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Toxicological information

Carcinogenicity

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Description of key information

Four main carcinogenicity studies are available with reliability 2 under Klimisch scale (Hagiwara et al. 2001 ; Hirose et al. 1993; Hirose et al., 1990 and Tanaka et al., 1995). The lower doses have been tested in rats in Hagiwara et al., 2001 study. In this study the following doses have been tested: 0, 0.1% , 0.2%, 0.4% and 0.8% (0, 33, 65, 141 and 318 mg/kg/day) and male rats have been treated during 104 weeks. At all tested doses significant submucosal hyperplasia and ulceration have been noted. Significant squamous cell hyperplasia in the forestomach has been also observed. From the dose level of 0.2% (65 mg/kg/day) benign tumours (adenomas) were observed on 23/25 rats, 25/25 rats and 25/25 rats for 0.2%, 0.4% and 0.8% respectively. From the dose level of 0.4% (141 mg/kg/day) malign tumours (adenocarcinomas) were observed on 1/25 rats and 2/25 rats for 0.4% and 0.8% respectively.

The available studies showed that the stomach is the main target organ with benign tumours observed at doses equal or higher than 0.2% (0.8% in the majority of cases) and malignant tumours were observed at doses of 0.4% and 0.8%.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Only 25 male rats were studied until week 104.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
Deviations:
not specified
GLP compliance:
not specified
Species:
rat
Strain:
Fischer 344/DuCrj
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Japan Inc., Kanagawa, Japan.
- Age at study initiation: 5 weeks old
- Housing: 5 to a plastic cage with hard wood chips (Beta Chips, Northeastern Co, NY) for bedding.
- Diet ad libitum: powdered diet MF (Oriental Yeast Co, Tokyo, Japan)
- Water: ad libitum
- Acclimation period: one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2°C
- Humidity (%): 55 +/- 10%
- Air changes (per hr): a positive air pressure was maintained with more than 15 air changes/hour.
- Photoperiod (hrs dark / hrs light): 12h light / 12h dark
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): The diet was prepared at monthly interval.
- Mixing appropriate amounts with (Type of food): Catechol was incorporated in Oriental MF basal diet at dietary levels of 0, 0.1, 0.2, 0.4 and 0.8 %
- Storage temperature of food: in the dark before use
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
104 weeks
Frequency of treatment:
continuously
Post exposure period:
none
Remarks:
Doses / Concentrations:
0, 0.1, 0.2, 0.4 and 0.8 % (0, 33, 65, 141 and 318 mg/kg/day)
Basis:
nominal in diet
No. of animals per sex per dose:
30 males per dose
Control animals:
yes, plain diet
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly for the first 14 weeks, then monthly for the remaining period.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
Food and water consumption was measured over a 2-day period before each weighing

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes (Serum Gastrin level analysis)
- Time schedule for collection of blood: Blood samples were taken after 34 weeks, and at the termination of the study (104 weeks).

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Other examinations:
* Stomach pathological examination: Gross observation was performed at necropsy. The stomachs were then embedded in paraffin wax, sectioned and stained with hematoxylin and eosin for histopathological examination. Representative proliferative lesions were also investigated by immunohistochemistry (ABC method) with antibodies to gastrin and somatostatin.
* Other organs (liver, kidneys, heart, brain, spleen pituitary, adrenals and thyroid) of each animal were weighted and organ-to-body weights ratios determined.
Statistics:
The significances of intergroup differences in numerical data obtained were assessed using the two-sided Student's t test. Insufficient homogeneity of variance was corrected with respect to the degree of freedom according to the method of Welch. 
The significance of differences in the incidences of proliferative lesions between the treated and control groups was evaluated with Fisher's exact probability test.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
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:
effects observed, treatment-related
Details on results:
CLINICAL SIGNS AND MORTALITY: No clinical abnormalities or mortalities related to catechol were observed. 

BODY WEIGHT AND WEIGHT GAIN: Body weight gain was retarded in rats exposed to 0.8% catechol from week 1 to the termination but not in those given 0.4% or less.

HAEMATOLOGY: Serum gastrin levels in rats fed 0.2% or more catechol were significantly elevated at week 34.

GROSS PATHOLOGY: Slight thickening of the pyloric region was apparent in the 0.8% and 0.4% groups at week 34. Marked to moderate thickening was also found in rats fed 0.2, 0.4 and 0.8% at the termination. Cystic enlargement or increase in size of regional lymph nodes of the stomach were found in 9 of 25 rats in the 0.4% group and 13 of 25 in the 0.8% group. 

HISTOPATHOLOGY: Submucosal hyperplasias and adenomas of the pyloric glands developed in the 0.4 and 0.8% groups, only very minor changes being noted in the 0.1 and 0.2% groups, at week 34. Incidences of adenocarcinoma development in the pylorus were 0 in the 0.1 and 0.2% groups, 1 in the 0.4% group and 2 or 3 (2 in the table of results/ 3 in the related text) in the 0.8% group, at the termination. 
These results were not statistically different from controls. Adenomas and submucosal hyperplasias were found in nearly all animals fed 0.2% catechol or more, the incidences of those in 0.1% group being 0 and 56% respectively.
Ulceration of the pylorus was found in 1, 1, 5, 9 and 15 rats of the 0, 0.1, 0.2, 0.4 and 0.8% groups, respectively.
Conclusions:
Positive
Executive summary:

The dose-dependence of Catechol glandular stomach carcinogenesis (Hagiwara et al., 2001) was investigated in male F344 rats.

Groups of 30 male rats were fed Catechol at dietary levels of 0 (control) to 0.8% for up to 104 weeks. Five rats of each group were killed at 34 weeks and the remaining animals were sacrificed at the termination, all undergoing histopathological examination.

Moderate retardation of body weight increase was observed in the 0.8% group, but no adverse effects were found in terms of survival. Submucosal hyperplasias and adenomas of the pyloric glands developed in the 0.4 and 0.8% groups, only very minor changes being noted in the 0.1 and 0.2% groups at week 34.

Incidences of adenocarcinoma development in the pylorus were 4% and 8% in 0.4% and 0.8% groups respectively, and0 inthe 0.1% and 0.2% groups, at the termination.

Adenomas and submucosal hyperplasias were found in nearly all animals fed 0.2% Catechol or more, the incidences of those in 0.1% group being 0 and 56% at 34 and 104 weeks respectively.

Serum gastrin levels were significantly increased in the 0.2, 0.4 and 0.8% groups at 34 weeks, and in all tested groups at the termination, at extents comparable with the induction of proliferative lesions in the pylorus.

The results thus demonstrated that dietary levels of 0.4% and 0.8% Catechol long-term induce adenocarcinomas in the pyloric glands, while 0.1 and 0.2% cause begnin proliferative lesions, all accompanied by increase in serum gastrin levels.

Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Test well described but only 30 mice/sex were treated at only one dose. The only dose tested of 0.8% induced a decrease higher than 10% of the body weight in treated animals compared to control, thus exceeding the maximum tolerated dose and should be considered as cytotoxic.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
Deviations:
yes
Remarks:
only one dose tested
GLP compliance:
not specified
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Japan Inc., Atsugi, Japan.
- Age at study initiation: 5 weeks old
- Housing: 5 to a plastic cage, assigned randomly, and maintained on hardwood chip bedding.
- Diet: they were allowed to free access to Oriental MF basal diet (Oriental Yeast Co., Tokyo, Japan)
- Water: tap water ad libitum
- Acclimation period: one week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2°C
- Humidity (%): 60 +/- 10%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12h light / 12h dark
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): twice a month
- Mixing appropriate amounts with (Type of food): Catechol was incorporated into Oriental MF basal diet, using a cake mixer, at a concentration of 0.8%.
- Storage: in the dark before use.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The analyses were carried out at Food Research Laboratories, Tokyo, Japan, using methanol extraction and HPLC method.
Duration of treatment / exposure:
96 weeks
Frequency of treatment:
continuously
Post exposure period:
none
Remarks:
Doses / Concentrations:
0.8% in the diet (ca. 960 mg/kg bw/d)
Basis:
nominal in diet
No. of animals per sex per dose:
30 animals of both sexes per group
Control animals:
yes, concurrent no treatment
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice a day

BODY WEIGHT: Yes
- Time schedule for examinations: weekly for the first 14 weeks and once every 4 weeks thereafter.

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
- Time schedule for examinations: food was measured over a 2 day period before weighing.

WATER CONSUMPTION: Yes
- Time schedule for examinations: water was measured over a 2 day period before weighing.

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Surviving mice were killed and subjected to complete necropsy. 
All organs were removed and tissues were processed in the usual way for histopathological examination. 
Three sections, each including polyploid tumours, were cut from the anterior and posterior walls of the forestomach and six sections from the glandular stomach. For the quantitative analyses of focal liver lesions, areas of liver sections were measured using a colour image processor.
Statistics:
Student's t-test and fisher's exact probability test were used for statistical analysis of the data.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
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:
effects observed, treatment-related
Details on results:
- Systemic toxicity:
A slight reduction in survival rate was observed in mice of both sexes treated with catechol. Final average body weights of catechol-treated mice of both sexes (male: 29.4 ± 3.9 g, female: 27.8 ± 2.4 g) were significantly (p < 0.01) lowered by 21.6% (male) and by 41% (female) than those of respective controls (male: 37.5 ± 6.4 g, female: 47.2 ± 7.3 g). 

- Organ weight:
The relative liver weights of catechol-treated mice of both sexes (male: 7.06 ± 2.06%, p < 0.05; female: 6.92 ± 2.64%, p < 0.01) were significantly higher than those of respective controls (male: 5.81 ± 2.57%; female: 3.60 ± 1.02%). 

- Lesion incidence:
At necropsy, neoplastic lesions were observed mainly in the glandular stomach of both sexes. Adenomas in the glandular stomach were found in the majority of mice: 29 out of 30 (97%) in males and 21 out of 29 females. No adenocarcinomas were found in mice of either sex. In the forestomach epithelium, although significant increase in papilloma development was not evident, incidences of squamous cell hyperplasia were significantly increased in mice of both sexes. In the liver, no significant differences were observed in the incidences of hyperplastic foci, hyperplastic nodules and hepatocellular carcinomas.
Conclusions:
Results are ambiguous as only adenomatous hyperplasias are observed but no adenocarcinoma.
Executive summary:

 In the study of Hirose (1993), mice (30 per group) were feed with diet containing 0.8% (ca. 960 mg/kg bw/d) of catechol during 96 weeks. The authors observed reduction of survival rate, diminution of body weight, increase in relative liver body weight, lesions in glandular stomach but no adenocarcinoma. In forestomach, development of papilloma and squamous hyperplasia. Results are ambiguous as only adenomatous hyperplasias are observed but no adenocarcinoma.

 

Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
The exposure period was only 24 weeks. Only 10-15 rats/group were used, only males treated at only one dose. This dose induced a body weight reduction of 10% or higher after only 24 weeks. The study was not carried out according to recognised international guidelines.
Principles of method if other than guideline:
tumour promotion
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., Kanagawa, Japan.
- Age at study initiation: 6 weeks old
- Housing: 5 to a plastic cage, assigned randomly, and maintained on hardwood chip bedding.
- Diet: they were allowed to free access to Oriental MF basal diet (Oriental Yeast Co., Tokyo, Japan)
- Water: tap water ad libitum
- Acclimation period: one week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 +/- 2°C
- Humidity (%): air-conditioned room
- Photoperiod (hrs dark / hrs light): 12h light / 12h dark
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
28 weeks
Frequency of treatment:
continuously
Post exposure period:
no
Remarks:
Doses / Concentrations:
0.8% (ca. 480 mg/kg bw/day)
Basis:
nominal in diet
No. of animals per sex per dose:
15 rats per group
Control animals:
yes, plain diet
Details on study design:
Groups of 15 rats were treated with a single i.p. injection of 100 mg/kg b.w. diethylnitrosamine (DEN). 
Two days after, they were sequentially given 4 i.p. injections of 20 mg/kg b.w. N-methylnitrosourea followed by 4 s.c. injections of 40 mg/kg b.w. dimethylhydrazine every 2 or 3 days. At the start of the DEN injections, they were treated with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine in the drinking water for 2 weeks, followed by 0.1% 2,2'-dihydroxy-di-n-propylnitrosamine (DHPN). The total multiple initiation period was 4 weeks. Starting 3 days after the termination of the DHPN treatment, they were administered 0.3% NaNO2 in the drinking water, and/or 0.8% catechol in powdered basal diet or basal diet alone until the 28th week.

Without the carcinogen pre-treatments, groups of 10 F344 male rats were treated with 0.3% NaNO2 in the drinking water and simultaneously administered 0.8% catechol in powdered basal diet for 24 weeks. Additional groups received 0.8% catechol or basal diet alone for the same period. 
Observations and examinations performed and frequency:
Food and water consumption were measured every 2-4 weeks during the chemical treatment test period.
Body weight and organ weight: Yes, no more precision.
Sacrifice and pathology:
All surviving rats were killed at the end of the exposure period, and complete necropsy was performed. Stomachs were removed and injected with 10% buffered formalin solution. Six strips each were cut from the anterior and posterior walls of the forestomach and 6 strips were cut from the pyloric region of the glandular stomach. Tissues were processed routinely and stained with haematoxylin and eosin. For quantitative analysis of preneoplastic GST-P-positive foci, acetone-fixed liver sections were stained immunohistochemically with anti-GST-P antibody and foci were counted by using a colour video image processor. Only animals surviving until the end of the experiment were included in the calculations.
Statistics:
The Fisher exact test and Student's t test were used for the statistical analysis of the data.
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
effects observed, treatment-related
Details on results:
* With carcinogen pre-treatments (10 rats/group):
- Final body weights of animals treated with catechol were significantly lower (-12%) than those of rats receiving basal diet alone. Simultaneous treatment with NaNO2 further reduced the body weights (-24%).
- In the forestomach, catechol significantly (p < 0.01) enhanced the incidence of papillomas and weakly (p < 0.05) the incidence of squamous cell carcinomas. Additional treatment with NaNO2 significantly enhanced the incidence of carcinoma in situ (p < 0.05) and squamous cell carcinomas (p < 0.001).
- In the glandular stomach, all rats (15/15) treated with catechol had submucosal hyperplasia, 12 of 15 had adenomas and 4 of 15 adenocarcinomas. NaNO2 slightly inhibited the development of submucosal hyperplasia in rats given catechol (9/14).
- In the liver, numbers and/or areas of GSTP-P-positive foci were reduced by the catechol treatment.
- In the other organs examined, catechol was shown to significantly reduce the incidence of thyroid follicular cell hyperplasia from 64% (basal diet) to 7% (catechol and catechol +NaNO2, p < 0.01), the incidence of follicular cell adenoma from 29% (basal diet) to 0% (catechol +NaNO2, p < 0.05) and the incidence of kidney nephroblastoma from 36% (basal diet) to 0% (catechol, p < 0.05). At the opposite, papilloma of oesophagus were increased to 50% after treatment with catechol +NaNO2 (p < 0.01) (was 0 in the basal diet group).

* Without carcinogen pre-treatments (10 rats/group):
- Final body weights of animals treated with catechol were significantly lower (-10%) than those of rats receiving basal diet alone. Simultaneous treatment with NaNO2 further reduced the body weights (-29%).
- The stomach contents and forestomach epithelia of rats treated with NaNO2 plus catechol demonstrated blackening and marked papillary projections with dense keratin-like material being evident scattered throughout the epithelium. Only mild hyperplasias were observed in the forestomach of 5 rats of the 10 that received catechol alone treatment.
- In the glandular stomach, all rats treated with catechol had submucosal hyperplasia and adenomas (10/10). The incidences of these lesions were remarkably reduced by combined treatment with NaNO2 (submucosal hyperplasia: 3/10 and adenomas: 1/10). None of them showed adenocarcinomas.
Conclusions:
Positive
Executive summary:

In the study of tumour promotion of Hirose (1990), rats (10 /group) received for 28 weeks, catechol in diet at 0 or 0.8% (ca. 480 mg/kg bw/day). Animals were pre-treated for 4 weeks of multiple initiation period with DEN, DHPN and NaNO2 by i.p,s.c.administration or drinking water.

* With carcinogen pre-treatments

- Final body weights of animals treated with catechol decreased.

 

- In the glandular stomach, all rats (15/15) treated with catechol had submucosal hyperplasia, 12 of 15 had adenomas and 4 of 15 adenocarcinomas.

- In the liver, numbers and/or areas of GSTP-P-positive foci were reduced by the catechol treatment.

- In the other organs examined, catechol was shown to significantly reduce the incidence of thyroid follicular cell hyperplasia from 64% (basal diet) to 7% (catechol and catechol +NaNO2, p < 0.01), the incidence of follicular cell adenoma from 29% (basal diet) to 0% (catechol +NaNO2, p < 0.05) and the incidence of kidney nephroblastoma from 36% (basal diet) to 0% (catechol, p < 0.05). At the opposite, papilloma of oesophagus were increased to 50% after treatment with catechol +NaNO2 (p < 0.01) (was0 inthe basal diet group).

 

* Without carcinogen pre-treatments:

- Final body weights of animals treated decreased

- The stomach contents and forestomach epithelia of rats treated with NaNO2 plus catechol demonstrated blackening and marked papillary projections with dense keratin-like material being evident scattered throughout the epithelium. Only mild hyperplasias were observed in the forestomach of 5 rats of the 10 that received catechol alone treatment.

- In the glandular stomach, all rats treated with catechol had submucosal hyperplasia and adenomas (10/10). The incidences of these lesions were remarkably reduced by combined treatment with NaNO2 (submucosal hyperplasia: 3/10 and adenomas: 1/10). None of them showed adenocarcinomas.

Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Only 30 rats per group were used, only males, treated at only 1 dose. The body weight of treated animals was decreased by 21.5% compared to control animals, thus exceeding the limit of 10% for the maximum tolerated dose recommended by the OECD guidelines.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
Deviations:
not specified
GLP compliance:
not specified
Species:
rat
Strain:
other: Wistar or Lewis or Sprague Dawley or WKY
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 weeks old
- Housing: generally 3 (5 for Wistar, WKY and Lewis strain) to a polycarbonate cage with hardwood Beat Chips (Northeastern Products Co. Warrensburg, NY USA) for bedding.
- Diet: free access to Oriental MF powdered diet (Oriental Yeast Co.; Tokyo, Japan)
- Water: free access to tap water
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2°C
- Humidity (%): 55 +/- 10%
- Air changes (per hr): more than 15 times/hr
- Photoperiod (hrs dark / hrs light): 12h light / 12h dark
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): every 2 weeks
- Mixing appropriate amounts with (Type of food): admixing the compound into powdered diet in stainless-steel mixer for 30 min.
- Storage temperature of food: at room temperature in the dark until used.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
104 weeks
Frequency of treatment:
continuously
Post exposure period:
None
Remarks:
Doses / Concentrations:
0.8%
Basis:
nominal in diet
No. of animals per sex per dose:
20-30 of each strain of rats
Control animals:
yes, concurrent no treatment
Details on study design:
Rats were given diets containing 0 (control group: 20 rats) and 0.8% catechol (30 rats) for 104 weeks. Animals surviving until the end of the study period were deprived of food, but not water, overnight and then killed under ether anaesthesia.
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS and DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily. Those showing abnormalities were isolated and returned to their groups if their condition improved but otherwise were killed and autopsied.

BODY WEIGHT: Yes
- Time schedule for examinations: weekly for the first 14 weeks and then every 4 weeks.


FOOD and WATER CONSUMPTION:
It was measured during 2-day periods before each time of weighing.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
For microscopic examinations, tissues were routinely embedded in paraffin wax, sectioned, and stained with haematoxylin and eosin.
Histopathological examinations were also performed on animals that died or were killed when they became moribund during the experiments.
Three sections of fixed stomach were cut from the anterior and posterior walls of the forestomach, and six sections from the glandular stomach. 
Other examinations:
The liver and kidneys of each animal were weighed, and organ/body weight ratio were calculated. Samples of these organs and the other organs were removed and fixed in formalin solution.
Statistics:
Pairwise comparisons for differences in body weight were analysed by F- and Student's t-tests. The results of histopathological examination were analysed by the Fisher's probability test.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
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:
effects observed, treatment-related
Details on results:
WISTAR:
* Body and organ weight gains:
Body weight gains of rats from 0.8% catechol-treated group (536 ± 74 g) were significantly (p < 0.01) decreased by 21.5% compared to control group (683 ± 130 g).

* Tumour incidences:
- In rats treated with catechol, the pyloric region of the glandular stomach was diffusely thickened, with focal development of small hollowed lesions. - In the glandular stomach of rats given catechol, incidences of submucosal hyperplasia, adenoma, adenocarcinoma, sarcoma, erosion/ulcer were 100, 97, 67, 10 (no significant difference with control group) and 43%, respectively. No histopathological changes were observed in control rats. Cytotoxicity was evidenced by erosion and ulceration in the glandular epithelium (control: 0 animals; 0.8 % catechol: 13 animals (43%), p < 0.01).
- In the forestomach of rats given catechol, incidences of hyperplasia, papilloma, squamous cell carcinoma were 73, 7 and 3%, respectively. In control rats, the incidence of hyperplasia was 25%. 
- Other organs were examined for neoplastic lesions. In Wistar rats given catechol, the incidence of islet tumours of the pancreas and pituary tumours were significantly lower than in controls.

WKY:
* Body and organ weight gains:
Body weight gains of rats from 0.8% catechol-treated group (350 ± 34 g) were significantly (p < 0.01) decreased by 20.1% compared to control group (438 ± 66 g). Final liver relative weights were also significantly (p < 0.01) increased.

* Tumour incidences:
- In rats treated with catechol, the pyloric region of the glandular stomach was diffusely thickened, with focal development of small hollowed lesions. - In the glandular stomach of rats given catechol, incidences of submucosal hyperplasia, adenoma, adenocarcinoma, sarcoma, erosion/ulcer were 100, 100, 10, 0 and 73%, respectively. Only one occurrence of sarcoma was observed in one rat of the control group. 
- Cytotoxicity was evidenced by erosion and ulceration in the glandular epithelium (control: 0 animals; 0.8 % catechol: 22 animals (73%), p < 0.05).
- In the forestomach of rats given catechol, incidences of hyperplasia, papilloma and squamous cell carcinoma were 73, 3 and 0%, respectively. In control rats, the incidence of hyperplasia was 25%. 
- Other organs were examined for neoplastic lesions. No significant differences in the incidences of tumours in catechol-treated and control groups were observed.

LEWIS:
* Body and organ weight gains:
Body weight gains of rats from 0.8% catechol-treated group were significantly (p < 0.01) decreased (426 ± 36 g) by 40 % when compared to control group (710 ± 65 g). Final liver and kidney relative weights were significantly (p < 0.01) increased from 1.91% bw in control to 2.33% bw (liver) and from 0.52% bw in control to 0.66% bw (kidneys).

* Tumour incidences:
- In rats treated with catechol, the pyloric region of the glandular stomach was diffusely thickened, with focal development of small hollowed lesions. - In the glandular stomach of rats given catechol, incidences of submucosal hyperplasia, adenoma, adenocarcinoma, sarcoma, erosion/ulcer were 100, 97, 73, 10 and 70%, respectively. These incidences were significantly different from those in control group, except the incidence of adenocarcinoma, which was similar to values observed in the control group. No histopathological changes were observed in control rats.
- Cytotoxicity was evidenced by erosion and ulceration in the glandular epithelium (control: 0 animal; 0.8 % catechol: 21 animals (70%), p < 0.05).
- In the forestomach of rats given catechol, incidences of hyperplasia, papilloma, squamous cell carcinoma were 67 (no significant difference with control group), 0 and 0%, respectively. In control rats, the incidence of hyperplasia was 45%. 
- Other organs were examined for neoplastic lesions. In Lewis rats given catechol, the incidence of pituary tumours was significantly lower than in controls.

SPRAGUE-DAWLEY:
* Body and organ weight gains:
Body weight gains of rats from 0.8% catechol-treated group were significantly (p < 0.01) decreased (637 ± 90 g) compared to control group (754 ± 131 g).

* Tumour incidences:
- In rats treated with catechol, the pyloric region of the glandular stomach was diffusely thickened, with focal development of small hollowed lesions. - In the glandular stomach of rats given catechol, incidences of submucosal hyperplasia, adenoma, adenocarcinoma, sarcoma, erosion/ulcer were 100, 100, 77, 0, 80%, respectively. No histopathological changes were observed in control rats.
- Cytotoxicity was evidenced by erosion and ulceration in the glandular epithelium (control: 0 animals; 0.8 % catechol: 24 animals (80%), p < 0.05).
- In the forestomach of rats given catechol, incidences of hyperplasia, papilloma, squamous cell carcinoma were 70, 20 and 3%, respectively. In control rats, the incidence of hyperplasia and papilloma was 33% and 0%, respectively. The significant differences observed between catechol-treated group and control group for hyperplasia and papilloma incidences were p < 0.05.
- Other organs were examined for neoplastic lesions. In SD rats given catechol, the incidence of pituary tumours was significantly lower than in controls.
Relevance of carcinogenic effects / potential:
The results reported provide further confirmation of carcinogenicity of Catechol to the glandular stomach, additionnally demonstrating clear strain differences in the induction of glandular stomach adenocarcinomas. Thus, incidences of malignant gastric lesions were much higher in Wistar, Lewis and SD rats (67-77%) than in the WKY strain (10%) even though adenomas occured at 100% in the latter.
Conclusions:
Positive. Differences in susceptibility to carcinogens might depends both on the carcinogen and on the target organ.
Executive summary:

In the study of Tanaka (1995), different strains of rats: Wistar, Lewis, Sprague Dawley or WKY were treated in diet with 0.8% of catechol for 104 weeks.

The carcinogenicity effect of Catechol to the glandular stomach, was present in all strains but there was clear strain differences in the induction of glandular stomach adenocarcinomas or adenomas.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
33 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Study with reliability 2 under Klimisch scale. The other studies are consistent with this study.
System:
gastrointestinal tract
Organ:
stomach

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Mode of Action Analysis / Human Relevance Framework

The mechanism through which pyrocatechol may express its carcinogenic potential is still not fully understood. Both stochastic genotoxic as well as non-genotoxic mechanisms are likely to play a role. A generally accepted hypothesis is that pyrocatechol induces oxidative DNA damage. At the same time, DNA methylation may play an important role in the early stage of stomach carcinogenesis. Another mechanism of induction of tumours in the glandular stomach by pyrocatechol could be associated with the 'gastrin hypothesis'.

The stomach is the main target organ with benign and malignant tumours. Other sites of tumorigenesis were also found (pancreas and oesophagus) but at higher doses. The several studies available clearly showed dose-response relationship with stomach benign tumors observed at doses equal or higher than 0.2% and stomach malignant tumours were observed at higer doses (0.4 and 0.8%). Based on the available studies a threshold can be identified for benign and malignant tumours.

Justification for classification or non-classification

28 studies of reliability 2 are oral carcinogenicity studies or tumour promotion study with catechol. They all demonstrated the carcinogenic effect of Catechol on glandular stomach on rats with formation of adenomas or adenocarcinomas. It is important to notice that the effects appeared at high dose 0.4% and mainly 0.8% for malignant tumours, at mid dose for begnin tumours (0.2%) and at low dose for hyperplasie (0.1%). The lowest doses tested presented submucosal hyperplasia indicating that the repeated administrations of important dose at the site of application (stomach) lead to toxic effect for which the severe form at high dose were carcinoma and adenocarcinoma. Three species were studied, Rat, Mouse and Hamster, and it was clearly demonstrated that Rat was the most sensitive.


 


Co-carcinoma studies permitted to better understand the mechanisms of co-carcinogenesis and tumour promotion. They all confirmed the carcinogenic effect of Catechol on glandular stomach in rats, and indicated that catechol could inhibited carcinogen effect of some substances on specific organs like the effect of BOP on pancreas in study of Maruyama on Hamster.


 


The RAC committee examined the carcinogenic effect of pyrocatechol for a harmonised classification proposal. The RAC committee conclusion (adopted 16 September 2016) regarding pyrocatechol carcinogenic properties was the following: 'According to 3.6.1.1 and 3.6.2.2.3 of Annex I of the CLP Regulation, since pyrocatechol can induce benign and malignant tumours in two species in both sexes (mainly) in the glandular stomach, RAC considers that pyrocatechol should be classified as Carc. Cat. 1B, H350 (May cause cancer)'.


 


Based on the 13th ATP of the CLP Regulation, pyrocatechol is officially classified in Europe as Carc. Cat. 1B, H350 (may cause cancer)

Additional information

 38 Studies are available to evaluate the carcinogenicity effect of catechol in animals. 28 were considered as reliability 2 according to Klimish scale and summarized below.:

- In the study of Hagiwara (2001), the dose-dependence of Catechol glandular stomach carcinogenesis was investigated in male F344 rats. Groups of 30 male rats were fed Catechol at dietary levels of 0, 0.1, 0.2, 0.4 and 0.8 % (0, 33, 65, 141 and 318 mg/kg/day) for up to 104 weeks. Five rats of each group were killed at 34 weeks and the remaining animals were sacrificed at the termination, all undergoing histopathological examination. Moderate retardation of body weight increase was observed in the 0.8% group, but no adverse effects were found in terms of survival. Submucosal hyperplasias and adenomas of the pyloric glands developed in the 0.4 and 0.8% groups, only very minor changes being noted in the 0.1 and 0.2% groups at week 34. Incidences of adenocarcinoma development in the pylorus were 4% and 8% in 0.4% and 0.8% groups respectively, and 0 in the 0.1% and 0.2% groups, at the termination. Adenomas and submucosal hyperplasias were found in nearly all animals fed 0.2% Catechol or more, the incidences of those in 0.1% group being 0 and 56% at 34 and 104 weeks respectively. Serum gastrin levels were significantly increased in the 0.2, 0.4 and 0.8% groups at 34 weeks, and in all tested groups at the termination, at extents comparable with the induction of proliferative lesions in the pylorus. The results thus demonstrated that dietary levels of 0.4% and 0.8% Catechol long-term induce adenocarcinomas in the pyloric glands, while 0.1 and 0.2% cause begnin proliferative lesions (Hyperplasia and ulceration from 0.1% and benign tumours - adenoma- from 0.2%), all accompanied by increase in serum gastrin levels.

- In the study of Hirose (1992), The potential reversibility of glandular stomach lesions induced by the catechol, was examined in groups of male F344 rats treated continuously with 0.8% catechol in the diet for 12, 24, 48, 72, or 96 weeks. After a return to basal diet for 84, 72, 48, 24, and 0 weeks, respectively, the animals were killed for histopathological examination. Incidences of submucosal hyperplasia, adenomas and adenocarcinomas, average number of tumors per rat, and the size of tumors in rats treated with catechol for 12, 24, 48, 72, and 96 weeks increased time dependently. After cessation of catechol treatment, although average number of tumors per rat slightly decreased, the size of tumors tended to increase. Labelling indices in both tumorous and non tumorous areas decreased after cessation of catechol treatment. The results thus indicate that whereas some submucosal hyperplasias or adenomas may regress, others have the potential to develop into adenomas or adenocarcinomas. However, tumor growth does depend to a certain extent on continued catechol treatment.

- In the study of Hirose (1993), carcinogenicity of Catechol was investigated in male and female F344 rats. Groups of 30 animals were treated with 0.8% catechol in powdered diet continously for 104 weeks. At necropsy, neoplastic lesions were observed mainly in the grandular stomach of animals (both sexes). Adenomas were found in all rats. In addition 15/28 (54%) and 12/28 (43%) of the male and female rats respectively, had well differenciated adenocarcinomas.

In the forestomach epithelium, although significant increase in papilloma development was not evident, incidences of squamous cell hyperplasia were significantly increased in rats of both sexes.

In other organs examined, incidence and numbers of liver hyperplastic foci per cm² liver section, were significantly lower in male rats. Although the incidence was no different, the number of hyperplastic foci were also significantly reduced in female rats.

Thus the present experiment clearly demonstrated that Catechol exerts carcinogenic activity in rat glandular stomach epithelium.

 

- In the study of Hirose (1997), 30 Fisher rats were exposed to catechol by diet at concentration of:

0.16% (ca. 19 mg/kg bw/d) for 104 weeks (carcinogenicity study),

0.16 and 0.032% (ca. 19 and 3.8 mg/kg bw/d) for 28 weeks (Medium-term multi organ carcinogenesis study)

The administration was performed with catechol alone or in combinaison with differents antioxidants: butylated hydroxyanisole (BHA), caffeic acid, sesamol, 4 -methoxyphenol and catechol.

The results after 104-weeks exposure, indicated a statistically significant decrease in body weight gain, and a slight increase (3%) of forestomach papillomas in catechol treated group as compared to the basal diet group (not statistically different).

After 28-weeks exposure: In the low dose group (0.032% catechol) none of the organs studied (thyroid, lung, tongue, forestomach, small and large intestine, liver, kidney, urinary bladder) showed a significant variation of the number of adenoma/carcinoma/papilloma etc... when compared to basal diet group values. In the group that received the combination of the five compounds at the lowest dose, only the incidence of papilloma in the forestomach was significantly (p < 0.05) different from that in the control group. 

Likewise, incidences of forestomach papillomas and/or carcinomas were statistically increased in the high dose-group only when rats were exposed to catechol in combination with 4 other mutagens.

 

-In the study of Hirose (1999), Rat (5 per group) were treated with catechol at different concentrations and for different durations :

-0.01,0.1, 0.5 or 1% in diet for 7 days and sacrified after 12h,1, 2, 3 and 7 days.

- 0.8% for 24 weeks.

The authors studied the evolution of the toxicological effect and described that catechol exerted first apoptosis, inflammation and erosion or ulceration. Catechol induced continuous strong cell-proliferation responsible of glandular stomach carcinogenesis. This effect had a threshold between 0.1 and 0.01%.

 

-The study of Shibata (1990a) was a DNA labelling. Rats (5 per group) were feed with 0.8 % of catechol for 8 weeks and received an i.p. injection of BrdU at 100 mg/kg bw at week 8. Number of cells per 2000 that incoportaed BrdU were counted for forestomach and pyloric gland epithelium and ABC histochemie was done. The authors observed hyperplasia of forestomach and elevation of DNA synthesis.

 

-In another study of Shibata (1990b) of DNA labelling, rats (5 per group) received for 4 weeks 0.8% of catechol and an i.p. injection of 100 mg/kg bw of BrdU. The number of cells incorporating BrdU into DNA per 2000 cells of forestomach were counted and ABC immunohistochemical method was used. The authors observed and increase in hyperplasia of forestomach epithelium, and an increase in DNA synthesis in pyloric gland cells.

 -In the study of Hirose (1990-1993), mice (30 per group) were feed with diet containing 0.8% (ca. 960 mg/kg bw/d) of catechol during 96 weeks. The authors observed reduction of survival rate, diminution of body weight, increase in relative liver body weight, lesions in glandular stomach but no adenocarcinoma. In forestomach, development of papilloma and squamous hyperplasia. Results are ambiguous as only adenomatous hyperplasias are observed but no adenocarcinoma.

 Tumour promotion:

- In the study of Hirose (1987), 19 rats were exposed to a single intragastrin dose of 150 mg/kg of MNNG, then rats received or not 1.5% of catechol diet for 4 weeks and 0.8% for 47 weeks. Other groups of rats received catechol alone or basal diet. The stomachs, intestines, livers and kidneys were removed and stomach inflated in 10% buffered formalin. The forestomach of rats given MNNG + catechol presented cell carcinoma. Catechol alone induces hyperplasia and papilloma. In the glandular stomach, MNNG alone induced adenomatous hyperplasia but did not developed tumor. The incidence of adenomatous hyperplasia and adenocarcinoma increased with treatment with MNNG + catechol compared to treatment with catechol alone.

- In the study of Wada (1988), Groups of 15 male rats were given a single intragastric administration of 150 mg/kg b.w. MNNG (N-Methyl-N'-nitro-N- nitrosoguanidine) at the beginning of the experiment. Starting 1 week later, they were given a diet containing 0.8 % catechol or basal diet alone for 51 weeks. Further groups of rats were treated with 0.8 % catechol (16 rats per group) or basal diet alone (15 rats per group) wihout MNNG pre-treatment. Rats were killed at the end of week 52. Body weigth gain and food intake were decerased in treated groups. Catechol alone induced adenoma in the glandular stomach of rats. In the forestomach, the groups rats MNNG-treated developed hyperplasia and the incidences of papilloma and squamous cell carcinoma increased In the glandular stomach, lesions predominantly developed in the pyloric region. Catechol induced submucosal hyperplasia in all rats and adenocarcinoma in 73% of rats pretreated with MNNG. Without MNNG, catechol induced submucosal hyperplasia in all rats and adenocarcinoma in one rat.

 

- In the study of Tanaka (1995), different strains of rats: Wistar, Lewis, Sprague Dawley or WKY were treated in diet with 0.8% of catechol for 104 weeks. The carcinogenicity effect of Catechol to the glandular stomach, was present in all strains but there was clear strain differences in the induction of glandular stomach adenocarcinomas or adenomas.

 

- In the study of Ito (1994), rats received 0.8% of catechol for 104 weeks. The carcinogenic effect on liver was checked regarding in particular the liver enzyme. Inhibitory effect on liver was observed with rats treated by catechol comparing to controls.

 

- In the study of Tatematsu (1993), the effect of methylation was studied in rat stomach carcinogenesis study. Rats were treated with catechol or MNNG. Catechol induced adenomas hyperplasia and increased specific methylation of CCGG sites of Pg1 gene in pyloric mucosa, same phenotype than for MNNG.

 

- In this study of La Voie (1985), The tumour promotion effect of catechol was studied on rat Fischer 344, treated by drinking water for 78 weeks or by instillation into urinary bladder for 15 weeks (30 rats per group) with catechol, with or without BBN. The concentrations of Catechol tested were 0.05% (50 mg/kg/d) in drinking water and 1 - 2% by direct instillation.

Animals receiving catechol alone in drinking water presented no effects.

The control group treated by instillation into urinary bladder presented papillomas, hence the interpretation of results by this route of exposure was not possible

- The study of Kawabe (1994) studied the tumour promotion effect of catechol on Rat (20 per group). Catechol was administered in diet at 0.8% (ca. 480 mg/kg bw/day) for 57 weeks after pre-treatment with 150 mg/kg bw of MNNG. The carcinogen effects were observed on glandular stomach and forestomach.

 

- The study of Yamagushi (1989) was a tumours promotion study. Catechol was administered in diet to rat (10/group) at 0.8% (ca. 480 mg/kg bw/day after pretreatment by i.p. of MNAN at 25 mg/kg bw.

The carcinogen effects were observed on forestomach, glandular stomach, nasal cavity, lung and tongue.

 

- In the study of Okasaki (1993), the tumour promotion effect of catechol was studies on Rat for 36 weeks. Catechol was administerd in diet at 0.8% (ca. 480 mg/kg bw/day) after pre-treatment with 0.1% of EHEN administered in drinking water for 3 weeks. No carcinogen effects were reported but toxic effects were observed on liver, kidney and body weight.

 

- In the study of Hirose (1991), the tumour promotion effect of catechol was studied on Rat (15 per group). The animals received 150 mg/kg bw of MNNG by gavage and 0.2 % of Catechol alone or in combination with other substances. After treatment with MNNG and catechol: Hyperplasia, oedema, were observed on glandular stomach. No adenocarcinoma was observed.

- In the study of tumour promotion of Hirose (1990), rats (10 /group) received for 28 weeks, catechol in diet at 0 or 0.8% (ca. 480 mg/kg bw/day). Animals were pre-treated for 4 weeks of multiple initiation period with DEN, DHPN and NaNO2 by i.p,s.c.administration or drinking water.

* With carcinogen pre-treatments

- Final body weights of animals treated with catechol decreased.

- In the glandular stomach, all rats (15/15) treated with catechol had submucosal hyperplasia, 12 of 15 had adenomas and 4 of 15 adenocarcinomas.

- In the liver, numbers and/or areas of GSTP-P-positive foci were reduced by the catechol treatment.

- In the other organs examined, catechol was shown to significantly reduce the incidence of thyroid follicular cell hyperplasia from 64% (basal diet) to 7% (catechol and catechol +NaNO2, p < 0.01), the incidence of follicular cell adenoma from 29% (basal diet) to 0% (catechol +NaNO2, p < 0.05) and the incidence of kidney nephroblastoma from 36% (basal diet) to 0% (catechol, p < 0.05). At the opposite, papilloma of oesophagus were increased to 50% after treatment with catechol +NaNO2 (p < 0.01) (was 0 in the basal diet group).

 

* Without carcinogen pre-treatments:

- Final body weights of animals treated decreased

- The stomach contents and forestomach epithelia of rats treated with NaNO2 plus catechol demonstrated blackening and marked papillary projections with dense keratin-like material being evident scattered throughout the epithelium. Only mild hyperplasias were observed in the forestomach of 5 rats of the 10 that received catechol alone treatment.

- In the glandular stomach, all rats treated with catechol had submucosal hyperplasia and adenomas (10/10). The incidences of these lesions were remarkably reduced by combined treatment with NaNO2 (submucosal hyperplasia: 3/10 and adenomas: 1/10). None of them showed adenocarcinomas.

 

- In the tumour promotion study of Kurata (1990), rats (20/group) received for 4 weeks a pretreatment of BBN in drinking water and for 32 weeks 0.8% of catechol in diet . Incidence of papillomas and carcinoma were slightly increase when rat received BBN + catechol compared to rat that received BBN alone.

- In the tumour promotion study of Hasegawa (1992), rats (15/group) were feed at 0.2 and 0.8 % in diet with catechol for 6 weeks. A pre-treatment by i.p. was done with 200 mg/kg bw of DEN. Main examination was done on liver with injection of BrdU before sacrifice. The body weight decrease (20%) in group treated at 0.8%. The incorporation of BrdU was increased in liver in a dose dependent manner. At 0.8% only, number of foci induction was suppressed and GST-P positive liver foci decreased indicating that glutathion rate decreased, probably to detoxify after exposure to 0.8% of catechol.

- In the tumour promotion study of Hasegawa (1990), rats (20 per group) received in drinking water 0.1% of DHPN for 2 weeks in pre-treatment or alone and 0.8% of catechol for 30 weeks. A group of rats received also only catechol treatment.

DHPN alone produced carcinogen effect on kidney, thyroid and lung.

The treatment with DHPN and catechol seemed decrease the incidence of effect after treatment with DHPN alone. Treatment with catechol alone had no effect (carcinoma or adenoma) on lungs, kidneys and thyroid, it induced submucosal and adenomatous hyperplasia in pyloric region of glandular stomach.

 

- In the tumour promotion study of Fukushima (1991), rats (15 per group) were feed for 16 weeks with or without 0.8% of catechol. The animals received by pre-treatment one i.p. injection of 100 mg/kg of DMP and 4 i.p. injections of 20 mg/kg of MNU and DHPN.

GST-P positive foci were measured. Catechol inhibited effect of GST-P positive foci and induced hyperplasia on forestomach and adenoma on glandular stomach. These effects increased after pre-treatment with DMP. Catechol had no effect on urinary bladder, thyroid, lung and oesophagus.

 

- In the tumour promotion study of Kajimura (1992), rats (15 per group) received catechol at 0.8% for 16 weeks after pre-treatment with DMD.

Hyperplasia and papillomas of the forestomach and submucosal glandular stomach were observed after treatment with catechol.

Carcinogen effects or hyperplasia were observed on urinary bladder, forestomach, glandular stomach and pyloric glands after treatment with DMD and catechol.

 

- In the tumour promotion study of Kobayashi (1999), mice (8 or 10 per group) received catechol in diet for 50 weeks at concentrations of:0.48,2.4, 12 or 16 mg/kg/d. Animals were pre-treated with MNU in drinking water for three weeks period at 120 ppm. In the MNU-catechol treated groups receiving catecholat 12or 16 mg/kg/d, an appreciable enhancement of pepsinogen 1 altered pyloric glands was noted. The incidences of adenomatous hyperplasias and carcinomas were affected in any of the catechol- treated groups as compraed with control.

Thus, the administration of catechol in the diet at low doses enhanced only preneoplastic, lesion development and not neoplastic lesion development.

 

- In the tumour promotion study of Kobayashi (199), mice (10 per group) were feed with diet containing0.05,0.2, 0.8 % of catechol for 35 weeks. Animals received a pre-treatment with MNU for 1 week in drinking water. Pepsinogen isoenzyme 1 (PAPG) was measured in stomach after necropsy. Decrease in body weight was observed after administration of Catechol with or without pre-treatment with MNU.

- In the group treated with MNU and catechol, the authors observed an increase in PAPG in dose dependent manner, adenoma and adenocarcinoma. Catechol had a promotion effect.

 

- In the study of Maruyama (1994), Hamster (5 per group) were feed (diet) for 30 weeks with 1.5% of catechol. Animals received a pre-treatment by subcutaneous injection once a week for 5 weeks at 500 mg/kg of BHP (an inducer of pancreatic tumours). Body weight decrease and liver weight increase. The combined multiplicity of pancreatic atypical hyperplasias and adenocarcinomas in hamsters from group treated with 1.5% catechol after BHP were significantly (p < 0.02) decreased when compared to control group. The multiplicity of cancers was lower in catechol-treated group than in BHP alone-treated group. - No liver lesions were found in hamsters administered catechol after saline. The incidences of gall bladder papillomas and carcinomas were not significantly different between group treated with 1.5% catechol after BHP and BHP alone-treated group.

 

- In the study of Maruyama (1991), the tumour promotion effect was studied on female Hamster (5 per group), treated by oral feed for 20 weeks with 0.75 or 1.5 % (c.a. 900 or 1800 mg/kg bw) of catechol. Animals received a pre-treatment with subcutaneous injection of 70 mg/kg bw of BOP (an pancreatic inducer). The authors observed a decrease in body weight and liver weight. No neoplastic lesions were evident in hamsters administered catechol after saline or BOP. The numbers of atypical pancreatic hyperplasias and adenocarcinomas in hamsters treated with 0.75% catechol after BOP were significantly decreased when compared to control group (BOP). 

No liver lesions were found in hamsters administered catechol after saline. Hepatocellular carcinomas were detected at an incidence of 1.7% in the group treated with 1.5% catechol after BOP (BOP control group: incidence = 5.6%). According to the authors, results indicate that catechol exerted a weak inhibitory effect on pancreatic carcinogenesis after initiation of female hamsters with BOP at low dose of 0.75 %