Registration Dossier

Administrative data

Description of key information

Oral (Rat-Wistar, males, GLP, similar to OECD TG423): LD50 between 500 and 1000 mg/kg 
[Schering AG, Report No. 8688; 1989-10-16]
Oral (Rat-Wistar, females, GLP, non-audited draft, similar to OECD TG423): LD50 > 500 mg/kg
[Schering AG, TX 94.125, 1994-11-14]
Dermal (Rat-Wistar, GLP, non-audited draft, similar to OECD TG402): LD50 > 2000 mg/kg
[Schering AG, Report No. X024, 1995-07-18]
Further study results are cited in RTECS database (April 2013):
Intraperitoneal (rat): TDLo: 340 mg/kg
[Clinical Pharmacology and Therapeutics. (American Society for Clinical Pharmacology and Therapeutics, St. Louis Mo Mosby-Year Book) V.1- 1960- v. 14, p. 727, 1976 (CLPTAT)]

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
04. to 17. July 1989
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
yes
Remarks:
, doses were 1000 and 500 mg/kg
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Strain: Wistar-Han-Schering
- Source: Schering
- Age at study initiation: not reported
- Weight at study initiation: 105-123 g
- Fasting period before study: about 19 h
- Housing: singly in conventional housing conditions
- Diet and water: ad libitum
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23
- Humidity (%): 48-60
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): not reported
Route of administration:
oral: gavage
Vehicle:
other: physiological saline containing 0.085 % Myrj 53
Doses:
500 and 1000 mg/kg bw
No. of animals per sex per dose:
3 males/dose
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed for clinical signs thrice on day 1 (30 min., 1 h, and 2 h after substance sdministration), twice on day 2 (in the morning and in the afternoon), and at least once daily throughout the rest of the study. Body weights were determined at study start (day 1), on day 7 and at termination of the study (day 14).
- Necropsy of survivors performed: yes
Sex:
male
Dose descriptor:
LD50
Effect level:
> 500 - < 1 000 mg/kg bw
Based on:
test mat.
Mortality:
All three animals of dose group 1000 mg/kg died on day 3 of the study. No mortalities were observed after administration of 500 mg/kg.
Clinical signs:
Compound-related clinical signs were apathy, disturbance of gait and squatting position. In addition prone position, unconsciousness, disturbance in respiration and increased diuresis were observed at lethal dose (1000 mg/kg). The surviving animals were without clinical signs from day 2 onwards.
Body weight:
In the surviving animals (500 mg/kg) the body weight gain observed on days 7 and 14 was within the normal range for male rats of this age and strain compared to historical data.
Gross pathology:
Macroscopic findings in animals which died before the end of the observation period were paleness of liver and kidneys and black-brown foci in glandular mucosa of stomach. Animals at the dose of 500 mg/kg were without macroscopic pathological findings.
Conclusions:
For acute oral toxicity classification is required as harmful (Xn, R22) according to Directive 67/548/EEC and as Category 4 (H302) according to Regulation (EC) 1272/2008.
Executive summary:

The single oral administration of the substance to male rats caused mortality at 1000 mg/kg in 3/3 animals on Day 3 of the study, whereas all three animals survived at 500 mg/kg. Compound-related clinical signs were apathy, disturbance of gait and squatting position and, additionally at lethal dose, prone position, unconsciousness, disturbance in respiration and increased diuresis. All surviving animals were without clinical signs from Day 2 up to the end of the 14 -day observation period. Macroscopic findings in animals which died prematurely were paleness of liver and kidneys and black-brown foci in glandular mucosa of stomach. Animals at the dose of 500 mg/kg were without macroscopic pathological findings. Thus, the LD50 after oral administration to male rats was concluded to be between 500 and 1000 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
discriminating dose
Value:
500 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
23. Feb to 22. March 1995
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
3 rats/sex and dose group
Principles of method if other than guideline:
According to Schlede et.al., A national validation study of the acute-toxic-class method - an alternative to the LD50 test, Arch. Toxicol. 66, 7, 1992, 455-470.
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Strain: HAN: WIST (SPF)
- Source: Schering AG
- Age at study initiation: not reported
- Weight at study initiation: males 106-112 g, females 101-111 g
- Fasting period before study: about 18.5 h
- Housing: singly in conventional housing conditions
- Diet and water: ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-21
- Humidity (%): 54-62
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
semiocclusive
Vehicle:
other: 0.9 % saline solution
Details on dermal exposure:
212-224 mg/male rat; 208-222 mg/female rat
The test substance was formulated with 0.9 mL physiological saline solution and then applied as a paste onto the skin.
Duration of exposure:
24 h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
3
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed for clinical signs several times on day 1 and at least once daily throughout the rest of the study. Body weights were determined at study start (day 1), on day 7 and at termination of the study (day 14).
- Necropsy of survivors performed: yes
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
No animal died in the course of the study.
Clinical signs:
No compound-related clinical signs were observed.
Body weight:
The body weight gain observed on days 7 and 14 was within the normal range for male or female rats of this age and strain compared to historical data.
Gross pathology:
Autopsy revealed no compound-related findings.
Conclusions:
No classification required for acute dermal toxicity according to Directive 67/548/EEC and Regulation (EC) 1272/2008.
Executive summary:

The single dermal administration of 2000 mg/kg to male and female rats was tolerated without compound-related clinical signs or effects on body weights during the 14 -day observation period. At necropsy no compound-related findings were detected. Thus, the LD50 for acute dermal toxicity was concluded to be above 2000 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw

Additional information

The single oral administration of the substance to male rats caused mortality at 1000 mg/kg in 3/3 animals on Day 3 of the study, whereas all three animals survived at 500 mg/kg. Compound-related clinical signs were apathy, disturbance of gait and squatting position and, additionally at lethal dose, prone position, unconsciousness, disturbance in respiration and increased diuresis. All surviving animals were without clinical signs from Day 2 up to the end of the 14 -day observation period. Macroscopic findings in animals which died prematurely were paleness of liver and kidneys and black-brown foci in glandular mucosa of stomach. Animals at the dose of 500 mg/kg were without macroscopic pathological findings. Thus, the LD50 after oral administration to male rats was concluded to be between 500 and 1000 mg/kg bw.

[Schering AG, Report No. 8688; 1989-10-16]

The single oral administration of the substance to female rats at doses of 250 and 500 mg/kg caused transient compound-related clinical signs (apathy and atactic gait). All animals were without compound-related findings from Day 2 onwards. No compound-related or suspected compound-related macroscopic findings were seen at necropsy. Thus, the LD50 after oral administration to female rats was concluded to be above 500 mg/kg bw.

[Schering AG, TX 94.125, 1994-11-14]

The single dermal administration of 2000 mg/kg to male and female rats was tolerated without compound-related clinical signs or effects on body weights during the 14 -day observation period. At necropsy no compound-related findings were detected. Thus, the LD50 for acute dermal toxicity was concluded to be above 2000 mg/kg bw.

[Schering AG, Report No. X024, 1995-07-18]

Further study results with androstendione are cited in RTECS database (April 2013):

The single intraperitoneal application to rats resulted in behavioral effects (- general anaesthetic, - alteration of classical conditioning; TDLo: 340 mg/kg [Clinical Pharmacology and Therapeutics. (American Society for Clinical Pharmacology and Therapeutics, St. Louis Mo Mosby-Year Book) V.1- 1960- v. 14, p. 727, 1976 (CLPTAT)].


Justification for selection of acute toxicity – oral endpoint
The more reliable study selected.

Justification for selection of acute toxicity – dermal endpoint
Only one study available.

Justification for classification or non-classification

For acute oral toxicity classification required as R22 (Harmful if swallowed) according to Directive 67/548/EEC or as Acute Tox. 4 (H302: harmful if swallowed) according to Regulation (EC) 1272/2008.

No classification required for acute dermal or inhalation toxicity according to Directive 67/548/EEC or according to Regulation (EC) 1272/2008.