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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
toxicity to reproduction
Remarks:
other: subacute repeated dose study
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
Data is from study report

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2014
Report Date:
2012

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD 407
Principles of method if other than guideline:
Repeated dose 28- days oral toxicity study of test chemical was performed in Sprague Dawley (SD) rats to assess the reproductive toxicity.
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material
(as cited in study report): Methyl 2-naphthyl ether (MNE) (Batch no. 0001)
- Molecular formula
(if other than submission substance): C11H10O
- Molecular weight
(if other than submission substance): 158.19999999999999 g/mol
-Substancetype: Organic
-Physicalstate: Solid
-Impurities (identity and concentrations): Impurity : 1.34 %

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
No Data Available
Sex:
male/female
Details on test animals and environmental conditions:
- Source: Central Animal Facility (CAF), NIPER, Sector-67, S.A.S. Nagar, Punjab, India
- Age at study initiation: 7 to 8 weeks old
- Weight at study initiation: Male 184.38-234.56 g, Female 176.90-208.56 g
- Fasting period before study: No data available
- Housing: Four rats per sex per cage were housed in sterilized solid bottom polypropylene cages with stainless steel grill tops with bedding of clean paddy husk. The cages were suspended on stainless steel racks in a controlled environment.
- Diet (e.g. ad libitum): Standard laboratory sterile extruded pelleted rodent feed (Provimi Animal Nutrition India Pvt. Ltd, Bangalore, India), ad libitum
- Water (e.g. ad libitum): Potable tap water filtered through Reviva Reverse Osmosis System (water filter cum purifier), adlibitum
- Acclimatization period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3°C
- Humidity (%):30-70 %
- Air changes (per hr): 25 ± 5 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light

IN-LIFE DATES: From: 11.04.2014 (Male), 13.04.2014 (Female); To: 17.05.2014 (Male), 19.05.2014 (Female)

Administration / exposure

Route of administration:
oral: gavage
Type of inhalation exposure (if applicable):
not specified
Vehicle:
other: Dissolved the chemical in Groundnut oil.
Details on exposure:
Details on exposure
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food: No data available

VEHICLE
- Justification for use and choice of vehicle (if other than water): Groundnut oil
- Concentration in vehicle: 0, 125, 250 or 500 mg/kg body weight/day
- Amount of vehicle (if gavage): 5 ml/kg body weight
- Lot/batch no. (if required): No data available
- Purity: No data available 98.66%

Details on mating procedure:
- M/F ratio per cage: No data available
- Length of cohabitation: No data available
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy: No data available
- After successful mating each pregnant female was caged (how): No data available
- Any other deviations from standard protocol: No data available
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No Data Available
Duration of treatment / exposure:
28 days
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Dose / conc.:
125 mg/kg bw/day (actual dose received)
Dose / conc.:
250 mg/kg bw/day (actual dose received)
Dose / conc.:
500 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
Total animals: 56
Control: 7 males, 7 females
125 mg/kg/day: 7males, 7 females
250 mg/kg/day: 7 males, 7 females
500 mg/kg/day: 7 males, 7 females
Control animals:
yes, concurrent vehicle
Details on study design:
No Data Available
Positive control:
No Data Available

Examinations

Parental animals: Observations and examinations:
The mortality and changes in body weight, food consumption and water consumption were recorded.
Oestrous cyclicity (parental animals):
No data available
Sperm parameters (parental animals):
No data available
Litter observations:
No data available
Postmortem examinations (parental animals):
The testes, ovaries and uterus were pathologically examined after termination. Examinations also included weight of brain, testes and ovaries (incl. paired ovaries and uterus, including cervix).
Postmortem examinations (offspring):
No data available
Statistics:
Statistical analysis was carried out by using Microsoft Excel and IBM SPSS statistics version -20. All analyses and comparisons were evaluated at the 5 % level, statistically significant differences (p0.05) indicated by appropriate notation. PAIRED T-Testing procedure was used to check the significance between above mentioned groups. For multiple comparisons Turkey’s HSD test was applied.
Reproductive indices:
No data available
Offspring viability indices:
No data available

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Abnormalities such as nasal discharge, red crust around the nostrils was observed in all treatment groups. In addition, a few cases of snuffling, eye lid swelling and hunched back posture were also observed in the treated groups.
Dermal irritation (if dermal study):
not specified
Mortality:
mortality observed, non-treatment-related
Description (incidence):
All animals except two animals of high dose group survived throughout the treatment period.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Treatment with 500 mg/kg body weight/day showed a significant reduction in body weights in male rats on the first, second and fourth week of treatment. In female rats, a significant decrease in body weight was observed on the first, second and third week of treatment.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No difference was observed among the groups.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
No difference in water consumption was observed among the groups.
Ophthalmological findings:
no effects observed
Description (incidence and severity):
No difference in opthalmological changes was observed among the groups.
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
In male rats, significant increase in the platelet count was observed along with decrease in MCV and MCH levels at 125 mg/kg body weight/day.
Treatment with 250 mg/kg body weight/day showed significantly decreased values of hemoglobin and MCHC in male rats. The level of MCHC was also found to be significantly decreased when treated with 500 mg/kg body weight/day.

In female rats, treatment with 125 mg/kg body weight/day showed significant alterations in platelet count and MCV. At 250 mg/kg body weight/day, a significant decrease was noticed in neutrophils along with altered values of MCV in female rats.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
In female animals, the level of total bile acid was decreased at 250 mg/kg body weight/day. A significant increase was noticed in the level of estrogen in the same group. A similar trend was also noticed at 125 and 500 mg/kg body weight/day, but was statistically non-significant.

At 250 and 500 mg/kg body weight/day the levels of potassium and albumin were found to be significantly increased. The cholesterol level in the 250 mg/kg body weight/day group was noticed to be significantly elevated in the mid-dose group.

In male rats, the level of testosterone was significantly increased after treatment with 500 mg/kg body weight/day.
Urinalysis findings:
not specified
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
No statistically significant difference was observed in the motor activity scores for any dose group when compared with the control animals.
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
The absolute organ weight of ovaries from all treated groups was found to be decreased significantly in female rats.
Significant increase in the relative weights of heart and testes was also noticed at 500 mg/kg body weight/day.
In female rats, at all dose levels, the relative weight of ovaries was decreased in comparison to the control group animals.
The relative weight of uterus was also decreased in the 125 or 250 mg/kg body weight/day groups.

The weight of uterus was found to be significantly decreased in 250 or 500 mg/kg body weight/day-treated male and female rats.

The weight of spleen was decreased in the 250 mg/kg body weight/day groups while treatment with 500 mg/kg body weight/day resulted in the decreased weight of kidney in both female and male rats. However, the absolute organ weight of male animals does not show any significant difference.

In male rats, the relative weight of liver was noticed to be increased at 125 mg/kg body weight/day.

At 250 mg/kg body weight/day, the relative weights of brain and heart were significantly decreased in females.

A significant decrease in the relative weight of spleen was observed at 250 or 500 mg/kg body weight/day.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Nasal discharge, red crust around nostril, perineum wet, bloated stomach, viscous oily secretion was found inside the thoracic cavity.

Small white solid mass slightly firm in consistency floating inside the urinary bladder was observed.

However, due to adaptive metabolic and physiological changes, anoxic/ hypoxic conditions during anesthesia and terminal sacrifice, these findings were considered to be of no toxicological significance.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No remarkable changes observed in control and the 500 mg/kg body weight/day-treated animals.

A few microscopic findings observed in 500 mg/kg body weight/day-treated animals included collapsed lung with focal inflammation, focal fatty change and excess of lymphocytes in liver, inflammation in small intestine, reactive spleen and excess of mucous in colon. However, these findings were also observed in the control animals.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
not specified

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Effect level:
125 mg/kg bw/day
Based on:
test mat.
Sex:
male
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
water consumption and compound intake
ophthalmological examination
haematology
clinical biochemistry
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
other: No effect observed
Dose descriptor:
LOAEL
Effect level:
250 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
organ weights and organ / body weight ratios
other: effect observed on reproductive organs

Target system / organ toxicity (P0)

Critical effects observed:
yes
Lowest effective dose / conc.:
125 mg/kg bw/day (nominal)
System:
female reproductive system
Organ:
ovary
Treatment related:
yes
Dose response relationship:
not specified
Relevant for humans:
not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not specified
Other effects:
not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not specified

Effect levels (F1)

Dose descriptor:
other: not specified
Generation:
other: not specified
Based on:
not specified
Sex:
not specified
Basis for effect level:
other: not specified
Remarks on result:
not measured/tested

Target system / organ toxicity (F1)

Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified

Overall reproductive toxicity

Reproductive effects observed:
not specified
Treatment related:
not specified

Any other information on results incl. tables

SUMMARY OF BODY WEIGHTS(g)

Male

 

 

Group

 

Dose mg/kg

 

 

 

Day1

 

 

Day8

 

 

Day15

 

 

Day22

 

 

Day28

 

Terminal

Day

 

 

1

 

 

Vehicle

Mean

211.80

242.34

262.97

283.01

300.76

296.93

S.D.

14.03

14.91

16.29

24.57

26.41

27.19

 

S.E.M.

6.62

6.15

6.20

8.68

8.78

9.16

 

 

2

 

 

125

Mean

218.02

243.85

260.27

279.35

296.61

291.98

S.D.

9.56

11.42

11.59

14.54

14.88

14.86

 

S.E.M.

4.38

4.68

4.45

5.21

5.02

5.09

 

 

3

 

 

250

Mean

210.57

221.01

241.60

267.42

286.08

282.17

S.D.

9.82

26.98

30.11

23.54

25.05

24.52

 

S.E.M.

4.67

12.21

12.46

8.80

8.76

8.69

 

 

4

 

 

500

Mean

214.35

212.06

223.41

240.97

256.81

256.24

S.D.

10.64

10.08

11.64

13.72

6.86

9.27

 

S.E.M.

4.96

4.76

5.21

5.70

     2.67

3.62

 

SUMMARY OF BODYWEIGHTS(g)

Female

 

 

Group

 

Dose mg/kg

 

 

 

Day1

 

 

Day8

 

 

Day15

 

 

Day22

 

 

Day28

 

Terminal

Day

 

 

1

 

 

Vehicle

Mean

191.17

200.82

208.91

215.94

227.15

219.85

S.D.

7.12

12.39

16.56

15.30

17.64

19.32

 

S.E.M.

3.72

6.17

7.93

7.09

7.77

8.79

 

 

2

 

 

125

Mean

192.17

201.14

208.56

214.38

220.79

216.51

S.D.

9.31

10.16

8.58

7.62

10.76

10.09

 

S.E.M.

4.85

5.05

4.11

3.55

4.87

4.66

 

 

3

 

 

250

Mean

194.94

202.08

209.12

216.24

228.85

226.38

S.D.

9.45

8.89

8.24

7.85

7.51

8.75

 

S.E.M.

4.85

4.40

3.94

3.63

3.28

3.87

 

 

4

 

 

500

Mean

190.49

182.52

192.46

205.74

216.14

212.37

S.D.

8.82

9.74

12.73

11.46

11.61

12.10

 

S.E.M.

4.63

5.34

6.61

5.57

5.37

5.70

SUMMARY OF HEMATOLOGY DATA Male

Group/Dose

 

WBC

3

(x10/

mm3)

RBC

6

(x10/

mm3)

PLT (x10/mm3)

Hct

(%)

Hgb

(g/dl)

MCV(fl)

MCH (pg)

MCHC(g/dl)

Lym

%

Mon

%

Nut

%

Eos

%

 

Bas%

 

 

1/0

 

Mean

12.06

69.49

4.34

23.27

1.17

0.99

10.15

52.77

53.54

16.40

31.07

16.67

600.2

9

±S.D.

2.24

9.56

1.11

9.04

1.07

0.33

0.63

1.40

2.92

0.51

0.97

1.00

76.78

± S.E.M.

18.59

13.76

25.46

38.85

91.51

33.35

6.17

2.65

5.45

3.11

3.12

5.99

12.79

 

 

 

2/125mg/kg

 

Mean

12.09

69.73

4.57

22.04

2.19

0.71

10.16

50.24*

51.00

15.49*

30.83

15.73

1118.

00*

 

±S.D.

2.18

5.30

0.71

6.81

2.70

0.17

0.53

1.93

2.36

0.71

0.83

0.80

383.1

9

±

S.E.M.

0.8

2.0

0.3

2.6

1.0

0.1

0.2

0.7

0.9

0.3

0.3

0.3

144.8

 

 

 

3/250mg/kg

 

Mean

14.97

63.19

4.66

28.04

2.36

0.93

9.93

52.76

52.41

15.81

29.99

15.70

614.8

6

 

±S.D.

2.34

11.26

0.75

12.16

2.83

0.20

0.24

2.50

3.03

0.80

0.18

0.96

173.0

5

±

S.E.M.

0.9

4.3

0.3

4.6

1.1

0.1

0.1

0.9

1.1

0.3

0.1

0.4

65.4

 

 

 

4/ 500mg/kg

 

Mean

9.10

53.17

3.28

16.91

2.29

0.60

7.32

38.41

39.25

11.61

21.62

11.87

476.4

9

 

±S.D.

5.76

31.42

2.26

6.52

1.66

0.35

4.89

25.12

25.52

7.57

14.70

7.70

295.4

8

± S.E.M.

2.6

14.1

1.0

2.9

0.7

0.2

2.2

11.2

11.4

3.4

6.6

3.4

132.1

 

 

SUMMARY OF HEMATOLOGY DATA Female

emaleGroup/Dose

 

WBC (x103/mm3)

RBC (x106/mm3)

PLT (x103/mm3)

 

Hct

(%)

 

Hgb

(g/dl)

 

MCV(fl)

 

MCH (pg)

 

MCHC (g/dl)

 

Lym

%

 

Mon

%

 

Nut

%

 

Eos

%

 

Bas%

 

 

Vehicle

Mean

11.66

62.20

4.41

30.31

1.39

0.87

10.18

49.90

50.74

15.44

30.97

15.71

994.57

±S.D.

2.19

8.62

1.09

8.69

1.61

0.17

0.55

2.34

2.56

0.68

0.31

0.84

520.25

± S..E..M.

 

0.8

 

3.3

 

0.4

 

3.3

 

0.6

 

0.1

 

0.2

 

0.9

 

1.0

 

0.3

 

0.1

 

0.3

 

196.6

 

 

2      /

125mg/kg

 

Mean

 

12.28

 

67.97

 

4.34

 

25.10

 

0.94

 

0.90

 

10.13

 

51.66*

 

52.26

 

15.86

 

30.71

 

16.06

518.71

±S.D.

4.51

6.98

0.78

6.78

0.47

0.18

0.47

1.36

1.39

0.73

0.71

0.45

114.08

±S.E.M.

 

1.7

 

2.6

 

0.3

 

2.6

 

0.2

 

0.1

 

0.2

 

0.5

 

0.5

 

0.3

 

0.3

 

0.2

 

43.1

 

 

3    / 250mg/kg

Mean

11.94

69.24

4.13

21.83*

2.93

1.07

10.18

51.76*

52.76

15.71

30.37

15.99

585.00

±S.D.

3.21

7.96

0.54

7.77

2.71

0.24

0.45

1.55

3.36

0.75

1.44

1.17

213.78

±S.E.M.

 

1.2

 

3.0

 

0.2

 

2.9

 

1.0

 

0.1

 

0.2

 

0.6

 

1.3

 

0.3

 

0.5

 

0.4

 

80.8

 

 

4       /

500mg/kg

Mean

11.37

66.26

4.36

26.57

1.06

1.03

10.00

51.77

51.79

15.79

30.47

15.79

614.29

±S.D.

2.10

9.91

0.99

9.88

1.34

0.19

0.73

0.85

3.90

0.57

0.92

1.41

139.13

±S.E

.M.

 

0.8

 

3.7

 

0.4

 

3.7

 

0.5

 

0.1

 

0.3

 

0.3

 

1.5

 

0.2

 

0.3

 

0.5

 

52.6

 

SUMMARY OF CLINICAL BIOCHEMISTRY DATA Male Rats

Group/Dose

 

Sod.(mmol/L)

Pot.(mmol/L)

ALB(g%)

CHOL(mg%)

CRT(mg%)

SGOT(IU/L)

SGPT (IU/L)

GLU(mg%)

TP(g%)

BUN(mg%)

TBA

Test

ng/L

nmol/L

 

 

1   /  0

Mean

131.5

7.0

3.9

83.9

0.9

33.1

32.9

117.0

6.5

12.5

490.1

4.363

±S.D.

8.6

0.5

0.3

18.1

0.2

4.0

5.1

7.1

0.4

3.0

44.82

1.02

±S.E.M.

3.2

0.2

0.1

6.8

0.1

1.5

1.9

2.7

0.1

1.1

16.94

0.387

 

 

 

2  /125 mg/kg

Mean

130.0

7.6

3.7

87.6

0.9

33.9

32.5

119.1

6.5

14.4

485.4

5.421

±S.D.

3.3

0.7

0.3

10.7

0.2

8.2

7.6

4.9

0.5

3.0

36.17

1.03

±S.E.M.

1.2

0.3

0.1

4.0

0.1

3.1

2.9

1.9

0.2

1.1

13.67

0.392

 

 

 

 

 

3 /250 mg/kg

Mean

130.1

7.1

3.7

87.7

0.9

65.4

30.0

121.0

6.7

12.1

465.4

4.716

±S.D.

9.8

1.0

0.2

17.4

0.1

90.0

7.0

9.5

0.5

2.8

35.10

1.28

±S.E.M.

3.7

0.4

0.1

6.6

0.1

34.0

2.6

3.6

0.2

1.1

13.26

0.487

 

 

 

4 / 500 mg/kg

 

Mean

 

124.5

 

11.0

 

3.7

 

96.2

 

0.9

 

31.1

 

30.5

 

121.6

 

6.4

 

13.7

485.2

*

 

6.289*

±S.D.

11.1

8.4

0.3

12.1

0.2

7.5

6.4

13.8

0.5

4.0

23.33

0.398

 

±S.E.M.

 

5.0

 

3.8

 

0.1

 

5.4

 

0.1

 

3.3

 

2.8

 

6.2

 

0.2

 

1.8

 

10.43

 

0.178

 

SUMMARY OF CLINICAL BIOCHEMISTRY DATA - Female

 

Group

/Dose

 

Sod.

Pot.

ALB

CHOL

CRT

SGOT

SGPT

GLU

TP

BUN

TBA

Est

(mmol/L)

(mmol/L)

(g%)

(mg%)

(mg%)

(IU/L)

(IU/L)

(mg%)

(g%)

(mg%)

ng/L

ng/L

 

1        /

0 mg/kg

Mean

139.2

7.2

3.3

93.0

1.1

32.3

39.9

110.4

7.0

12.9

485

9.156

±S.D.

9.3

0.6

0.3

14.5

0.2

15.3

21.7

14.2

0.5

4.3

30.60

1.47

±S.E.M.

3.5

0.2

0.1

5.5

0.1

5.8

8.2

5.4

0.2

1.6

11.56

0.558

 

 

2     /

125 mg/kg

Mean

136.6

7.8

3.4

98.0

1.1

28.8

39.6

100.0

7.3

12.5

475.1

9.869

±S.D.

4.3

0.9

0.1

17.1

0.4

7.4

9.0

8.9

0.5

2.1

30.59

1.27

±S.E.M.

1.6

0.3

0.1

6.5

0.1

2.8

3.4

3.4

0.2

0.8

11.56

0.482

 

 

 

 

3     /

250 mg/kg

Mean

141.6

8.1

3.8

119.9

1.1

27.9

40.0

100.2

7.0

12.5

425.5*

10.478*

±S.D.

7.3

0.9

0.4

24.7

0.2

6.0

8.1

9.0

0.6

2.8

52.38

1.33

±S.E.M.

2.8

0.4

0.2

9.3

0.1

2.3

3.0

3.4

0.2

1.1

19.79

0.505

 

 

4     /

500 mg/kg

Mean

137.0

8.1

3.7

113.4

1.1

32.3

43.5

100.1

7.0

14.1

448.5

9.842

±S.D.

5.9

0.8

0.2

23.6

0.2

8.4

9.8

5.8

0.6

2.3

31.16

1.93

 

±S.E.M.

 

2.2

 

0.3

 

0.1

 

8.9

 

0.1

 

3.2

 

3.7

 

2.2

 

0.2

 

0.9

 

13.93

 

0.73

 

SUMMARY OF ABSOLUTE ORGAN WEIGHTS(g) - Male Rats

Group/ Dose

 

 

Brain

 

Thymus

 

Liver

 

Kidneys

 

Adrenals

 

Ovaries

 

Spleen

 

Heart

 

Epididymides

 

 

1

Vehicle

Mean

1.79

0.30

10.72

1.98

0.03

2.79

1.04

0.55

0.88

±S.D.

0.28

0.06

1.48

0.30

0.01

0.27

0.15

0.11

0.09

±S.E.M.

0.11

0.02

0.56

0.11

0.01

0.10

0.05

0.04

0.03

 

 

2

(125) mg/kg

 

Mean

1.89

0.46

11.54

2.09

0.07

2.75

1.05

0.54

0.89

 

±S.D.

0.12

0.16

0.70

0.11

0.08

0.22

0.06

0.13

0.08

±S.E.M.

0.05

0.06

0.26

0.04

0.03

0.08

0.02

0.05

0.03

 

3

(250)mg/kg

 

Mean

1.87

0.32

11.25

2.04

0.04

2.81

1.10

0.63

0.91

 

±S.D.

0.07

0.06

1.96

0.23

0.01

0.14

0.12

0.19

0.10

±S.E.M.

0.02

0.02

0.74

0.09

0.00

0.05

0.05

0.07

0.04

 

 

4

 (500)

mg/kg

Mean

1.79

0.28

10.61

1.93

0.04

2.87

1.03

0.54

0.88

±S.D.

0.07

0.05

0.51

0.17

0.01

0.13

0.06

0.11

0.05

±S.E.M.

0.03

0.02

0.19

0.06

0.00

0.05

0.02

0.04

0.02

 SUMMARY OF ABSOLUTE ORGAN WEIGHTS(g)

 Femalerats

Group/ Dose

 

 

Brain

 

Thymus

 

Liver

 

Kidneys

 

Adrenals

 

Ovaries

 

Spleen

Heart

 

Uterus

1/0

   (mg/kg)

Mean

1.79639

0.69686

8.13916

1.66367

0.0451

0.14289

0.63041

0.79684

0.46711

±S.D.

0.13458

0.547

0.47047

0.18627

0.01172

0.02302

0.11848

0.11455

0.07792

±S.E.M.

0.05087

0.20675

0.17782

0.0704

0.00443

0.0087

0.04478

0.04329

0.02945

 

2/(120)

mg/kg

Mean

1.78147

0.28884

8.15586

1.55246

0.04734

0.08319*

0.63869

0.77013

0.39303

±S.D.

0.11628

0.1304

1.06437

0.16655

0.00937

0.01815

0.24329

0.06459

0.08246

±S.E.M.

0.04395

0.04929

0.40229

0.06295

0.00354

0.00686

0.09196

0.02441

0.03117

 

2/

 

250 mg/kg

Mean

1.6069

0.3289

8.3645

1.566

0.0395

0.0935*

0.4718

0.7185

0.4667*

 

±S.D.

 

0.27569

 

0.12711

 

0.78925

 

0.15522

 

0.01286

 

0.02423

 

0.11176

 

0.06134

 

0.07708

±S.E.M.

0.1042

0.04804

0.29831

0.05867

0.00486

0.00916

0.04224

0.02319

0.02913

 

4  /

(500) mg/kg

Mean

1.75207

0.42151

7.9445

1.525*

0.04407

0.07481

0.49059*

0.70961

0.34757*

±S.D.

0.12692

0.20921

0.63133

0.13336

0.00665

0.01518

0.09178

0.02657

0.10007

±S.E.M.

0.04797

0.07907

0.23862

0.05041

0.00251

0.00574

0.03469

0.01004

0.03782

SUMMARY OF RELATIVE ORGAN WEIGHTS Male Rats

 

Group/Dose

 

 

Brain

 

Thymus

 

Liver

 

Kidneys

 

Adrenals

 

Testes

 

Splee n

 

Heart

 

epididymide s

 

1/

 

0

Mean

0.6051

0.1009

3.6170

0.6680

0.0110

0.9447

0.1846

0.2970

0.3521

±S.D.

 

0.1132

 

0.0236

 

0.4211

 

0.0880

 

0.0052

 

0.1114

 

0.0407

 

0.0210

 

0.0527

±S.E.M.

 

0.0428

 

0.0089

 

0.1592

 

0.0333

 

0.0020

 

0.0421

 

0.0154

 

0.0079

 

0.0199

 

 

 

 

2/

125 mg/kg

Mean

 

0.6466

 

0.1549

 

3.9569*

 

0.7236

 

0.0243

 

0.9377

 

0.1856

 

0.3060

 

0.3599

±S.D.

 

0.0330

 

0.0515

 

0.2711

 

0.0369

 

0.0274

 

0.0434

 

0.0428

 

0.0262

 

0.0299

±S.E.M.

 

0.0125

 

0.0195

 

0.1025

 

0.0139

 

0.0104

 

0.0164

 

0.0162

 

0.0099

 

0.0113

 

 

 

3  /

250 mg/kg

Mean

 

0.6674

 

0.1140

 

3.9886

 

0.7207

 

0.0143

 

1.0007

 

0.2209

 

0.3220

 

0.3883

±S.D.

 

0.0627

 

0.0252

 

0.6023

 

0.0431

 

0.0021

 

0.0816

 

0.0608

 

0.0367

 

0.0346

±S.E.M.

 

0.0237

 

0.0095

 

0.2277

 

0.0163

 

0.0008

 

0.0309

 

0.0230

 

0.0139

 

0.0131

 

 

 

4   /

500 mg/kg

Mean

 

0.5317

 

0.0868

 

3.1877

 

0.5684

 

0.0110

 

0.8401

 

0.1709

 

0.2618*

 

0.3071*

±S.D.

 

0.3033

 

0.0461

 

1.7161

 

0.3359

 

0.0062

 

0.4873

 

0.0898

 

0.1468

 

0.1775

±S.E.M.

 

0.1357

 

0.0206

 

0.7675

 

0.1502

 

0.0028

 

0.2179

 

0.0402

 

0.0656

 

0.0794

SUMMARY OF RELATIVE ORGAN WEIGHTS- Females

Group/Dose

 

 

Brain

Thymu s

 

Liver

 

Kidneys

Adrenal s

 

Ovaries

 

uterus

 

Spleen

 

Heart

 

 

1/0

Mean

 

0.8181

 

0.3176

 

3.7199

 

0.7573

 

0.0200

 

0.0654

 

0.2107

 

0.2849

 

0.3614

±S.D.

0.0380

0.2566

0.3170

0.0667

0.0045

0.0141

0.0202

0.0354

0.0334

±S.E.M.

0.0144

0.0970

0.1198

0.0252

0.0017

0.0053

0.0076

0.0134

0.0126

 

 

2 / 125 mg/kg

Mean

 

0.8227

 

0.1324

 

3.7541

 

113.7454

 

0.0214

 

*0.0380

 

0.1824

 

0.2926

 

0.3557

±S.D.

0.0439

0.0598

0.3280

299.0822

0.0053

0.0090

0.0439

0.1052

0.0323

±S.E.M.

0.0166

0.0226

0.1240

113.0424

0.0020

0.0034

0.0166

0.0398

0.0122

 

3  /          250 mg/kg

Mean

 

0.7137

 

0.1443

 

3.6900

 

0.6917

 

0.0171

 

0.0406*

 

0.2054

 

0.2077*

 

0.3169*

±S.D.

0.1425

0.0553

0.2348

0.0629

0.0053

0.0089

0.0298

0.0487

0.0212

±S.E.M.

0.0539

0.0209

0.0887

0.0238

0.0020

0.0034

0.0113

0.0184

0.0080

 

4    /  500mg/kg

Mean

0.8253

0.1970

3.7417

0.7173

0.0203

0.0349*

0.1636

0.2304*

0.3341

±S.D.

0.0546

0.0920

0.2484

0.0423

0.0028

0.0080

0.0463

0.0405

0.0130

±S.E.M.

0.0206

0.0348

0.0939

0.0160

0.0011

0.0030

0.0175

0.0153

0.0049

Applicant's summary and conclusion

Conclusions:
NOAEL was considered to be 125 mg/kg bw for male rats and LOAEL was considered to be 250 mg/kg body weight/day for female when Sprague Dawley male and female rats were exposed daily to the test chemical by oral route for 28 days.
Executive summary:

In a 28 days repeated dose toxicity study, the effect of the test chemical was evaluated in male and female Sprague Dawley rats. The test chemical was administered by oral gavage in the concentration of 0, 125, 250 or 500 mg/kg body weight/day. The results showed that the test chemical significantly increased the level of testosterone in the 500 mg/kg body weight/day group as well as it significantly increased the level of estrogen in the 250 mg/kg body weight/day group .The relative and absolute organ weight of ovaries decreased when treated with 125, 250 or 500 mg/kg body weight/day. In similarity, the relative and absolute organ weight of uterus decreased in the 125 or 500 mg/kg body weight/day groups.No significant changes in were detected in hematology,clinical biochemistry,mortality ororgan weight, and no effects were observed in water consumption,opthalmoscopic examination or locomotor activity. In male rats, the relative organ weights of the testes and epididymides increased when rats were treated with 500 mg/kg body weight/day. Histopathology performed on reproductive organs after treatment with 500 mg/kg body weight/day did not reveal any toxic lesions as compared to control. Hence, NOAEL was considered to be 250 mg/kg bw for male rats and LOAEL was considered to be 125 mg/kg body weight/day for female when Sprague Dawley male and female rats were exposed daily to the test chemical by oral route for 28 days.