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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because a pre-natal developmental toxicity study is available
Cross-reference
Reason / purpose:
data waiving: supporting information
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
No data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
Meets generally accepted scientific standards with acceptable restrictions. Deficiencies: Food consumption not reported Uterine weights not determined Test substance identification (Batch etc) missing No details on housing conditions/source of animals Administration only during periods of organogenesis, not until day before pregnancy
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
other: no data
Deviations:
not specified
Principles of method if other than guideline:
Adult female Dutch-belted rabbits were dosed on Day 0 with a single injection of 0.4 mL human chorionic gonadotropin (400 IU) via the marginal ear vein. After three hours each doe was artificially inseminated with 0.3 mL diluted semen from a donor buck using 20 x 10E06 motile sperm. Dosing by oral intubation with a control (Vehicle at level equivalent to group receiving the highest dose) or test article in a water suspension at 1.28, 5.95, 27.6 and 128.0 mg/kg was carried out daily on Days 6 to 18 of gestation. The positive control 6-aminonicotinamide at 2.5 mg/kg was dosed on Day 9. Observations of body weight, appearence, behaviour, and food consumption were performed. On Day 29 all does underwent Caesarean section. Number of corpora lutea, implantation sites, resorption sites and live/dead foetuses recorded. Body weights of live pups recorded. Urogenital tract of each dam examined for anatomical normality. All foetuses examined grossly for presence of external congenital abnormalities. Live foetuses of each litter were then placed in an incubator for 24 hours for evaluation of neonatal survival. All pups underwent detailed visceral examination. All foetuses were cleared in potassium hydroxide, stained with alizarin red S dye and examined for skeletal defects.
GLP compliance:
no
Remarks:
Study predates GLP
Limit test:
no
Species:
rabbit
Strain:
Dutch
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Outbred
- Age at study initiation: No data
- Weight at study initiation: 2.17 - 2.51 kg
- Fasting period before study: No data
- Housing: Individually housed in mesh-bottomed cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: No data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%): No data

IN-LIFE DATES: No data
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
VEHICLE: Water
- Amount of vehicle (if gavage): 1 mL/kg bw at doses equal to or below 250 mg/kg bw and 2 mL/kg at doses up to 500 mg/kg bw
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: artificial insemination
- Proof of pregnancy: No data
Duration of treatment / exposure:
13 days (Day 6 to Day 18 of gestation)
Frequency of treatment:
Daily
Duration of test:
29 days
No. of animals per sex per dose:
Table 1 Number of animals dosed
Material Dose (mg/kg) Total
Mated Pregnant
Sham 0.0 17 11
6-AN 2.5 15 10
FDA 71-61 1.28 15 12
5.95 16 12
27.6 20 9
128.0 15 11
Control animals:
yes, sham-exposed
other: positive control: 2.5 mg/kg 6-aminonicotinamide (6-AN)
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Appearence, behaviour, food consumption and weight observed daily.
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: Yes
- Time schedule for examinations: Body weights recorded on days 0, 6, 12, 18 and 29.
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
- Organs examined: uterus and urogenital tract
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes
Fetal examinations:
- External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: Yes
Statistics:
No data
Indices:
No data
Historical control data:
No
Details on maternal toxic effects:
Maternal toxic effects:no effects
Dose descriptor:
NOAEL
Effect level:
> 128 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: no effects observed
Abnormalities:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No dose related response observed.
Dose descriptor:
NOAEL
Effect level:
> 128 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects observed
Abnormalities:
no effects observed
Developmental effects observed:
no

Table 2 Reproduction data

Dose (mg/kg)

Sham

6-AN

1.28

5.95

27.6

128.0

Pregnancies

 

 

 

 

 

 

Total No.

11

10

12

12

9

11

Died or aborted (before Day 29)

1

0

0

2

0

0

To term (on Day 29)

10

10

12

10

9

11

Corpora Lutea

 

 

 

 

 

 

Total no.

175

132

146

191

140

159

Average/dam mated

14.6

12.0

12.2

13.6

9.33

12.2

Live litters

 

 

 

 

 

 

Total No.*

10

6

12

9

9

11

Implant Sites

 

 

 

 

 

 

Total No.

53

42

70

64

44

80

Average/dam*

5.30

4.20

5.83

6.40

4.89

7.27

Resorptions

 

 

 

 

 

 

Total No*

--

18

3

9

1

7

Dams with 1 or more sites resorbed

--

6

2

3

1

5

Dams with all sites resorbed

--

4

--

1

--

--

Per cent partial resorptions

--

60.0

16.7

30.0

11.1

45.5

Per cent complete resorptions

--

40.0

--

10.0

--

--

Live foetuses

 

 

 

 

 

 

Total No

52

19

67

55

43

73

Average/dam*

5.20

1.90

5.58

5.50

4.78

6.64

Sex ratio (M/F)

0.73

5.00

0.63

1.04

1.26

0.92

Dead Foetuses

 

 

 

 

 

 

Total No.*

1

5

--

--

--

73

Dams with 1 or more dead

1

2

--

--

--

--

Dams with all dead

--

--

-

--

--

--

Per cent partial dead

10.0

20.0

--

--

--

--

Per cent all dead

--

--

--

--

--

--

Average foetus weight (g)

42.2

29.7

37.0

36.0

40.0

35.8

* Includes only those dams examined at term

** Positive control: 2.5 mg/kg 6-AN dosed on Day 9

 

Table 3 Summary of skeletal findings

Findings

Dose (mg/kg)

Sham

6-AN

1.28

5.95

27.6

128.0

Live foetuses examined (at term)

52/10

19/6

67/12

55/9

43/9

72/11a

Sternebrae

 

 

 

 

 

 

Incomplete oss.

2/2

1/1

 

1/1

2/2

 

Scrambled

 

 

 

 

 

 

Bipartite

 

1/1

 

1/1

 

1/1

Fused

 

3/2

 

 

 

 

Extra

 

1/1

2/1

 

 

6/4

Missing

 

2/2

 

 

 

 

Other

 

 

 

 

 

 

Ribs

 

 

 

 

 

 

Incomplete oss.

 

 

 

 

 

 

Fused/split

 

5/2

 

 

3/1

 

Wavy

 

 

 

 

 

 

Less than 12

 

 

 

 

 

 

More than 13

 

 

 

 

 

 

Other

 

 

 

 

 

 

Vertebrae

 

 

 

 

 

 

Incomplete oss.

 

 

 

 

 

 

Scrambled

 

4/2

 

 

 

 

Fused

 

 

 

 

 

 

Extra ctrs. oss.

 

 

 

 

 

 

Scoliosis

 

4/3

 

 

 

 

Tail defects

 

13/4

 

 

1/1

1/1

Other

 

 

 

 

 

 

Skull

 

 

 

 

 

 

Incomplete closure

 

1/1

 

 

 

 

Missing

 

 

 

 

 

 

Craniostosis

 

 

 

 

 

 

Other; facial bones, inc

 

1/1

 

 

 

 

Extremities

 

 

 

 

 

 

Incomplete oss.

 

 

 

 

 

 

Missing

 

 

 

 

 

 

Extra

 

 

 

 

 

 

Miscellaneous

 

 

 

 

 

 

* Numerator = Number of foetuses affected; Denominator = Number of litters affected

** Positive control: 2.5 mg/kg 6-AN dosed on Day 9

a One pup lost in processing

 

Table 4 Summary of soft tissue abnormalities

Material

Dose level (mg/kg)

Dam

Number of pups

Description

6-AN

2.5

Z 6479

1

Medial rotation of hind limbs

 

 

Z 6488

1

Medial rotation of hind limbs

 

 

Z 6489

1

Siamese pups (combined stomach and head)

 

 

Z 6490

3

Anopia, Medial rotation of hind limbs

 

 

 

2

Anopia

FDA 71-61

27.6

M 6051

2

Anopia

Conclusions:
Under the conditions of the study, the test material administered to pregnant rabbits for 13 days up to a dose level of 128 mg/kg bw showed no maternal or developmental toxicity. The NOAEL for both maternal and fetotoxicity is > 128 mg/kg bw.

Data source

Materials and methods

Results and discussion

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion