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Diss Factsheets

Administrative data

Endpoint:
fertility, other
Remarks:
Fertility and general reproduction toxicity study
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature

Data source

Reference
Reference Type:
review article or handbook
Title:
PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
Author:
Thornton-Jones SR
Year:
2004
Bibliographic source:
NDA 21-044, DEPARTMENT OF HEALTH AND HUMAN SERVICES, PUBLIC HEALTH SERVICE, FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH

Materials and methods

GLP compliance:
yes

Test material

1
Reference substance name:
Hydromorphone hydrochloride
EC Number:
200-762-6
EC Name:
Hydromorphone hydrochloride
Cas Number:
71-68-1
Molecular formula:
C17H19NO3.ClH
IUPAC Name:
Hydromorphone hydrochloride

Test animals

Species:
rat
Strain:
other: CD(SD)IGS BR VAF/Plus
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Details on mating procedure:
- M/F ratio per cage: 1/1
- Length of cohabitation: 21 days
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
28 days before cohabitation (maximum 15 days) and continuing through the day before sacrifice (at least 10 weeks prior to sacrifice) - males
Once daily beginning 15 days before cohabitation and continuing through day 7 of pregnancy - females
No. of animals per sex per dose:
25
Control animals:
yes
Details on study design:
- Dose selection rationale: doses selected based on previous oral (gavage) dose range-finding study

Examinations

Parental animals: Observations and examinations:
MORTALITY AND CLINICAL SIGNS: Yes
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly and days 0, 3, 6, 7, 8, 10 and 13 of pregnancy (females)

FOOD CONSUMPTION: Yes
- Time schedule for examinations: weekly and days 0, 3, 6, 7, 8, 10 and 13 of pregnancy (females)

Oestrous cyclicity (parental animals):
Examination of vaginal cytology for 14 days prior to dosing initiation, for 14 days beginning with day after first administration and then until spermatoza were observed in vaginal smear.
Postmortem examinations (parental animals):
GROSS NECROPSY
After cohabitation period - males
Day 13 pregnancy - females

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Description (incidence and severity):
Excessive chewing, chromorhinorrhea, hyperactivity, chormodacryorrhea, misaligned incisors
Description (incidence):
One mid-dose male died on day 42
Description (incidence and severity):
Rats gained weight until 5 weeks after which weight loss occurred from weeks 5 to 6.
Description (incidence and severity):
Food consumption was reduced in males from the first week of dosing onward. In females, reduced consumption was observed in high dose females during the first week of gestation but was coparable to control animals during the second week after dosing.

Reproductive function / performance (P0)

Description (incidence and severity):
The number of eustrous stages per 14 days was comparable across the 4 dosage groups
Description (incidence and severity):
No effects on sperm motility, count and density.
Description (incidence and severity):
No effects on number of days cohabitation, number of rats mated, or number of pregnancies.

Details on results (P0)

Caesarean sectioning and litter parameters were comparable among the 4 dose groups.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
< 0.5 other: mg/kg
Based on:
test mat.
Sex:
not specified
Basis for effect level:
clinical signs
body weight and weight gain
food consumption and compound intake

Target system / organ toxicity (P0)

Critical effects observed:
not specified

Results: F1 generation

General toxicity (F1)

Description (incidence and severity):
No dead feotuses.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
5 other: mg/kg
Based on:
test mat.
Sex:
not specified
Remarks on result:
other: No test material-related effects were observed at the highest dose

Target system / organ toxicity (F1)

Critical effects observed:
no

Overall reproductive toxicity

Reproductive effects observed:
no

Applicant's summary and conclusion

Conclusions:
Administration of the test material resulted in adverse clinical signs at all doses, reduced body weight gain and the two highest doses and reduced food consumption at the highest dose. No test-material related effects on mating and fertility were observed. The NOAEL for maternal toxicity was < 0.5 mg/kg. The NOAEL for reproductive effects was 5 mg/kg.