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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
May 18, 2016 to April 20, 2017
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
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
3-dodecyl-1-(2,2,6,6-tetramethyl-4-piperidyl)pyrrolidine-2,5-dione
EC Number:
279-242-6
EC Name:
3-dodecyl-1-(2,2,6,6-tetramethyl-4-piperidyl)pyrrolidine-2,5-dione
Cas Number:
79720-19-7
Molecular formula:
C25H46N2O2
IUPAC Name:
3-dodecyl-1-(2,2,6,6-tetramethylpiperidin-4-yl)pyrrolidine-2,5-dione
Test material form:
liquid: viscous
Specific details on test material used for the study:
Identification Hostavin 3055
Appearance Clear, medium viscous, slightly yellowish liquid
Chemical Name [3-dodecyl-1-(2,2,6,6-tetramethyl-4-piperidyl)pyrrolidin-2,5- dione]
Formulation Type 98.3 % 3-dodecyl-1-(2,2,6,6-tetramethyl-4-piperidyl)pyrrolidine 2,5- dione
Source Clariant India Limited
Manufacturer Clariant India Limited
Reliable Tech Park, Gut No. 31,
Village Elthan, Thane-Belapur Road,
Airoli, Navi Mumbai 400 708, India
Batch number DEF2101115
CAS No. 79720-19-7
Purity (%) 98.3% (w/w)
Molecular weight 406 g/mol
Molecular formula C25H46N2O2
Manufacture Date July 08, 2013
Expiry Date July 07, 2020
Stability of test item Stable at room temperature
Storage conditions Room Temperature (20 to 30°C)

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source:Animal Breeding, RCC Laboratories India Private Limited
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at pretreatment : 12-14 weeks
- Weight at treatment start day :Male :295.4 to 420.4 g; Female : 229.8 to 324.8 g;
- Housing:
In groups of two/three by sex and concentration in Polycarbonate cages (Approximate internal dimensions of 365 mm x 202 mm x 180 mm height) with corn cob bedding for acclimatization. Pregnant females were caged individually with corn cob bedding. Results of analyses for contaminants will be archived at RCC Laboratories India Private Limited
- Water: ad libitum
- Acclimation period: 6 days under laboratory conditions

ENVIRONMENTAL CONDITIONS
- Temperature (°C):22.3°C to 23.3°C
- Humidity (%): 52 to 68%
- Air changes (per hr): above10
- Photoperiod (hrs dark / hrs light): 12:12
IN-LIFE DATES: From:June 01, 2016 To:August 26, 2016 (last necropsy)

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: Groundnut oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

VEHICLE
- Justification for use and choice of vehicle (if other than water): test item homogenously mixed with vehicle groundnut oil
- Concentration in vehicle: 10, 2.5 and 0.5 mg/mL
- Amount of vehicle (if gavage): 100 ml/ dose
:
Details on mating procedure:
- M/F ratio per cage:1:1
- Length of cohabitation: 14 days max
- Proof of pregnancy:sperm in vaginal smear referred to as day 0 of pregnancy
- After 14 days of unsuccessful pairing replacement of first male by another male with proven fertility.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentration analysed in the formulation of Group 2, Group 3 and Group 4 on middle of experiment (week 3 of gestation (29/07/2016)) was in agreement with the target concentration (i.e., ranged between 99.57 to 99.71 %). The formulations of Group 2, Group 3 and Group 4 collected on treatment start date and treatment end date were homogenous (i.e. % coefficient of variation ranged in between 0.01 to 0.16)
Duration of treatment / exposure:
Males were dosed from day 1 to day 42. This includes two weeks prior to mating, mating and post mating period.
Females were dosed throughout the study (approximately 1 - 63 days). This includes two weeks prior to mating, mating, gestation and lactation period (at least 13 days after delivery up to the day before scheduled sacrifice).
Frequency of treatment:
Once Daily, seven days a week
Doses / concentrationsopen allclose all
Dose / conc.:
5 mg/kg bw/day
Remarks:
Low dose
Dose / conc.:
25 mg/kg bw/day
Remarks:
Intermediate Dose
Dose / conc.:
100 mg/kg bw/day
Remarks:
High dose
No. of animals per sex per dose:
12 male and 12 female
Control animals:
yes
Details on study design:
- Dose selection rationale: The dose range was selected based on the results of the 28 days study (RCC No. 6093)

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
DETAILED CLINICAL OBSERVATIONS: Yes
BODY WEIGHT: Yes
- Time schedule for examinations:
Males :Weekly irrespective of the phases (Day 1 = 1st day of dosing)Day 1, Day 8, Day 15
Day 22, Day 29, Day 36 and Day 42
Females : Premating Day 1, Day 8 and Day 15
Mating Not performed
Gestation Day 0, Day 7, Day 14, Day 20
and within 24 hours post-partum
Lactation Day 1, Day 4, Day 13
• Pups were weighed on day 0 to 1 (within 24 hour of delivery or day 1), day 4 and day 13

Oestrous cyclicity (parental animals):
Estrous cycle was monitored for two weeks during the pre-exposure period to select the study females with regular estrous cyclicity
Sperm parameters (parental animals):
Parameters examined in [all/P/F1/F2] male parental generations:
testis weight, epididymis weight, sperm count in epididymides, enumeration of cauda epididymal sperm reserve, sperm morphology
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
maximum of pups/litter

PARAMETERS EXAMINED
The following parameters were examined in [F1 / F2 / F3] offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, behavioural abnormalities, anogenital distance (AGD), presence of nipples/areolae in male pups

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities
Postmortem examinations (parental animals):
Necropsy performed at the end of the treatment period revealed no abnormality attributable to treatment in any animal of low, mid and high dose groups. Bursal cyst was observed in one female animal of low dose group and considered an incidental finding.
One female animal of high dose (G4) group which was found dead on 22nd day of gestation period revealed reddish discharge from vagina and improper placement of foetuses in uterus resulting in dystocia. Autolytic changes were set in at the time of necropsy
Postmortem examinations (offspring):
No abnormality attributable to treatment was observed in any of the pups in low, mid and high dose groups
Statistics:
Statistical analysis was performed using statplus program.
ANOVA, t-test, normality and homogenity test was performed
Reproductive indices:
REPRODUCTIVE INDICES

MATING PERFORMANCE AND FERTILITY
No treatment-related effects were detected on mating performance. All the female animals of control, low, intermediate and high dose groups showed positive evidence of mating. No significant difference was observed in the pre-coital interval of female animals between control, low, intermediate and high dose group.
Oestrous cyclicity was checked for all the female animals. Uneven oestrous cyclicity was observed in two animals of vehice control (Animal numbers 17 and 22), two animals of Low dose (Animal numbers 42 and 48), two animals of mid dose (Animal numbers 68 and 72) and two animals of high dose (Animal numbers 93 and 94) which was reflected as non pregancy during the study. Regular oestrous cycle was observed in all other animals of different groups in the study.
Mating index for all the groups was 100% (as confirmed by presence of sperm in the vaginal smear).
The pregnancy index for all the groups is 83%.
Of the litters born, litter size at birth and subsequently on days 1 and 4 post partum were comparable to controls.
There were no treatment-related effects in fertility of treated animals.
GESTATION AND PARTURITION
There were no differences in gestation lengths. The gestation length for treated females was comparable to controls. All animals showed gestation lengths between 22 to 23 days. Only in one of the high dose group animal, gestation length was 24 days and in one control group animal gestation length was 25 days.
The parturition index was 100% in control, low and intermediate dose group. In high dose group the parturition index was 90%
Offspring viability indices:
LITTER RESPONSES
PRE NATAL & POST NATAL LOSS
The pre and post natal loss in all treated groups was comparable with control group.
8.6.3.2 LITTER SIZE AND LIVE BIRTH
Of the litters delivered, in all the treatment groups, litter size at birth and subsequently on Day 1 and 4 post-partum were comparable to controls. No significant difference in the live birth was noted between control and treated groups.
No nipple retention was found in any of the litter from vehicle control, low, mid and high dose groups.
SEX RATIO
Sex ratio was calculated as percent (%) male. No significant difference in sex ratio was observed in any of the treated groups when compared with vehicle control.
OFFSPRING GROWTH AND DEVELOPMENT
Offspring body weight on day 1, 4 and 13 was recorded. No significant changes in the offspring body weight of Low, mid and high dose groups was observed on day 1, 4 and 13 when compared with control group. No significant difference in the Anogenital distances (AGD) between control and treated animals were observed.
LITTER WEIGHTS
No significant changes were observed in the litter weights on day 1 and 13 post-partum between control and treated groups

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No clinical signs were observed in the control (0 mg/kg bodyweight), low (5 mg/kg body weight), mid (25 mg/kg body weight) and high dose group (100 mg/kg body weight) male and female animals with exception of two animals, one animal each from control and high dose group. In lactation phase one female animal (Animal no. 13) from vehicle control group showed cannibalism (eating its own pups). In high dose group (100 mg/kg body weight) dystocia was observed in one female animal (Animal no. 90) and found dead on gestation day 22
Dermal irritation (if dermal study):
no effects observed
Mortality:
mortality observed, non-treatment-related
Description (incidence):
There were no mortalities observed in control, low, mid and high group animals with exception of one female animal from high dose group died on gestation day 22
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
No adverse effect on body weight and bodyweight gain (%) was detected for treated animals when compared with vehicle control
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
No adverse effects on food consumption were detected for treated animals when compared with vehicle control
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:
no effects observed
Description (incidence and severity):
No toxicologically releavant findings were noted in thyroxine (T4) and thyroid stimulating hormone (TSH) levels in parent animals (males, females) and pups (male and female) .
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Microscopic examination revealed no abnormality attributable to the treatment in reproductive organs studied at the highest dose level tested i.e., 100 mg/kg body weight
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
effects observed, non-treatment-related
Description (incidence and severity):
Oestrous cyclicity was checked for all the female animals. Uneven oestrous cyclicity was observed in two animals of vehice control (Animal numbers 17 and 22), two animals of Low dose (Animal numbers 42 and 48), two animals of mid dose (Animal numbers 68 and 72) and two animals of high dose (Animal numbers 93 and 94) which was reflected as non pregancy during the study. Regular oestrous cycle was observed in all other animals of different groups in the study.
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
Detailed histological examination was performed on testes using PAS-H stain with special emphasis on stages of spermatogenesis and histopathology of interstitial testicular cell structure and epididymides of male animals and ovaries of female animals in order to identify treatment related effects
Reproductive performance:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment-related effects were detected on mating performance. All the female animals of control, low, intermediate and high dose group showed positive evidence of mating. No significant difference was observed in the pre-coital interval of female animals between control, low, intermediate and high dose group.
No treatment related effects on the oestrous cycle was observed
Mating index for all the groups was 100% (as confirmed by presence of sperm in the vaginal smear).
The pregnancy index for all the groups is 83%.
Of the litters born, litter size at birth and subsequently on days 1 and 4 post partum were comparable to controls.
There were no treatment-related effects in fertility of treated animals.
Gestation and parturition:
There were no differences in gestation lengths. The gestation length for treated females was comparable to controls. All animals showed gestation lengths between 22 to 23 days. Only in one of the high dose group animal, gestation length was 24 days.
The parturition index was 100% in control, low and intermediate dose group. Whereas, in high dose group the parturition index was 90%.

Effect levels (P0)

Key result
Dose descriptor:
NOEL
Effect level:
>= 100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food efficiency
clinical biochemistry
organ weights and organ / body weight ratios
gross pathology
histopathology: neoplastic
reproductive function (oestrous cycle)
reproductive function (sperm measures)
reproductive performance
Remarks on result:
not determinable due to absence of adverse toxic effects

Results: P1 (second parental generation)

General toxicity (P1)

Mortality:
no mortality observed

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Description (incidence and severity):
The pre- and postnatal loss was comparable in treated and control groups
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No significant differences in litter weight, live birth as well as offspring body weights on days 1, 4 and 13 was noted between control and treated groups,
Food consumption and compound intake (if feeding study):
not examined
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
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No significant differences were observed in absolute thyroid weight in male and female pups of all treatment groups at day 13, except a significant increase in males of the mid dose group. This not dose-related effect was not attributed to treatment.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No nipple retention was found in any of the litters from treated and control groups
Histopathological findings:
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
No significant difference in sex ratio was observed in any of the treated groups compared to controls

Effect levels (F1)

Key result
Dose descriptor:
NOEL
Generation:
F1
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
clinical signs
mortality
body weight and weight gain
gross pathology
Remarks on result:
not determinable due to absence of adverse toxic effects

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Any other information on results incl. tables

TABULAR SUMMARY REPORT OF EFFECTS ON REPRODUCTION/DEVELOPMENT

Parameters

Group 1

Group 2

Group 3

Group 4

Pairs started (N)

12

12

12

12

Females showing evidence of copulation (N)

12

12

12

12

Females achieving pregnancy (N)

10

10

10

10

Conceiving Days 1 - 5 (N)

11

12

11

9

Conceiving Days ≥ 6 (N)

1

0

1

3

Pregnancy = 21 Days (N)

0

0

0

0

Pregnancy = 22 Days (N)

6

7

6

5

Pregnancy = 23 Days (N)#

4

3

4

5

Dams with live young born (N)

10

10

10

9*

Dams with live young at Day 4 post partum (N)

10

10

10

9

Implants/dam (mean)

10.8

10.4

10.4

10.3

Live pups/dam at birth (mean)

7.6

7.8

7.5

8.6

Live pups/dam at Day 4 (mean)

6.9

7.8

7.5

8.6

Sex ratio % males at Day 1 post partum

34.21

41.03

41.33

50.85

Sex ratio % males at Day 4 post partum

34.21

41.03

41.33

38.96

Litter weight at Day 1 (mean)

4.18

4.21

4.17

3.84

Litter weight at Day 4 (mean)

8.21

8.21

8.10

8.07

Pup weight at Day 1 Male (mean)

4.56

4.53

4.54

4.16

Pup weight at Day 4 Male (mean)

8.67

8.70

8.67

8.38

Pup weight at Day 1 Female (mean)

3.97

3.99

3.92

3.65

Pup weight at Day 4 Female (mean)

7.92

7.88

7.68

7.80

Male with nipple retention on day 13

0

0

0

0

ABNORMAL PUPS (Based on gross finding) 

Dams with 0

9

10

10

9

Dams with 1

0

0

0

0

Dams with 2

0

0

0

0

Dams with more than 2 abnormal pups

0

0

0

0

*One female was found dead due to dystocia. ;

# Pregnancy = 25 Days in one dam (animal number 14) of group 1; 24 Days in one dam (animal number 89) of group 4

TABULAR SUMMARY REPORT OF EFFECTS ON REPRODUCTION/DEVELOPMENT

Parameters

Group 1

Group 2

Group 3

Group 4

LOSS OF OFFSPRING  

Pre-natal (Implantations minus live births) 

Females with 0

0

2

3

2

Females with 1

2

1

0

3

Females with 2

1

1

2

2

Females with 3

2

3

1

0

Females with >4

4

3

4

2

@Post-natal (live births minus alive at post natal Day 4) 

Females with 0

9

10

10

9

Females with 1

0

0

0

0

Females with 2

0

0

0

0

Females with 3

0

0

0

0

Females with >4

1

0

0

0

Post-natal (live births minus alive at post natal Day 13) 

Females with 0

0

0

0

0

Females with 1

0

0

0

0

Females with 2

9

10

10

9

Females with 3

0

0

0

0

@Mortality observed in all the off springs of one dam (Animal number 13) in group 1

Applicant's summary and conclusion

Conclusions:
The administration of the test item to Wistar rats by oral gavage, at dose levels of 5, 25 and 100 mg/kg/day, resulted in no treatment-related clinical signs, changes in the body weights, feed consumption and microscopic effects in male and female animals. No treatment-related effects on reproduction/ development such as mating index, fertility index, gestation length, pre-natal loss, post-natal loss, sex ratio and offspring growth and development. Therefore, a ‘No Observed Effect Level’ (NOEL) for reproductive toxicity is considered to be highest dose employed in the study i.e.,100 mg/kg/day.

No Observed Effect Level (NOEL) for Reproduction / Developmental Toxicity : 100 mg/kg body weight
Executive summary:

Study Title: Reproduction / Developmental Toxicity Screening Test in Wistar Rats with Hostavin 3055

The study was designed to investigate the potential adverse effects of the test item on reproduction (including offspring development) and is compatible with the requirements of the OECD Guidelines for Testing of Chemicals No. 421 “Reproduction/Developmental Toxicity Screening Test ", Adopted by the Council on 28thJuly 2015”.

The test item (formulated in refined ground nut oil) was administered by oral gavage to three groups, each of twelve male and twelve female Wistar rats, for up to 42 days for males, up to two weeks premating phase, two weeks pairing, three weeks gestation and 13 days lactation for females, at dose levels of 5, 25 and 100 mg/kg/day. A control group of ten males and ten females were dosed with vehicle control (Refined ground nut oil).

The following observation and examinations were evaluated:

Clinical signs (daily), body weights and feed consumption (once weekly).

Pairing of animals within each dose group was undertaken on a one male: one female basis within each treatment group on Day 15 of the study, with females subsequently being allowed to litter and rear their offspring to Day 13 of lactation.

During the lactation phase, daily clinical observations were performed on all surviving offspring, together with litter size and offspring weights.

Males were sacrificed on Day 43, followed by the sacrifice of all females on Day 14 post-partum.Pups were sacrificed on Day 13 postpartum. Macroscopy at termination was performed for all animals.

Male and female animals were screened for T4 and TSH parameters from each dose group. Selected offspring were also screened for T4 and TSH parameters from each dose group.

Wet weight of organs were recorded for testes, epididymis, seminal vesicles, prostate gland,Levator ani plus bulbocavernosus muscle complex, Cowper’s glands and glans penis from males, Ovaries, uterus from females. Thyroid (after fixation) from male, female and one pup/sex/litter was weighed. 

Histopathology was performedon the preserved organs for epididymis, testes and ovaries of control and high dose groups. Histopathology was not extended to the other dose groups since no test item related lesions observed in the high dose group.

 

 

RESULTS

Analytics

Analysis of homogeneity and dose concentration of the prepared dose formulations revealed acceptable levels.

Mortality:

There were no mortalities observed in control, low, mid and high group animals with exception of one female animal from high dose group died on gestation day 22.

Clinical signs:

No clinical signs were observed in the control (0 mg/kg bodyweight), low (5 mg/kg body weight), mid (25 mg/kg body weight) and high dose group (100 mg/kg body weight) male and female animals with exception of two animals, one animal each from control and high dose group. In lactation phase one female animal (Animal no. 13) from vehicle control group showed cannibalism (eating its own pups). In high dose group (100 mg/kg body weight) dystocia was observed in one female animal (Animal no. 90) and found dead on gestation day 22.

Body weight:

No adverse effect on body weight and bodyweight gain (%) was detected for treated animals when compared with vehicle control

Feed Consumption:

No adverse effects on food consumption were detected for treated animals when compared with vehicle control.

Clinical Biochemisty:

No toxicologically releavant findings were noted in thyroxine (T4) and thyroid stimulating hormone (TSH) levels in parent animals (males, females) and pups (male and female) .

Mating performance and Fertility:

No treatment-related effects were detected on mating performance. All the female animals of control, low, intermediate and high dose group showed positive evidence of mating. No significant difference was observed in the pre-coital interval of female animals between control, low, intermediate and high dose group.

No treatment related effects on the oestrous cycle was observed 

Mating index for all the groups was 100% (as confirmed by presence of sperm in the vaginal smear).

The pregnancy index for all the groups is 83%.

Of the litters born, litter size at birth and subsequently on days 1 and 4 post partum were comparable to controls.

There were no treatment-related effects in fertility of treated animals.

Gestation and parturition:

There were no differences in gestation lengths. The gestation length for treated females was comparable to controls. All animals showed gestation lengths between 22 to 23 days. Only in one of the high dose group animal, gestation length was 24 days.

The parturition index was 100% in control, low and intermediate dose group. Whereas, in high dose group the parturition index was 90%.

Litter Responses:

Pre natal & Post natal loss

The pre and post natal loss in all treated groups was comparable with control group. 

Litter Size and Live birth:

Of the litters delivered, in all the treatment groups, litter size at birth and subsequently on Day 1 and 4 post-partum were comparable to controls. No significant difference in the live birth was noted between control and treated groups.

No nipple retention was found in any of the pups from control and treated groups.

Sex ratio:

Sex ratio was calculated as percent (%) male. No significant difference in sex ratio was observed in any of the treated groups when compared with vehicle control.

Offspring Growth and Development:

Offspring body weight on day 1, 4 and 13 were recorded. No significant changes in the offspring body weight of Low, mid and high dose groups was observed on day 1, 4 and 13 when compared with control group. 

Litter weights

No significant changes were observed in the litter weights on day 1 and 13 post partum between control and treated groups.

Organ weight:

No significant difference was observed in absolute and relative organ weights between the control and treated groups in male and female animals. In case of pups, no significant differences were observed in absolute thyroid weight (after fixation) in male and female pups of all treatment groups on post natal day 13 except significant increase in absolute thyroid weight which was observed in male pups of mid dose (G3) group when compared with control (G1) group. This significant difference canot be attributed to the treatment.  

Macroscopic findings

Necropsy performed at the end of the treatment period revealed no abnormality attributable to treatment in any animal of low, mid and high dose groups. Bursal cyst was observed in one female animal of low dose group and considered an incidental finding.

One female animal of high dose (G4) group which was found dead on 22ndday of gestation period revealed reddish discharge from vagina and improper placement of foetuses in uterus resulting in dystocia. Autolytic changes were set in at the time of necropsy.

No abnormality attributable to treatment was observed in any of the pups in low, mid and high dose groups.  

Microscopic findings

Microscopic examination revealed no abnormality attributable to the treatment with test item HOSTAVIN3055in reproductive organs studied at the highest dose level testedi.e.,100 mg/kg body weight