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EC number: 203-624-3 | CAS number: 108-87-2
- 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
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Acceptable, well documented publication which meets basic scientific principles.
Data source
Reference
- Reference Type:
- publication
- Title:
- The Metabolism of Methylcyclohexane
- Author:
- Elliot, T.H. et al.
- Year:
- 1 965
- Bibliographic source:
- Biochem J 95:70-76
Materials and methods
- Objective of study:
- distribution
- excretion
- metabolism
- Principles of method if other than guideline:
- Distribution, metabolism and excretion studies of radiolabelled methylcyclohexane in rabbits following oral administration.
- GLP compliance:
- no
Test material
- Reference substance name:
- Methylcyclohexane
- EC Number:
- 203-624-3
- EC Name:
- Methylcyclohexane
- Cas Number:
- 108-87-2
- Molecular formula:
- C7H14
- IUPAC Name:
- methylcyclohexane
- Details on test material:
- - Name of test material (as cited in study report): methylcyclohexane
- Substance type: pure substance
- Physical state: liquid
- Analytical purity: ca. 95%
- Impurities (identity and concentrations): ≤ 5% cyclohexane, < 1% toluene
- Specific activity (if radiolabelling): 238 µC/g
Constituent 1
- Radiolabelling:
- yes
- Remarks:
- 14C-methylcyclohexane
Test animals
- Species:
- rabbit
- Strain:
- Chinchilla
- Sex:
- not specified
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Individual metabolism cages: yes
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on exposure:
- Methylcyclohexane was administered with water by stomach tube. No further details on dosing solutions/mixtures were reported.
- Duration and frequency of treatment / exposure:
- Single administration
Doses / concentrations
- Remarks:
- Doses / Concentrations:
Experiment 1: 2.26 mmol/kg bw (equivalent to ca. 222 mg/kg bw)
Experiment 2: 2.10 mmol/kg bw (equivalent to ca. 206 mg/kg bw)
Experiment 3: 2.41 mmol/kg bw (equivalent to ca. 237 mg/kg bw)
- No. of animals per sex per dose / concentration:
- 1 rabbit per experiment
- Control animals:
- no
- Details on dosing and sampling:
- PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, expired air and other tissues not further specified
- Time and frequency of sampling: according to the authors, urine was continuously collected for about 58-68 h after dosing until it was found to contain negligible radioactivity. Faeces and expired air were collected in the animal chamber during the same period of time.
METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine
- Time and frequency of sampling: according to the authors, urine was continuously collected for about 58-68 h after dosing until it was found to contain negligible radioactivity.
- From how many animals: 3 animals (samples not pooled)
- Method type(s) for identification: end window counter, paper chromatography and autoradiography
TREATMENT FOR CLEAVAGE OF CONJUGATES (if applicable): Glucuronides were hydrolysed by treatment with HCl.
Results and discussion
- Preliminary studies:
- After the administration of methylcyclohexane (432 mg/kg bw) to rabbits, 42% of the dose was excreted as glucuronides and 2% as ethereal sulphate, but there was no increase in mercapturic acid excretion.
Urine after the administration of the hydro carbon had pH 8 and gave an intense naphtharesorcinol reaction. It did not reduce Benedict's solution or give a precipitate with Brady's reagent, and there was no blue colour with 2,6-dichloro-quinonechloroimide in sodium hydrogen carbonate solution or a red colour with ferric chloride, these tests showing the absence of ketones and phenols. From the same urine, methyl (trans-4-methyl-cyclohexyl tri-O-acetyl-β-D-glucosid)uronate was isolated and characterised both by comparison with an authentic specimen and by identification of the hydrolysis products.
Paper chromatography of the fresh urine revealed only one glucuronide spot, whose RF values (0.27 in solvent A and 0.79 in solvent B) were identical with those of trans-4-methylcyclohexyl glucuronide. However, since isomeric 2-, 3- and 4-methyl-cyclohexyl glucuronide have virtually identical RF values, the presence of these other glucuronides could not be excluded. The absence of any significant amount of 1-methylcyclohexyl glucuronide could nevertheless be established (Elliott et al., 1965, Biochem J 95:59 pp.).
The radioautographs revealed the presence of six radioactive spots, only one of which was intense, and this was the only spot (RF 0.57 in solvent I and 0.72 in solvent II) that gave a positive reaction for glucuronides. None of the spots reacted with ninhydrin, indicating that amino acids that might have been formed by transamination were absent. The spray for carboxylic acids gave a positive reaction with two spots, one of which corresponded to the glucuronide metabolite and the other (RF 0.84 in both solvent systems) to hippuric acid. However, the presence of the small amount of free benzoic acid and the possibility of the presence of traces of 1-methylcyclohexanol and cyclohexylmethanol could not be demonstrated conclusively by this method.
Main ADME resultsopen allclose all
- Type:
- absorption
- Results:
- 64.7 - 93.2% of dose (mean: 82.4%), calculated from radioactivity distribution in tissues, urine and expired CO2 and methylcyclohexane
- Type:
- distribution
- Results:
- tissues (not further specified): 2.8 - 5.9% of dose (mean: 4.2%)
- Type:
- metabolism
- Results:
- Major metabolites: glucuronide conjugates of trans-4-methylcyclohexanol (11.6 - 19.4% of dose; mean: 14.7%), cis-3-methylcyclohexanol (8.9 - 15% of dose; mean: 11.5%), and trans-3-methylcyclohexanol (8.5 - 11.9% of dose; mean: 10.5%)
- Type:
- excretion
- Results:
- Urine: 54.2 - 77.4% of dose (mean: 65.4%); faeces: 0.4 - 0.7% of dose (mean: 0.53%); expired as CO2: 3.3 - 8.6% of dose (mean: 5.6%); expired as methylcyclohexane: 1.3 - 15.9% of dose (mean: 7.2%)
Toxicokinetic / pharmacokinetic studies
- Details on absorption:
- Calculated from the reported radioactivity distribution found in tissues, urine and expired CO2 and methylcyclohexane, approx. 64.7, 89.2 and 93.2% methylcyclohexane was absorbed following administration of 222, 206 and 237 mg/kg bw, respectively, most of which was further metabolised within ca. 58-68 h post-dose. The authors noted that the lower overall radioactivity value in the first animal (222 mg/kg bw) was due to an incomplete recovery of radioactivity from the expired air.
- Details on distribution in tissues:
- About 58-68 h after oral administration of 222, 206 and 237 mg methylcyclohexane/kg bw, 5.9, 3.8 and 2.8% of the radioactivity was respectively recovered in the tissues. No further details on individual organs were reported.
- Details on excretion:
- About 58-68 h after administration of 222, 206 and 237 mg methylcyclohexane/kg bw, 54.2, 64.5 and 77.4% of the respective dose was excreted in the urine; 4.6, 20.9 and 13.0% was excreted in the expired air (3.3, 5.0 and 8.6% as CO2 and 1.3, 15.9 and 4.4% as parent compound, respectively), and 0.5, 0.4 and 0.7% in the faeces, respectively. The authors pointed out that the recovery of radioactivity from the expired air was incomplete in the first experiment (animal given 222 mg/kg bw).
Metabolite characterisation studies
- Metabolites identified:
- yes
- Details on metabolites:
- The major metabolites found in the urine were the glucuronide conjugates of trans-4-methylcyclohexanol (11.6-19.4% of the dose), cis-3-methylcyclohexanol (8.9-15%), and trans-3-methyl-cyclohexanol (8.5-11.9%). Minor metabolites included glucuronides of cis-4-methylcyclohexanol (2.0-2.8%) and of cis- and trans-2-methyl-cyclohexanol (0.3-0.7% and 1.1-1.2%, respectively). No 1-methylcyclohexanol was found. Small amounts of cyclohexylmethanol (≤ 0.3%) and free and conjugated benzoic acid (1.6-2.2%; about 0.5 and 1.5% being free benzoic and hippuric acid, respectively) suggested some minor aromatisation of the cyclohexane ring via hydroxylation and carboxylation of the methyl group.
Any other information on results incl. tables
Table 1. Distribution of 14C after a single dose of 14C-methylcyclohexane in rabbits.
|
Experiment 1 |
Experiment 2 |
Experiment 3 |
Mean values |
Dose (mg/kg bw) |
222 |
206 |
237 |
222 |
Radioactivity found (% of dose) in: |
||||
Expired air as CO2 |
3.3 |
5.0 |
8.6 |
5.6 |
Expired air as methylcyclohexane |
1.3 |
15.9 |
4.4 |
7.2 |
Tissues |
5.9 |
3.8 |
2.8 |
4.2 |
Faeces |
0.5 |
0.4 |
0.7 |
0.5 |
Urine |
54.2 |
64.5 |
77.4 |
65.4 |
Total radioactivity accounted for: |
65.2* |
89.6 |
93.9 |
82.9 |
* The low value was due to incomplete recovery of radioactivity from the expired air.
Table 2. Metabolites of 14C-methylcyclohexane in the urine of rabbits after hydrolysis.
|
Experiment 1 |
Experiment 2 |
Experiment 3 |
Mean values |
Dose (mg/kg bw) |
222 |
206 |
237 |
222 |
Duration of experiment (h) |
60 |
58 |
68 |
62 |
Radioactivity found (% of dose) in metabolite sought: |
||||
1-Methylcyclohexanol |
- |
- |
- |
- |
(±)-cis-2-Methylcyclohexanol |
0.3 |
0.5 |
0.7 |
0.5 |
(±)-trans-2-Methylcyclohexanol |
1.1 |
1.2 |
1.2 |
1.2 |
(±)-cis-3-Methylcyclohexanol |
8.9 |
10.5 |
15.0 |
11.5 |
(±)-trans-3-Methylcyclohexanol |
8.5 |
11.1 |
11.9 |
10.5 |
cis-4-Methylcyclohexanol |
2.8 |
2.4 |
2.0 |
2.4 |
trans-4-Methylcyclohexanol |
13.1 |
11.6 |
19.4 |
14.7 |
Cyclohexylmethanol |
< 0.2 |
0.3 |
< 0.3 |
≤ 0.3 |
(±)-2-Methylcyclohexanone* |
0 |
0 |
0 |
0 |
(±)-3-Methylcyclohexanone* |
0 |
0 |
0 |
0 |
4-Methylcyclohexanone* |
0 |
0 |
0 |
0 |
Cyclohexanecarboxylic acid |
0 |
0 |
0 |
0 |
Total benzoic acid |
1.6 |
1.8 |
2.2 |
1.9 |
Cyclohexanol** |
2.4 |
2.6 |
- |
2.5 |
Sum of radioactivities of metabolites sought in the urine |
39.1 |
42.0 |
52.7 |
44.6 |
Total radioactivity in urine |
54.2 |
64.5 |
77.4 |
65.4 |
* The hydrolysis procedure was omitted.
** Cyclohexanol is derived from cyclohexane contained in the 14C-methylcyclohexane sample.
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results (migrated information): no bioaccumulation potential based on study results
In this study, the kinetics of 14C-labelled methylcyclohexane was investigated in rabbits given single oral doses of approx. 206-237 mg/kg bw. About 58-68 h after administration, 65.4% of the dose was excreted in the urine, 12.8% in expired air (5.6% as CO2, 7.2% as methylcyclohexane), 0.5% in the faeces; 4.2% remained in the carcass. In a separate experiment, 42 and 2% of the dose were found to be excreted as glucuronide and sulphate conjugates, respectively, in rabbits given ca. 432 mg/kg bw.
The major metabolites found in the urine were the glucuronide conjugates of trans-4-methylcyclohexanol (14.7% of the dose), cis-3-methylcyclohexanol (11.5%), and trans-3-methyl-cyclohexanol (10.5%). Minor metabolites included glucuronides of cis-4-methylcyclohexanol (2.4%) and of cis- and trans-2-methyl-cyclohexanol (0.5% and 1.2%, respectively). No 1-methylcyclohexanol was found. Small amounts of cyclohexylmethanol (≤ 0.3%) and free and conjugated benzoic acid (1.9%; about 0.5 and 1.5% being free benzoic and hippuric acid, respectively) suggested some minor aromatisation of the cyclohexane ring via hydroxylation and carboxylation of the methyl group.
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