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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The purity of the test substance was known. The protocol was described in details but only one dose was tested. The results on the mucosal thickness and proliferative indices in the upper digestive tract of rats given guaiacol were detailed but the results on the other tissues were not reported. The GLP were not mentioned.

Data source

Reference
Reference Type:
publication
Title:
Effects of combined treatment with phenolic compounds and sodium nitrite on two-stage carcinogenesis and cell proliferation in the rat stomach.
Author:
Kawabe M., Takaba K., Yoshida Y., Hirose M.
Year:
1994
Bibliographic source:
Japonese Journal Cancer Research, 85, 17-25.

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Sub-acute study: Groups of five male F344 rats were given 2% guaiacol (approximately 1500 mg/kg bw) supplemented diet for 4 weeks and then killed under ether anesthesia.
GLP compliance:
not specified
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Guaiacol was purchased from Wako Pure Chemical Industries, Osaka, Japan: its purity was > 98.0 %.

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS:
- Source: Charles River Japan, Inc.
- Age at study initiation: 5 week old
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: 5 to a plastic cage on hardwood chip bedding
- Diet: Oriental MF basal diet (Oriental Yeast Co., Tokyo), ad libitum
- Water: tap water, ad libitum
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS:
- Temperature (°C): 22 +/- 2°C
- Humidity (%): no data
- Air changes: air conditionned room
- Photoperiod: 12h light / 12h dark

IN-LIFE DATES: no data

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
For 4 weeks
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
2% (1500 mg/kg bw - estimated by calculation)
Basis:
nominal in diet
No. of animals per sex per dose:
5
Control animals:
yes, concurrent no treatment
Details on study design:
Groups of five male F344 rats were given 2% guaiacol (approximately 1500 mg/kg bw) supplemented diet for 4 weeks and then killed under ether
anesthesia. They received a single ip injection of 20 mg/kg bw bromodeoxyuridine (BrdU) one hour before killing. Stomachs and esophagi were
removed and injected with 10 % buffered formalin solution.

Examinations

Observations and examinations performed and frequency:
EXAMINATIONS:
* CAGE SIDE OBSERVATIONS : No data
* DETAILED CLINICAL OBSERVATIONS : No data
* BODY WEIGHT: Yes
* FOOD CONSUMPTION AND COMPOUND INTAKE: No data
* FOOD EFFICIENCY: No data
* WATER CONSUMPTION AND COMPOUND INTAKE: No data
* OPHTHALMOSCOPIC EXAMINATION: No data
* HAEMATOLOGY: No data
* CLINICAL CHEMISTRY: No data
* URINALYSIS: No data
* NEUROBEHAVIOURAL EXAMINATION (FOB): No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Other examinations:
After opening along the greater curvature, six trips, 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 sections were stained with hematoxylin and eosin and used
for demonstration of anti-BrdU binding. The observations for the other tissues were not reported.
Mucosal thickness of the forestomach, of the glandular stomach and of the esophagus were measured and expressed as the mean of data for different areas within each region. For the analysis of BrdU labeling indices, the data were expressed as number of labeled cells / 100 basal cells in the esophagus and number of labeled cells / crypt in the glandular stomach, respectively.
Statistics:
Student's t test and Fisher's exact probability test were used for statistical evaluation of the data.

Results and discussion

Results of examinations

Body weight and weight changes:
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:
The body weights of animals treated with guaiacol were 10 to 33% less than the basal diet alone values.
Relative liver and kidney weights were increased by guaiacol. Significant increase in the thickness of the forestomach mucosa in the prefundic or mid
regions was observed in rats treated with guaiacol. In the glandular stomach and in the esophagus, either thickness or labeling indices were
significantly increased in rats given guaiacol.

Effect levels

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Dose descriptor:
NOAEL
Effect level:
< 1 500 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
other: Increase of relative liver and kidney weight and increase of the thickness of glandular stomach and oesophagus
Dose descriptor:
LOAEL
Effect level:
1 500 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
other: Increase of relative liver and kidney weight and increase of the thickness of glandular stomach and oesophagus

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Based on the test condition of this study, a LOAEL of 1500 mg/kg/day was identified in rats for an increase of relative liver and kidney weights and foran increase in the thickness of the glandular stomach and esophagus. Consequently the NOAEL for such effects is lower than 1500 mg/kg/day
Executive summary:

In a subacute toxicity study (Kawabe, 1994) Guaiacol was administered to 5 Fisher 344 male rats per dose in diet at dose levels of 2%, corresponding to 1500 mg/kg bw/day (estimated by calculation) for 28 days.

 

The body weights of animals treated with guaiacol were 10 to 33% less than the basal diet alone values.

Relative liver and kidney weights were increased by guaiacol. Significant increase in the thickness of the forestomach mucosa in the prefundic or mid regions was observed in rats treated with guaiacol. In the glandular stomach and in the esophagus, either thickness or labelling indices were significantly increased in rats given guaiacol. Forestomach is specific to rodents. Therefore, the thickness increase of the forestomach observed in rats is not physiologically relevant to humans.

Based on this study, a LOAEL of 1500 mg/kg b.w/day was identified in rats for an increase of relative liver and kidney weights and for an increase in the thickness of glandular stomach and esophagus. The NOAEL is consequently lower than 1500 mg/kg for such effects.

This subacute toxicity study in the Fisher rats satisfies the guideline requirement for a subacute oral study.