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Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study with acceptable restrictions (Hematology and clinical chemistry was performed only in males; Urinalysis not conducted)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1990

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
yes
Remarks:
Hematology and clinical chemistry was performed only in males; Urinalysis not conducted
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Japan, Inc., Yokohama, Japan
- Age at study initiation: about 10 weeks
- Weight at study initiation: males: 329.9 - 4045.8 g (males), 217.6 - 254.9 g (females)
- Housing: stainless steel cage for administration period, policabonate cage with wood chip during gestation and lactation period
- Diet: ad libitum (MF, Oriental Yeast Co., Ltd., Itabashi-ku, Japan)
- Water: ad libitum
- Acclimation period: at least 13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 - 26
- Humidity (%): 53 - 61
- Air changes: 13 - 15 times/day
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
0.5% w/v sodium solution
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
Test item was diluted in the vehicle once or twice a week. Diluted test item was stored in dark and cool place.

VEHICLE
- Amount of vehicle (if gavage): 2.5 mL/kg
- Lot/batch no. (if required): M7T4661
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Detail information was not available.
Duration of treatment / exposure:
Males, 49 days
Females, from 14 days before mating to day 3 of lactation
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
4, 20 and 100 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on the result of preliminary study, maximum dose was set as 100 mg/kg bw/day.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily (before and after administration)

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: Day 1, 4, 8, 11, 15, 18, 22, 25, 29, 32, 36, 39, 43, 46 and 49 for males; Day 1, 4, 8, 11 and 15 during pre-mating, Day 0, 4, 7, 10, 14, 17 and 21 during gestation, Day 0 and 4 during lactation

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption: Yes

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: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: The day after last administration
- Anaesthetic used for blood collection: Yes (Pentobarbital)
- Animals fasted: Yes
- How many animals: all male animals
- Parameters checked: Leucocyte, erythrocyto, hemoglobin, hematocrit, platelet MCV, MCB, MCBC, reticulocyte, prothrombin time, APTT, fibrinogen, differential leucocyte count (eosinophil, neutro-stab., neutro-seg., lymphocyte, basophil and monocyte)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: The day after last administration
- Animals fasted: Yes
- How many animals: all male animals
- Parameters checked: total protein, albumin, A/G ratio, GOT, GPT, gamma GTP, ALP, total cholesterol, triglycerides, phospholipids, total bilirubin, glucose, creatinine, inorganic phosphorus, calcium, sodium, potassium, chloride.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

OTHER: Myelogram
- Time schedule for collection of blood: The day after last administration
- Animals fasted: Yes
- How many animals: all male animals
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
Bartlett test for body weight, food consumption, hematological result, myelogram, biochemistry result, duration of mating, count of estrus, estrous cycle, organ weight, gestational days, number of corpora lutea, number of implantations, number of litter, number of live newborns, body weight of live newbornes. In case of normal distribution, Dunnet multiple comparison was used to compare the control group. In case of not normal distribution, Steel multiple comparison was used. Chi-square test was used for percentage of succesful mating, percentage of the number of copulated, gestation inde and sex ratio of live newborns. Wilcoxon test was used for implant index, percentage of stillborns, birth index, sex ration of live newborns and viability index at day 4. Mann-Whitney U test was used for histopathological findings. For all test, p values < 0.05 was significant.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
No deaths
Mortality:
mortality observed, treatment-related
Description (incidence):
No deaths
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Depression of body weight gain in both sexes of the 100 mg/kg group bw/day
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Decrease of food consumption were observed in both sexes of the 100 mg/kg bw/day group.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Hematological examination showed decreases in reticulocyte rate and hematocrit values and shortening of the activated partial thromboplastin time and prothrombin time in males of the 100 mg/kg bw/day group.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Increase of albumin, A/G ratio, triglycerides, phospholipids, total bilirubin, BUN, creatinine, inorganic phosphorus and calcium, decrease of glucose, GOT, GPT and potassium (100 mg/kg bw/day, males), decrease in alkaline phosphatase (20 mg/kg bw/day)
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Weights of the liver, the spleen and the testis increased in males and/or females of the 100 mg/kg bw/day group.
Gross pathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
see "Details on results"
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
No mortality was observed.
One male in 100 mg/kg bw/day group lost hair of loin between day 8 and 47. One female of 100 mg/kg bw/day lost hair between 8 and 17 days of administration and between 0 and 19 days of festation. Another female (not pregnant) of 100 mg/kg bw/day group lost also hair from 21 to 37 days of administration.

BODY WEIGHT AND WEIGHT GAIN
Decrease in body weight was observed in both sexes of 100 mg/kg bw/day group until 8 days of administration. Thereafter, animals started to gain but the suppression of body weight gain was noted for a whole administration period.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Decrease in food consumption was observed in both sexes of 100 mg/kg bw/day group during the administration period. Females in 4 mg/kg bw/day group showed the decrease of food consumption at Day 4 and 8 and no changes were observed in 20 mg/kg bw/day group. Therefore, these slight changes were not considered as a toxicological effect caused by the test item.

HAEMATOLOGY
Hematological examination showed decreases in erythrocyte and hematocrit values, increase in MCV, MCH, MCHC and reticulocyte rate and shortening of the activated partial thromboplastin time and prothrombin time in males of the 100 mg/kg bw/day group. Increase in MCH and MCHC were observed in 20 mg/kg bw/day group. However the values were within the normal range and differences and therefore not considered toxicologically relevant . Shortening of prothrombin time and PTT didn't have a toxicological meaning since thrombus was not observed. In addition, neutro-seg of differential leucocyte count was increased and lymphocytes were decreased. However, these changes were not observed in higher dosing groups. It could be considered as not relevant changes.

CLINICAL CHEMISTRY
Blood chemical examination showed increases in albumin, the A/G ratio, triglycerides, phospholipids, total bilirubin, BUN, creatinine, inorganic phosphorus and calcium, decreases in glucose, GOT, GPT and potassium in males of the 100 mg/kg bw group, and decrease in alkaline phosphatase in males of the 20 mg/kg bw or more groups. Changes in calcium was considered as a secondly effect following increase in albumin. Test item could effect on kidneys.

ORGAN WEIGHTS
Relative and the absolute weight of the adrenals increased in males of 20 mg/kg bw/day and more groups. Relative and the absolute weight of thymus decreased in males of 100 mg/kg bw/day group. In 100 mg/kg bw/day group, the absolute weight of heart, thyroids, kidneys, epididymides decreased, and the relative weight of brain, lungs, liver, spleen and testes increased.
In females of 100 mg/kg bw/day group, the absolute weight of heart, thymus and ovaries decreased, and the relative weight of brain, lung, liver, spleen and kidneys increased. In addition, the absolute weight of heart decreased in females of 20 mg/kg bw/day group.
Changes in brain, lungs, heart and thyroids were observed only in absolute weight and there was not correspondent histopathological findings. Therefore, this change didn't have a toxicological meaning.

GROSS PATHOLOGY
One male in control group and three males of 100 mg/kg group showed black red spot in glandular stomach. One male of 100 mg/kg bw showed rough surface of kidney. Four males of 100 mg/kg bw showed enlargement of testis. In addition, one male of both control and 100 mg/kg bw group showed diaphragm hernia of liver, one male of 100 mg/kg bw group showed light gray macule of lung, one male of control group showed a white spot in testis, one male of 100 mg/kg bw group showed light gray nodule of testis, one male of control and 20 mg/kg bw group showed light gray nodule of epididymis.
One female of 100 mg/kg group showed atrophy of thymus at the terminal sacrifice. One female which was imminently sacrificed due to death of all newborns showed black red spot in mucosa of glandular stomach and light gray coloration of kidney. Three animals of 100 mg/kg bw group which were non-delivery showed no abnormalities. No abnormalities were also found in two non-pregnant females of 100 mg/kg bw group.

HISTOPATHOLOGY: NON-NEOPLASTIC
Two males and females of 100 mg/kg bw/day group showed centrilobular hypertrophy. One female of 100 mg/kg bw/day showed vacular degeneraion of hepatocyte. Nine males and six females showed basophilic material in bile duct. Two animals of both sexes in 100 mg/kg bw/day showed deposits of hemosiderin in the Kupffer cells in the liver. In glandular stomach, one male of control group and three males of 100 mg/kg bw/day showed erosion. This effect suggested that test item could cause toxicological effect on glandular stomach. One female of 100 mg/kg bw/day showed ulcer in glandular stomach. In the kidney, necrosis of the tubules in one female of 100 mg/kg bw/day group, basophilic tubules dilatation of tubules in two males of control and 20 mg/kg bw/day and all animals in both sexes of 100 mg/kg bw/day, infiltration of lymphocytes in nine males and eight females of 100 mg/kg bw/day, infiltration of neutrophil in one female of 100 mg/kg bw/day, dilatation tubule in one male and female of 100 mg/kg bw/day were noted. In the spleen, extramedullary hematopoiesis in three males and nine females and deposits of hemosiderin in the red pulp in all animals of both sexes of 100 mg/kg bw were noted. In the femur, decreased hematopoiesis was noted in eleven males of the 100 mg/kg bw group. In the thymus, atrophy was noted in one male and for females of 100 mg/kg bw/day group. In adrenal, necrosis of cortex was noted in one female of 100 mg/kg bw/day. The change in adrenal was not considered as a compound-related effect but it was caused by the stress of pregnant and delivery. In addition, no changes like this were found in other females and males. In the testis, dilatation of seminiferous tubule in four males, vacuolization of the Sertoli cells in two males, degeneration of germ cells in one male, multinucleated giant cells in one male were note in 100 mg/kg bw/day group. In the epididymis, infiltration of lymphocytes in two males, germ cell debris in the lumen in one male, edema in one male were noted in 100 mg/kg bw/day group. These effects on testis and epididymis were may be caused by the circulation disorder since these changes are similar to the effects caused by administration of cadmium chloride. However, fertility was not affected by the test item in males.
In addition, necrosis of hepatocyte, accumulation of foam cell, mineralization of artery, hemorrhage of lungs and thymus, myocardial degeneration, atrophy of seminiferous tubule, granuloma of spermatic of testis and epididymis were regarded as not relevant toxicological effect but changes caused naturally.

OTHER FINDINGS
Bone marrow examination showed decreases in nucleated cell counts and the M/E ratio, and decrease in cell counts of neutrophils, eosinophils, lymphocytes, basophilic erythroblasts, and polychromatophilic and orthochromatophilic erythroblasts in males of the 100 mg/kg bw/day group. Test item could inhibit hematopoiesis.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
20 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Decrease in body weight and food consumption in males and females. Effect on hematology and clinical chemistry in males.
Dose descriptor:
NOEL
Effect level:
4 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Effects on hematology and clinical chemistry in males at the dose levels 20 and 100 mg/kg bw/day

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Table 1. Body weights of male rats treated with the test item in the combined repeat dose and reproductive/developmental toxicity screening test

Group and dose

Control

4 mg/ kg bw

20 mg/kg bw

100 mg/kg bw

Days of treatment

Body weight (g)

1

370±17.6 (12)

370.6 ± 20.6 (12)

371.2 18.3 (12)

371.8 ±18.7 (12)

4

386.1 ± 21.3 (12)

384.2 ± 22.6 (12)

384.6 ± 19.6 (12)

358. 6 ± 22.7 ** (12)

8

397.6 ± 26.7 (12)

394.5 ±26.3 (12)

394.2 ± 22.2 (12)

323.4 ± 32.7 **

11

409.5 ± 30.5 (12)

405.2 ± 29.3 (12)

401.6 ±23.7 (12)

329.6 ± 27.2 ** (12)

15

419.7 ± 33.2 (12)

416.7 ±30.6 (12)

413.9 ± 25.4 (12)

337.3 ± 30.4 ** (12)

18

423.6 ± 35.1 (12)

422.2 ± 27.7 (12)

422.5 ± 27.6 (12)

333.3 ± 28.2 ** (12)

22

435.3 ± 37.9 (12)

433.3 ± 30.2 (12)

432.8 ± 28.5 (12)

338. 4 ±30.3 ** (12)

25

446.6 ± 39.9 (12)

443. 5± 32.3 (12)

440.4 ± 30.7 (12)

347.5 ± 33.9 ** (12)

29

457.2 ± 41.2 (12)

454.3 ± 33.7 (12)

450.4 ± 32.3 (12)

353.7 ±39.0** (12)

32

464.7 ± 41.8 (12)

463. 8 ± 35.6 (12)

458.3 ± 34.3 (12)

359.6 ±41.3 ** (12)

36

477.1 ± 43.4 (12)

478.3 ± 37.2 (12)

473.2 ± 38.7 (12)

368.3 ±40.9 ** (12)

39

487.0 ± 44.8 (12)

487.2 ± 37.6 (12)

482.0 ± 40.1 (12)

378.1 ± 41.7 ** (12)

43

495.7 ± 47.2 (12)

496.5 ±38.6 (12)

490.8 ± 41.2 (12)

386.2 ± 44.2 ** (12)

46

502.8 ± 47.1 (12)

502.6 ± 38.2 (12)

495.9 ± 41.1 (12)

389. 3 ± 39.8**

49

509.7 ± 48.5 (12)

512.3 ± 39.5 (12)

506.1 ± 42.6 (12)

394.3 ±38.2 ** (12)

**: p <0.01 (significantly different from control)

Values are mean ± SD and the values in parentheses represent the number of animals

 

Table 2. Body weights of female rats treated orally with the test item in the combined repeat dose and reproductive /developmental toxicity screening test

Group and dose

Control

4 mg/ kg bw

20 mg/kg bw

100 mg/kg bw

Days of treatment

Body weight (g)

Days of premating

 

1

231.6±9.0 (12)

234.9 ± 8.7 (12)

235.8 ± 18.3 (12)

235.6 ±8.1 (12)

4

241.4 ± 9.9 (12)

239.5 ± 8.5 (12)

241.5 ± 8.7 (12)

228. 3 ± 8.3 ** (12)

8

245.8 ± 11.6 (12)

245. 3 ± 10.8 (12)

247.1 ± 22.2 (12)

207.3 ± 13.1 **

11

248.3 ± 15.8 (12)

253.9 ± 12.4 (12)

251.1 ±11.8 (12)

224.0 ± 10.8. ** (12)

15

255.4 ± 17.1 (12)

259.1 ±14.6 (12)

258.8 ± 25.4 (12)

224.3 ± 10.8 ** (12)

Days of gestation

0

260.5 ± 15.5 (12)

260.0 ± 14.1 (12)

263.0 ± 13.9 (12)

224.8 ± 10.5** (12)

4

287.2 ± 16.8 (12)

280.4 ± 13.2 (12)

284.0 ± 18.3 (12)

232. 7 ±12.8 ** (12)

7

299.7 ± 17.1 (12)

294. 6 ± 10.8 (12)

296.5 ± 21.3 (12)

238.4 ± 9.4 ** (12)

10

311.0 ± 18.3 (12)

308.2 ± 13.7 (12)

308.2 ± 22.4 (12)

246.9 ±11.2** (12)

14

330.3 ± 19.6 (12)

326. 5 ± 13.9 (12)

327.2 ± 25.6 (12)

256.2 ±13.8 ** (12)

17

361.2 ± 22.0 (12)

359.5 ± 15.0 (12)

356.2 ± 25.4 (12)

272.8 ±20.6 ** (12)

21

409.9 ± 24.1 (12)

412.0 ± 16.4 (12)

408.2 ± 32.0 (12)

292.1 ± 34.0 ** (12)

Days of lactation

0

303.0 ± 18.9 (12)

293.9 ± 15.3 (12)

298.3 ± 30.3 (12)

238. 7 ± 7.9 (6)**

4

327.8 ± 19.4 (12)

322.2 ± 16.0 (12)

324.0 ± 33.5 (12)

254.2 ±15.3 ** (5)

**: p <0.01 (significantly different from control)

Values are mean ± SD and the values in parentheses represent the number of animals

 

Table 3. Food consumption of male rats treated with test item in the combine repeat dose and reproductive/developmental toxicity screening test

Group and dose

Control

4 mg/ kg bw

20 mg/kg bw

100 mg/kg bw

Days of treatment

Food consumption (g/day/rat))

2

26.7±2.5 (12)

26.0 ± 3.1 (12)

25.8 ± 3.1 (12)

17.7 ±3.5 ** (12)

4

28.4 ± 2.3 (12)

26.4 ± 2.6 (12)

27.1 ± 3.2 (12)

16. 9 ± 4.8 ** (12)

8

27.2 ± 3.1 (12)

25.8 ±2.1 (12)

26.6 ± 3.1 (12)

7.1 ± 7.5 **

11

27.7 ± 3.1 (12)

26.4 ± 3.4 (12)

27.0 ±3.2(12)

18.7 ± 3.1 ** (12)

15

26.4 ± 3.1(12)

25.4 ±2.3 (12)

25.8 ± 2.1 (12)

20.1 ± 4.2 ** (12)

30

26.4 ± 1.7 (12)

26.9 ± 2.2 (12)

26.5 ± 2.1 (12)

20.4 ± 4.3 ** (12)

32

27.6 ± 2.0 (12)

26.6 ± 2.1 (12)

26.4 ± 1.8 (12)

19. 4 ±4.3 ** (12)

36

27.0 ± 2.0(12)

27.3± 2.2 (12)

27.6 ± 2.7 (12)

21.1 ± 3.5 ** (12)

39

27.3 ± 2.3 (12)

27.1 ± 2.7 (12)

27.3 ± 2.4 (12)

21.1 ±4.1** (12)

43

27.1 ± 2.5 (12)

27. 3 ± 2.0 (12)

27.2 ± 2.9 (12)

24.0 ±8.0 ** (12)

46

28.9 ± 2.7 (12)

27.9 ± 2.3 (12)

27.6 ± 2.1 (12)

25.0 ±8.8 ** (12)

49

28.9 ± 2.4 (12)

29.2 ± 2.7 (12)

28.0 ± 2.9 (12)

23.3 ± 3.6 ** (12)

**: p <0.01 (significantly different from control)

Values are mean ± SD and the values in parentheses represent the number of animals

Table 4. Food consumption of females rats treated orally with test item in the combined repeat dose and reproductive/developmental toxicity screening test

Group and dose

Control

4 mg/ kg bw

20 mg/kg bw

100 mg/kg bw

Days of treatment

Body weight (g)

Days of premating

 

2

16.1±3.7 (12)

17.3 ± 2.7 (12)

16.9 ± 2.7 (12)

12.3 ±2.2 (12)**

4

20.7 ± 2.0 (12)

17.7 ± 3.1 *(12)

20.8 ± 2.4 (12)

12. 6± 2.2 ** (12)

8

21.0 ± 2.0 (12)

18.1 ± 2.3*(12)

20.2 ± 2.3 (12)

7.4 ± 5.0 ** (12)

11

18.7 ± 3.2 (12)

20.0± 1.5 (12)

19.6 ±1.9 (12)

16.1 ± 2.4. ** (12)

15

19.6 ± 3.2 (12)

20.3 ±1.5 (12)

20.7 ± 2.4 (12)

14.2 ± 3.8 ** (12)

Days of gestation

1

18.1 ± 2.1 (12)

16.1 ± 2.4 (12)

16.6 ± 3.4 (12)

10.2 ± 3.5** (12)

4

21.6 ± 2.4 (12)

19.8 ± 2.1 *(12)

20.9 ± 3.5 (12)

14.2 ± 3.3 ** (12)

7

22.4 ± 2.1 (12)

22. 0 ± 1.8 (12)

21.1± 3.0 (12)

13.6 ± 2.3 ** (12)

10

22.5 ± 2.6 (12)

22.0 ± 2.3 (12)

22.4 ± 4.1 (12)

14.0 ±2.4** (12)

14

22.0 ± 1.1 (12)

21.8 ± 2.4 (12)

21.4 ± 4.0 (12)

13.8 ±1.7 ** (12)

17

23.9 ± 1.8 (12)

24.0 ± 1.8 (12)

23.5 ± 33 (12)

14.7 ±3.1 ** (12)

21

17.7 ± 4.4 (12)

18.6 ± 3.8 (12)

18.7 ± 5.6 (12)

13.1 ± 3.0 ** (12)

Days of lactation

1

15.3 ± 6.7 (12)

12.9 ± 6.5 (12)

12.6 ± 8.0 (12)

13.0 ± 9.6 (6)

4

40.1 ± 4.4 (12)

37.1 ± 2.6 (12)

39.0 ± 5.9 (12)

25.0 ±4.1 ** (5)

**: p <0.01 (significantly different from control)

Values are mean ± SD and the values in parentheses represent the number of animals    

 

Table 5. Hematological findings of male rats treated orally with the test item in the combined repeat dose and reproductive/developmental toxicity screening test

Group and dose

Control

4 mg/ kg bw

20 mg/kg bw

100 mg/kg bw

No. of animals

12

12

12

12

Erythrocyte (10²/µL)

902 ± 30

905 ± 52

872 ± 29

806 ± 59**

Hematocrit (%)

48.5 ± 1.8

49.2 ± 2.9

47.7 ± 1.5

44.9 ± 3.0 **

MCV

54 ± 2

55 ±2

55 ± 2

56 ± 2*

MCH (pg)

17.0 ± 0.4

17.1 ± 0.6

17.7 ± 0.5*

18.8 ± 0.6 **

MCHC (%)

31.7 ± 0.5

31.5 ± 0.5

32.3 ± 0.6*

33.6 ± 0.5**

Reticulocyte (%)

33 ± 5

33 ± 2

35 ± 4

38 ± 5*

Prothrombin time (sec)

14.6 ± 1.8

14.8 ± 3.5

13.3 ± 1.4

12.0 ± 0.5 **

APIT (sec)

26.3 ± 2.7

24. 5± 2.8

25.1 ± 2.5

23.3 ± 2.7*

Lymphocyte (%)

86.3 ± 7.3

78.7 ± 5.5*

82.7 ± 8.6

84.9 ± 5.7

Neutro-Seg (%)

10.8 ± 6.1

18. 8 ± 4.7**

15.7 ± 8.2

13.5± 4.7

**: p <0.01 (significantly different from control)

Values are mean ± SD and the values in parentheses represent the number of animals 

Table 6. Biochemical findings of male rats treated orally with the test item in the combined repeat dose and reproductive/developmental toxicity screening tes

Group and dose

Control

4 mg/ kg bw

20 mg/kg bw

100 mg/kg bw

No. of animals

12

12

12

12

Albumin (g/dL)

3.6 ± 0.2

3.6 ± 0.2

3.6 ± 0.2

3.8 ±0.2**

A/G ratio

1.98 ± 0.17

2.06 ± 0.18

2.14 ± 0.24

2.47 ± 0.28 **

GOT (IU/I)

106 ± 18

103 ±19

93 ± 12

80 ±25**

GPT (IU/I)

25 ± 6

27 ± 7

23 ± 8

17 ± 5 **

ALP (IU/I)

192 ± 28

188 ± 49

158 ± 21*

132 ± 20**

Triglycerides (mg/dL)

32 ± 15

32 ± 10

40 ± 17

57 ± 25*

Phospholipidis (mg/dL)

89 ± 13

87 ± 11

90 ± 16

111 ±18 **

T.bilirubin (mg/dL)

0.0 ± 0.0

0.0 ± 0.0

0.0 ± 0.0

0.1 ± 0.0**

Glucose (mg/dL)

105 ± 15

115 ± 11

103 ± 14

74 ±7*

Creatinine (mg/mg/dL)

0.5 ± 0.1

0. 6 ± 0.1

0.5 ± 0.2

0.7. ± 0.2**

IP (mg/dL)

6.5 ± 0.5

6.7 ± 0.7

7.1 ± 0.7

7.9 ± 0.7**

Ca (mg/dL)

9.6 ± 0.4

9.7 ± 0.3

9.8 ± 0.2

10.4 ± 0.5 **

K (mgEq/L)

4.25 ± 0.18

4.29 ± 0.21

4.16 ± 0.12

4.05 ± 0.21*

Applicant's summary and conclusion

Executive summary:

Thiourea dioxide was studied for oral toxicity in rats in an OECD Guideline 422 combined repeat dose and reproductive/developmental toxicity screening test at doses of 0, 4, 20 and 100 mg/kg bw/day.