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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1968
Report date:
1968
Reference Type:
study report
Title:
Unnamed
Year:
1969
Report date:
1969

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
yes
Remarks:
(no neurobehavioural assessment and no detailed clinical examinations, no ophthalmoscopic examinations)
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Bumetrizole
EC Number:
223-445-4
EC Name:
Bumetrizole
Cas Number:
3896-11-5
Molecular formula:
C17 H18 Cl N3 O
IUPAC Name:
2-tert-butyl-6-(5-chloro-2H-benzotriazol-2-yl)-4-methylphenol
Test material form:
solid
Specific details on test material used for the study:
- Name of test material (as cited in study report): CH 3504

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Central Instititute for Nutrition and Food Research colony
- Age: Weanling rats
- Weight at study initiation: males, 45 - 64 g; females 45 - 62 g
- Housing: Wire screen cages (5 to a cage)
- Diet: ad libitum
- Water: ad libitum
- Acclimation: no data

ENVIRONMENTAL CONDITIONS: no data

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): every 2 weeks
- Mixing appropriate amounts with stock diet (see table 1 for composition)



Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
25 mg/kg bw/day (actual dose received)
Remarks:
males (dose equivalent to 400 ppm nominal concentration. Calculated by average food consumption and average body weights after 13 weeks)
Dose / conc.:
62 mg/kg bw/day (actual dose received)
Remarks:
males (dose equivalent to 1000 ppm nominal concentration. Calculated by average food consumption and average body weights after 13 weeks)
Dose / conc.:
153.9 mg/kg bw/day (actual dose received)
Remarks:
males (dose equivalent to 2500 ppm nominal concentration. Calculated by average food consumption and average body weights after 13 weeks)
Dose / conc.:
637.4 mg/kg bw/day (actual dose received)
Remarks:
males (dose equivalent to 10,00 ppm nominal concentration. Calculated by average food consumption and average body weights after 13 weeks)
Dose / conc.:
28.9 mg/kg bw/day (actual dose received)
Remarks:
females (dose equivalent to 400 ppm nominal concentration. Calculated by average food consumption and average body weights after 13 weeks)
Dose / conc.:
70.6 mg/kg bw/day (actual dose received)
Remarks:
females (dose equivalent to 1000 ppm nominal concentration. Calculated by average food consumption and average body weights after 13 weeks)
Dose / conc.:
176 mg/kg bw/day (actual dose received)
Remarks:
females (dose equivalent to 2500 ppm nominal concentration. Calculated by average food consumption and average body weights after 13 weeks)
Dose / conc.:
740.1 mg/kg bw/day (actual dose received)
Remarks:
females (dose equivalent to 10,00 ppm nominal concentration. Calculated by average food consumption and average body weights after 13 weeks)
No. of animals per sex per dose:
10
Control animals:
yes, plain diet

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes; mortality and abnormalities in condition and behaviour

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: once per week

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes, but as g food/rat/day
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
- Time schedule for examinations: in the fisrt 4 weeks and then in week 11 and 12

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: 12th week
- Anaesthetic used for blood collection: no data
- Animals fasted: no data
- How many animals: all animals
- Parameters checked in table No. 2 were examined.

CLINICAL CHEMISTRY: Yes
- How many animals: 5 animals/sex/dose
- Parameters checked: glutamic pyruvic transaminase (SGPT), glutamic oxalo-acetic transaminase (SGOT) and alkaline phosphatase (SAP), glucose-6-phosphatase (G6Pase) and glucose-6- phosphate dehydrogenase (G6PD).

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No


Sacrifice and pathology:
GROSS PATHOLOGY: Yes
- Organ weight: heart, liver, kidney, spleen, testicle/ovary, thymus, pituitary, thyroid and adrenal

HISTOPATHOLOGY: Yes
- How many animals: all animals of the control and high dose groups
- Parameters checked: heart, *liver, *kidney, spleen, testicle/ovary, thymus, pituitary, *thyroid and adrenal, lung, salivary glands (sub-maxillary, sub-lingual and parotid), prostate, epididermis, coagulating gland, seminal vesicle, trachea, oesophagus, thoracic aorta, spinal cord, femoral nerve, skeletal muscle, uterus, preputial gland, external lacrimal gland, fore- and glandular stomach, duodenum, ileum, caecum, mandibular and mesenteric lymph nodes, pancreas, urinary bladder, skin and bone marrow (sternum).

*checked in the 400, 1000 and 2500 ppm dose groups

Results and discussion

Results of examinations

Details on results:
CLINICAL SIGNS AND MORTALITY: No deaths occurred and no abnormalities in condition or behaviour were observed.

BODY WEIGHT AND WEIGHT GAIN: There were no significant differences between the treated and control rats.

FOOD CONSUMPTION AND COMPOUND INTAKE: There was no compound effect at any of the dosing intervals.

FOOD EFFICIENCY: There was no compound effect at any of the dosing intervals.

HAEMATOLOGY: The haemoglobin content and packed cell volume of males were slightly, though significantly (p < 0.01) decreased at the 1000, 2500, and 10000 ppm feeding levels by 6, 6.6 and 5.4% compared to controls for haemaglobin content and at 2500 and 10000 ppm feeding levels by 5.6 and 5.1% compared to control for packed cell content. At the respective lower feeding levels these effects were not observed. These small differences did not show a dose relationship. In females, such effects were not seen. Therefore the low values in males are not explained as compound effects but rather as the result of relatively high values in male controls except for a slight decrease in haemoglobin content at 0.1% females, however, no distinct differences in haematological data between the treated and control rats were noticed.

CLINICAL CHEMISTRY: The alkaline phosphatase activity of females was slightly decreased at the highest feeding level. A trend towards lower SAP activity with increasing levels of the compound was not observed. A slight increase in G6Pase activity at the two highest levels in either sex was noticed.

ORGAN WEIGHTS: None of the organs showed considerable differences between groups. Relative weights of liver and kidney in percent of body weight were slighly increased at the highest feeding level. The difference was significant in females only. Kidney increased by 6% conpared to controls (p < 0.05) and liver increased by 10.7% compared to controls (p < 0.01).

GROSS PATHOLOGY: Gross autopsy findings were essentially negative.

HISTOPATHOLOGY: NON-NEOPLASTIC: No changes were fond in spleen, brain, testicle, epididymis, ovary, thymus, pituitary, submaxillary and partotid gland, seminal vesicle, coagulating gland, aorta, spinal cord, femoral nerve, oesophagus, stomach, duodenum, ileum, manibular and mesenteric lymph nodes, uterus, skin and bone marrow. The abnormalities that were found in liver, kidneys, thyroid, lungs, trachea, heart, bladder, caecum, colon, sublingual muscle, preputial gland and prostate are common findings in the strain of rat used. Some of the abnormalities, e.g. nephrocalcinosis in kidneys, activated appearance of the thyroid gland and interstitial pneumonitis (lung) occurred more frequently and to a distinctly higher degree in one or several test groups than in the control group. However, the incidence of all three phenomena in the control group was strikingly low and, moreover, their severity in treated animals was not dose-dependent. Therefore, none of the histopathological changes observed may be ascribed to the ingestion of the test substance.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Remarks:
(systemic)
Effect level:
ca. 637 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: corresponding to 10000 ppm in diet. No adverse effects seen in any parameter at the highest dose level tested.
Dose descriptor:
NOAEL
Remarks:
(systemic)
Effect level:
ca. 740 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: corresponding to 10000 ppm in diet. No adverse effects seen in any parameter at the highest dose level tested.

Target system / organ toxicity

Critical effects observed:
no

Any other information on results incl. tables

Table 3: Average body weights (g) after 12 weeks

 

 

Week

 

 

0

2

4

6

8

10

12

 

Concentration

 

 

 

 

 

 

 

Male

0

52.6

111.6

179.2

235.4

271.6

292.6

311.6

400

52.8

113.8

182.6

239.3

274.6

291.3

310.3

1000

52.6

117.8

193

254.3

287.5

309.1

331

2500

52.9

115.1

184.6

249.2

284.7

304.6

328.1

10000

53

111

176.9

235

272.6

293.9

313.2

 

 

 

 

 

 

 

 

 

Female

0

51.2

97.3

129.2

152.8

170.6

182.3

186.1

400

51.1

100.3

131.2

154.7

170

182.7

189.6

1000

51

96.9

126.6

151

169.7

181.7

187.9

2500

51

98.2

130.5

154.4

172.2

184.3

192

10000

50.9

94.8

130.5

158.3

175

185.4

193.7

 

Table 4: Average food consumption in g/rat/day after 12 weeks and food efficiency

 

Average food consumption

 

Food efficiency

 

Week

 

weeks

 

 

1

2

3

4

11

12

 

1 to 4

11 + 12

Male

0

8.3

11.8

14.3

16.5

16.2

16.5

 

0.35

0.08

400

8.3

13

14.9

17.4

15.8

18.7

 

0.35

0.08

1000

8.8

12.8

15.8

18.2

16.4

17.9

 

0.36

0.09

2500

8.7

12.5

15.4

17.4

16.4

17.3

 

0.35

0.10

10000

8.3

12.4

14.8

16.8

17

17.6

 

0.34

0.08

 

 

 

 

 

 

 

 

 

 

 

Female

0

7.7

10.2

11

11.3

10.6

10.5

 

0.28

0.03

400

8.6

11.1

12.1

12.2

11.3

11.7

 

0.26

0.04

1000

8

10.6

11.4

11.7

11.9

10.9

 

0.26

0.04

2500

7.9

11.1

11.9

12

11.1

11.6

 

0.27

0.05

10000

7.7

11

12.9

13

12.3

12.5

 

0.25

0.05

 

Applicant's summary and conclusion