Heparin, sodium salt

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Limited study summary. Not GLP.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1986

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The Sprague-Dawley rats were used in this teratogenicity study. The test substance was administered into dorsal region by subcutaneous route once daily on days 5-16 of pregnancy.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

nonasodium 2-({6-[(2-carboxylato-4-hydroxy-6-{[6-hydroxy-5-(sulfonatoamino)-4-(sulfonatooxy)-2-[(sulfonatooxy)methyl]oxan-3-yl]oxy}-5-(sulfonatooxy)oxan-3-yl)oxy]-4-hydroxy-5-(sulfonatoamino)-2-[(sulfonatooxy)methyl]oxan-3-yl}oxy)-4-hydroxy-3-(sulfonatooxy)-3,4-dihydro-2H-pyran-6-carboxylate

EC Number:

700-834-1

Cas Number:

9041-08-1

Molecular formula:

not applicable (UVCB substance)

IUPAC Name:

nonasodium 2-({6-[(2-carboxylato-4-hydroxy-6-{[6-hydroxy-5-(sulfonatoamino)-4-(sulfonatooxy)-2-[(sulfonatooxy)methyl]oxan-3-yl]oxy}-5-(sulfonatooxy)oxan-3-yl)oxy]-4-hydroxy-5-(sulfonatoamino)-2-[(sulfonatooxy)methyl]oxan-3-yl}oxy)-4-hydroxy-3-(sulfonatooxy)-3,4-dihydro-2H-pyran-6-carboxylate

Details on test material:

Batch No.: not specified
Purity: not specified

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: Female 8 weeks of age, male 10 weeks of age
- Weight at study initiation: Female and male weighing 200±10 g
- Housing: The animals were housed in Makrolon cages in an air-conditioned room.
- Diet (e.g. ad libitum): Females received pelletted dry diet Altromin MT and males diet Altromin R.
- Water (e.g. ad libitum): Tap water was available ad libitum.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-23°C
- Humidity (%): 55-60%
- Air changes (per hr): Ventilation was 12 times/h
- Photoperiod (hrs dark / hrs light): Lighting schedule was 12:12 light/dark (from 7:00 a.m. to 7:00 p.m.)

No additional data

Administration / exposure

Route of administration:

subcutaneous

Vehicle:

physiological saline

Details on exposure:

The test substance was dissolved in physiological solution and administered into dorsal region, by subcutaneous route, at 1-10 mg/kg at a volume of 5 mL/kg. For comparison was used conventional heparin (H) with activity of 163 USP/mg at 1-10 mg/kg by s.c. route (5 mL/kg).

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

- M/F ratio per cage: 1/3
- Length of cohabitation: one night
- Proof of pregnancy: sperm in vaginal smear referred to as day 1 of pregnancy

No additional data

Duration of treatment / exposure:

On days 5-16 of pregnancy.

Frequency of treatment:

Once daily

Duration of test:

21 days

Doses / concentrations

Remarks:

Doses / Concentrations:
1, 10 mg/kg
Basis:
actual ingested

No. of animals per sex per dose:

10 females

Control animals:

yes, concurrent vehicle

Details on study design:

None stated

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: During the gestation the animals were daily observed for any changes in appearance or behaviour and mortality.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: During the gestation the animals were daily observed for any changes in appearance or behaviour and mortality.

BODY WEIGHT: Yes
- Time schedule for examinations: Body weight was measured at selected intervals (1, 7, 14, 21 days).

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: The uterus and the fetuses were examined, the number and location of viable, dead and resorbed fetuses were recorded.

No additional data

Ovaries and uterine content:

None stated

Fetal examinations:

Viable fetuses were weighed, examined externally and the cranial, thoracic and abdominal organs were examined by dissection.
The skeletons were examined after they had been fixed in 70% alcohol, cleared with potassium hydroxide and stained with alizarin red-S.

Statistics:

The results were statistically analyzed by Student's t-test for independent samples.

Indices:

None stated

Historical control data:

None stated

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
The test substance administered to rats during organogenensis period, up to 10 mg/kg, showed no embryotoxic and fetotoxic activity, since the drugs did not make a change, in comparison to the controls, in number of implantation sites, resorptions and fetal mortality.

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

>= 10 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: other:

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Visceral and skeletal macroscopic alterations did not appear in the living fetuses.
No differences from controls were reported in appearance, behaviour or body weight of the dams up to 10 mg/kg/d.

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The test substance administered to rats during organogenensis period, up to 10 mg/kg, showed no embryotoxic and fetotoxic activity, since the drugs did not make a change, in comparison to the controls, in number of implantation sites, resorptions and fetal mortality.