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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
Carcinogenicity
Administrative data
Description of key information
There was some evidence of carcinogenicity of the test substance in male rats (kidney tumors, preputial gland carcinomas). The kidney tumors can be attributed to an α2u-globulin associated mechanism. The observed nephropathy in male rats is therefore irrelevant to other species. As the preputium is only investigated histopathologically when gross lesions are found, neither true tumor incidences from this study nor from historical controls are available. Therefore, the higher incidence of preputial gland tumors in high dose male rats cannot be put into perspective. There was equivocal evidence of carcinogenicity for male mice (liver tumors, mesenchymal tumors of the integumentary system). There was no evidence of carcinogenicity of the test substance in female rats and mice.
Key value for chemical safety assessment
Carcinogenicity: via oral route
Link to relevant study records
- Endpoint:
- carcinogenicity: 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 to male and female F344/N rats by gavage in corn oil 5 days/week for 103 weeks. Body weights and clinical signs were recorded weekly during the first 13 weeks and then monthly. Animals were killed with carbon dioxide. Necropsies were performed on all animals, and tissues were examined for gross lesions and masses. Tissues were preserved in 10% neutral buffered formalin, embedded in paraffin, sectioned, stained with hematoxylin and eosin, and examined for non-neoplastic and neoplastic lesions.
- GLP compliance:
- no
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratories, Portage MI
- 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: NIH-07 pellets, Zeigler Brothers, Gardners PA
- 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 exposure:
- Dosing volume: 5 mL/kg bw
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 103 weeks
- Frequency of treatment:
- 5 days/week
- Post exposure period:
- none
- Dose / conc.:
- 250 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 500 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 50
- Control animals:
- yes, concurrent vehicle
- Observations and examinations performed and frequency:
- CLINICAL OBSERVATIONS AND FREQUENCY
Clinical signs: weekly during the first 13 weeks and then monthly
Mortality: not specified
Body weight: weekly during the first 13 weeks and then monthly
Hematology: no
Urinalysis: no
Biochemistry: no - Sacrifice and pathology:
- ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC):
- Macroscopic: tissues were examined for gross lesions and masses
- Microscopic: gross lesions and tissue masses, skin, mammary gland, thymus, heart, lungs and bronchi, trachea, thyroid gland, parathyroids, esophagus, stomach, colon, small intestines, mesenteric lymph node, pancreas, spleen, liver, kidneys, adrenal glands, urinary bladder, prostate/testes or ovaries/uterus, brain, pituitary gland, eyes (if grossly abnormal), thoracic vertebrae, including bone marrow and spinal cord - Statistics:
- - mortalities: life table analysis
- tumor incidence: life table analysis, incidental tumor test - Clinical signs:
- no effects observed
- Description (incidence and severity):
- No compound-related clinical signs were observed.
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- Animals killed at termination
Males: 33 (control) / 33 (250 mg/kg) / 14 (500 mg/kg)
Females: 30 (control) / 23 (250 mg/kg) / 20 (500 mg/kg)
Non-accidental deaths:
Males: 13 (control) / 12 (250 mg/kg) / 30 (500 mg/kg)
Females: 19 (control) / 21 (250 mg/kg) / 16 (500 mg/kg)
500 mg/kg bw, m: increased mortality (after week 98)
Gavage-related trauma accounted for all accidental deaths.
The adjusted survival curves (accidental deaths censored) suggest that the test substance was associated with early deaths of several high dose male and female rats, and with a steep decline in survival of high dose male rats after about week 90. - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Body weights of high dose male rats averaged 5% less than controls, and body weights of female rats averaged 8% less than controls during the second year of the studies.
- 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:
- not specified
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Kidneys:
- Mineralization, primarily in the medullary collecting ducts, was increased in dosed male rats, and decreased in dosed female rats.
- The incidence of nephropathy was increased in dosed female rats.
These effects were not pronounced, however, and there was no evidence of renal injury in the prechronic studies, in which higher doses were given than in the 2-year study.
Adrenal cortex, m:
- fatty metamorphosis (7/50, 21/50, 26/50) (lesions in which adrenal cortical cells contained cytophalsmic vacuoles) - Histopathological findings: neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Kidneys:
- In male rats variety of proliferative lessions in kidneys (hyperplasia, adenoma, and adenocarcinoma of the proximal tubule, and hyperplasia of the transitional cell epithelium in the renal pelvis).
The observed incidences of these lesions were relatively low in dosed male rats, but the overall dose-response trend was statistically significant (P < 0.05) when survival differences were taken into account.
Preputial gland, m:
- carcinoma (0/50, 0/50, 5/50) - Lesions were noted macroscopically and generally were greater than 1 cm.
Histopathology of preputial gland was only performed on high dose group.
Conclusion:
Some evidence of carcinogenicity is observed in male rats (renal tubular cell adenomas and adenocarcinomas, carcinomas of the preputial gland).
No evidence of carcinogenicity is observed in female rats.
The kidney tumors are probably attributed to an a2µ-globulin mechanism, see additional remarks (chapter 7.12). - Dose descriptor:
- LOAEL
- Effect level:
- 250 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- histopathology: neoplastic
- histopathology: non-neoplastic
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 250 mg/kg bw/day (actual dose received)
- Organ:
- kidney
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- no
- Endpoint:
- carcinogenicity: 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 to male and female B6C3F1 mice by gavage in corn oil 5 days/week for 103 weeks. Body weights and clinical signs were recorded weekly during the first 13 weeks and then monthly. Animals were killed with carbon dioxide. Necropsies were performed on all animals, and tissues were examined for gross lesions and masses. Tissues were preserved in 10% neutral buffered formalin, embedded in paraffin, sectioned, stained with hematoxylin and eosin, and examined for non-neoplastic and neoplastic lesions.
- GLP compliance:
- no
- Species:
- mouse
- Strain:
- B6C3F1
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratories, Portage MI
- 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: NIH-07 pellets, Zeigler Brothers, Gardners PA
- 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 exposure:
- Dosing volume: 10 mL/kg
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 103 weeks
- Frequency of treatment:
- 5 days/week
- Post exposure period:
- none
- Dose / conc.:
- 250 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 500 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 50
- Control animals:
- yes, concurrent vehicle
- Observations and examinations performed and frequency:
- CLINICAL OBSERVATIONS AND FREQUENCY
Clinical signs: weekly during the first 13 weeks and then monthly
Mortality: not specified
Body weight: weekly during the first 13 weeks and then monthly
Hematology: no
Urinalysis: no
Biochemistry: no - Sacrifice and pathology:
- ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC):
- Macroscopic: tissues were examined for gross lesions and masses
- Microscopic: gross lesions and tissue masses, skin, mammary gland, thymus, heart, lungs and bronchi, trachea, thyroid gland, parathyroids, esophagus, stomach, colon, small intestines, mesenteric lymph node, pancreas, spleen, liver, kidneys, adrenal glands, urinary bladder, prostate/testes or ovaries/uterus, brain, pituitary gland, eyes (if grossly abnormal), thoracic vertebrae, including bone marrow and spinal cord - Statistics:
- - mortalities: life table analysis
- tumor incidence: life table analysis, incidental tumor test - Clinical signs:
- no effects observed
- Description (incidence and severity):
- No compound-related clinical signs were observed.
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- Animals killed at termination:
Males: 16 (control) / 16 (250 mg/kg) / 19 (500 mg/kg)
Females: 26 (control) / 35 (250 mg/kg) / 34 (500 mg/kg)
Non-accidental deaths:
Males: 28 (control) / 34 (250 mg/kg) / 29 (500 mg/kg)
Females: 23 (control) / 14 (250 mg/kg) / 11 (500 mg/kg)
The test substance did not adversely affect survival of male or female mice, although several dosed mice died early in the study. Adjusted survival among dosed females was somewhat better than for vehicle controls. Fighting among the group housed male mice may have contributed to the poor survival. - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- The body weights of high dose females averaged about 5% less than controls during the second year of the study. No effect on body weight was noted in any other group of dosed mice.
- 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:
- effects observed, treatment-related
- Description (incidence and severity):
- Several tumor types were increased marginally in dosed male mice:
- Hepatocellular neoplasms (adenomas and carcinomas) occurred with a positive trend (P < 0.05) (control, 18/48; low dose, 18/50;
high dose, 29/50). The incidence of liver neoplasia in female mice was 4/5 0, 6/50, 8/50.
- Mesenchymal tumors of the integumentum consisting primarily of subcutaneous fibrosarcomas, were observed at increased incidence in high dose male mice (control, 6/48; low dose 8/50; high dose, 14/50) (P < 0.05). These tumors often appeared as firm nodular masses, sometimes associated with ulceration of the overlying skin.
- The incidence of lymphomas or leukemias (8/48, 19/50, 5/50) (primarily lymphomas, one leukemia was noted in a control mouse, and none in dosed male mice) was increased marginally in low dose male mice, but this inerease was not statistically significant by life table analysis. - Dose descriptor:
- LOAEL
- Effect level:
- 250 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- histopathology: neoplastic
- Dose descriptor:
- NOAEL
- Effect level:
- 250 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- body weight and weight gain
- Critical effects observed:
- no
Referenceopen allclose all
Table 1: Survival of male and female rats
|
Vehicle control |
250 mg/kg |
500 mg/kg |
Animals initially in study (all groups) |
50 |
50 |
50 |
Male rats Natural deaths before termination * Accidentally killed Killed at termination Survival P values ** |
13 4 33 <0.001 |
12 5 33 0.917 |
30 6 14 <0.001 |
Female rats Natural deaths before termination Accidentally killed Killed at termination Survival P values |
19 1 30 0.748
|
21 6 23 0.537 |
16 14 20 0.886 |
* Includes animals that were killed in a moribund condition.
** The vehicle control column contains results of the life table trend test; the columns for dosed groups contain the life table exact pairwise comparisons with the vehicle controls.
Table 2: Renal lessions in male and female rats
|
Vehicle control |
250 mg/kg |
500 mg/kg |
Number examined in each group |
50 |
50 |
50 |
Male rats Nephropathy Tubule mineralization Epithelial hyperplasia of the renal pelvis Tubular cell hyperplasia Tubular cell adenoma * Tubular cell adenocarcinoma * |
49 1 0 0 0 0 |
47 31 5 1 0 3 |
46 20 5 4 2 1 |
Female rats Nephropathy Tubule mineralization Epithelial hyperplasia of the renal pelvis Tubular cell hyperplasia |
21 10 0 0 |
39 4 0 0 |
32 2 1 1 |
* The incidence of tubular cell adenomas and adenocarcinomas (combined) showed a statistically significant (P < 0.05) dose-related increase.
Table 1: Survival of male and female mice
|
Vehicle control |
250 mg/kg |
500 mg/kg |
Animals initially in study (all groups) |
50 |
50 |
50 |
Male mice Natural deaths before termination Accidentally killed Animals missing Killed at termination Survival P values |
28 5 1 16 0.699 |
34 0 0 16 0.844 |
29 2 0 19 0.780 |
Female mice Natural deaths before termination Accidentally killed Killed at termination Survival P values |
23 1 26 0.045
|
14 1 35 0.086 |
11 5 34 0.077 |
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- LOAEL
- 250 mg/kg bw/day
- Study duration:
- chronic
- Species:
- other: rat and mouse
Carcinogenicity: via inhalation route
Endpoint conclusion
- Endpoint conclusion:
- no study available
Carcinogenicity: via dermal route
Endpoint conclusion
- Endpoint conclusion:
- no study available
Justification for classification or non-classification
The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance is considered to be classified for carcinogenicity cat. 2, H351 under Regulation (EC) No. 1272/2008, as amended for the 14th time in Regulation (EU) 2020/217.
Additional information
In a 2-year study (Bucher et al., 1986) Fischer-344 rats (50 animals/dose/sex) were exposed by gavage to daily doses (5 days/week) of 0, 250, or 500 mg/kg isophorone in corn oil. The overall survival rate was low (males 33/50, 33/50, 14/50; females 30/50, 23/50, 20/50). Increased mortality was observed after week 98 in males in the 500 mg/kg bw dose group. Compound related clinical signs were not observed. Throughout the study, the mean body weights of high dose males averaged 5 % lower than vehicle controls. During the second year, the mean body weights of high dose females averaged 8 % lower than vehicle controls.
Dosed males showed proliferative lesions of the kidney (tubular cell hyperplasia: 0/50, 1/50, 4/50; tubular cell adenoma: 0/50, 0/50, 2/50; tubular cell adenocarcinoma: 0/50, 3/50, 1/50; epithelial hyperplasia of the renal pelvis: 0/50, 5/50, 5/50) and an increased mineralization of the medullary collecting ducts (1/50, 31/50, 20/50). Low dose males revealed more severe nephropathy than is commonly observed in aging F344 rats. Female rats only showed a statistically significant increase in nephropathy (21/50, 39/50, 32/50) with no further findings in the kidneys.
Carcinomas of the preputial gland were increased in high dose males only (0/50, 0/50, 5/50). The preputium is only investigated histopathologically when gross lesions are found, therefore neither true tumor incidences from this study nor from historical controls are available.
In a parallel 2-year gavage study with B6C3F1 mice (50 animals/dose/sex) animals were dosed daily (5 days/week) with 0, 250, or 500 mg/kg isophorone in corn oil. The survival of male mice was low (16/50, 16/50, 19/50) in contrast to female mice, where there was a trend towards increased survival of dosed animals relative to the controls (26/50, 35/50, 34/50). In high dose males, there was an increased incidence of hepatocellular adenomas and carcinomas (18/48, 18/50, 29/50). Mesenchymal tumors of the integumentary system (6/48, 8/50, 14/50) were increased in high dose males. An increased incidence of lymphomas or leukemias was noted in low dose males only (8/48, 19/50, 5/50). These results were interpreted as chemically related marginal increases in number of neoplasms (equivocal evidence).
Investigations on α2u-globulin induced nephropathy:
Various chemicals are known to induce nephropathy in male rats only. Only 60 % of α2u-globulin is reabsorbed in the kidney of male rats. 40 % of this low molecular weight protein remains in the filtrate and is excreted to the urine. The amount of α2u-globulin in female rats is 120 times lower and the protein is nearly absent in mice and in men. Chemicals that induce α2u-globulin nephropathy bind to the protein in the liver of the animals; these conjugates are difficult to hydrolyse and induce the formation of hyaline droplets which accumulate in the tubules (Charbonneau and Swenberg, 1988; Swenberg et al., 1989).
Isophorone as well as the proposed metabolites isophorol and dihydroisophorone form protein complexes with α2u-globulin in vivo, (SDS-page and immunoblotting after 14 d isophorone administration; GC/MS determination of isolated protein complexes) (Saito et al., 1992; Strasser et al., 1988). The degradation of α2u-globulin via lysosomal proteinases was decreased by 33 % (Lehman-McKeeman et al., 1990). In a further experiment with male NCI-Black-Reiter rats (strain is unable to synthesize the hepatic form of the low molecular weight protein α2u -globulin) isophorone administration, which clearly induced kidney lesions in male F344 rats, failed to induce nephropathy, α2u-globulin or the formation of hyaline droplets (Dietrich and Swenberg, 1990). It is thus concluded that the observed nephropathy in male rats is caused via the α2u-globulin mechanism and therefore irrelevant to other species.
Charbonneau M and Swenberg JA (1988). Studies on the Biochemical Mechanism of α2u-Globulin Nephropathy in Rats. Chemical Industry Institute of Toxicology Vol. 8, No. 6
Swenberg JA, Short B, Borghoff S, Strasser J and Charbonneau M (1989). The Comparative Pathology of α2u-Globulin Nephropathy. Toxicol Appl Pharmacol. 1989 Jan; 97 (1):35–46
Strasser J, Charbonneau M, Borghoff SJ, Turner MJ, Swenberg JA (1988). Renal protein droplet formation in male Fischer 344 rats after isophorone (IPH) treatment. Toxicologist 8:136 (abstract)
Lehman-McKeeman LD, Rivera-Torres MI, Caudill D. (1990). Lysosomal degradation of α2u-globulin and α2u-globulin-xenobiotic conjugates. Toxicol Appl Pharmacol. May 1990; 103 (3):539–548
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