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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with restrictions (only two dose levels, limited documentation (clinical signs, gross pathology))
Cross-reference
Reason / purpose:
reference to same study
Reference
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 two dose levels, limited documentation (clinical signs, gross pathology)
Reason / purpose:
reference to same study
Principles of method if other than guideline:
The carcinogenicity of glycine was assessed in rats by application in the drinking water.
GLP compliance:
no
Species:
rat
Strain:
Fischer 344/DuCrj
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Co. Japan, Inc. Atsugi
- Age at study initiation: 6 wks
- Housing: in plastic cages (3/sex/cage)
- Diet (ad libitum): pellet diet (CRF-1, Charles River, Japan)
- Water (ad libitum)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 ± 2
- Humidity (%): 55 ± 5
Route of administration:
oral: drinking water
Vehicle:
unchanged (no vehicle)
Duration of treatment / exposure:
108 wks
Frequency of treatment:
continuously via drinking water
Dose / conc.:
2.5 other: % (nominal in water)
Remarks:
equivalent to 1534 mg/kg bw/day for males and 1587 mg/kg bw/day for females (actual ingested)
Dose / conc.:
5 other: % (nominal in water)
Remarks:
equivalent to 3280 mg/kg bw/day for males and 3082 mg/kg bw/day for females (actual ingested)
No. of animals per sex per dose:
50
Control animals:
other: drinking water without test substance
Details on study design:
- Dose selection rationale: on the basis of a preliminary subacute experiment (not further specified)
Observations and examinations performed and frequency:
BODY WEIGHT: Yes
- Time schedule for examinations: every one or two weeks

FOOD CONSUMPTION: Yes
- Time schedule for examinations: every four weeks

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: daily

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at week 108
- How many animals: all survivors
- Parameters checked: white/red blood cells, heamoglobin (Hb), haematocrit (Ht)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at week 108
- How many animals: all survivors
- Parameters checked: glutamic oxalacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), creatine phosphokinase (CPK), blood urea nitrogen (BUN), creatinine (CRE), Urea (UA), total protein (TP), albumin/globulin rate (A/G rate), blood glucose (BG), phospholipid (PL), total cholesterol (Tch), triglyceride (TG), natrium, potassium, calcium, chloride

URINALYSIS: Yes
- Parameters checked: leukocytes, nitrite, urobilinogen, protein, pH, ketone, glucose
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (all animals, including those that died or were sacrificed upon becoming moribund during the experiment)
HISTOPATHOLOGY: Yes (all organs were examined and samples were fixed in 10% buffered neutral formalin, embedded in paraffin, and routinely stained with hematoxylin and eosin; histological analysis of tumors in renal pelvis)
Statistics:
Wilcoxon t-test or chi-squared test
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
5% dose group: slightly increased mortality in females compared to controls
Mortality:
mortality observed, treatment-related
Description (incidence):
5% dose group: slightly increased mortality in females compared to controls
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
2.5 and 5% dose group: slight dose-dependent inhibition of mean body weight gain in both sexes
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
5% dose group: significant changes of Hb and HT in males and females
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
2.5 and 5% dose group, males and females: significantly changes in CPK, BUN, TP, Tch and TG were observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
2.5 and 5% dose group: papillary necrosis and transitional hyperplasia was observed in male and female animals (no cases seen in the controls)
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
2.5 and 5% dose group, females: kidney papillomas were seen, which were not observed in controls
Details on results:
CLINICAL SIGNS AND MORTALITY
Mortality of females of the high dose group was slightly increased when compared to controls (number of surviving females and males: 31, 46, 41 and 40, 45, 40 for the high, low, control group).

BODY WEIGHT AND WEIGHT GAIN
2.5 and 5% dose group, males and females: Mean body-weights were slightly but dose-dependently inhibited when compared to controls over the hole study period (only growth curves were given).

HAEMATOLOGY
5% dose group, males: A slight but not significant increase in white blood cells was observed. The Hb was significantly increased when compared to controls.
5% dose group, females: A slight but not significant increase in white blood cells and a slight but not significant decrease in red blood cells was observed. The Hb and HT were significantly decreased when compared to controls.
2.5% dose group, females: A slight but not significant increase in white blood cells and a slight but not significant decrease in red blood cells was observed.

CLINICAL CHEMISTRY
2.5 and 5% dose group, males and females: The CPK values were significantly decreased when compared to controls in both sexes and both dose groups. BUN was significantly increased in both sexes of the 5% dose group.
2.5 and 5% dose group, females: A significant and dose-dependent decrease of TP and Tch and a significant and dose-dependent increase in TG was observed.
Some sporadic effects on isolated parameters were observed which were considered as not treatement-related (see Table 1 "Any other information on results incl. tables").

URINALYSIS
No significant differences in urinalysis data between treated and control male and female animals were observed. The only change was increased numbers of erythrocytes in glycine-treated male and female rats. This was expected from haemorrhage in necrotic renal papillae (see histopathology).

ORGAN WEIGHTS
No significant effects on the relative organ weights were observed in the treated groups when compared to controls.

HISTOPATHOLOGY: NON-NEOPLASTIC
The incidences of papillary necrosis in the kidney of male rats fed 2.5 and 5% glycine were 4 and 7%, while the corresponding figures for females were 30 and 32%. Since necrosis of the renal papillae was limited to glycine-treated rats it was very likely linked to the induction of papillomas. Transitional hyperplasia in renal pelvis was observed in 2 female animals of the 2.5% dose group. Calcification indices in kidney were 39, 32 and 42% of the 0, 2.5 and 5% groups. Endometrial polyps in the uterus were increased in both treatment group females (see Table 2/3 "Any other information on results incl. tables").
Overall, for the males, tumors were found in 90% of the high dose group, 97% of the low dose group and in 90% of the controls, while the corresponding figures for females were 59, 65 and 39%. These tumors were considered to be spontaneous in nature (see Table 3 "Any other information on results incl. tables").

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
One renal cell tumor was seen in one male of the high dose group. Renal pelvis papillomas were found in 8% of the low dose group and in 6% of the high dose group females, but not in the controls. Since spontaneous tumors in this tissues are very rare, they were considered as treatment-related (see Table 3 "Any other information on results incl. tables").
Dose descriptor:
LOAEL
Remarks:
carcinogenicity
Effect level:
1 561 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: histopathology
Dose descriptor:
NOAEL
Remarks:
carcinogenicity
Effect level:
< 1 561 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: histopathology
Critical effects observed:
not specified

Table 1: Clinical chemistry data for rats treated with the test substance (mean values ± standard deviation)

 

Males

Females

Group (%)

0

2.5

5

0

2.5

5

No. of rats

40

45

40

41

46

31

GOT (K-U)

122 ± 72

120 ± 57

114 ± 27

130 ± 53

117 ± 40

136 ± 68

GPT (K-U)

51 ± 34

55 ± 37

53 ± 12

59 ± 22

56 ± 12

66 ± 16

LDH (K-U)

2879 ± 772

2710 ± 972

2514 ± 819

2572 ± 1369

2666 ± 836

2556 ± 952

ALP (KA-U)

16 ± 6

15 ± 5

17 ± 5

19 ± 9

19 ± 5

25 ± 7*

CPK (IU/L)

754 ± 321

563 ± 217*

509 ± 197*

706 ± 392

545 ± 160*

446 ± 158*

BUN (mg/dL)

18 ± 3

17 ± 2

21 ± 3*

18 ± 2

17 ± 2

21 ± 3*

CRE (mg/dL)

0.6 ± 0.07

0.5 ± 0.10*

0.5 ± 0.11*

0.5 ± 0.06

0.5 ± 0.06

0.5 ± 0.07

UA (mg/dL)

2.3 ± 1.5

1.9 ± 0.6

2.5 ± 1.3

2.8 ± 1.8

2.0 ± 0.9*

2.5 ± 1.7

TP (g/dL)

6.9 ± 0.5

6.6 ± 0.3*

6.8 ± 0.4

7.5 ± 0.7

7.1 ± 0.5*

6.8 ± 0.7*

A/G (rate)

0.6 ± 0.09

0.7 ± 0.06*

0.7 ± 0.06*

0.8 ± 0.07

0.8 ± 0.06

0.8 ± 0.09

BG (mg/dL)

131 ± 46

127 ± 30

140 ± 51

136 ± 35

127 ± 15

125± 27

PL (mg/dL)

216 ± 62

205 ± 54

214 ± 61

211 ± 37

205 ± 36

202 ± 34

Tch (mg/dL)

150 ± 51

130 ± 39

129 ± 42

117 ± 22

104 ± 19*

98 ± 17*

TG (mg/dL)

175 ± 82

162 ± 59

198 ± 78

154 ± 73

209 ± 102*

226 ± 105*

Na (mEq/L)

144 ± 2

141 ± 2*

143 ± 2

141 ± 3

139 ± 1*

141 ± 4

K (mEq/L)

5.3 ± 0.7

4.6 ± 0.8*

5.3 ± 1.0

5.0 ± 0.9

4.4 ± 0.5*

4.7 ± 0.8

Ca (mg/dL)

11.1 ± 0.9

10.3 ± 0.5*

11.2 ± 1.1

11.2 ± 1.4

10.6 ± 0.6*

10.7 ± 1.1

Cl (mEq/L)

99 ± 1.9

101 ± 2.3*

99 ± 3.5

99 ± 2.0

98 ± 2.3

97± 4.3

*p<0.05, compared to control

Table 2: Histological findings for the urinary system for rats treated with the test substance

No. of affected rats (%)

 

Males

Females

Test substance concentration (%)

0

2.5

5

0

2.5

5

Effective No. of rats

40

45

40

41

46

31

Urinary system

 

 

 

 

 

 

Kidney

 

 

renal cell tumor

0

0

1(2)

0

0

0

papillary necrosis

0

2(4)

3(7)

0

14(30)

10(32)

calcification

0

0

0

16(39)

15(32)

13(42)

Pelvis

 

 

transitional hyperplasia

0

0

0

0

2(4)

0

transitional cell tumor

1(2)

0

0

0

0

0

papilloma

0

0

0

0

4(8)

2(6)

Table 3: Organ distribution and histological diagnosis for tumors in rats treated with the test substance

 

No. of affected rats (%)

 

Males

Females

Test substance concentration (%)

0

2.5

5

0

2.5

5

Effective No. of rats

40

45

40

41

46

31

Tumor development

 36(90)

44(97) 

36(90) 

 27(59)

30(65) 

12(39) 

Genital system

Testis

interstitial cell tumor

35(87)

44(97)

36(90)

-

-

-

Prostate

adenoma

1(2)

2(4)

2(4)

-

-

-

calcification

-

-

-

-

-

-

Uterus

endometrial polyp

-

-

-

5(12)

18(39)

12(38)

endometrial sarcoma

-

-

-

0

1(2)

0

adenocarcinoma

-

-

-

1(2)

0

0

Mammary gland

firboma

0

0

0

1(2)

0

0

adenoma

0

0

0

0

1(2)

1(3)

Endocrine system

Pituitary gland

adenoma

9(22)

6(13)

7(17)

13(31)

12(26)

9(29)

Thyroid gland

C-cell adenoma

4(10)

1(2)

3(7)

4(9)

3(6)

2(6)

C-cell carcinoma

0

2(4)

1(2)

1(2)

1(2)

0

papillary adenoma

1(2)

0

1(2)

0

2(4)

0

papillary adenocarcinoma

0

1(2)

0

0

0

0

Adrenal gland

pheochromocytoma

5(13)

7(15)

5(13)

0

1(2)

0

Pancreas

islet cell tumor

6(15)

1(2)

2(4)

0

1(2)

0

Digestive system

Liver

neoplastic nodule

1(2)

0

0

0

0

1(3)

Respiratory system

Lung

adenoma

0

2(4)

0

0

1(2)

0

Urinary system

Kidney

renal cell tumor

0

0

1(2)

0

0

0

transitional cell tumor

1(2)

0

0

0

0

0

papilloma

0

0

0

0

4(8)

2(6)

Urinary bladder

papilloma

0

0

0

0

0

0

Body cavity

Peritoneum

mesothelioma

2(5)

2(4)

1(2)

0

0

0

Hematopoietic system

Leukemia

 

4(10)

6(13)

3(7)

6(14)

9(17)

3(9)

Integument, musculoskeletal system

Subcutis

fibroma

3(8)

0

0

4(10)

2(4)

0

 

lipoma

0

1(2)

0

0

0

1(2)

 

preputial/clitoral gland tumor

3(6)

2(4)

2(4)

0

0

1(2)

 

fibrosarcoma

0

0

1(2)

0

0

0

Data source

Reference
Reference Type:
publication
Title:
Carcinogenicity study of glycine in Fischer 344 rats
Author:
Kitahori, Y. et al.
Year:
1994
Bibliographic source:
J Toxicol Pathol 7: 471-480

Materials and methods

Principles of method if other than guideline:
The carcinogenicity of glycine was assessed in rats by application in the drinking water.
GLP compliance:
no
Limit test:
no

Test material

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

Test animals

Species:
rat
Strain:
Fischer 344/DuCrj
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Co. Japan, Inc. Atsugi
- Age at study initiation: 6 wks
- Housing: in plastic cages (3/sex/cage)
- Diet (ad libitum): pellet diet (CRF-1, Charles River, Japan)
- Water (ad libitum)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 ± 2
- Humidity (%): 55 ± 5

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
unchanged (no vehicle)
Duration of treatment / exposure:
108 wks
Frequency of treatment:
continuously via drinking water
Doses / concentrationsopen allclose all
Dose / conc.:
2.5 other: %
Remarks:
nominal in water
Dose / conc.:
5 other: %
Remarks:
nominal in water
Dose / conc.:
1 534 mg/kg bw/day (actual dose received)
Remarks:
males
Dose / conc.:
3 280 mg/kg bw/day (actual dose received)
Remarks:
males
Dose / conc.:
1 587 mg/kg bw/day (actual dose received)
Remarks:
females
Dose / conc.:
3 082 mg/kg bw/day (actual dose received)
Remarks:
females
No. of animals per sex per dose:
50
Control animals:
other: drinking water without test substance
Details on study design:
- Dose selection rationale: on the basis of a preliminary subacute experiment (not further specified)

Examinations

Observations and examinations performed and frequency:
BODY WEIGHT: Yes
- Time schedule for examinations: every one or two weeks

FOOD CONSUMPTION: Yes
- Time schedule for examinations: every four weeks

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: daily

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at week 108
- How many animals: all survivors
- Parameters checked: white/red blood cells, heamoglobin (Hb), haematocrit (Ht)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at week 108
- How many animals: all survivors
- Parameters checked: glutamic oxalacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), creatine phosphokinase (CPK), blood urea nitrogen (BUN), creatinine (CRE), Urea (UA), total protein (TP), albumin/globulin rate (A/G rate), blood glucose (BG), phospholipid (PL), total cholesterol (Tch), triglyceride (TG), natrium, potassium, calcium, chloride

URINALYSIS: Yes
- Parameters checked: leukocytes, nitrite, urobilinogen, protein, pH, ketone, glucose
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (all animals, including those that died or were sacrificed upon becoming moribund during the experiment)
HISTOPATHOLOGY: Yes (all organs were examined and samples were fixed in 10% buffered neutral formalin, embedded in paraffin, and routinely stained with hematoxylin and eosin; histological analysis of tumors in renal pelvis)
Statistics:
Wilcoxon t-test or chi-squared test

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
5% dose group: slightly increased mortality in females compared to controls
Mortality:
mortality observed, treatment-related
Description (incidence):
5% dose group: slightly increased mortality in females compared to controls
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
2.5 and 5% dose group: slight dose-dependent inhibition of mean body weight gain in both sexes
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
5% dose group: significant changes of Hb and HT in males and females
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
2.5 and 5% dose group, males and females: significantly changes in CPK, BUN, TP, Tch and TG were observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
2.5 and 5% dose group: papillary necrosis and transitional hyperplasia was observed in male and female animals (no cases seen in the controls)
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
2.5 and 5% dose group, females: kidney papillomas were seen, which were not observed in controls
Details on results:
CLINICAL SIGNS AND MORTALITY
Mortality of females of the high dose group was slightly increased when compared to controls (number of surviving females and males: 31, 46, 41 and 40, 45, 40 for the high, low, control group).

BODY WEIGHT AND WEIGHT GAIN
2.5 and 5% dose group, males and females: Mean body-weights were slightly but dose-dependently inhibited when compared to controls over the hole study period (only growth curves were given).

HAEMATOLOGY
5% dose group, males: A slight but not significant increase in white blood cells was observed. The Hb was significantly increased when compared to controls.
5% dose group, females: A slight but not significant increase in white blood cells and a slight but not significant decrease in red blood cells was observed. The Hb and HT were significantly decreased when compared to controls.
2.5% dose group, females: A slight but not significant increase in white blood cells and a slight but not significant decrease in red blood cells was observed.

CLINICAL CHEMISTRY
2.5 and 5% dose group, males and females: The CPK values were significantly decreased when compared to controls in both sexes and both dose groups. BUN was significantly increased in both sexes of the 5% dose group.
2.5 and 5% dose group, females: A significant and dose-dependent decrease of TP and Tch and a significant and dose-dependent increase in TG was observed.
Some sporadic effects on isolated parameters were observed which were considered as not treatement-related (see Table 1 "Any other information on results incl. tables").

URINALYSIS
No significant differences in urinalysis data between treated and control male and female animals were observed.

ORGAN WEIGHTS
No significant effects on the relative organ weights were observed in the treated groups when compared to controls.

HISTOPATHOLOGY: NON-NEOPLASTIC
The incidences of papillary necrosis in male rats fed 2.5 and 5% glycine were 4 and 7%, while the corresponding figures for females were 30 and 32%. Since necrosis of the renal papillae was limited to glycine-treated rats it was very likely linked to the induction of papillomas. Transitional hyperplasia in renal pelvis was observed in 2 female animals of the 2.5% dose group. Calcification indices in kidney were 39, 32 and 42% of the 0, 2.5 and 5% groups (see Table 2 "Any other information on results incl. tables").

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
For the males, tumors were found in 90% of the high dose group, 97% of the low dose group and in 90% of the controls, while the corresponding figures for females were 59, 65 and 39%. These tumors were considered to be spontaneous in nature (see Table 3 "Any other information on results incl. tables").
One renal cell tumor was seen in one male of the high dose group. Kidney papillomas were found in 8% of the low dose group and in 6% of the high dose group females, but not in the controls. Since spontaneous tumors in this tissues are very rare, they were considered as treatment-related (see Table 3 "Any other information on results incl. tables").

Effect levels

open allclose all
Dose descriptor:
LOAEL
Effect level:
1 561 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: clinical chemistry; histopathology
Dose descriptor:
NOAEL
Effect level:
< 1 561 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
histopathology: non-neoplastic
histopathology: neoplastic

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Table 1: Clinical chemistry data for rats treated with the test substance (mean values± standard deviation)

 

Males

Females

Group (%)

0

2.5

5

0

2.5

5

No. of rats

40

45

40

41

46

31

GOT (K-U)

122 ± 72

120 ± 57

114 ± 27

130 ± 53

117 ± 40

136 ± 68

GPT (K-U)

51 ± 34

55 ± 37

53 ± 12

59 ± 22

56 ± 12

66 ± 16

LDH (K-U)

2879 ± 772

2710 ± 972

2514 ± 819

2572 ± 1369

2666 ± 836

2556 ± 952

ALP (KA-U)

16 ± 6

15 ± 5

17 ± 5

19 ± 9

19 ± 5

25 ± 7*

CPK (IU/L)

754 ± 321

563 ± 217*

509 ± 197*

706 ± 392

545 ± 160*

446 ± 158*

BUN (mg/dL)

18 ± 3

17 ± 2

21 ± 3*

18 ± 2

17 ± 2

21 ± 3*

CRE (mg/dL)

0.6 ± 0.07

0.5 ± 0.10*

0.5 ± 0.11*

0.5 ± 0.06

0.5 ± 0.06

0.5 ± 0.07

UA (mg/dL)

2.3 ± 1.5

1.9 ± 0.6

2.5 ± 1.3

2.8 ± 1.8

2.0 ± 0.9*

2.5 ± 1.7

TP (g/dL)

6.9 ± 0.5

6.6 ± 0.3*

6.8 ± 0.4

7.5 ± 0.7

7.1 ± 0.5*

6.8 ± 0.7*

A/G (rate)

0.6 ± 0.09

0.7 ± 0.06*

0.7 ± 0.06*

0.8 ± 0.07

0.8 ± 0.06

0.8 ± 0.09

BG (mg/dL)

131 ± 46

127 ± 30

140 ± 51

136 ± 35

127 ± 15

125± 27

PL (mg/dL)

216 ± 62

205 ± 54

214 ± 61

211 ± 37

205 ± 36

202 ± 34

Tch (mg/dL)

150 ± 51

130 ± 39

129 ± 42

117 ± 22

104 ± 19*

98 ± 17*

TG (mg/dL)

175 ± 82

162 ± 59

198 ± 78

154 ± 73

209 ± 102*

226 ± 105*

Na (mEq/L)

144 ± 2

141 ± 2*

143 ± 2

141 ± 3

139 ± 1*

141 ± 4

K (mEq/L)

5.3 ± 0.7

4.6 ± 0.8*

5.3 ± 1.0

5.0 ± 0.9

4.4 ± 0.5*

4.7 ± 0.8

Ca (mg/dL)

11.1 ± 0.9

10.3 ± 0.5*

11.2 ± 1.1

11.2 ± 1.4

10.6 ± 0.6*

10.7 ± 1.1

Cl (mEq/L)

99 ± 1.9

101 ± 2.3*

99 ± 3.5

99 ± 2.0

98 ± 2.3

97± 4.3

*p<0.05, compared to control

Table 2: Histological findings for the urinary system for rats treated with the test substance

No. of affected rats (%)

 

Males

Females

Test substance concentration (%)

0

2.5

5

0

2.5

5

Effective No. of rats

40

45

40

41

46

31

Urinary system

 

 

 

 

 

 

Kidney

 

 

renal cell tumor

0

0

1(2)

0

0

0

papillary necrosis

0

2(4)

3(7)

0

14(30)

10(32)

calcification

0

0

0

16(39)

15(32)

13(42)

Pelvis

 

 

transitional hyperplasia

0

0

0

0

2(4)

0

transitional cell tumor

1(2)

0

0

0

0

0

papilloma

0

0

0

0

4(8)

2(6)

Table 3: Organ distribution and histological diagnosis for tumors in rats treated with the test substance

No. of affected rats (%)

 

Males

Females

Test substance concentration (%)

0

2.5

5

0

2.5

5

Effective No. of rats

40

45

40

41

46

31

Tumor development

 

 

 

 

 

 

Genital system

Testis

interstitial cell tumor

36(90)

44(97)

36(90)

27(59)

30(65)

12(39)

Prostate

adenoma

35(87)

44(97)

36(90)

-

-

-

calcification

1(2)

2(4)

2(4)

-

-

-

Uterus

endometrial polyp

-

-

-

5(12)

18(39)

12(38)

endometrial sarcoma

-

-

-

0

1(2)

0

adenocarcinoma

-

-

-

1(2)

0

0

Mammary gland

firboma

0

0

0

1(2)

0

0

adenoma

0

0

0

0

1(2)

1(3)

Endocrine system

Pituitary gland

adenoma

9(22)

6(13)

7(17)

13(31)

12(26)

9(29)

Thyroid gland

C-cell adenoma

4(10)

1(2)

3(7)

4(9)

3(6)

2(6)

C-cell carcinoma

0

2(4)

1(2)

1(2)

1(2)

0

papillary adenoma

1(2)

0

1(2)

0

2(4)

0

papillary adenocarcinoma

0

1(2)

0

0

0

0

Adrenal gland

pheochromocytoma

5(13)

7(15)

5(13)

0

1(2)

0

Pancreas

islet cell tumor

6(15)

1(2)

2(4)

0

1(2)

0

Digestive system

Liver

neoplastic nodule

1(2)

0

0

0

0

1(3)

Respiratory system

Lung

adenoma

0

2(4)

0

0

1(2)

0

Urinary system

Kidney

renal cell tumor

0

0

1(2)

0

0

0

transitional cell tumor

1(2)

0

0

0

0

0

papilloma

0

0

0

0

4(8)

2(6)

Urinary bladder

papilloma

0

0

0

0

0

0

Body cavity

Peritoneum

mesothelioma

2(5)

2(4)

1(2)

0

0

0

Hematopoietic system

Leukemia

 

4(10)

6(13)

3(7)

6(14)

9(17)

3(9)

Integument, musculoskeletal system

Subcutis

fibroma

3(8)

0

0

4(10)

2(4)

0

 

lipoma

0

1(2)

0

0

0

1(2)

 

preputial/clitoral gland tumor

3(6)

2(4)

2(4)

0

0

1(2)

 

fibrsarcoma

0

0

1(2)

0

0

0

Applicant's summary and conclusion