Hydromorphone

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

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:

no

Test material

Test material information

Constituent 1

Reference substance name:

Hydromorphone

EC Number:

207-383-5

EC Name:

Hydromorphone

Cas Number:

466-99-9

Molecular formula:

C17H19NO3

IUPAC Name:

(1S,5R,13R,17R)-10-hydroxy-4-methyl-12-oxa-4-azapentacyclo[9.6.1.0^{1,13}.0^{5,17}.0^{7,18}]octadeca-7(18),8,10-trien-14-one

Results and discussion

Results of examinations

Details on results:

A 12-day range-finding study in female rats resulted in one death at 50 mg/kg/day (Day 5), 2 deaths at 150 mg/kg/day (Days 4 and 6) and one death at 200 mg/kg/day (Day 4).
Decreased body weights were observed at all doses and clinical signs including reduced activity, incoordination, increased heart rate, shallow breathing, increased muscle tone, rigidity, focused gaze, salivation and unresponsiveness to external stimuli were observed.
Macroscopic observations at necropsy were pale discolouration of the kidneys, dilation of the ureters and urinary bladder dilation, thickening, dark discolouration, pale/dark areas, clots and dark fluid.

A sub-chronic toxicity study in female rabbits for 13 consecutive days resulted in two deaths at 100 mg/kg/day (Day 1). Clinical signs at 50 – 100 mg/kg/day were reduced activity, decreased muscle tone and dilated or constricted pupils. Treatment-related gross pathology observations were spongy/collapsed lungs, dark areas and pale or dark frothy fluid in the lungs, bronchi or trachea.

In a sub-chronic study in beagle dogs for 30 days, decreased body weight was observed in groups administered 65 mg/day and clinical signs consistent with known effects of opioid drugs at all doses.

Effect levels

Dose descriptor:

NOAEL

Remarks:

Rabbits

Effect level:

<= 25 other: mg/kg/day

Based on:

test mat.

Remarks:

13 days

Sex:

female

Basis for effect level:

clinical signs

mortality

Applicant's summary and conclusion

Conclusions:

A 12-day range-finding study in female rats resulted in one death at 50 mg/kg/day (Day 5), 2 deaths at 150 mg/kg/day (Days 4 and 6) and one death at 200 mg/kg/day (Day 4).
Decreased body weights were observed at all doses and clinical signs including reduced activity, incoordination, increased heart rate, shallow breathing, increased muscle tone, rigidity, focused gaze, salivation and unresponsiveness to external stimuli were observed.
Macroscopic observations at necropsy were pale discolouration of the kidneys, dilation of the ureters and urinary bladder dilation, thickening, dark discolouration, pale/dark areas, clots and dark fluid.

A sub-chronic toxicity study in female rabbits for 13 consecutive days resulted in two deaths at 100 mg/kg/day (Day 1). Clinical signs at 50 – 100 mg/kg/day were reduced activity, decreased muscle tone and dilated or constricted pupils. Treatment-related gross pathology observations were spongy/collapsed lungs, dark areas and pale or dark frothy fluid in the lungs, bronchi or trachea.

In a sub-chronic study in beagle dogs for 30 days, decreased body weight was observed in groups administered 65 mg/day and clinical signs consistent with known effects of opioid drugs at all doses.