Estr-4-ene-3,17-dione

Endpoint summary

Description of key information

The acute toxicity (LD50) of norandrostendion in rats is > 1000 < 2000 mg/kg bw after oral administration (Kurth, 1996) or > 2000 mg/kg bw after dermal administration (Kurth, 1996).

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:

July to Aug 1995

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

1996

Deviations:

yes

Remarks:

In contrast to annex 3c of OECD TG 423 in its version of 1996 the starting dose (2000 mg/kg) was not applied to the second sex (females) although only 1/3 males died after application of 2000 mg/kg.

GLP compliance:

not specified

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

other: HAN: WIST (SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Schering AG
- Weight at study initiation: males: 98-118 g, females: 89-95 g
- Fasting period before study: ca. 19-21 hours
- Housing: 1 animal/cage
- Diet (e.g. ad libitum): pell. Altromin® R, ad libitum 24 hours per day
- Water (e.g. ad libitum): demineralized acidified water, pH 2-3, ad libitum
- Acclimation period: 7 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23-24°C
- Humidity (%): 42-60%
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

other: physiological saline with 0.085% (w/v) Myrj 53

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 20 and 200 mg/mi

Doses:

200 mg/kg (both sexes), 2000 mg/kg (only males)

No. of animals per sex per dose:

3

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of weighing: start (day 1), on day 8 and at the end (day 14) of the study
- Necropsy of survivors performed: yes
- Clinical signs including body weight

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 1 000 - < 2 000 mg/kg bw

Based on:

test mat.

Mortality:

One animal died after application of 2000 mg/kg on day 1 (3.5 hours post application) of the test.

Clinical signs:

other:

Body weight:

other body weight observations

Remarks:

within normal range for rats (M+F) of the age and strain

Gross pathology:

Autopsy revealed no compound-related findings.

Conclusions:

A single oral administration of the test substance by gavage to male rats at the limit-dose 2000 mg/kg was lethal for 1/3 animals. 200 mg/kg were tolerated without mortalities, clinical effects, effects on body weight gain and gross pathological findings in both sexes. According to OECD TG 423 the oral LD50 of the test substance is therefore: 1000 < LD50 < 2000 mg/kg body weight.

Executive summary:

In an acute oral toxicity study similar to OECD TG 423, fasted Wistar rats were given a single oral dose by gavage of Norandrostendione in physiological saline with 0.085% (w/v) Myrj 53 at doses of 200 mg/kg (both sexes), 2000 mg/kg (only males) and observed for 14 days.

The administration of the test item at 2000 mg/kg bw resulted in transient clinical signs (apathy, prone position, unconsciousness, disturbances in gait and in respiration and eyelid closure). The surviving animals of this dose group were without findings from day 1 (4.5 hours after application) onwards. All animals treated with 200 mg/kg were without findings over the whole study period. The body weight gain observed on day 8 and at the end (day 14) of the test was within the normal range tor rats (M+F) of the age and strain. Autopsy revealed no compound-related findings.

The LD50 of the test item in male and female rats after a single oral application is > 1000 mg/kg body weight, probably near 2000 mg/kg.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

> 1 000 - < 2 000 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:

Aug to Sep 1995

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

1981

Deviations:

yes

Remarks:

3 instead of 5 animals/sex used

GLP compliance:

yes

Remarks:

- but a QA check was not performed

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: HAN: WIST (SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Schering AG
- Weight at study initiation: males: 104-116 g, females: 97 -102 g
- Fasting period before study: ca. 18.5-19.5 hours
- Housing: 1/cage
- Diet (e.g. ad libitum): pell. Altromin® R, ad libitum 24 hours per day
- Water (e.g. ad libitum): demineralized acidified water, pH 2-3, ad libitum
- Acclimation period: 7 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23-24°C
- Humidity (%): 58-62%
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

occlusive

Vehicle:

other: 0.9% (w/v) NaCl-solution

Duration of exposure:

24 hours

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

3

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: day 1, 7 and 14
- Necropsy of survivors performed: yes

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No animal died in the course 'of the test.

Clinical signs:

other: A single dermal application of 2000 mg/kg was tolerated without compound-related findings.

Body weight:

other body weight observations

Remarks:

The body weight gain on days 7 and 14 was within the normal range for rats of this age and strain, which are routinely used in the laboratory.

Gross pathology:

No compound- related clinical findings could be detected at the end of the study on day 14. Autopsy revealed no compound-related findings.

Other findings:

the administration was tolerated without any local irritations

 

Conclusions:

A single dermal administration of the test substance to male and female rats at the limit-dose 2000 mg/kg was tolerated without mortalities, compound-related clinical findings, effects on body weight gain and gross pathological findings. According to OECD TG 402 the dermal LD50 of the test substance is therefore > 2000 mg/kg body weight.

Executive summary:

In an acute dermal toxicity study similar to OECD TG 402 performed as a combined study on acute toxicity and on local tolerance Wistar rats (3/sex) were dermally exposed to Norandrostendione in physiological saline for 24 hours at a limit dose of 2000 mg/kg bw. Animals then were observed for 14 days.

The administration of the test substance was tolerated without any clinical or macroscopic pathological finding. The dermal LD50 of the test substance is therefore > 2000 mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

Additional information

For the assessment of acute toxicity, studies on Norandrostenedione are available. Studies on the source substance Norethisterone are included to justify the read-across for higher tier toxicological endpoints.

 

Oral studies

An acute oral toxicity study in rats was performed according to OECD TG 423 (limit test). A single oral administration of Norandrostenedione by gavage to male rats at the limit-dose 2000 mg/kg was lethal for 1/3 animals, whereas 200 mg/kg were well tolerated. The oral LD50 of the test substance is therefore: 1000 < LD50 < 2000 mg/kg body weight, which leads to a self-classification of acute toxic cat. 4 according to CLP (Kurth, 1996).

 

In an acute oral toxicity study similar to OECD TG 423, fasted females SD rats were given a single oral dose by gavage of Norandrostendione and observed for 14 days.

300 mg/kg bw was selected as the initial dose. In each group, three female SD rats were exposed to one dose. The first group and the second group were exposed
to 300 mg/kg bw; the third group and the fourth group were exposed to 2000 mg/kg bw.

First group (300 mg/kg bw): observation of moribund state: no animals died in the test period. Clinical observation: no abnormalities were seen in any of the animals. Gross necropsy: no abnormalities were seen in any of the animals. Body weight: in the test period, all animals continued to gain weight after exposure.
Second group (300 mg/kg bw): observation of moribund state: no animals died in the test period. Clinical observation: no abnormalities were seen in any of the animals. Gross necropsy: no abnormalities were seen in any of the animals. Body weight: in the test period, all animals continued to gain weight after exposure.
Third group (2000 mg/kg bw): observation of moribund state: one animal died in the test period. Clinical observation: one animal spontaneously reduced movements and lay on its side; no abnormalities were seen in any of the other animals. Gross necropsy: one animal had changes of a dark red colour in the lungs; no abnormalities were seen in any of the other animals. Body weight: in the test period, all surviving animals continued to gain weight after exposure.
Fourth group (2000 mg/kg bw): observation of moribund state: one animal died in the test period. Clinical observation: one animal spontaneously reduced movements and lay on its side; no abnormalities were seen in any of the other animals. Gross necropsy: one animal had changes of a dark red colour in the lungs; no abnormalities were seen in any of the other animals. Body weight: in the test period, all surviving animals continued to gain weight after exposure.

In this study, the oral LD50 of Norandrostendione in female SD rats was larger than 2000 mg/kg bw (Lei, 2020).

 

Dermal study

A combined acute dermal toxicity and local tolerance study in rats with 24h semi-occlusive exposure to the skin comparable to TG 402 & 404 was used with Norandrostenedione. This study was conducted as limit test (2000 mg/kg) and showed no compound-related findings. According to OECD TG 402 the dermal LD50 of the test substance is therefore > 2000 mg/kg body weight.

 

In conclusion, Norandrostenedione is classified for acute oral toxicity Cat. 4. However, the dermal LD50 is above 2000 mg/kg (limit test). 

 

 

Acute oral toxicity studies for Norethisterone and Norandrostenedione

	Norandrostenedione
CAS no.	734-32-7
Study type	Acute oral (key studies)
Report no./author/year	X050 (Draft), Kurth, 1996
GLP/ OECD TG/ deviations	GLP not specified, similar to OECD 423; In contrast to annex 3c of OECD TG 423 in its version of 1996 the starting dose (2000 mg/kg) was not applied to the second sex (females) although only 1/3 males died after application of 2000 mg/kg.
Species; animals/ group	Rat (Wistar), n= 3 animals/sex/group
Doses/ route/ schedule	200 (both sexes) – 2000 mg/kg (only males), p.o., single treatment
Formulation	Batch No. 21401335, stability unknown Vehicle: physiological saline with 0.085% Myrj 53
observation period	14d
Results	1/3 male died after application of 2000 mg/kg on day 1 (3.5 hours post application) main clinical findings after application of 2000 mg/kg were apathy, prone position, unconsciousness, disturbances in gait and in respiration and eyelid closure. The surviving animals of this dose group were without findings from day 1 (4.5 hours after application) onwards 200 mg/kg were tolerated without mortalities, clinical effects, effects on body weight gain and gross pathological findings in both sexes LD50 > 1000 < 2000 mg/kg (male/female)
Reliability	2
Report no./author/year	G1901B0160, Lei, 2020
GLP/ OECD TG/ deviations	GLP, similar to OECD TG 423; Chinese guideline: Ministry of Environmental Protection of the People’s Republic of China. Guidelines of Chemical Testing (HJ/T 153-2004) Appendix A 423 Acute Oral Toxicity Test: Acute Toxicity Stepwise Method
Species; animals/ group	Rat (Sprague-Dawley), n= 6 females/group
Doses/ route/ schedule	First group: 300 mg/kg b.w.; Second group: 300 mg/kg b.w.; Third group: 2000 mg/kg b.w.; Fourth group: 2000 mg/kg b.w. p.o., single treatment
Formulation	Batch no.: 39541905010 Concentration in vehicle (water): 30, 200 mg/mL Dose volume: 10 mL/kg b.w.
observation period	14 d
Results	300 mg/kg bw: no mortality in the test period; 2000 mg/kg bw: 2/6 animals died; these animals showed spontaneously reduced movements and lay on its side; dark red colour in the lungs; no abnormalities were seen in any of the other animals   LD50(female)>2000 mg/kg bw
Reliability	1

 

 

Justification for classification or non-classification

With regard to acute oral toxicity the following self classification for norandrostendion is recommended according to Regulation (EC) No. 1272/2008 (CLP) :

Acute Tox. 4 (H302: Harmful if swallowed).

No classification is required for acute dermal toxicity according to Regulation (EC) No. 1272/2008 (CLP).