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EC number: 202-653-9 | CAS number: 98-29-3
- 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
4-tert butylpyrocatechol may be considered as a weak nongenotoxic forestomach carcinogen with strong promoting activity when chronically administered by the oral route to the rat. The target organ and the administration route are irrelevant to the worker situation.
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:
- other: Test procedure and results described in sufficient details. However only one dose was tested, for 51 weeks, so that it is not sufficient to evaluate the carcinogenic potential of 4-tert-butylpyrocatechol as recommended by specific guidelines.
- GLP compliance:
- not specified
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS:
- Source: Charles River Japan, inc., Atsugi, Japan
- Age at study initiation: 6-week old
- Weight at study initiation: no data
- Housing: 4 to 5 to a plastic cage
- Food consumption: Oriental M basal diet ad libidum
- Water consumption: tap water ad libidum
- Acclimation period: one week
ENVIRONMENTAL CONDITIONS
- Temperature: 22-24°C
- Humidity (%): no data
- Air changes: conditioned air
- Photoperiod: 12-h light / 12-h dark cycle
In life dates: no data - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- DIET PREPARATION
- Rate of preparation of diet: once a month
- Storage: in dark until use - Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 51 weeks
- Frequency of treatment:
- daily
- Remarks:
- Doses / Concentrations:
0 and 1.5% (with or without MNNG pretreatment) (nominal), 1.5% = equivalent to approximately 700 mg/kg bw
Basis: - No. of animals per sex per dose:
- 10 in the basal diet control group; 15 in the TBC, and MNNG (basal diet) groups; 16 in the MNNG+TBC group
- Control animals:
- yes, plain diet
- Details on study design:
- At 6 weeks of age, one group was given 150 mg/kg bw of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in dimethylsulfoxide by stomach tube. Starting 1 week later, rats were given basal diet containing 1.5% TBC or basal diet alone for 51 weeks.
Further groups were administered the 1.5% TBC-supplemented diet or basal diet alone for 51 weeks without MNNG pretreatment. - Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: No data
DETAILED CLINICAL OBSERVATIONS: No data
BODY WEIGHT: Yes
- Time schedule: once every 2 to 4 weeks
FOOD CONSUMPTION AND COMPOUND INTAKE:
- Time schedule: once every 2 to 4 weeks
FOOD EFFICIENCY: No data
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: No
CLINICAL CHEMISTRY: No
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
- Sacrifice and pathology:
- Stomach, esophagus, intestines, liver, and kidney were removed, the liver and and kidneys being weighed and fixed in 10% buffered formalin solution.The esophagus, stomach, and intestines were injected with formalin and later opened via an incision along the greater curvature. After fixation, 6 sections each were cut from the anterior and posterior walls of the forestomach and glandular stomach. Tissues were processed routinely for histopathological examination. Animals which survived until the end of experiment were included in the effective numbers.
- Statistics:
- Student's test and Fisher's exact test
- Clinical signs:
- not specified
- Mortality:
- not specified
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not specified
- 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
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- not specified
- Details on results:
- BODY WEIGHT
At the end of the experiment, the body weights of animals given MNNG+TBC, or TBC without carcinogen pretreatment were 12 to 31.4% lower than those in the groups treated with MNNG and/or basal diet (BD) alone.
ORGAN WEIGHTS
The relative liver weights expressed as g/100 g body weight of animals treated with MNNG+TBC or with TBC without carcinogen pretreatment and the relative kidney weights of all treated animals were significantly higher than the respective control values.
GROSS PATHOLOGY
Grossly, only small tumours were observed in the forestomach epithelia in animals treated with MNNG alone. In the case of animals receiving MNNG+TBC, the forestomach were filled with tumour masses.
In the glandular stomach, some rats given MNNG+TBC had single polypoid lesions in the pyloric region, only one rat treated with MNNG alone having a polypoid lesion in the fundic region.
HISTOPATHOLOGY
Microscopically, the lesions in the forestomach could be classified into hyperplasia, papilloma, carcinoma in-situ, and squamous cell carcinoma. Hyperplasia was further classified into mild, moderate, severe, and marked (>1.0mm) depending on the thickness of the mucosa.
Hyperplasia was evident in all rats treated with MNNG. The incidence of papilloma and carcinoma in situ were not significantly different among the groups receiving MNNG treatment, whereas the incidences of squamous cell carcinomas were significantly higher in rats given MNNG+TBC (75%, P<0.01) than in the control group.
Hyperplasia was found in all rats given TBC alone. Lesions were distributed diffusely throughout the forestomach epithelium, and were characterised by upward hyperplasia.
Lesions in the glandular stomach were classified into adenomatous hyperplasia and adenocarcinoma categories. The lesions were mostly located in the pyloric region, where the incidence of adenomatous hyperplasias in rats treated with MNNG+TBC were significantly higher than in the control group (31.3%, P<0.05). The incidence of adenocarcinomas in rats treated with MNNG+TBC (18.8%) was higher than the control group value (0%), but the difference was not statistically significant. - Conclusions:
- TBC treatment significantly enhances forestomach and glandular stomach carcinogenesis in rats pretreated with MNNG.
It can not be ruled out that TBC may be a weak forestomach complete carcinogen, since it induced a small incidence (1/15 rats) of papillomas in forestomach epithelium without pretreatment with carcinogen. However, its hypothetical carcinogenic activity would appear less potent than its promoting activity.
TBC may be a nongenotoxic forestomach and /or glandular stomach weak carcinogens with a strong promoting activity. - Executive summary:
In a one-year tumour promotion study, 4 -tert-butylpyrocatechol (TBC) was administered to 15 to 16 Fischer 344 male rats in diet at dose levels of 0 or 1.5% (equivalent to ca. 700 mg/kg) for 51 weeks, with or without pretreatment with a single administration of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), a rat forestomach carcinogen.
The body weight of treated animals was lower than that of the respective controls. The relative liver and kidney weights of all treated animals were significantly higher than the respective control values. In the case of animals receiving MNNG+TBC, the forestomachs were filled with tumour masses. In the glandular stomach, some rats given MNNG+TBC had single polypoid lesions in the pyloric region. The incidence of squamous cell carcinomas was significantly higher in rats given MNNG+TBC than in the control group (12/16 rats). Adenomatous hyperplasia was found in the
pyloric region of the glandular stomach of all rats given TBC alone (with no pre-treatment). Lesions were distributed diffusely throughout the forestomach epithelium, and were characterised by upward hyperplasia. The incidence of adenomatous hyperplasia in rats treated with MNNG+TBC was significantly higher than in the control group (5/16 rats).
Based on the results of this one-year tumour promotion study, TBC may be a weak nongenotoxic forestomach carcinogen with a strong promoting activity in the rat.
Reference
Incidences of forestomach lesions
Number (%) of rats with |
|||||
Treatment | number of rats per group | Hyperplasia | Papilloma | Carcinoma in situ | Squamous cell carcinoma |
MNNG + basal diet | 15 | 15 (100) | 11 (73.3) | 3 (20) | 3 (20) |
MNNG + TBC | 16 | 16 (100) | 15 (93.8) | 4 (25) | 12 (75)p < 0.01 |
Basal diet | 10 | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
TBC | 15 | 15 (100)p < 0.001 | 1 (6.7) | 0 (0) | 0 (0) |
Incidences of glandular stomach lesions
Number (%) of rats with | |||||
Fundic region |
Pyloric region | ||||
Treatment | number of rats per group | Adenomatous hyperplasia | Adenocarcinoma | Adenomatous hyperplasia | Adenocarcinoma |
MNNG + basal diet | 16 | 0 (0) | 0 (0) | 5 (31.3)p < 0.05 | 3 (18.8) |
MNNG + TBC | 16 | 1 (6.7) | 0 (0) | 0 (0) | 0 (0) |
Basal diet | 10 | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
TBC | 15 | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
Grade of forestomach hyperplasia
Number (%) of rats with hyperplasia | |||||
Treatment | number of rats per group | Mild | Moderate | Severe | Marked |
Basal diet | 10 | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
TBC | 15 | 15 (100)p < 0.001 | 15 (100)p < 0.001 | 4 (26.7) | 0 (0) |
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
Justification for classification or non-classification
Based on the mode of action of tumour-promoting activity and on the lack of relevance of the target organ and the route of exposure potentially at risk in rats, 4-tert-butylpyrocatechol is not classified for carcinogenicity according to the criteria of UN/EU GHS.
Additional information
The carcinogenic potential of 4 -tert butylpyrocatechol (TBC) was indirectly studied in a one-year tumour promotion study in rats (Hirose et al., 1989), where TBC and other dihydroxybenzene derivatives were administered in the diet for 51 weeks (as potential promoting agents) following a single oral administration of a known forestomach and glandular stomach carcinogen, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG, as an initiating agent). Two distinct groups of rats, one with and one without pre-treatment by MNNG, were given TBC. Two distinct control groups receiving basal diet, one with and one without pre-treatment by MNNG, were included. This study was considered as a key study based on its validity 2 according to the Klimisch cotation criteria.
With pre-treatment by the carcinogen, the administration of TBC significantly increased the incidence of squamous cell carcinomas in the forestomach and the incidence of adenomatous hyperplasia in the pyloric region of the glandular stomach, compared to the respective controls. But without pre-treatment by the carcinogen, only one case of papilloma was observed in the forestomach, versus none in the respective control group, without reachinig statistical significance. Therefore, TBC significantly enhances the forestomach and glandular stomach carcinogenesis in the rat in case of co-administration with a recognized carcinogen.
It can not be ruled out that TBC be a weak forestomach carcinogen in the rat per se, based on the minimal incidence of benign tumours as papillomas seen in that species, but it should rather be considered as a weak nongenotoxic forestomach carcinogen with strong promoting activity resulting from its hyperplasiogenic effects when chronically administered by the oral route, as previously described for structurally-related antioxidants (1).
However, a functional human counterpart for the rodent forestomach does not exist. Histologically related organs in humans are oesophagus and stomach, but tissue dosimetry for these tissues is different from the rodent situation, where forestomach is a holding compartment, which allows the tissue considerably longer exposure to the chemical than oesophagus where transit time is rapid in case of oral administration (2). Furthermore, the oral route of administration is irrelevant to the worker situation.
Therefore, no classification is warranted for carcinogenicity.
(1) Ito N, Hirose M, Fukushima S, Tsuda H, Shirai T, Tatematsu M. Studies of antioxidants: their carcinogenic and modifying effects on chemical carcinogenesis. Food Chem Toxicol 24(10/11): 1071 - 82, 1986.
(2) Proctor DM, Gatto NM, Hong SJ & Allamneni KP. Mode-of-action framework for evaluating the relevance of rodent forestomach tumors in cancer risk assessment.Toxicol. Sci.98(2): 313 -26, 2007.
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