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Administrative data

Endpoint:
developmental toxicity
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
Teratologische Untersuchungen eines niedermolekularen Polyvinylpyrrolidon-Jod-Komplexes an Kaninchen
Author:
Siegemund B., Weyers W.,
Year:
1987
Bibliographic source:
Arzneim.-Forsch./Drug Res., Vol. 37(3), 340-341, 1987

Materials and methods

Principles of method if other than guideline:
The test substance was tested for its developmental effects after intramuscular application in rabbits.
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Reference substance name:
Reaction mass of iodine and 2-Pyrrolidinone, 1-ethenyl-, homopolymer
EC Number:
913-404-5
Molecular formula:
Unspecified
IUPAC Name:
Reaction mass of iodine and 2-Pyrrolidinone, 1-ethenyl-, homopolymer
Details on test material:
- Purity: ≥ 92%- pH: ≥ 1 - ≤ 5 (aqueous preparation)
Specific details on test material used for the study:
- Name of the test substance: polyvinylpyrrolidone-iodine complex (PVP-Jod-Komplexe)

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS - Age at study initiation: 3.5 to 4 month - Housing: Full wired cages, individual - Diet: Altromin ® Standard Diät. Nr. 3110; Altromin, Lage/Lippe ad libitum - Water: ad libitum ENVIRONMENTAL CONDITIONS - Temperature (°C): 20 - 23 - Humidity (%): 65 - Air changes (per hr): 10 - Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:
intramuscular
Vehicle:
water
Details on mating procedure:
Each female animal was bred successively with 3 different males of the same breeding and origin. After visual determination of at least 2 copulations, the animals were selected for testing with the test substance.
Duration of treatment / exposure:
day 6 to day 18 of gestation
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
16 mg/kg bw/day
Dose / conc.:
35 mg/kg bw/day
Dose / conc.:
75 mg/kg bw/day
No. of animals per sex per dose:
12 control animals, 15 low dose group animals, 15 middle dose group animals, and 15 high dose group animals
Control animals:
yes
Details on study design:
Day "0" of gestation was the day of copulations. The administration of the substance was carried out from day 6 to day 18 of gestation via percutaneous injection into the lumbar muscles. This application form was chosen to investigate the worst case (after local application complete absorption takes place). The administration volume was 0.5 mL/kg body weight. The control group received physiological saline. The middle dosage chosen in this study, is about the amount that is needed for wiping a 20 x 20 cm large treatment field. For the treatment area a person of ca 70 kg was assumed. At day 29 pups were born via C-Section.

Examinations

Maternal examinations:
- General examinations - Body weight development- Number of pregnant animals- Number of aborted pregnancies and number of aborted pregnancies with resorptions or malformations.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes- Number of resorptions- Mean placenta weight- Number of corpora lutea- Number of implantations
Fetal examinations:
The following examinations were recorded:- Mean fetal weight- The number of living and dead fetussus- Number of Runts - Malformations

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No influence on the general state of the females was observed. In one animal the middle dose group was in week two of gestation a complete paralysis of both hind limbs observed. The animal was euthanized at day 24 of pregnancy.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
A clear dose-related effect on the body weight gain was observed. Weight gain was about 13.4% (16 mg/kg) to 9.5% (75 mg/kg) in treated animals, versus 16.7% in controls. Only the hig high dose was significantly different from control.
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 specified
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:
not examined
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
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:
not specified
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not examined
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
not examined
Other effects:
no effects observed

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
35 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
body weight and weight gain

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined
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:
no effects observed
Skeletal malformations:
not specified
Visceral malformations:
not specified
Other effects:
no effects observed
Details on embryotoxic / teratogenic effects:
Malformations were observed in both control as well as test groups. In one fetus in the control group perirenal bleeding was observed. Three fetuses from the lower dose group had ectopic kidneys. In an animal of the same group, the kidneys were fused, and a misshapen liver was found in another animal. Another ectopic kidney was observed in one animal of the medium dose. In the high dose group an animal was observed with only one kidney. In another, a malformation of the diaphragm was present. A dose response relationship was not observed for these malformations.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
>= 75 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects

Fetal abnormalities

Key result
Abnormalities:
effects observed, non-treatment-related

Overall developmental toxicity

Key result
Developmental effects observed:
no

Any other information on results incl. tables

Table 1. Results of examinations

 

Control

Low dose

Middle dose

High dose

Number of animals used

12

14

15

15

Pregnant animals

10

9

10

9

Aborted pregnancies

0

0

0

0

- With resorptions

5

5

7

4

- With malformations

0

0

0

0

Number of living fetuses

70

67

66

71

Number of dead fetuses

1

0

2

0

Number of Runts

1

2

1

1

Number of resorptions

7

9

13

8

Number of malformations

1

5

1

2

Numbers per pregnancy (average ± SD)

Living fetuses

7.0 ± 2.16

7.4 ± 2.87

7.4 ± 1.87

8.8 ± 1.80

Dead fetuses

0.1 ± 0.32

0.0

0.22 ± 0.44

0.0

Resorptions

0.7 ± 0.95

1.0 ± 1.12

1.44 ± 1.13

1.0 ± 1.41

Implantations

7.8 ±2.39

8.44 ± 2.60

9.11 ± 1.83

9.88 ± 1.96

Corpus luteum

9.3 ± 1.83

10.67 ± 1.58

9.89 ± 1.90

11.00 ± 4.09

Resorption of implantations (%)

8.04 ± 9.96

12.58 ± 15.29

15.13 ± 10.93

9.19 ± 12.2

preimplantation losses (%)

18.2 ± 20.4

27.5 ± 20.4

10.4 ± 17.6

11.6 ± 16.9

Postimplantation losses (%)

9.13 ± 9.57

12.58 ± 15.27

18.08 ± 14.15

9.18 ± 12.2

Malformations

1.43

7.46

1.52

2.82

Mean fetal weight

42.6 ± 5.56

39.8 ± 7.47

36.3 ± 4.14

37.3 ± 2.41

Mean placenta weight

4.23 ± 0.76

4.07 ± 0.77

3.79 ± 0.79

3.74 ± 0.24

Applicant's summary and conclusion