Registration Dossier

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2015-2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2017
Report Date:
2017

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
The animal room was air-conditioned with adequate (above 10) air changes per hour The experimental room was continuously monitored for tem¬pera¬ture and relative humidity. The ranges for room tem¬pera¬ture and relative humidity were 20.5°C to 22.3°C and 51 to 65%, respectively. The animals were provided with a light cycle of 12 hours light and 12 hours dark.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Dosing per gavage commenced on day 5 of gestation and continued until day 19 of gestation. Dose volume was 10 mL per kg body weight.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Stability and homogeneity analysis. Dose formulation anaylsis.
Details on mating procedure:
Animals were paired as one male and one female in the evening hours and following morning each female was examined for vaginal smear or the presence of a copulation plug in the vagina. The presence of sperm in the vaginal smear was taken as positive evidence of mating (Day 0 of gestation).The maximum mating period observed was of eight days. During the mating phase, animals were housed on one male: one female basis. After successful mating, the females were returned to their original cage and housed individually during gestation.
Duration of treatment / exposure:
Day 5 of gestation until day 19 of gestation
Frequency of treatment:
Once daily
Duration of test:
The dosing commenced on day 5 of gestation and continued until day 19 of gestation.
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
24 female animals per dose group
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
Clinical signs were recorded at same time(s) each day taking into consideration the peak period of anticipated effects after dosing. The condition of the animals was recorded including mortality, moribundity, pertinent behavioral changes, and all signs of overt toxicity. Body weights were examined during the acclimatization period once weekly, on first day of pairing and weekly thereafter as well as on gestation days 0, 3, 5, 8, 11, 14 17 and 20.
Ovaries and uterine content:
At termination, the uteri were removed and the pregnancy status of the animals was ascertained. Gravid uteri including the cervix were weighed. The uteri of females were examined for the presence and number of implantation sites and the number of corpora lutea in the ovaries were determined for pregnant animals. The uterine content was examined for number of resorption, live and/or dead foetuses. The degree of resorption was described in order to estimate the relative time of death of the conceptus. Uteri that appear non-gravid were further examined by 5% ammonium sulphide staining to reveal any early resorption or post implantation loss.
Fetal examinations:
Each foetus was subjected to external examination, which included all visible structures, surfaces and orifices (including the oral cavity). One-half of the fetuses (alternating foetuses within the litter) independent of sex were processed for skeletal alterations (odd number) and remaining half (even number) of each litter were examined for visceral (soft tissue) alterations. On completion of external examination the foetuses selected for skeletal evaluation were eviscerated and placed in 70% isopropyl alcohol.
Statistics:
Statistical analysis was performed using statplus program. All the data was checked for Normality with Shapiro-Wilk W test and for Homogeneity with Bartlett Chi-Square test. Each group of animals was subjected to Analysis of Variance (ANOVA). Values were given as mean ± standard deviation (SD).
Indices:
Pre-implantation loss, post-implantation loss, sex ratio, variation incidence

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
In high dose (1000 mg/kg) group animals, burrowing followed by dullness and dyspnoea was observed shortly after dosing which subsided to normal after 3 hours post dosing from first day to last day of dosing. Only dullness was observed in some of the animals in intermediate dose (300 mg/kg) group following each gavage treatment which subsides to normal after 3 hours post dosing from first day to last day of dosing.
Mortality:
no mortality observed
Description (incidence):
No mortality was observed in any of the treated animal through out the scheduled treatment period.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No significant difference in the body weight and body weight gain (%) was observed in pregnant female animals of low (100 mg/kg), intermediate (300 mg/kg) and high dose (1000 mg/kg) groups. A statistically significant decrease in body weight was observed in high dose (1000 mg/kg) group when compared with low dose (100 mg/kg) group only on 20th day of gestation. However, this change was within the normal range with respect to age and sex of the strain of animals used. Hence, the changes in body weight and body weight gain were considered as biological variation without any toxicological relevance.
Detailed data see the tables in section "Any other information on results inc. tables"
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Feed consumption of pregnant female animals at low (100 mg/kg), intermediate (300 mg/kg) and high dose (1000 mg/kg) groups was not significantly different throughout the treatment period. A statistically significant decrease in feed consumption was observed in high dose (1000 mg/kg) group when compared with control (0 mg/kg), low (100 mg/kg) and intermediate dose (300 mg/kg) groups only on day 11th of gestation, and in control (0 mg/kg) group animals only on day 14th of gestation. These changes were within the normal range with respect to age and sex of the strain of animals used. Hence, these changes in feed consumption were considered as biological variation and thus not of toxicological relevance.
Detailed data see the tables in section "Any other information on results inc. tables"
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
Daily observations revealed no indications of general and functional pertinent behavioral changes.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
No abnormality was observed in any of the female animals from control, low, intermediate and high dose groups. Bursal cyst was observed in right ovary of one female animal of low dose group as an incidental finding.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
No abortion noted througout the study period.
Data see tables in section "Any other information on results inc. tables"
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
No pre- and/or post-implantation losses observed.
Data see tables in section "Any other information on results inc. tables"
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
No litter losses by resorption observed.
Data see tables in section "Any other information on results inc. tables"
Early or late resorptions:
no effects observed
Description (incidence and severity):
No late resorptions observed.
Data see tables in section "Any other information on results inc. tables"
Dead fetuses:
no effects observed
Description (incidence and severity):
No dead fetuses observed.
Data see tables in section "Any other information on results inc. tables"
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
No changes on pregnancy duration observed.
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.DescriptionIncidenceAndSeverityEffectsOnPregnancyDuration): No effects on pregnancy duration observed.
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
All the female animals of control, low, intermediate and high dose groups showed positive evidence of mating. At necropsy, three females each of control, high and low dose groups and four females of intermediate dose group were found non pregnant. As all dose groups are comparably involved and no dose response occurred, this finding is not of toxicological relevance.
Detailed data see tables in section "Any other information on results inc. tables"
Other effects:
no effects observed
Description (incidence and severity):
No significant difference was observed in the sex ratio of foetuses in low, intermediate and high dose groups or other reproductive indices.
Detailed data see tables in section "Any other information on results inc. tables"
Details on maternal toxic effects:
No maternal effects of toxicological relevance observed throughout the study period.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: overall findings
Remarks on result:
not determinable due to absence of adverse toxic effects

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
No significant difference was observed in litter and foetus weight of low, intermediate and high dose groups.
Detailed data see tables in section "Any other information on results inc. tables"
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): No changes in fetal/pub body weights recorded.
Detailed data see tables in section "Any other information on results inc. tables"
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
No significant differences were observed in early and late resorptions and in the number of live foetuses in all treatment groups.
Detailed data see tables in section "Any other information on results inc. tables"
Changes in sex ratio:
no effects observed
Description (incidence and severity):
No significant difference was observed in the sex ratio of foetuses in low, intermediate and high dose groups.
Detailed data see tables in section "Any other information on results inc. tables"
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
No significant difference was observed in litter size and the foetus weights in low, intermediate and high dose groups.
Detailed data see tables in section "Any other information on results inc. tables"
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
External examination of foetuses revealed one small sized foetus in control, six in low dose, eight in intermediate dose and three in high dose group. However, statistical significant differences in respective body weights were not observed. As the external variations observed were randomly distributed across the groups and in the absence of any dose response relationship, these findings were considered as incidental and of no toxicological relevance.
Detailed data see tables in section "Any other information on results inc. tables"
Skeletal malformations:
no effects observed
Description (incidence and severity):
Skeletal examination of foetuses revealed variations common in type and distribution for the strain of rats used. They were isolated and when expressed on a foetus/litter basis, no statistical significant differences between treatment groups and control animals were observed.
Skeletal examination at the dose levels of 100, 300 and 1000 mg/kg body weight thus did not indicate any test item-related effects.
Detailed data see tables in section "Any other information on results inc. tables"
Visceral malformations:
no effects observed
Description (incidence and severity):
Variations observed during visceral examination of foetuses revealed variations common in type and incidence for the strain of rats used and were randomly distributed across all groups. A dose response relationship was not observed. Therefore these findings were considered as incidental findings and of no toxicological relevance.
Detailed data see tables in section "Any other information on results inc. tables"
Other effects:
no effects observed
Description (incidence and severity):
No effects observed
Details on embryotoxic / teratogenic effects:
No effects observed

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects
Remarks on result:
not determinable due to absence of adverse toxic effects

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Any other information on results incl. tables

SUMMARY OF MORTALITY AND CLINICAL SIGNS

 

Group

1

2

3

4

Dose (mg/kg bw)

0

100

300

1000

Mortality

Nil

Nil

Nil

Nil

Clinical signs

Nil

Nil

Dullness

Excessive burrowing,

Dullness,

Dyspnoea

 

BODY WEIGHTS (G) – SUMMARY

FEMALE

Group

Body weights (G)

Gestation Day

 

0

3

5

8

11

14

17

20

Group 1

Mean

227.25

232.75

238.29

246.21

256.15

266.79

281.79

306.38

SD

10.01

9.73

9.59

9.57

11.22

12.63

18.22

25.60

Min

210.2

214.4

218.2

224.8

232.2

245.2

251.4

263.1

Max

244.2

250.2

253.8

260.4

270.2

290.2

323.4

352.1

N

21

21

21

21

21

21

21

21

Group 2

Mean

228.79

235.81

242.44

250.46

259.14

270.67

286.48

310.64

SD

10.46

10.67

11.56

11.34

12.33

15.51

15.11

17.30

Min

212.4

218.3

224.1

232.1

238.2

243.4

260.2

274.3

Max

244.6

251.4

267.1

273.8

282.2

294.1

310.5

338.2

N

21

21

21

21

21

21

21

21

Group 3

Mean

225.28

231.71

238.18

246.19

256.07

266.52

279.71

298.19

SD

11.39

10.20

10.37

11.19

11.86

13.16

14.74

19.09

Min

209.1

218.1

224.0

230.4

238.2

247.1

259.1

269.2

Max

245.3

249.2

256.8

270.4

281.3

292.1

310.1

332.1

N

20

20

20

20

20

20

20

20

Group 4

Mean

224.95

231.49

238.42

246.10

255.90

266.32

278.81

293.96#

SD

10.61

10.47

10.32

9.68

10.54

11.75

13.28

14.84

Min

210.6

220.1

226.3

233.2

240.1

249.2

259.2

268.1

Max

246.8

252.8

255.2

260.2

271.1

286.2

304.1

321.4

N

21

21

21

21

21

21

21

21

#Significant at p ≤ 0.05 level with group 2

BODY WEIGHT GAIN (%) - SUMMARY

FEMALE

Group

Body weights Gain (%)

Gestation Day

 

3

5

8

11

14

17

20

Group 1

Mean

2.43

4.88

8.39

12.77

17.44

24.02

34.91

SD

1.00

1.61

2.44

3.48

3.90

6.33

10.90

N

21

21

21

21

21

21

21

Group 2

Mean

3.08

5.99

9.52

13.30

18.32

25.28

35.84

SD

1.43

2.74

3.27

3.15

4.59

5.24

6.22

N

21

21

21

21

21

21

21

Group 3

Mean

2.89

5.77

9.33

13.72

18.35

24.19

32.41

SD

1.26

1.65

2.48

2.98

3.00

3.38

6.34

N

20

20

20

20

20

20

20

Group 4

Mean

2.92

6.02

9.47

13.84

18.50

24.03

30.82

SD

1.21

1.92

2.82

3.75

4.95

5.01

6.90

N

21

21

21

21

21

21

21

 

FEED CONSUMPTION - SUMMARY

FEMALE

Group

FEED CONSUMPTION (G/ANIMAL/DAY)

Gestation Day

 

0 - 3

3 - 5

5 - 8

8 - 11

11 - 14

14 - 17

17 - 20

Group 1

Mean

17.40

19.26

20.26

21.99

23.99

24.16

23.85

SD

1.48

3.45

1.87

1.72

2.15

2.79

2.88

Group 2

Mean

18.06

19.15

19.62

21.91

23.09

23.43

22.91

SD

2.03

3.96

2.76

2.48

1.48

1.82

2.88

Group 3

Mean

17.59

19.97

19.47

22.04

23.23

23.55

23.38

SD

2.53

5.38

3.28

2.58

2.40

2.26

3.17

Group 4

Mean

17.04

17.93

18.71

19.10*#@

21.41*

22.31

22.10

SD

2.10

4.12

3.00

3.57

3.17

2.42

2.54

*Significant at p ≤ 0.05 level with group 1

#Significant at p ≤ 0.05 level with group 2

@Significant at p ≤ 0.05 level with group 3

PREGNANCY STATUS

GROUP

G1

G2

G3

G4

DOSE (mg/kg bw)

0

100

300

1000

FEMALE ANIMALS MATED

24

24

24

24

PREGNANT FEMALE ANIMALS

21

21

20

21

 

MACROSCOPIC FINDINGS- FEMALE

GROUP

G1

G2

G3

G4

DOSE (mg/kg bw)

0

100

300

1000

ANIMALS EXAMINED

24

24

24

24

ANIMALS WITHOUT ABNORMALITY

24

24

24

24

ANIMALS AFFECTED

0

0

0

0

MATERNAL DATA - SUMMARY

 

Parameter

Group

G1

G2

G3

G4

Dose (mg/kg bw)

0

100

300

1000

No. of Dams

21

21

20

21

Gravid Uterine Weight

Mean

43.9637

53.2278

45.9287

49.9408

SD

16.0935

10.1451

14.7209

18.3332

No. of CL

Mean

11.96

12.92

12.92

12.58

SD

2.73

1.77

2.34

2.80

No. of Implantation

Mean

8.13

9.92

8.38

9.13

SD

4.24

4.15

4.83

4.76

No. of Foetuses

Mean

8.38

10.14

9.00

9.71

SD

3.35

2.31

3.36

3.98

Early Resorption

Mean

0.79

0.88

0.88

0.54

SD

0.88

1.15

1.08

0.88

Late Resorption

Mean

0.00

0.17

0.00

0.08

SD

0.00

0.64

0.00

0.28

Pre implantation loss

Mean

3.83

3.00

4.54

3.46

SD

4.31

3.41

4.32

3.71

%

30.90

24.41

35.89

29.12

Post implantation loss

Mean

0.79

1.04

0.92

0.63

SD

0.88

1.20

1.10

1.01

%

12.59

14.49

12.01

9.14

Dam with resorption/s

Number

13

12

12

8

LITTER DATA - SUMMARY

 

Parameter

Group

G1

G2

G3

G4

Dose (mg/kg bw)

0

100

300

1000

No. of Dams

24

24

24

24

No. of Litters

21

21

20

21

Total No. of Foetuses

176

213

180

204

Mean Litter Size

8.38

10.14

9.00

9.71

No. of Live Foetuses

Number

176

213

179

204

Mean

8.38

10.14

8.95

9.71

SD

3.35

2.31

3.32

3.98

No. of Dead Foetuses

Number

0

0

1

0

Mean

0

0

0.05

0

SD

0.00

0.00

0.22

0.00

No. of Live Male Foetuses

Number

93

96

96

101

Mean

4.43

4.57

4.80

4.81

SD

2.58

1.89

2.12

2.52

No. of Live Female Foetuses

Number

83

117

83

103

Mean

3.95

5.57

4.15

4.90

SD

1.69

2.13

2.08

2.41

GROUP MEAN FOETUS WEIGHTS

 

Group

Foetus weight/Litter

(G)

Foetus Weight (G)

Male

Female

Group 1

Mean

3.3814

3.3354

3.4330

SD

0.6200

0.6853

0.5369

N

176

93

83

Group 2

Mean

3.3860

3.4788

3.3099

SD

0.5341

0.5384

0.5205

N

213

96

117

Group 3

Mean

3.3906

3.4430

3.3300

SD

0.6227

0.6619

0.5720

N

179

96

83

Group 4

Mean

3.3245

3.3427

3.3066

SD

0.7148

0.7441

0.6879

N

204

101

103

 

GROUP MEAN SEX RATIO

 

Group

Sex ratio (%) Male

Group 1

Mean

49.08

SD

17.36

N

176

Group 2

Mean

45.26

SD

16.60

N

213

Group 3

Mean

54.83

SD

17.99

N

180

Group 4

Mean

50.21

SD

17.08

N

204

 

EXTERNAL FINDINGS

 

Group

G1

G2

G3

G4

Dose (mg/kg bw)

0

100

300

1000

No. of Litter Examined

21

21

20

21

No. of Foetuses Examined

176

213

179

204

Variation Incidence – Number (%)

No. of Foetus with Variations

Total Variations

1(0.57)

6(2.82)

8(4.47)

3(1.47)

a)Foetus small in size

1(0.57)

6(2.82)

8(4.47)

3(1.47)

VISCERAL FINDINGS

 

Group

G1

G2

G3

G4

Dose (mg/kg bw)

0

100

300

1000

No. of Litter Examined

21

21

20

21

No. of Foetuses Examined

84

103

84

97

Variation Incidence – Number (%)

No. of Foetus with Variations

Total Variations

19(22.62)

18(17.48)

15(17.86)

22(22.68)

Spleen: Small in size

8(9.52)

7(6.80)

5(5.95)

7(7.22)

Spleen: Pale

5(5.95)

4(3.88)

4(4.76)

8(8.25)

Ureters: Convoluted

6(7.14)

7(6.80)

6(7.14)

7(7.22)

SKELETAL FINDINGS

Group

G1

G2

G3

G4

Dose (mg/kg bw)

0

100

300

1000

No. of Litter Examined

21

21

20

21

No. of Foetuses Examined

92

110

95

107

Variation Incidence – Number (%)

Hyoid

Not ossified

1(1.09)

0

0

0

Incompletely ossified

1(1.09)

0

0

4(3.74)

Bipartite

1(1.09)

0

0

0

Absent

1(1.09)

0

0

0

Thoracic Vertebra

Dumbbell shaped

21(22.83)

26(23.64)

18(18.95)

34(31.78)

Bipartite

3(3.26)

10(9.09)

12(12.63)

4(3.74)

Lumbar Vertebra

Not ossified

0

1(0.91)

0

0

Dumbbell shaped

0

1(0.91)

0

0

Sacral Vertebra

Not ossified

1(1.09)

0

0

0

Incompletely ossified

1(1.09)

0

0

0

Caudal Vertebra

Not ossified

6(6.52)

4(3.64)

0

5(4.67)

Sternal centers (1)

Not ossified

10(10.87)

11(10.00)

9(9.47)

12(11.21)

Incompletely ossified

10(10.87)

6(5.45)

12(12.63)

14(13.08)

Sternal centers (2)

Not ossified

5 (5.43)

3(2.73)

0

5(4.67)

Incompletely ossified

4(4.35)

0

3(3.16)

0

Misshapen/Irregular shaped

0

2(1.82)

1(1.05)

0

Manubrium

Not ossified

11 (11.96)

5(4.55)

1(1.05)

7(6.54)

Incompletely ossified

3(3.26)

0

4(4.21)

0

 

SKELETAL FINDINGS (CONTD.)

Group

G1

G2

G3

G4

Dose (mg/kg bw)

0

100

300

1000

No. of Litter Examined

21

21

20

21

No. of Foetuses Examined

92

110

95

107

Variation Incidence – Number (%)

Xyphiod

Not ossified

25 (27.17)

27(24.55)

41(43.16)

41(38.32)

Incompletely ossified

13(14.13)

17(15.45)

8(8.42)

4(3.74)

Ribs - Left

Waviness

1 (1.09)

0

0

9(8.41)

Ribs - Right

Waviness

1 (1.09)

0

0

10(9.35)

Supernumerary

0

0

0

1(0.93)

Metacarpals - Left

Not ossified

0

2(1.82)

0

1(0.93)

Incompletely ossified

1(1.09)

0

0

0

Metacarpals - Right

Not ossified

0

2(1.82)

0

1(0.93)

Incompletely ossified

1(1.09)

0

1(1.05)

0

Metatarsal - Left

Not ossified

1(1.09)

4(3.64)

0

1(0.93)

Incompletely ossified

3(3.26)

0

0

0

Metatarsal - Right

Not ossified

1(1.09)

4(3.64)

0

2(1.87)

Incompletely ossified

3(3.26)

0

0

0

Pubis - Left

Incompletely ossified

0

0

1(1.05)

0

Pubis - Right

Not ossified

0

0

1(1.05)

0

 

                                                                

Applicant's summary and conclusion

Conclusions:
The No Observed Adverse Effect Level (NOAEL) of test item HOSTAPON TPHC for maternal and embryofoetal toxicity in Wistar female rats via oral route was found to be the highest dose level employed i.e., 1000 mg/kg body weight/day
Executive summary:

The test item,HOSTAPON TPHC(formulated in distilled water) was administered once daily by oral gavage to three treatment groups of twenty four pregnant female Wistar rats per group from day 5 to day 19 of gestation at dose levels of 100, 300 and 1000 mg/kg body weight/day. A control group of twenty four females were administered with vehicle (distilled water)alone.

Female animals treated at 1000mg/kg bw/day(high dose) showed burrowing followed by dullness and dyspnoea while female animals treated at 300 mg/kg bw/day (intermediate dose) showed only dullness shortly after each administration. These findings recovered to normal after 3 hours post dosing each day. These temporary effects can be regarded unspecific in nature due to minor local irritative effects caused by test item administration.

The evaluation of the reproductive organs of the dam, pre and post implantation loss, gravid uterine weight, litter size, viability of the foetus, litter weight and foetus weight, sex ratio of the foetus and the external, visceral and skeletal examination of the foetus revealed that HOSTAPON TPHC did not cause any maternal as well as embryo foetal toxicity up to the highest dose of 1000 mg/kg bw/day tested.