Prasterone

Repeated dose toxicity: other routes

Administrative data

Endpoint:

chronic toxicity: other route

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

other information

Study period:

April - Oct 1968

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Chronic study on rats with intramuscular administration; basic scientific principles are met; study conducted before GLP principles were implemented

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1971

Report date:

1971

Materials and methods

Principles of method if other than guideline:

Chronic study conducted on groups of 30 rats/sex with intramuscular administration of substances. One dose group received an analogue of Androst-5-en-17-one, 3-hydroxy-, (3.beta.)-, at a limit dose of 200 mg/kg. Schedule for dosing: every third week for a period of initially 78 weeks, but study was terminated after 28 weeks due to unexpected cases of otitis media. An interim sacrifice was conducted in week 25. Investigations performed: clinical investigations, hematology, clinical chemistry including urine diagnostic, necropsy, organ weights and histopathological examinations.

GLP compliance:

no

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

3 ß-Heptanoyloxy-5-androsten-17-one

IUPAC Name:

3 ß-Heptanoyloxy-5-androsten-17-one

Constituent 2

Reference substance name:

Prasterone enantate

IUPAC Name:

Prasterone enantate

Test animals

Species:

rat

Strain:

not specified

Sex:

male/female

Administration / exposure

Route of administration:

intramuscular

Vehicle:

other: phenyl benzoate - castor oil (4+6)

Duration of treatment / exposure:

Initially 78 weeks, with an interim sacrifice for groups of rats after 25 and 52 weeks. Due to unexpected cases of otitis media the study was terminated after 28 weeks.

Frequency of treatment:

Every third week

Doses / concentrations

Remarks:

Doses / Concentrations:
0 and 200 mg/kg bw

No. of animals per sex per dose:

30

Control animals:

yes, concurrent vehicle

Results and discussion

Effect levels

Dose descriptor:

dose level:

Effect level:

200 mg/kg bw/day

Sex:

male/female

Basis for effect level:

other: Hormonal effects mainly on reproductive tissue.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Findings:

Site of injection: organised substance cysts, frequently also in intermusculary connective or adipose tissue; slight damage of muscles. These findings were ascribed to the vehicle used.

Indications for decreased weight

Protein metabolism: Tendency of increased urea concentration in serum.

Reproductive organs, males: Testes, epididymis, seminal vesicles, prostate: Indications for decreased weight

Reproductive organs, females: Ovary: high decrease of weight with follicular atrophy; [Bursa ovarii: Hydrops]; [Oviduct: Hydrops, purulent salpingitis]; [Uterus: Hydrops, pyometra, purulent endometritis]

Mammary gland: proliferation

Pituitary: Decrease or loss of basophile cells in frontal lobe

Adrenals: [slight decrease in lipid content and formation of vacuoles in cortex]

Applicant's summary and conclusion

Executive summary:

A chronic study was conducted on groups of 30 rats/sex with a structural analogue/precursor of Androst-5-en-17-one, 3-hydroxy-, (3.beta.)-. The substance was administered every third week in the vehicle phenyl benzoate - castor oil (4 +6) by intramuscular injection. Doses were 0 and 200 mg/kg bw. Initially, the study was scheduled for 78 weeks, with an interim sacrifice at week 25 and 52. Due to unexpected cases of otitis media observed for animals of interim sacrifice in week 25, the study was already terminated after 28 weeks in total. Clinical investigations, hematology, clinical chemistry including urine diagnostic, necropsy, organ weights and histopathological examinations were performed starting from week 1 before the study until study termination.

At the site of injection local irritant effects (organized substance cysts, slight damage of muscles) were observed. These findings were ascribed to the vehicle used.

Indications for decreased body weights were observed. For clinical chemistry a tendency of increased urea in serum was seen.

Necropsy and histopathology revealed effects on reproductive organs, both for males and females. For males indications for a decrease in weight for testes and accessory reproductive glands were seen. For females especially weight decrease in the ovary was observed accompanied by the histopathological finding of follicular atrophy .

Mammary glands revealed proliferation.

In the pituitary decrease or loss of basophile cells in the frontal lobe was detected.

Thus, a repeated dose of 200 mg/kg bw on male and female rats leads mainly to regressive changes on reproductive tissues, as the result of the hormonal effect of the substance.