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EC number: 201-126-0 | CAS number: 78-59-1
- 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:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Objective of study:
- distribution
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- The distribution of isophorone in the organism was studied after ingestion.
- GLP compliance:
- not specified
- Radiolabelling:
- yes
- Remarks:
- 14C
- Species:
- rabbit
- Strain:
- other: New Zealand
- Sex:
- female
- Route of administration:
- oral: gavage
- Vehicle:
- olive oil
- Duration and frequency of treatment / exposure:
- once
- Dose / conc.:
- 4 000 other: mg/kg bw
- No. of animals per sex per dose / concentration:
- 1
- Control animals:
- not specified
- Details on study design:
- Blood sample determination (0.5 hours after ingestion). Extraction of organs and GC analysis (identification of isophorone via Kovats index).
- Type:
- distribution
- Results:
- Distribution of isophorone in organs from high to low amounts: Stomach > ovaries > adrenal > spleen, liver > kidney, brain, heart > lung
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Objective of study:
- distribution
- Qualifier:
- no guideline required
- Principles of method if other than guideline:
- The distribution of isophorone in organism was studied after inhalation 4 hours exposure
- GLP compliance:
- not specified
- Radiolabelling:
- not specified
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Route of administration:
- inhalation
- Vehicle:
- not specified
- Duration and frequency of treatment / exposure:
- 4 hours
- Dose / conc.:
- 2 000 other: mg/kg bw
- Remarks:
- corresponding to 400 ppm
- No. of animals per sex per dose / concentration:
- 3
- Control animals:
- not specified
- Type:
- distribution
- Results:
- Distribution of isophorone in organs from high to low amounts: Kidney > Pancreas, adrenals, liver, brain
- Details on distribution in tissues:
- Rapid diffusion and distribution of isophorone through the body.
The total amount of isophorone measured in organs decreased with increasing post-exposure period. - Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Objective of study:
- distribution
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- The distribution of isophorone in the organism was studied after ingestion.
- GLP compliance:
- not specified
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Route of administration:
- oral: gavage
- Vehicle:
- other: olive oil
- Duration and frequency of treatment / exposure:
- once
- Dose / conc.:
- 1 000 other: mg/kg bw
- Dose / conc.:
- 4 000 other: mg/kg bw
- No. of animals per sex per dose / concentration:
- 3
- Control animals:
- not specified
- Details on study design:
- Blood sample determination (0.5 hours after ingestion). Extraction of organs and GC analysis (identification of isophorone via Kovats index).
- Type:
- distribution
- Results:
- 4000 mg/kg: Distribution of isophorone in organs (no differences between sex and time of death) from high to low amounts: Stomach > pancreas > adrenal > spleen > ovaries, tubes > brain, heart, lung, kidney > testes > liver.
- Type:
- distribution
- Results:
- 1000 mg/kg: Traces of isophorone in the stomach (1-5 µg/g).
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Objective of study:
- metabolism
- Qualifier:
- no guideline required
- GLP compliance:
- not specified
- Species:
- rabbit
- Strain:
- New Zealand White
- Sex:
- not specified
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Weight at study initiation: ca 2.5 kg - Route of administration:
- oral: gavage
- Vehicle:
- other: pure substance followed by ca. 20 ml water
- Duration and frequency of treatment / exposure:
- single dose
- Dose / conc.:
- 1 000 other: mg/kg bw
- No. of animals per sex per dose / concentration:
- not reported
- Control animals:
- not specified
- Details on dosing and sampling:
- Air sampling for 6 hours after dosing. Urine sampling 24 and 48 hours after dosing.
Exhaled air (only of a part of the animals, not of all): absorption on charcoal. Urine sampling for 48 hours.
ANALYSIS
Urine: enzymatic hydrolysis by beta-glucuronidase (buffered at pH 4.7, 37 ºC), extraction, gas chromatography, identification using Kovats index.
Charcoal: elution with dichloromethane, gas chromatography, identification using Kovats index. - Metabolites identified:
- yes
- Details on metabolites:
- The following substances were identified in rabbit urine, however in varying ratios:
- Unreacted isophorone.
- 3,5,5-trimethylcyclohexan-1-one (dihydroisophorone).
- 3,5,5-trimethyl-2-cyclohexen-1-ol (isophorol - main metabolite in rabbits) eliminated as glucuronide.
- 3,5,5-trimethylcyclohexan-1-ol (CAS 116-02-9), cis (933-48-2) and trans (767-54-4) isomers.
These compounds were identified only via GC and correlation to Kovats indices.
Further compounds were seen, but could not be identified.
5,5-dimethyl-2-cyclohexen-1-one-3-carboxylic acid was extracted, isolated and identifled (GC, IR) in the urine of rabbits.
Substances found in the expired air of rabbits: Uunreacted isophorone - Conclusions:
- The main metabolite of rabbits after isophorone administration was 5,5-dimethyl-2-cyclohexene-1-one-3-carboxylic acid found as glucuronide conjugate in the urine (after 48 hours).
Further detoxifications that occur in rabbits: hydrogenation of the 1-one-, the 2-ene- and both positions.
No distincion was made between alpha-isophorone, CAS-78-59-1, and beta-isophorone, CAS 471-01-2. - Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Objective of study:
- metabolism
- Qualifier:
- no guideline required
- GLP compliance:
- not specified
- Species:
- rat
- Strain:
- Wistar
- Sex:
- not specified
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Weight at study initiation: ca 250 g - Route of administration:
- oral: gavage
- Vehicle:
- olive oil
- Duration and frequency of treatment / exposure:
- single dose
- Dose / conc.:
- 1 000 other: mg/kg bw
- No. of animals per sex per dose / concentration:
- not reported
- Control animals:
- not specified
- Details on dosing and sampling:
- Air sampling for 6 hours after dosing. Urine sampling 24 and 48 hours after dosing.
Exhaled air (only of a part of the animals, not of all): absorption on charcoal. Urine sampling for 48 hours.
ANALYSIS
Urine: enzymatic hydrolysis by beta-glucuronidase (buffered at pH 4.7, 37 ºC), extraction, gas chromatography, identification using Kovats index.
Charcoal: elution with dichloromethane, gas chromatography, identification using Kovats index. - Metabolites identified:
- yes
- Details on metabolites:
- The following substances were identified in rat urine, however, in varying ratios:
- Unreacted isophorone
- 3,5,5-trimethylcyclohexan-1-one (dihydroisophorone - main metabolite in rats)
- 3,5,5-trimethyl-2-cyclohexen-1-ol (isophorol) eliminated as glucuronide
- 3,5,5-trimethylcyclohexan-1-ol (CAS 116-02-9), cis- (933-48-2) and trans- (767-54-4) isomers
These compounds were identified only via GC and correlation to Kovats indices.
Further compounds were seen, but could not be identified.
Substances found in expired air of rats: Unreacted isophorone. - Conclusions:
- The main metabolite in rats after isophorone administration is 3,5,5-trimethylcyclohexan-1-one (dihydroisophorone) in the urine (after 48 hours).
Further detoxifications that occur in rat: hydrogenation of the 1-one-position.
No distinction was made between alpha-isophorone, CAS-78-59-1, and beta-isophorone, CAS 471-01-2. - Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Objective of study:
- excretion
- GLP compliance:
- not specified
- Species:
- rat
- Strain:
- not specified
- Sex:
- male
- Route of administration:
- oral: gavage
- Dose / conc.:
- 500 other: mg/kg bw
- Details on study design:
- 500 mg/kg isophorone was administered in a single dose to male rats. Additionally, 500 mg/kg isophorone was administered to male rats for 8 consecutive days. Urine, feces and expired air were collected and the amount of radioactivity was determined.
- Details on excretion:
- 80 % of radioactivity was excreted after 96 h. 50-65 % of radioactivity was excreted via urine (single-dose and repeated-dose). Slight difference between single-dose and repeated-dose administration: single-dose treated rats excrete a slightly higher amount of isophorone via feces compared to repeated-dose treated rats.
- Conclusions:
- Isophorone is rapidly excreted - mainly via glucuronidation. No evidence of bioaccumulation in rats.
Referenceopen allclose all
MORTALITY
4000 mg/kg:
1/1 female rabbits: 1 hour after ingestion.
CONCLUSION
Rapid diffusion and distribution of isophorone through the body.
No bioaccumulation.
MORTALITY
1/3 male and 1/3 female rats: immediately.
1/3 male and 1/3 female rats: 1.5 hour after ingestion.
1/3 male and 1/3 female rats: 3 hours after ingestion.
MORTALITY
4000 mg/kg:
3/3 male rats: 1 hour after ingestion.
3/3 female rats: 1, 3, 5 hours after ingestion. 1000 mg/kg: 6/6 rats 48 hours after ingestion
CONCLUSION
Rapid diffusion and distribution of isophorone through the body.
No bioaccumulation.
Description of key information
Upon oral and inhalative administration, isophorone is well absorbed and rapidly distributed through the body of rats and rabbits. While part of the absorbed isophorone is excreted unchanged via urine and exhaled air, metabolites are mainly excreted as glucuronides. The tendency of isophorone to bioaccumulate is very low, since within 24 hours after administration more than 93% of orally administered isophorone was excreted by rats.
Key value for chemical safety assessment
- Bioaccumulation potential:
- no bioaccumulation potential
Additional information
Absorption
Isophorone is well absorbed via the oral and inhalative route (Dutertre-Catella, 1976). Already 10 minutes after oral administration of 1 g 14C isophorone/kg to 2 rabbits, remarkable isophorone concentrations in the blood (0-102 μg/ml) were detected, which started to decrease from 75 – 141 μg/ml after 30 minutes and 88 - 94 μg/ml after 1 hour down to less than 0.5 μg/ml at 21 hours post treatment (Dutertre-Catella, 1976). Good dermal absorption can be concluded from the systemic effects in the acute toxicity studies.
Distribution
In male and female rats and rabbits isophorone is rapidly distributed. One hour after a single oral administration (4 g/kg) of 14C isophorone the highest concentrations were found in the stomach, pancreas, adrenals, spleen and liver of rats and rabbits. After inhalation (400 ppm) for 4 hours, the highest concentrations were obtained in the kidney, adrenals, liver, pancreas and brain of rats immediately after the termination of inhalation (Dutertre-Catella, 1976). 48 hours after oral administration of 1 g/kg isophorone to male and female rats, only traces of isophorone could be determined in the stomach and no isophorone was measured in the other organs (Dutertre-Catella, 1976).
Metabolism
After oral application of 1 g isophorone (3,5,5-trimethyl-2-cyclohexene-1-one)/kg bw, one main metabolite in rats and rabbits is 5,5-dimethyl-1-cyclohexene-3-one-1-carboxylic acid. This metabolite is formed by oxidation of the 3-methyl group of isophorone and then glucuronidated (Dutertre-Catella et al., 1978). Further metabolites may be formed through hydrogenation at the 1-one or/and 2-ene-position or after further oxidation processes. Dihydroisophorone (3,5,5-rimethylcyclohexanone), isophorol (3,5,5-trimethyl-2-cyclohexen-1-ol) and 3,5,5-trimethylcyclohexan-1-ol (cis- and trans-isomer), 6-Oxoisophorone (3,5,5-trimethyl-2-cyclohexen-1,6-dione), 4-Oxoisophorone (3,5,5-trimethyl-2-cyclohexen-1,4-dione), 4-hydroxyisophorone (4-hydroxy-3,5,5-trimethyl-2-cyclohexen-1-one) and 6-ydroxyisophorone (6-hydroxy-3,5,5-trimethyl-2-cyclohexen-1-one) were identified via GC/Kovats indices and GC/MS (Dutertre-Catella et al., 1978). Isophorol is eliminated as glucuronide (Dutertre-Catella et al., 1978). Dihydroisophorone is mainly found in the urine of rats, while rabbits produce primarily isophorol (Dutertre-Catella et al., 1978).
There are data to suggest that the glutathione system is also involved in the metabolism of isophorone. After i.p. administration of 500 mg isophorone/kg to sexually matured rats the glutathione depletion in liver, testes and epididymis was measured. In the liver 40 % reduction of the glutathione content was determined (maximum: 4 h after application), 82 % reduction was measured in testes (maximum: 4 h after application) and 72 % in the epididymis (maximum: 8 h after application) (Gandy et al., 1990).
Excretion
After administration of 400 ppm isophorone to rats (4 h), a part of the isophorone was expired unchanged (Dutertre-Catella, 1976). Also in the urine of orally treated rabbits and rats unreacted isophorone could be isolated (Dutertre-Catella et al., 1978).
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