were recorded.
- Storage: Urine samples were stored frozen under nitrogen protective gas at −20 °C until analysis.
- Method type(s) for identification: Gas chromatographic–mass spectrometric analyses (GC–PCI–MS and MS/MS); Concentration of the proposed CRN metabolites Δ3-caren-10-ol (CRN-10-OH), Δ3-caren-10-carboxylic acid (chaminic acid, CRN-10-COOH), and Δ3-caren-3,4-diol (CRN-3,4-OH) were determined using a very specific and sensitive GC–MS/MS procedure. Other CRN metabolites were investigated using GC–PCI–MS Q1 scan analyses.
- Urine samples were analysed according to the procedure of Schmidt et al. (2013). - Statistics:
- None
Results and discussion
Main ADME results
- Type:
- metabolism
Metabolite characterisation studies
- Metabolites identified:
- yes
- Details on metabolites:
- - None of the volunteers reported any negative or physiological effects due to the exposure. Some mentioned a distinct smell of the exhaled breath, which vanishes rapidly, about 1–2 h after exposure. In total, 71 samples from four human volunteers were analysed.
- Renal excretion of CRN-10-COOH in the pre-exposure samples was 2.8 ± 1.4 μg/h. The urinary CRN-10-COOH concentration increased distinctly within 1–3.5 h after oral administration to maximum levels of 113.0–1172.9 μg/L (19.6–68.8 μg/h) and declined afterwards to the base levels within the 24-h observation period. The conjugation shares of CRN-10-COOH in the excretion maximum ranged between 94 and 97 % of the metabolite concentration. Whereas CRN-10-OH and CRN-3,4-OH were not detected in any of the samples.
- Renal excretion kinetics of CRN-10-COOH showed an elimination half-life of about 3 h. The cumulative excretion of CRN-10-COOH within 24 h after exposure correlated with about 2 % of the applied dose.
- At the end of the observation time, a slight elevation of the cumulative excretion amount of CRN-10-COOH was determined in the urine of two volunteers.
Analysis of unknown (+) 3 carene metabolites in urine
Since only about 2 % of the oral dose was excreted as CRN-10-COOH and, moreover, CRN-10-OH and CRN-3,4-OH were not found to be relevant human urinary metabolites, samples were analysed for further unknown major metabolites using GC–PCI–MS Q1 full scans. These analyses revealed six characteristic peaks of unknown urinary CRN metabolites. The percentages of the total renal metabolite excretion were estimated to be about 3 % (CRN-M1), 1 % (CRN-M2), 5 % (CRNM3), 4 % (CRN-M4), 11 % (CRN-M5), and 2 % (CRNM6), respectively.
Any other information on results incl. tables
Table 7.1.1/1: Data on the renal excretion kinetics of 3-caren-10-carboxylic acid after oral intake of 10 mg (+)-3-carene by four healthy human volunteers
Parameters |
Unit |
Mean |
SD |
Min |
Max |
Dose |
μmol |
75.5 |
5.0 |
68.9 |
78.2 |
RE,max |
μg/h |
40.0 |
21.7 |
19.6 |
68.8 |
tmax |
h |
2.4 |
1.4 |
0.9 |
3.5 |
t1/2 |
h |
3a(3)b |
<1a(2)b |
2b |
5b |
AUC0→tf |
μmol |
1.0a(1.3)b |
<0.1a(0.5)b |
0.9b |
1.9b |
Vtotal |
L |
1.6 |
0.7 |
1.0 |
2.5 |
RE,max maximum renal excretion; tmax time to reach maximum renal excretion; t1/2 elimination half-life; AUC0→tf area under the renal excretion vs. time curve (from time 0 to final sampling timetf);Vtotal summarized excreted urine volume
a Values calculated from the log-normal fitted mean renal elimination curve (n=4)
b Values calculated from the individual excretion data
Applicant's summary and conclusion
- Conclusions:
- The results of the study indicate that CRN-10-COOH is a relevant product of the human in vivo metabolism of delta-3-carene.
- Executive summary:
In a metabolism study, four healthy human volunteers were orally exposed to a single dose of 10 mg delta-3 -carene [(+)-delta-3-carene] via spiked gelatin capsules. Each volunteer gave one urine sample before administration and subsequently collected each urine sample within 24 h after administration. The concentration of the proposed CRN metabolites delta-3-caren-10-ol (CRN-10-OH), delta-3 -caren-10-carboxylic acid (chaminic acid, CRN-10-COOH), and delta-3-caren-3,4-diol (CRN-3,4-OH) were determined using a very specific and sensitive GC-MS/MS procedure. Other CRN metabolites were investigated using GC-PCI-MS Q1 scan analyses.
CRN-10-COOH was detected in each urine sample with maximum concentration (113.0-1172.9 µg/L)) 2-3 h after administration, whereas CRN-10-OH and CRN-3,4-OH were not detected in any of the samples. The renal excretion kinetics of CRN-10-COOH showed an elimination half-life of about 3 h. The cumulative excretion of CRN-10-COOH within 24 h after exposure correlated with about 2% of the applied dose. The GC-PCI-MS Q1 scan analysis indicated several additional human CRN metabolites: 3% (CRN-M1), 1% (CRN-M2), 5% (CRNM3), 4% (CRN-M4), 11% (CRN-M5), and 2% (CRNM6), respectively.
The results of the study indicate that CRN-10-COOH is a relevant product of the human in vivo metabolism of delta-3-carene.
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