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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
Description of key information
In subchronic toxicity studies, oral administration of isophorone caused no significant toxic effects. At high doses (>= 1000 mg/kg bw/d), mortality was observed.
NOAEL (rat, 90 days) = 102.5 mg/kg bw/day;
NOAEL (rat and mouse, 13 weeks) = 500 mg/kg bw/day;
NOAEL (dog, 90 days) = 150 mg/kg bw/day (highest tested dose)
After inhalational administration nose and eye irritation and blood and liver changes were observed (NOAEL (rat, 28 days) < 250 mg/m³).
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: oral
- 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
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- Male and female CFE rats were orally treated with three different doses of the test substance administered via their diet daily for a period of 90 days.
- GLP compliance:
- no
- Limit test:
- no
- Species:
- rat
- Strain:
- other: CFE
- Sex:
- male/female
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 90 days
- Frequency of treatment:
- daily
- Dose / conc.:
- 750 ppm
- Remarks:
- corresponds to 57 mg/kg bw/d in males and 78.9 mg/kg bw/d in females
- Dose / conc.:
- 1 500 ppm
- Remarks:
- corresponds to 102.5 mg/kg bw/d in males and 163.8 mg/kg bw/d in females
- Dose / conc.:
- 3 000 ppm
- Remarks:
- corresponds to 233.8 mg/kg bw/d in males and 311.8 mg/kg bw/d in females
- No. of animals per sex per dose:
- 20
After 4 weeks, 5 animals per sex and dose group were killed for blood analysis. - Control animals:
- yes, concurrent no treatment
- Details on study design:
- Post-exposure period: none
- Observations and examinations performed and frequency:
- Clinical signs: daily
Mortality: daily
Body weight: weekly
Food consumption: weekly
Water consumption: weekly
Ophthalmoscopic examination: no
Hematology: after 4 weeks and at the end of the study: determination of hemoglobin, hematocrit, erythrocyte counts, leukocyte counts, and differential leukocyte determinations
Biochemistry: after 4 weeks and at the end of the study: blood glucose, blood urea nitrogen, serum glutamic oxaloacetic transaminase, serum alkaline phosphatase, total serum protein, total serum bilirubin, serum albumin, lactic acid dehydrogenase, cholesterol, calcium, phosphate, and uric acid
Urinalysis: after 4 weeks and at the end of the study: pH, glucose, ketones, albumin, occult blood, microscopic examination of sediment - Sacrifice and pathology:
- ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC)
Organ weights: Organ-body weight ratios: heart, liver, kidney, adrenals, thyroid, brain, testes
Macroscopic: After 4 weeks and at study termination: lungs, heart, intestines, kidneys, spleen, liver, urinary bladder
Weights: Heart, liver, kidney, adrenals, thyroid, brain, testes (males) for 10 males and 10 females of each dose level
Microscopic: At study termination: 5 males and 5 females each from high dose and control groups: brain, pituitary, eye, thyroid, lung, heart, liver, kidney, adrenals, urinary bladder, mediastinal lymph node, pancreas, spleen, colon, bone marrow, skeletal muscle, testes and prostate (male), ovary and uterus (female). 5 males and 5 females each from medium and low dose groups: liver, kidney. - Statistics:
- All data were evaluated statistically.
- Clinical signs:
- no effects observed
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- 1 male (control group), 1 female (3000 ppm): deaths were due to intercurrent infection
- Description (incidence and severity):
- - 3000 ppm, males: significantly reduced body weight gain (P < 0.01); further observed changes returned to normal in the subsequent weeks
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Description (incidence and severity):
- - kidney, testes, males: slightly increased mean organ to body weight ratio (considered not compound-related by the authors; not statistically significant)
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Dose descriptor:
- NOAEL
- Remarks:
- corresponding to 311.8 mg/kg bw/d
- Effect level:
- 3 000 ppm
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: no adverse effects up to and including the highest tested dose
- Dose descriptor:
- NOAEL
- Remarks:
- corresponding to 102.5 mg/kg bw/d
- Effect level:
- 1 500 ppm
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: reduced body weight gain
- Critical effects observed:
- no
- Endpoint:
- sub-chronic toxicity: oral
- 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
- Remarks:
- Restrictions: no organ weight determination, no clinical biochemistry
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- The test substance was administered at doses of 0- 1000 mg/kg body weight per day by gavage in corn oil to groups of 10 F344/N rats of each sex, 5 days/week, for 13 weeks.
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Harlan Industries, Indianapolis IN
- Age at study initiation: 6 - 8 weeks
- Weight at study initiation: not specified
- Fasting period before study: not specified
- Housing: 5 animals per cage
- Diet, ad libitum: Purina Rat Chow, Ralston Purina, St. Louis, MO
- Water, ad libitum: not further specified
- Acclimation period: 15 - 18 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 27°C, average 23°C
- Humidity (%): 29 - 74%, average 56%
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on oral exposure:
- - Total volume applied: 1 mL/animal
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 13 weeks (91 days)
- Frequency of treatment:
- 5 days/week
- Dose / conc.:
- 62.5 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 125 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 250 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 500 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Post-exposure period: none
- Observations and examinations performed and frequency:
- CLINICAL OBSERVATIONS AND FREQUENCY
Clinical signs: weekly
Mortality: not specified
Body weight: weekly
Hematology: no
Urinalysis: no
Biochemistry: no - Sacrifice and pathology:
- ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC)
Organ weight: no
Macroscopic: tissues were examined for gross lesions and masses
Microscopic: Skin, mammary gland, sciatic nerve, salivary gland, mandibular lymph node, thymus, heart, lungs, trachea, thyroid gland, parathyroids, esophagus, stomach, duodenum, jejunum, ileum, colon, rectum, mesenteric lymph node, pancreas, spleen, liver, kidneys, adrenal glands, urinary bladder, seminal vesicles, prostate/testes or ovaries/uterus, brain, pituitary gland, bone marrow, spinal cord, and nasal cavity. - Statistics:
- Survival, body weight, dose-related effects were statistically evaluated
- Clinical signs:
- not specified
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- 1 female at 1000 mg/kg bw/d
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Dose descriptor:
- NOAEL
- Effect level:
- 500 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- mortality
- Critical effects observed:
- not specified
- Endpoint:
- sub-chronic toxicity: oral
- 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
- Remarks:
- Restrictions: no organ weight determination, no clinical biochemistry
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- The test substance was administered at doses of 0- 1000 mg/kg body weight per day by gavage in corn oil to groups of 10 B6C3F1 mice of each sex, 5 days/week, for 13 weeks.
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- mouse
- Strain:
- B6C3F1
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Harlan Industries, Indianapolis IN
- Age at study initiation: 6 - 8 weeks
- Weight at study initiation: not specified
- Fasting period before study: not specified
- Housing: 5 animals per cage
- Diet, ad libitum: Purina Rat Chow, Ralston Purina, St. Louis, MO
- Water, ad libitum: not further specified
- Acclimation period: 15 - 18 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 27°C, average 23°C
- Humidity (%): 29 - 74%, average 56%
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on oral exposure:
- - Total volume applied: 0.5 mL/animal
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 13 weeks (91 days)
- Frequency of treatment:
- 5 days/week
- Dose / conc.:
- 62.5 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 125 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 250 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 500 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Post-exposure period: none
- Observations and examinations performed and frequency:
- CLINICAL OBSERVATIONS AND FREQUENCY
Clinical signs: weekly
Mortality: not specified
Body weight: weekly
Hematology: no
Urinalysis: no
Biochemistry: no - Sacrifice and pathology:
- ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC)
Organ weight: no
Macroscopic: tissues were examined for gross lesions and masses
Microscopic: Skin, mammary gland, sciatic nerve, salivary gland, mandibular lymph node, thymus, heart, lungs, trachea, thyroid gland, parathyroids, esophagus, stomach, duodenum, jejunum, ileum, colon, rectum, mesenteric lymph node, pancreas, spleen, liver, gallbladder, kidneys, adrenal glands, urinary bladder, seminal vesicles, prostate/testes or ovaries/uterus, brain, pituitary gland, bone marrow, spinal cord, and nasal cavity. - Statistics:
- Survival, body weight, dose-related effects were statistically evaluated.
- Clinical signs:
- not specified
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- 3 of ten 1000 mg/kg dose females and 1 of ten 1000 mg/kg dose males died before the end of the studies.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Body weights of males in the 250, 500 and 1000 mg/kg groups were approximately 10% less than those of controls.
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Dose descriptor:
- NOAEL
- Effect level:
- 500 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- mortality
- Critical effects observed:
- not specified
Referenceopen allclose all
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 102.5 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
Repeated dose toxicity: inhalation - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: inhalation
- 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
- Remarks:
- Restriction: one dose only
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- Four groups of male and female albino rats (10 per sex and dose) were exposed to the test substance (as vapour) in filtered room air at a concentration of 0.25 mg/L air for 6h per day, on 5 days per week, for a duration of 4 weeks. The animals were observed at frequent intervals for signs of irritation. At the end of the 4-week study period, hematological dererminations were carried out in 5 animals per sex per group. Terminal body weights were recorded and the animals were necropsied. Lung, liver, kidneys, adrenal and spleen were examined histopathologically in 3 animals per sex per dose.
- GLP compliance:
- no
- Limit test:
- yes
- Species:
- rat
- Strain:
- other: Charles River Caesarian-derived albino rats
- Sex:
- male/female
- Route of administration:
- inhalation
- Type of inhalation exposure:
- not specified
- Details on inhalation exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 1000 L stainless steel and glass exposure chambers
- Method of holding animals in test chamber: not specified
- Source and rate of air: Air flow through the chamber was maintained by a positive pressure rotary pump located at the exhaust side of the chamber.
- Method of conditioning air: not specified
- System of generating particulates/aerosols: The vapours were generated by metering the liquid into a positive pressure spray nozzle with a Harvard infusion pump. The resultant aerosol was introduced into a large, triple necked distilling flask. A heating mantle was used to maintain the flask at a temperature adequate to vaporize the entering aerosol.
- Temperature, humidity, pressure in air chamber: not specified
- Air flow rate: The air flow rate was monitored by a rotameter
- Air change rate: not specified
- Treatment of exhaust air: not specified
TEST ATMOSPHERE
- Brief description of analytical method used: The analytical concentration of the chamber was determined daily by analysis of samples with a Beckman BD spectrometer. Each sample was obtained by drawing a known volume of the chamber atmosphere through a scrubber containing methanol as absorbent. The concentration of test material in each sample was ascertained from a standard curve which was prepared by plotting known concentrations of standard solution against percent transmission of the solutions. The concentration of the experimental atmosphere was calculated from the volume of chamber atmosphere which had been passed through the scrubber and the total liquid volume of the sample.
- Samples taken from breathing zone: not specified
VEHICLE (if applicable)
- filtered room air - Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- 28 d
- Frequency of treatment:
- 6 hours/day; 5 days/week
- Dose / conc.:
- 0.25 mg/L air (nominal)
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- Post-exposure period: none
- Observations and examinations performed and frequency:
- - Clinical signs: at frequent intervals
- Mortality: at frequent intervals
- Body weight: at study initiation and termination
- Haematology: at study initiation and termination, identical 50 % of animals of each group - Sacrifice and pathology:
- ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC):
- Macroscopic: brain, pituitary, trachea, thyroid, parathyroid, lungs, heart, liver, spleen, stomach, small intestine, large intestine, adrenals, kidneys, urinary bladder, gonads, femur
- organ weights: lungs, liver, kidneys, adrenal, spleen
- Microscopic: lungs, liver, kidneys, adrenal, spleen for three males and three females of each group - Statistics:
- performed on body and organ weights
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Slight nasal bleeding on day 3, reddish-brown discoloration of the fur surrounding the nasal regions on days 6 through 8
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Body weight only of male rats was significantly reduced compared to control.
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Differential blood count: increase of the percentage of lymphocytes (pre-exposure: 81.6 and 80.2 % among males and females, respectively; post-exposure: 84.6 and 86.0 %, respectively), decrease in the percentage of segmented neutrophiles (pre-exposure: 17.4 and 18.2 % among males and females, respectively; post-exposure: 14.6 and 13.3 %, respectively).
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Absolute and relative liver weight only of male rats were significantly reduced compared to control.
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Dose descriptor:
- NOAEL
- Remarks on result:
- not determinable
- Remarks:
- no NOAEL identified
- Critical effects observed:
- not specified
- Endpoint:
- chronic toxicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- test procedure in accordance with national standard methods with acceptable restrictions
- Remarks:
- Restrictions: insufficient documentation, one dose only
- Principles of method if other than guideline:
- The method followed is not described in the OECD SIDS Initial Assessment Report
- GLP compliance:
- not specified
- Limit test:
- yes
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Weight at study initiation: approximately 200 g - Route of administration:
- inhalation
- Type of inhalation exposure:
- not specified
- Vehicle:
- air
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 18 months
- Frequency of treatment:
- 6 hours/day; 5 days/week
- Dose / conc.:
- 250 ppm
- Remarks:
- corresponds to 1.436 mg/L air
- No. of animals per sex per dose:
- 10
The report suggests that two identical groups of males and two groups of females were exposed in addition to the unexposed control groups, corresponding to a total of six groups. As the presentation of results does not refer to absolute numbers of animals but only to percentages of total animals, their misinterpretation can be excluded. - Control animals:
- yes, concurrent vehicle
- Details on study design:
- Post-exposure period: none
- Observations and examinations performed and frequency:
- Mortality and signs of irritation: daily
Body weight: weekly
Hematology: monthly during first 10 months
Urinanalysis: weekly - Sacrifice and pathology:
- Macroscopic and microscopic examination.
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Signs of irritation: Slight irritation of conjunctiva, no opacity of cornea, by end of third week bloody exsudate from nose indicating irritation of mucosa
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- 40 % each of males and females, controls as well as exposed, died; time not reported
- Body weight and weight changes:
- no effects observed
- Haematological findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Description (incidence and severity):
- More or less pronounced hemorrhages of the lungs were observed in exposed and control animals likewise. Discoloration of the livers was also observed in the control group independent on exposure. The other organs inspected appeared normal.
- Description (incidence and severity):
- Lesions in lungs were found in both exposed and control animals. Microvacuolisation in livers was more pronounced in exposed animals than in controls. The other organs were normal, or changes were considered to be insignificant.
- Dose descriptor:
- NOAEL
- Remarks on result:
- not determinable
- Remarks:
- no NOAEL identified
- Critical effects observed:
- not specified
Referenceopen allclose all
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- LOAEC
- 250 mg/m³
- Study duration:
- subacute
- Experimental exposure time per week (hours/week):
- 30
- Species:
- rat
Repeated dose toxicity: inhalation - local effects
Link to relevant study records
- Endpoint:
- chronic toxicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- test procedure in accordance with national standard methods with acceptable restrictions
- Remarks:
- Restrictions: insufficient documentation, one dose only
- Principles of method if other than guideline:
- The method followed is not described in the OECD SIDS Initial Assessment Report
- GLP compliance:
- not specified
- Limit test:
- yes
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Weight at study initiation: approximately 200 g - Route of administration:
- inhalation
- Type of inhalation exposure:
- not specified
- Vehicle:
- air
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 18 months
- Frequency of treatment:
- 6 hours/day; 5 days/week
- Dose / conc.:
- 250 ppm
- Remarks:
- corresponds to 1.436 mg/L air
- No. of animals per sex per dose:
- 10
The report suggests that two identical groups of males and two groups of females were exposed in addition to the unexposed control groups, corresponding to a total of six groups. As the presentation of results does not refer to absolute numbers of animals but only to percentages of total animals, their misinterpretation can be excluded. - Control animals:
- yes, concurrent vehicle
- Details on study design:
- Post-exposure period: none
- Observations and examinations performed and frequency:
- Mortality and signs of irritation: daily
Body weight: weekly
Hematology: monthly during first 10 months
Urinanalysis: weekly - Sacrifice and pathology:
- Macroscopic and microscopic examination.
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Signs of irritation: Slight irritation of conjunctiva, no opacity of cornea, by end of third week bloody exsudate from nose indicating irritation of mucosa
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- 40 % each of males and females, controls as well as exposed, died; time not reported
- Body weight and weight changes:
- no effects observed
- Haematological findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Description (incidence and severity):
- More or less pronounced hemorrhages of the lungs were observed in exposed and control animals likewise. Discoloration of the livers was also observed in the control group independent on exposure. The other organs inspected appeared normal.
- Description (incidence and severity):
- Lesions in lungs were found in both exposed and control animals. Microvacuolisation in livers was more pronounced in exposed animals than in controls. The other organs were normal, or changes were considered to be insignificant.
- Dose descriptor:
- NOAEL
- Remarks on result:
- not determinable
- Remarks:
- no NOAEL identified
- Critical effects observed:
- not specified
- Endpoint:
- short-term repeated dose toxicity: inhalation
- 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
- Remarks:
- Restriction: one dose only
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- Four groups of male and female albino rats (10 per sex and dose) were exposed to the test substance (as vapour) in filtered room air at a concentration of 0.25 mg/L air for 6h per day, on 5 days per week, for a duration of 4 weeks. The animals were observed at frequent intervals for signs of irritation. At the end of the 4-week study period, hematological dererminations were carried out in 5 animals per sex per group. Terminal body weights were recorded and the animals were necropsied. Lung, liver, kidneys, adrenal and spleen were examined histopathologically in 3 animals per sex per dose.
- GLP compliance:
- no
- Limit test:
- yes
- Species:
- rat
- Strain:
- other: Charles River Caesarian-derived albino rats
- Sex:
- male/female
- Route of administration:
- inhalation
- Type of inhalation exposure:
- not specified
- Details on inhalation exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 1000 L stainless steel and glass exposure chambers
- Method of holding animals in test chamber: not specified
- Source and rate of air: Air flow through the chamber was maintained by a positive pressure rotary pump located at the exhaust side of the chamber.
- Method of conditioning air: not specified
- System of generating particulates/aerosols: The vapours were generated by metering the liquid into a positive pressure spray nozzle with a Harvard infusion pump. The resultant aerosol was introduced into a large, triple necked distilling flask. A heating mantle was used to maintain the flask at a temperature adequate to vaporize the entering aerosol.
- Temperature, humidity, pressure in air chamber: not specified
- Air flow rate: The air flow rate was monitored by a rotameter
- Air change rate: not specified
- Treatment of exhaust air: not specified
TEST ATMOSPHERE
- Brief description of analytical method used: The analytical concentration of the chamber was determined daily by analysis of samples with a Beckman BD spectrometer. Each sample was obtained by drawing a known volume of the chamber atmosphere through a scrubber containing methanol as absorbent. The concentration of test material in each sample was ascertained from a standard curve which was prepared by plotting known concentrations of standard solution against percent transmission of the solutions. The concentration of the experimental atmosphere was calculated from the volume of chamber atmosphere which had been passed through the scrubber and the total liquid volume of the sample.
- Samples taken from breathing zone: not specified
VEHICLE (if applicable)
- filtered room air - Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- 28 d
- Frequency of treatment:
- 6 hours/day; 5 days/week
- Dose / conc.:
- 0.25 mg/L air (nominal)
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- Post-exposure period: none
- Observations and examinations performed and frequency:
- - Clinical signs: at frequent intervals
- Mortality: at frequent intervals
- Body weight: at study initiation and termination
- Haematology: at study initiation and termination, identical 50 % of animals of each group - Sacrifice and pathology:
- ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC):
- Macroscopic: brain, pituitary, trachea, thyroid, parathyroid, lungs, heart, liver, spleen, stomach, small intestine, large intestine, adrenals, kidneys, urinary bladder, gonads, femur
- organ weights: lungs, liver, kidneys, adrenal, spleen
- Microscopic: lungs, liver, kidneys, adrenal, spleen for three males and three females of each group - Statistics:
- performed on body and organ weights
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Slight nasal bleeding on day 3, reddish-brown discoloration of the fur surrounding the nasal regions on days 6 through 8
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Body weight only of male rats was significantly reduced compared to control.
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Differential blood count: increase of the percentage of lymphocytes (pre-exposure: 81.6 and 80.2 % among males and females, respectively; post-exposure: 84.6 and 86.0 %, respectively), decrease in the percentage of segmented neutrophiles (pre-exposure: 17.4 and 18.2 % among males and females, respectively; post-exposure: 14.6 and 13.3 %, respectively).
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Absolute and relative liver weight only of male rats were significantly reduced compared to control.
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Dose descriptor:
- NOAEL
- Remarks on result:
- not determinable
- Remarks:
- no NOAEL identified
- Critical effects observed:
- not specified
Referenceopen allclose all
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- LOAEC
- 250 mg/m³
- Study duration:
- subacute
- Species:
- rat
Repeated dose toxicity: dermal - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
Oral
Male and female Fischer rats were administered 0, 125, 250, 500, 1000 and 2000 mg isophorone/kg bw/day in a 16 day and 0, 62.5, 125, 250, 500 and 1000 mg/kg bw/day in a 13 week investigation, the former being a dose finding study for the latter.
In the dose finding study, one of five males and four of five females that received 2000 mg/kg bw/day isophorone died.
In the 13-week study, one of ten females of the tope dose group died. The NOAEL is therefore 500 mg isophorone/kg bw/day for male and female rats (Bucher, 1986).
In a 90-day study with male and female CFE rats dosed with 750, 1000, or 3000 ppm isophorone via diet – corresponding to 57.0, 102.5, 233.8 mg/kg bw/day for males and to 73.9, 163.8 and 311.8 mg/kg bw/day for females – for 13 weeks, the only observed effect was a reduced body weight gain (-12 to -13%) in male rats at 3000 ppm (during weeks 6,7,8,9,10 and 11). The NOAEL derived from this study is 102.5 mg/kg bw/day for male and 311.8 mg/kg bw/day for female rats. (Rohm & Haas, 1972)
After administration of isophorone up to 2000 mg/kg bw/day to male and female B6C3F1 mice for 16 days, the reported effect was mortality at 2000 mg/kg.
In the 13 week study with dosages up to 1000 mg/kg bw/day, 3 of 10 females that received the top dose died. Body weights of males in the 250, 500 and 1000 mg/kg groups were approximately 10% less than those of controls. The NOAEL is 500 mg isophorone/kg bw/day. (Bucher, 1986)
In a further 90-day study (Rohm & Haas, 1972), beagle dogs (4 animals/dose/sex) were given orally gelatine capsules containing doses of 35, 75, or 150 mg isophorone per kg bodyweight. As the only minor clinical signs, incidences of soft stool were noted in the two upper dose levels.
Therefore, the NOAEL is 150 mg/kg bw/day for male and female beagle dogs.
Inhalation
Studies are available for rats, mice, rabbits, and guinea pigs.
In rats exposed for 4 weeks to 250 mg/m³ isophorone reduced body weights in males, changes in haematological parameters and reduced liver weights in males and females were found (Exxon, 1968).
In a study with 6 weeks duration, at doses ≥ 287 mg/m³ congested kidneys, dilated Bowman’s capsules and lung changes (irritation, congestion) were found in rats and in guinea pigs (Smyth et al., 1942). Further findings observed in this study were blood cell changes, albuminuria at doses and eye and nasal irritations at 2874 mg/m³. Eye and nose irritations have also been observed in a more recent study in Wistar rats and rabbits at 1436 mg/m³ after 18 months exposure. In addition at this concentration slightly increased microvacuolization of the livers was observed (Dutertre-Catella, 1976).
No effects were found in histopathological examinations of the respiratory tract of Swiss mice after exposure to 164 and 513 mg/m³ for up to 14 days (Zissu, 1995).
Justification for classification or non-classification
The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. Based on the available oral and inhalation repeated dose toxicity studies the substance is not considered to be classified for repeated dose toxicity under Regulation (EC) No. 1272/2008, as amended for the 14th time in Regulation (EU) 2020/217.
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