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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:
30 Apr - 11 Sep 2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2019
Report date:
2019

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
adopted 22 Jan 2001
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
Government of India, Department of Science and Technology, New Delhi, India
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Ethylene di(acetate)
EC Number:
203-881-1
EC Name:
Ethylene di(acetate)
Cas Number:
111-55-7
Molecular formula:
C6H10O4
IUPAC Name:
2-(acetyloxy)ethyl acetate
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Expiration date of the batch: 20 Oct 2019

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: 15 to 25 °C
- Solubility and stability of the test substance in the vehicle were confirmed by analytical methods


Test animals

Species:
rat
Strain:
Wistar
Remarks:
Han_Tac: WH
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Vivo Bio Tech Ltd., Medak District, Telangana, India
- Age at study initiation: 13 - 14 weeks
- Weight at study initiation: 186.55 to 260.87 g
- Housing: in sterilised standard polysulfone rat cages (size 425 x 266 x 185 mm) with a stainless steel top grill having facilities for pelleted food and water supply, steam sterilised clean corn cob as bedding
Pre-mating: two rats of the same sex per cage
Mating: female rats were cohabited with males in a 1:1 ratio in the same cage
Post-mating/Treatment: After mating confirmation, females were housed individually

- Diet: Teklad Certified (2014C) Global 14% Protein Rodent Maintainance Diet - Pellet, Envigo, Madison, Wisconsin, ad libitum
- Water: Deep bore-well water passed through an activated charcoal filter and exposed to UV rays in 'Aquagard' on-line water filter-cum-purifier (Eureka Forbes Limited, Mumbai, India), ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 57 - 67
- Air changes (per hr): 12 - 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Dose formulations were prepared at 4 days intervals. The required quantities were weighed and a small volume of vehicle (corn oil) was added and mixed well using a glass rod. The final volume was made up with the vehicle to receive the required final concentration. The volume was made up to the upper meniscus during dose formulation.

VEHICLE
- Justification for use and choice of vehicle: Based on a solubility test, the test item forms uniform suspension in corn oil. Hence, corn oil was used as vehicle for dose formulation preparations.
- Concentration in vehicle: 25, 75 and 250 mg/mL
- Amount of vehicle (if gavage): 4 mL/kg bw
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Dose formulations were analysed for the test item concentration at the initiation of treatment and at termination of treatment period (1-3 days before termination). For each set, duplicate samples were drawn from the top, middle and bottom-layers of each preparation and in case of the control duplicate samples from the middle layer were drawn. The test item in the dose formulation was determined using Gas Chromatograph with Flame Ionisation Detection (FID). The test item was used as the analytical standard.
The results were considered acceptable, if the overall mean result of all layers was within ± 15.0% of the claimed concentration and the relative standard deviation was equal or less than 10.0%. The results of dose formulations were within the acceptable limits for all dose groups.
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: overnight
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as Day 0 of pregnancy
Duration of treatment / exposure:
Day 5 - 19 of gestation
Frequency of treatment:
daily, 7 days/week
Duration of test:
Day 20 of gestation
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
24 parental females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Dose levels were selected based on a preliminary range-finding study, in which animals were orally exposed to up to 1000 mg/kg bw/day for 14 days (Study N3725). The results indicated that treatment did not cause any adverse effects up to the highest dose of 1000 mg/kg bw/day during the 14 day treatment period. Therefore, 100, 300 and 1000 mg/kg bw/day were selected as the dose levels for the main study.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: gestation days 0, 3, 5, 8, 11, 14, 17 and 20

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

WATER CONSUMPTION : No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: gravid uterus, cervix
Ovaries and uterine content:
The ovaries and uterine content was examined after termination:
Examinations included:
- Pregnancy status
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: Gross evaluation of placenta
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: all per litter
Statistics:
- Levene’s test for homogeneity of intra group variances
- Analysis of Variance (ANOVA) was performed after suitable transformation of data on maternal body weight, body weight in interval, gravid uterine weight, body weight change corrected to gravid uterine weight, maternal food consumption
- Dunnett’s pairwise comparison of the treated group means with the control group (in case of statistical significance)
- Analysis of Covariance (ANCOVA) for analysis of fetal weight for male and female taking litter size as covariante for group
- Kruskal wallis test for group comparison regarding the number of corpora lutea, number of implantations, early and late resorptions, pre-implantation and post-implantation loss, external, visceral and skeletal observations for variations
- Cochran Armitage trend test followed by Fisher’s exact test for group association testing the incidence of with and without resorptions in dams
Indices:
Maternal parameters:
- Mean number of corpora lutea/group = Total number of corporar lutea/Total number of pregnant animals
- Mean number of implantations/group = Total number of implantations/Total number of pregnant animals
- Embryonic resorption index [%] = Number of early resorptions/Number of implantations x 100
- Fetal resorption index [%] = Number of late resorptions/Number of implantations x 100
- Pre-implantation loss per group [%] = (Number of CL – Number of implantations)/Number of CL x 100
- Post-implantation loss per group [%] =n Number of (early + late) resorptions/ Total number of implantations x 100
- Implantation index [%] = Number of implantations sites/Number of corpora lutea x 100

Litter data:
- Mean litter size per group = Total number of fetuses/Total number of pregnant animals
- Percentage of abnormal fetuses = Total abnormal fetuses/Total number of fetuses x 100
- Percentage of live fetuses per group (Live fetus index) = Number of live fetuses/Total number of fetuses x 100
- Percentage of dead fetuses per group (Dead fetus index) = Number of dead fetuses/Total number of fetuses x 100
- Percentage of male fetuses per group = Number of male fetuses/Total number of fetuses x 100
- Sex ratio (F:M) = Number of females/Number of males
- Corrected body weight (Carcass weight) = Terminal body weight (body weight gain on GD20) – unopened uterine weight
- Corrected body weight gain = Corrected body weight – body weight on GD5
Historical control data:
Historical data was provided to allow comparison with concurrent controls. The following data was given:
- Mean maternal body weight during gestation
- Body weight gain during gestation
- Food intake
- Maternal data
- Litter data
- External observations
- Visceral observations
- Sekeletal observations

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
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):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
no effects observed

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Remarks:
systemic
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: no effects observed

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
1000 mg/kg bw/day: one small fetus
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
1000 mg/kg bw/day: increase in percental fetal incidence of delayed skeletal ossification
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
1000 mg/kg bw/day: single incidence of moderate renal pelvis dilation of kidney
Details on embryotoxic / teratogenic effects:
EXTERNAL MALFORMATIONS:
There was an incidence of a small fetus in the high dose group. This finding was not of any toxicological significance as this is commonly observed in rat fetuses.

SKELETAL MALFORMATIONS:
There was a statistically significant increase in the percent fetal incidence of delayed skeletal ossification in one of the bone component (Forelimb metacarpal 1/4) observed in the 1000 mg/kg bw/day dose group as compared to the vehicle control group. The effect was considered not significant because historical data shows that this normal variation was commonly observed in rat fetuses.
Furthermore, there was a statistically significant increase in the percent fetal incidence of asymmetrical ossification of sternum numbers 4 and 5 in the high dose group (1000 mg/kg bw/day). As maternal and litter parameters at this dose were not affected, the finding was not considered as an adverse effect.

VISCERAL MALFORMATIONS:
There was a single incidence of moderate renal pelvis dilation of kidney in the high dose group. This finding was comparable to historical data and hence is not of any significance.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Remarks:
developmental
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effect observed

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Any other information on results incl. tables

Table 1: Summary of clinical signs and mortality:

  Group No. G1 G2 G3 G4
Observations Dose (mg/kg/day) 0 100 300 1000

 Total No. of rats found sperm positive 

 24 24 24 24
Clinical signs NAD NAD NAD NAD
Mortality -------------None------------

NAD: no abnormality detected

Table 2: Summary on maternal group body weight

Group Dose No. Of Group mean body weight (g) on gestation day (GD)
No. (mg/kg/day) Rats$   0 3 5 8 11 14 17 20
G1 0 23 Mean 218.5 227.63 233.22 240.46 253.65 264.62 289.32 314.74
  SD 14.83 14.47 15.34 16.65 17.38 18.26 21.07 27.76
G2 100 24 Mean 221.82 230.99 236.15 243.92 257.93 268.5 293.56 314.59
  SD 14.7 14.43 14.09 15.6 16.95 18.11 20.71 21.58
G3 300 23 Mean 219.76 229 234.99 242.64 257.12 268.53 291.09 311.35
  SD 14.47 14.59 14.02 14.71 16.43 17.66 21.48 24.43
G4 1000 22 Mean 222.73 231.41 236.7 242.8 255.86 266.43 288.86 309.12
      SD 16.21 16.84 17.08 17.13 17.55 19.06 21.08 21.81

$: Pregnant rats

Table 3: Summary of food intake (g/rat/day):

Period of treatment

(days of gestation)

Group No.

G1

G2

G3

G4

Dose (mg/kg/day)

0

100

300

1000

No. of Rats$

23

24

23

22

Intermittent food intake

0-3

Mean

15.63

16.13

16.33

15.61

 

SD

1.74

1.44

1.28

1.61

3-5

Mean

17.40

17.78

17.87

17.56

 

SD

2.30

1.33

1.47

2.11

5-8

Mean

16.21

16.66

16.95

15.99

 

SD

2.38

2.15

1.47

1.74

8-11

Mean

17.30

17.84

18.05

17.17

 

SD

2.44

1.55

1.54

1.60

11-14

Mean

18.04

18.74

19.14

18.36

 

SD

2.34

1.53

1.26

2.07

14-17

Mean

19.08

19.36

19.54

18.87

 

SD

2.61

1.93

2.14

2.06

17-20

Mean

16.51

16.78

17.34

16.91

 

SD

3.37

2.70

3.10

4.11

$: Pregnant rats

Table 4: Summary of maternal data

Parameters Group No. G1 G2 G3 G4
Dose (mg/kg/day) 0 100 300 1000
No. of Rats$ 23 24 23 22
Gravid uterine weight (g) Mean 64.47 68.22 61.54 58.91
SD 13.38 12.24 17.11 12.54
Number of Corpora lutea Mean 13.22 14 13.52 14
SD 1.95 2.43 1.86 1.8
Number of Implantations Mean 11.74 12.79 11.87 11.59
SD 2.47 2.6 2.91 2.26
Early Resorptions Mean 0.3 0.46 0.78 0.82
SD 0.56 0.72 1.28 1.22
Late Resorptions Mean 0.04 0 0.04 0.14
SD 0.21 0 0.21 0.35
Pre-implantation Loss Mean 1.48 1.21 1.65 2.41
SD 1.65 1.35 1.56 2.17
Post-implantation Loss Mean 0.35 0.46 0.83 0.95
SD 0.65 0.72 1.3 1.17
Dams with any Resorption Total 6 9 9 12
Early Resorptions (%) Mean 2.62 3.52 7.19 7.83
SD 4.63 5.21 12.15 12.55
Late Resorptions (%) Mean 0.33 0 0.31 1.21
SD 1.6 0 1.49 3.14
Pre-implantation Loss (%) Mean 11.27 8.95 13.69 16.82
SD 12.82 10.62 17.76 13.66
Post-implantation Loss (%) Mean 2.95 3.52 7.5 9.04
SD 5.25 5.21 12.24 12.15
Implantation Index (%) Mean 88.73 91.05 86.31 83.18
SD 12.82 10.62 17.76 13.66

$: Pregnant rats

Table 5: Summary of litter data

Parameters Group No. G1 G2 G3 G4
Dose (mg/kg/day) 0 100 300 1000
No. of Rats$ 23 24 23 22
No. of litters 23 24 23 22
Total no. of fetuses 262 296 254 234
Mean litter size 11.4 12.3 11 10.6
Total live fetuses  
a. Number 262 296 254 234
b.  Weight (g) Mean 3.76 3.8 3.73 3.61
  SD 0.47 0.2 0.22 0.27
Live male fetuses  
a. Number 136 163 136 119
b.  Weight (g) Mean 3.85 3.88 3.78 3.73
  SD 0.45 0.23 0.22 0.26
Live female fetuses  
a. Number 126 133 118 115
b.  Weight (g) Mean 3.65 3.7 3.7 3.55
  SD 0.54 0.2 0.29 0.32
Sex Ratio - Male : Female 1:0.93 1:0.82 1:0.87 1:0.97
(% of male fetuses)   -51.90% -55.10% -53.50% -50.90%

$: Pregnant rats

Table 6: Summary of gross pathological findings

Group No. G1 G2 G3 G4
Parameters Dose (mg/kg/day) 0 100 300 1000
         
1.  No. of rats subjected to caesarean section 24 24 24 24
2.  No. of rats pregnant at caesarean section 23 24 23 22
3.  No. of rats showing gross pathology 0 0 0 0

Table 7: Summary of fetal external observations (incidence and percentage)

Group No. G1 G2 G3 G4
Dose (mg/kg/day) 0 100 300 1000
No. of litters examined 23 24 23 22
No. of fetuses examined 262 296 254 234
  Fetus Litter Fetus Litter Fetus Litter Fetus Litter
  Inc. % Inc. % Inc. % Inc. % Inc. % Inc. % Inc. % Inc. %
                                 
Normal Variant None
                                 
Minor Anomalies                                
Small fetus 0 0 0 0 0 0 0 0 0 0 0 0 1 0.43 1 4.55
                                 
Major Malformations None

Table 8: Summary of fetal visceral observations (incidence and percentage)

Group No. G1 G2 G3 G4
Dose (mg/kg/day) 0 100 300 1000
No. of litters examined 23 24 23 22
No. of fetuses examined 127 140 120 112
  Fetus Litter Fetus Litter Fetus Litter Fetus Litter
  Inc. % Inc. % Inc. % Inc. % Inc. % Inc. % Inc. % Inc. %
                                 
Normal Variant                                
Kidney-renal pelvis dilation 1 0.79 1 4.35 0 0 0 0 0 0 0 0 0 0 0 0
(slight)                                
Minor Anomalies                                
Kidney-renal pelvis dilation 0 0 0 0 0 0 0 0 0 0 0 0 1 0.89 1 4.55
(moderate)                                
Major Malformations None

Table 9: Summary of fetal skeletal observations (incidencde and percentage)

Group No. G1 G2 G3 G4
Dose (mg/kg/day) 0 100 300 1000
No. of litters examined 23 24 23 22
No. of fetuses examined 127 140 120 112
  Fetus Litter Fetus Litter Fetus Litter Fetus Litter
Variant Inc. % Inc. % Inc. % Inc. % Inc. % Inc. % Inc. % Inc. %
DSO:Ileum 1 0.74 1 4.35 0 0 0 0 0 0 0 0 0 0 0 0
DSO:Ischium,Pubis 1 0.74 1 4.35 0 0 0 0 0 0 0 0 0 0 0 0
DSO:Stern:# 2 0 0 0 0 0 0 0 0 0 0 0 0 1 0.82 1 4.55
DSO:Stern:# 3 0 0 0 0 0 0 0 0 0 0 0 0 1 0.82 1 4.55
DSO:Stern:# 5 2 1.48 2 8.7 10 6.41 8 33.33 6 4.48 4 17.39 6 4.92 3 13.64
DSO:Stern:# 6 3 2.22 3 13.04 5 3.21 5 20.83 4 2.99 2 8.7 6 4.92 3 13.64
DSO:Stern:# 1-6 1 0.74 1 4.35 0 0 0 0 0 0 0 0 2 1.64 2 9.09
DSO:Stern:# 4-6 1 0.74 1 4.35 0 0 0 0 0 0 0 0 0 0 0 0
DSO:Stern:# 5,6 2 1.48 2 8.7 1 0.64 1 4.17 2 1.49 2 8.7 8 6.56 4 18.18
DSO:Stern:# 2,4-6 0 0 0 0 0 0 0 0 0 0 0 0 1 0.82 1 4.55
                                 
DSO:CV:centra:1/7 0 0 0 0 0 0 0 0 0 0 0 0 1 0.82 1 4.55
DSO:CV:centra:2/7 1 0.74 1 4.35 0 0 0 0 1 0.75 1 4.35 3 2.46 3 13.64
DSO:CV:centra:3/7 3 2.22 1 4.35 2 1.28 2 8.33 4 2.99 4 17.39 13 10.66 11 50
DSO:CV:centra:4/7 9 6.67 5 21.74 8 5.13 6 25 13 9.7 10 43.48 14 11.48 12 54.55
DSO:CV:centra:5/7 3 2.22 3 13.04 7 4.49 5 20.83 8 5.97 6 26.09 8 6.56 6 27.27
DSO:CV:centra:6/7 8 5.93 5 21.74 10 6.41 5 20.83 17 12.69 8 34.78 11 9.02 7 31.82
DSO:CV:centra:7/7 3 2.22 2 8.7 2 1.28 2 8.33 1 0.75 1 4.35 7 5.74 6 27.27
DSO:CdV:centra:1/4 9 6.67 6 26.09 8 5.13 4 16.67 16 11.94 8 34.78 18 14.75 10 45.45
DSO:CdV:centra:2/4 1 0.74 1 4.35 0 0 0 0 0 0 0 0 2 1.64 2 9.09
DSO:CdV:centra:3/4 0 0 0 0 0 0 0 0 1 0.75 1 4.35 1 0.82 1 4.55
DSO:CdV:centra:4/4 3 2.22 1 4.35 0 0 0 0 0 0 0 0 3 2.46 3 13.64
                                 
DSO:CdV:arch:1/2 6 4.44 5 21.74 2 1.28 1 4.17 15 11.19 10 43.48 19 15.57 6 27.27
DSO:CdV:arch:2/2 3 2.22 1 4.35 0 0 0 0 0 0 0 0 4 3.28 4 18.18
DSO:TV:centra:1-13 1 0.74 1 4.35 0 0 0 0 0 0 0 0 0 0 0 0
DSO:LV:centra:6/6 1 0.74 1 4.35 0 0 0 0 0 0 0 0 0 0 0 0
DSO:SV:centra:4/4 1 0.74 1 4.35 0 0 0 0 0 0 0 0 0 0 0 0
DSO:SV:arch:4/4 1 0.74 1 4.35 0 0 0 0 0 0 0 0 0 0 0 0
DSO:F limb:Metacarp.:1/4 8 5.93 5 21.74 4 2.56 3 12.5 25 18.66 13 56.52 35 28.69* 14 63.64
DSO:F limb:Metacarp.:3/4 1 0.74 1 4.35 0 0 0 0 0 0 0 0 0 0 0 0
DSO:F limb:Pr. Phal:1/2 3 2.22 3 13.04 2 1.28 2 8.33 4 2.99 4 17.39 2 1.64 1 4.55
DSO:F limb:Pr. Phal:2/2 43 31.85 14 60.87 42 26.92 13 54.17 46 34.33 17 73.91 66 54.1 19 86.36
                                 
DSO:F limb:Dt. Phal:1/4 0 0 0 0 0 0 0 0 3 2.24 2 8.7 26 21.31 11 50
DSO:F limb:Dt. Phal:2/4 0 0 0 0 0 0 0 0 2 1.49 2 8.7 2 1.64 2 9.09
DSO:F limb:Dt. Phal:4/4 5 3.7 2 8.7 0 0 0 0 2 1.49 2 8.7 9 7.38 6 27.27
DSO:H limb:Metatar.:1/4 1 0.74 1 4.35 0 0 0 0 0 0 0 0 3 2.46 3 13.64
DSO:H limb:Metatar.:3/4 1 0.74 1 4.35 0 0 0 0 0 0 0 0 0 0 0 0
DSO:H limb:Dt. Phal:1/5 4 2.96 3 13.04 9 5.77 4 16.67 18 13.43 9 39.13 26 21.31 11 50
DSO:H limb:Dt. Phal:5/5 6 4.44 3 13.04 0 0 0 0 3 2.24 3 13.04 16 13.11 8 36.36
INO/PO:Skull bones 1 0.74 1 4.35 0 0 0 0 0 0 0 0 0 0 0 0
INO/PO:Parietal 0 0 0 0 0 0 0 0 0 0 0 0 1 0.82 1 4.55
INO/PO:Pa, Ipa 3 2.22 3 13.04 0 0 0 0 2 1.49 2 8.7 3 2.46 3 13.64
                                 
INO/PO:Inter pariet. 0 0 0 0 0 0 0 0 0 0 0 0 2 1.64 1 4.55
INO/PO:Supraocci 0 0 0 0 0 0 0 0 0 0 0 0 1 0.82 1 4.55
INO/PO:Pubis 0 0 0 0 0 0 0 0 0 0 0 0 1 0.82 1 4.55
INO/PO:Fr, Pa, Ipa 0 0 0 0 0 0 0 0 0 0 0 0 1 0.82 1 4.55
INO/PO:Stern:# 1 4 2.96 2 8.7 0 0 0 0 0 0 0 0 3 2.46 3 13.64
INO/PO:Stern:# 2 7 5.19 6 26.09 5 3.21 5 20.83 5 3.73 4 17.39 15 12.3 8 36.36
INO/PO:Stern:# 3 4 2.96 2 8.7 0 0 0 0 0 0 0 0 1 0.82 1 4.55
INO/PO:Stern:# 4 3 2.22 3 13.04 1 0.64 1 4.17 2 1.49 2 8.7 6 4.92 5 22.73
INO/PO:Stern:# 5 41 30.37 17 73.91 51 32.69 21 87.5 47 35.07 20 86.96 36 29.51 16 72.73
INO/PO:Stern:# 6 13 9.63 10 43.48 16 10.26 11 45.83 19 14.18 10 43.48 20 16.39 13 59.09
                                 
INO/PO:CV:centra:1/7 0 0 0 0 0 0 0 0 3 2.24 3 13.04 1 0.82 1 4.55
INO/PO:CV:centra:2/7 1 0.74 1 4.35 0 0 0 0 4 2.99 4 17.39 2 1.64 2 9.09
INO/PO:CV:centra:3/7 1 0.74 1 4.35 1 0.64 1 4.17 1 0.75 1 4.35 1 0.82 1 4.55
INO/PO:CV:centra:4/7 0 0 0 0 1 0.64 1 4.17 0 0 0 0 1 0.82 1 4.55
INO/PO:TV:centra:1/13 0 0 0 0 0 0 0 0 0 0 0 0 1 0.82 1 4.55
                                 
HYPOPLASTIC:Stern:# 1 0 0 0 0 0 0 0 0 0 0 0 0 1 0.82 1 4.55
HYPOPLASTIC:Stern:# 2 2 1.48 1 4.35 1 0.64 1 4.17 0 0 0 0 1 0.82 1 4.55
HYPOPLASTIC:Stern:# 3 0 0 0 0 0 0 0 0 0 0 0 0 1 0.82 1 4.55
HYPOPLASTIC:Stern:# 5 10 7.41 6 26.09 13 8.33 9 37.5 7 5.22 6 26.09 4 3.28 3 13.64
                                 
SPLIT:TV:centra:1/13 0 0 0 0 0 0 0 0 0 0 0 0 1 0.82 1 4.55
DB:TV:centra:1/13 4 2.96 3 13.04 2 1.28 2 8.33 6 4.48 5 21.74 10 8.2 8 36.36
DB:TV:centra:2/13 1 0.74 1 4.35 1 0.64 1 4.17 1 0.75 1 4.35 1 0.82 1 4.55
ASY DB:TV:centra:1/13 1 0.74 1 4.35 4 2.56 4 16.67 1 0.75 1 4.35 1 0.82 1 4.55
ASY OSSI:stern:# 3,4 0 0 0 0 3 1.92 3 12.5 1 0.75 1 4.35 2 1.64 2 9.09
ASY OSSI:stern:# 4 0 0 0 0 0 0 0 0 2 1.49 2 8.7 2 1.64 2 9.09
ASY OSSI:stern:#2-4 0 0 0 0 0 0 0 0 0 0 0 0 1 0.82 1 4.55
ASY OSSI:stern:#4,5 0 0 0 0 0 0 0 0 1 0.75 1 4.35 5 4.10* 5 22.73
RUDIMENTARY: RIB(Rt/Lt/B):# 14 31 22.96 17 73.91 35 22.44 16 66.67 35 26.12 17 73.91 35 28.69 15 68.18
ACCESSORY: RIB(Rt/Lt/B):# 14 1 0.74 1 4.35 2 1.28 2 8.33 1 0.75 1 4.35 3 2.46 3 13.64
                                 
WAVY:RIB(Rt/Lt/B)(+/++):1/13 1 0.74 1 4.35 0 0 0 0 0 0 0 0 0 0 0 0
WAVY:RIB(Rt/Lt/B)(+/++):2/13 2 1.48 2 8.7 0 0 0 0 1 0.75 1 4.35 0 0 0 0
WAVY:RIB(Rt/Lt/B)(+/++):3/13 1 0.74 1 4.35 0 0 0 0 0 0 0 0 0 0 0 0
WAVY:RIB(Rt/Lt/B)(+/++):5/13 0 0 0 0 0 0 0 0 1 0.75 1 4.35 0 0 0 0
EXTRA:RIB(Rt/Lt/B):# 14 0 0 0 0 0 0 0 0 0 0 0 0 3 2.46 2 9.09
EXTRA:LV:centra & arch #7 0 0 0 0 0 0 0 0 0 0 0 0 3 2.46 3 13.64

Applicant's summary and conclusion

Conclusions:
The test item had no effect on intrauterine development.