Registration Dossier

Administrative data

Endpoint:
reproductive toxicity, other
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
documentation insufficient for assessment

Data source

Reference
Reference Type:
publication
Title:
MATERNAL AND FOETAL DISTRIBUTION OF H3-DIHYDROMORPHINE IN THE TOLERANT AND NONTOLERANT RAT
Author:
Yeh SY & Woods LA
Year:
1970
Bibliographic source:
JOURNAL OP PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 174, No. 1: 9 – 13.

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Pregnant Sprague-Dawley female rats were made tolerant to the test material by initiating s.c. injections of 2 mg/kg (base) of drug, twice daily, 30 hours after breeding and increasing the dosage to 15 mg/kg. Control nontolerant pregnant animals were treated in an identical manner except that they were injected with saline. Foetuses were removed by caesarean section at intervals of one-half to four hours after s.c. injection of 7 mg/kg (base) of H3- test material to the maternal rat on the 21st day of gestation. Free and conjugated-levels of test material were assessed in maternal and foetal tissues and plasma.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: Weighing 250 to 300 g.
- Diet: Ad libitum
- Water: Ad libitum

ENVIRONMENTAL CONDITIONS
- Maintained under constant environmental conditions.

Administration / exposure

Route of administration:
subcutaneous
Vehicle:
physiological saline
Details on exposure:
About 30 hours after breeding, the pregnant female rats were begun on s.c. injections (gluteal region), twice daily, of non-labelled test material HCl in saline. Two dosage regimens of test material were used. The first was 4 mg/kg (base) initially, increased by 4 mg/kg every 2 days to a final dosage of 28 mg/kg for the last 8 days. Because this regimen gave a small number of full-term pregnancies, a lower dosage of test material was used, initially 2 mg/kg and increased at 2-day intervals to 4, 7, 10 and 15 mg/kg, which was maintained for the last 12 days. The injection volume was 2 mL/kg. Control non-tolerant pregnant rats were injected with equal volumes of saline.
Analgesia after injection of 7 mg/kg of drug in both the control and tolerant pregnant animal groups on the 18th day of gestation was tested with the hot plate method and compared with the effect in non-pregnant female rats. The pregnant rats were injected s.c. with 7 mg/kg (base) of tritium-labelled test material between 12 and 16 hours after the last injection of test material on the 21st day of gestation.
Details on mating procedure:
Males were mixed with females in a ratio of 1:3 in the evening, and the next morning the pregnant animals, confirmed by the vaginal smear test, were separated.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
4 mg/kg (base) initially, increased by 4 mg/kg every 2 days to a final dosage of 28 mg/kg for the last 8 days.
2 mg/kg (base) initially, increased at 2-day intervals to 4, 7, 10 and 15 mg/kg, which was maintained for the last 12 days.
Frequency of treatment:
4 mg/kg (base) initially, increased by 4 mg/kg every 2 days to a final dosage of 28 mg/kg for the last 8 days.
2 mg/kg (base) initially, increased at 2-day intervals to 4, 7, 10 and 15 mg/kg, which was maintained for the last 12 days.
Doses / concentrationsopen allclose all
Dose / conc.:
28 other: mg/kg
Remarks:
4 mg/kg (base) initially, increased by 4 mg/kg every 2 days to a final dosage of 28 mg/kg for the last 8 days.
Dose / conc.:
15 other: mg/kg
Remarks:
2 mg/kg (base) initially, increased at 2-day intervals to 4, 7, 10 and 15 mg/kg, which was maintained for the last 12 days.
No. of animals per sex per dose:
Not specified
Control animals:
yes, concurrent vehicle
Details on study design:
None specified

Examinations

Postmortem examinations (parental animals):
At the time of sacrifice the animals were anesthetized with ether and the foetuses were delivered by caesarean section with extreme care to avoid contamination by radioactive fluids from the mother. Maternal blood was withdrawn from the abdominal aorta, and the maternal brain, liver, kidneys and about 4 square inches of skin of the injection site (including muscle) were removed, blotted dry, wrapped in aluminium foil and frozen. All samples were collected within 10 minutes after anesthetization.

Postmortem examinations (offspring):
The foetuses were wiped, counted and weighed. The blood of foetuses was collected through decapitation, with heparin being used as an anticoagulant, and the livers, kidneys and brains were removed and pooled for each litter. All samples were collected within 10 minutes after anesthetization.
Statistics:
Two-tailed t test was used to compare the mean concentration of the drug in the tissue at P < 0.05 level.

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

Clinical signs:
not examined
Mortality:
not examined
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The larger dose of test material administered chronically reduces gain of maternal body weight.
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
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

Reproductive function / performance (P0)

Reproductive function: estrous cycle:
not specified
Reproductive function: sperm measures:
not examined
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
The larger dose of test material administered chronically reduces the number of litters and gain of maternal body weight but has no effect on the foetal body weight and the number of foetuses per litter.

Effect levels (P0)

Remarks on result:
not measured/tested

Target system / organ toxicity (P0)

Critical effects observed:
not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:
not examined
Mortality / viability:
not examined
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The larger dose of test material administered had no effect on the foetal body weight.
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:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined
Other effects:
not examined

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not examined

Details on results (F1)

The larger dose of test material administered chronically reduces the number of litters but has no effect on the foetal body weight and the number of foetuses per litter.

Effect levels (F1)

Remarks on result:
not measured/tested

Applicant's summary and conclusion

Conclusions:
The larger dose of test material administered chronically reduces the number of litters and gain of maternal body weight but has no effect on the foetal body weight and the number of foetuses per litter.
Executive summary:

Pregnant Sprague-Dawley female rats were made tolerant to the test material by initiating s.c. injections of 2 mg/kg (base) of drug, twice daily, 30 hours after breeding and increasing the dosage to 15 mg/kg. Control nontolerant pregnant animals were treated in an identical manner except that they were injected with saline. Foetuses were removed by caesarean section at intervals of one-half to four hours after s.c. injection of 7 mg/kg (base) of H3- test material to the maternal rat on the 21st day of gestation. Free and conjugated-levels of test material were assessed in maternal and foetal tissues and plasma.

The larger dose of test material administered chronically reduces the number of litters and gain of maternal body weight but had no effect on the foetal body weight and the number of foetuses per litter.