Registration Dossier

Administrative data

Description of key information

There are no acute toxicity studies conducted with gestonorone acetate; read-across withs of studies with gestonorone caproate (ZK 5623):
Oral (Mouse, non-GLP): LD50 > 4000 mg/kg (Günzel 1968; Günzel 1968)
Oral (Rat, non-GLP): LD50 > 4000 mg/kg (Günzel 1968)
Subcutaneous (Mouse, non-GLP): LD50 > 4000 mg/kg (Günzel 1968; Günzel 1968)
Subcutaneous (Guinea pig-White Pirbright, non-GLP): LD50 > 8000 mg/kg (Anonymous 1965)
Intraperitoneal (Mouse, non-GLP): LD50 > 4000 mg/kg(Günzel 1968; Günzel 1968)
Intraperitoneal (Mouse-NMRI, non-GLP): LD50 = 6000 mg/kg (Anonymous 1965)
Intraperitoneal (Rat-Wistar, non-GLP): LD 50 = 7000 mg/kg (Anonymous 1965)
Intramuscular (Dog-Beagle, female, non-GLP): LD50 > 150 mg/kg (2000 g/dog) (Anonymous 1966)

Acute oral LD50 > 3458.54 mg/kg based on read across with gestonorone caproate and calculation according to the molecular weight.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
not applicable
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Species:
mouse
Strain:
not specified
Sex:
female
Details on test animals or test system and environmental conditions:
weight 18 - 20 g
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
1.2 g CMC ad 100 ml Aqua dest.
Doses:
4000 mg/kg
No. of animals per sex per dose:
10
Control animals:
no
Sex:
female
Dose descriptor:
LD50
Effect level:
> 4 000 mg/kg bw
Based on:
test mat.

The single oral administration of a microcristalline suspension of ZK 5623 (gestonorone caproate) to female mice at a dose of 4000 mg/kg caused transient clinical signs (apathy) immediately after administration. All animals were without compound-related clinical signs from Day 2 onwards. 2 of 10 animals showed miliary grey-white spots in the liver. 1 of 10 animals showed miliary grey-white spots in the cortex of the left kidney. Two mesenteric lymph nodes were increased in size.

The acute oral toxicity of ZK 5623 in mice is above 4000 mg/kg body weight.

Executive summary:

The single oral administration of a microcristalline suspension of ZK 5623 (gestonorone caproate) to female mice at a dose of 4000 mg/kg caused transient clinical signs (apathy) immediately after administration. The LD50 >4000 mg/kg was established after application of gestonoron caproate.

Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
Justification for analogue approach:
As no acute toxicity data of gestonorone acetate is available, a read-across to gestonorone caproate (CAS 1253-28-7) was performed. A search for structure-analogue substances using the QSAR OECD Toolbox 4.0 recommended gestonorone caproate as one out of 19 category substances for a read-across approach (for additional information see QSAR OECD Toolbox Report on gestonorone acetate in "Attached justification"). Usually esters are hydrolysed in the presence of water or in organisms due to enzymatic degradation by esterases. As a result, the respective alcohol derivative (gestonorone (CAS 2137-18-0)) and carboxylic acid are generated. This is demonstrated by the QSAR toolbox 4.0 in the case of gestonorone acetate (CAS 2137-18-0) by the hydrolysis simulator (acidic, basic, neutral), the rat liver S9 metabolism simulator and the skin metabolism simulator.
Reason / purpose for cross-reference:
read-across source
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 4 000 mg/kg bw
Based on:
test mat.

The differences in molecular weight of gestonorone caproate (414.58 g/mol) and gestonorone acetate (358.46 g/mol) were considered. 4000 mg/kg of gestonorone caproate correlates to 3458,54 mg/kg

gestonorone acetate.

Executive summary:

The single oral administration of a microcristalline suspension of ZK 5623 (gestonorone caproate) to male and female rats at a dose of 4000 mg/kg was tolerated without any compound-related clinical or macroscopic pathological signs. The acute oral toxicity of ZK 5623 (gestonorone caproate) in rats is above 4000 mg/kg body weight.

4000 mg/kg of gestonorone caproate correlates to 3458.54 mg/kg gestonorone acetate.

Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
Justification for analogue approach:
As no acute toxicity data of gestonorone acetate is available, a read-across to gestonorone caproate (CAS 1253-28-7) was performed. A search for structure-analogue substances using the QSAR OECD Toolbox 4.0 recommended gestonorone caproate as one out of 19 category substances for a read-across approach (for additional information see QSAR OECD Toolbox Report on gestonorone acetate in "Attached justification"). Usually esters are hydrolysed in the presence of water or in organisms due to enzymatic degradation by esterases. As a result, the respective alcohol derivative (gestonorone (CAS 2137-18-0)) and carboxylic acid are generated. This is demonstrated by the QSAR toolbox 4.0 in the case of gestonorone acetate (CAS 2137-18-0) by the hydrolysis simulator (acidic, basic, neutral), the rat liver S9 metabolism simulator and the skin metabolism simulator.
Reason / purpose for cross-reference:
read-across source
Sex:
male
Dose descriptor:
LD50
Effect level:
> 4 000 mg/kg bw
Based on:
test mat.

The single oral administration of a microcristalline suspension of ZK 5623 (gestonorone caproate) to male mice at a dose of 4000 mg/kg caused transient clinical signs (apathy) immediately after administration. All animals were without compound-related clinical signs from Day 2 onwards. 2 of 10 animals showed occasionally miliary grey-white spots in the liver. The acute oral toxicity of ZK 5623 in mice is above 4000 mg/kg body weight.

The differences in molecular weight of gestonorone caproate (414.58 g/mol) and gestonorone acetate (358.46 g/mol) were considered.4000 mg/kg of gestonorone caproate correlates to 3458.54 mg/kg.

Executive summary:

The single oral administration of a microcristalline suspension of ZK 5623 (gestonorone caproate) to male mice at a dose of 4000 mg/kg caused transient clinical signs (apathy) immediately after administration. The LD50 >4000 mg/kg was established for gestonorone caproate in male mice.

The differences in molecular weight of gestonorone caproate (414.58 g/mol) and gestonorone acetate (358.46 g/mol) were considered. 4000 mg/kg of gestonorone caproate correlates to 3458.54 mg/kg gestonorone acetate.

Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
Justification for analogue approach:
As no acute toxicity data of gestonorone acetate is available, a read-across to gestonorone caproate (CAS 1253-28-7) was performed. A search for structure-analogue substances using the QSAR OECD Toolbox 4.0 recommended gestonorone caproate as one out of 19 category substances for a read-across approach (for additional information see QSAR OECD Toolbox Report on gestonorone acetate in "Attached justification"). Usually esters are hydrolysed in the presence of water or in organisms due to enzymatic degradation by esterases. As a result, the respective alcohol derivative (gestonorone (CAS 2137-18-0)) and carboxylic acid are generated. This is demonstrated by the QSAR toolbox 4.0 in the case of gestonorone acetate (CAS 2137-18-0) by the hydrolysis simulator (acidic, basic, neutral), the rat liver S9 metabolism simulator and the skin metabolism simulator.
Reason / purpose for cross-reference:
read-across source
Sex:
female
Dose descriptor:
LD50
Effect level:
> 4 000 mg/kg bw
Based on:
test mat.

The single oral administration of a microcristalline suspension of ZK 5623 (gestonorone caproate) to female mice at a dose of 4000 mg/kg caused transient clinical signs (apathy) immediately after administration. All animals were without compound-related clinical signs from Day 2 onwards. 2 of 10 animals showed miliary grey-white spots in the liver. 1 of 10 animals showed miliary grey-white spots in the cortex of the left kidney. Two mesenteric lymph nodes were increased in size.

The acute oral toxicity of ZK 5623 in mice is above 4000 mg/kg body weight.

The differences in molecular weight of gestonorone caproate (414.58 g/mol) and gestonorone acetate (358.46 g/mol) were considered.4000 mg/kg of gestonorone caproate correlates to 3458.54 mg/kg.

Executive summary:

The single oral administration of a microcristalline suspension of ZK 5623 (gestonorone caproate) to female mice at a dose of 4000 mg/kg caused transient clinical signs (apathy) immediately after administration. The LD50 >4000 mg/kg was established after application of gestonoron caproate.

The differences in molecular weight of gestonorone caproate (414.58 g/mol) and gestonorone acetate (358.46 g/mol) were considered.4000 mg/kg of gestonorone caproate correlates to 3458.54 mg/kg.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
14.05. - 04.06.1971
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
not applicable
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
not specified
Sex:
male/female
Route of administration:
oral: unspecified
Vehicle:
not specified
Doses:
4000 mg/kg
No. of animals per sex per dose:
no data
Control animals:
no
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 4 000 mg/kg bw
Based on:
test mat.
Executive summary:

The single oral administration of a microcristalline suspension of ZK 5623 (gestonorone caproate) to male and female rats at a dose of 4000 mg/kg was tolerated without any compound-related clinical or macroscopic pathological signs. The acute oral toxicity of ZK 5623 (gestonorone caproate) in rats is above 4000 mg/kg body weight.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
not applicable
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Species:
mouse
Strain:
not specified
Sex:
male
Details on test animals or test system and environmental conditions:
weight: 17 - 23 g
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
1.2 g CMC ad 100 ml Aqua. dest
Doses:
4000 mg/kg
No. of animals per sex per dose:
10
Control animals:
no
Details on study design:
- Duration of observation period following administration: 19 days
- Frequency of observations and weighing:
- Necropsy of survivors performed: yes
- Other examinations performed: gross pathology
Sex:
male
Dose descriptor:
LD50
Effect level:
> 4 000 mg/kg bw
Based on:
test mat.

The single oral administration of a microcristalline suspension of ZK 5623 (gestonorone caproate) to male mice at a dose of 4000 mg/kg caused transient clinical signs (apathy) immediately after administration. All animals were without compound-related clinical signs from Day 2 onwards. 2 of 10 animals showed occasionally miliary grey-white spots in the liver. The acute oral toxicity of ZK 5623 in mice is above 4000 mg/kg body weight.

Executive summary:

The single oral administration of a microcristalline suspension of ZK 5623 (gestonorone caproate) to male mice at a dose of 4000 mg/kg caused transient clinical signs (apathy) immediately after administration. The LD50 >4000 mg/kg was established for gestonorone caproate in male mice.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
3 458.54 mg/kg bw
Quality of whole database:
The studies are of suffiecient quality. (Klimisch Score = 2)

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

There are no acute toxicity studies conducted with ZK 5624 (gestonorone acetate). Results of studies conducted with a different ester of gestonorone (gestonorone caproate, ZK 5623) are regarded as representative as most likely ester cleavage occurs in vivo after administration.

The single oral administration of a microcristalline suspension of gestonorone caproate (ZK 5623) to male and female mice at a dose of 4000 mg/kg caused transient clinical signs (apathy) immediately after administration. All animals were without compound-related clinical signs from Day 2 onwards. No compound-related macroscopic pathological signs were observed. The acute oral toxicity of ZK 5623 in mice is above 4000 mg/kg body weight. (Günzel 1968; Günzel 1968)

The single oral administration of a microcristalline suspension of gestonorone caproate to male and female rats at a dose of 4000 mg/kg was tolerated without any compound-related clinical or macroscopic pathological signs. The acute oral toxicity of gestonorone caproate in rats is above 4000 mg/kg body weight. (Guenzel 1971)

The single subcutaneous administration of a microcristalline suspension of gestonorone caproate (ZK 5623) to male and female mice at a dose of 4000 mg/kg was tolerated without any compound-related clinical or macroscopic pathological signs. The acute subcutaneous toxicity of ZK 5623 in mice is above 4000 mg/kg body weight. (Günzel 1968; Günzel 1968)

The single subcuatenous administration of a microcristalline suspension of gestonorone caproate (ZK 5623) to male and female guinea pigs at 8000 and 16000 mg/kg revealed transient apathy at the high dose. All animals were without symptoms from Day 2 onwards during the observation period. The acute subcutaneous toxicity of ZK 5623 in guinea pigs is above 8000 mg/kg body weight. (Anonymous, 1965)

The single intraperitoneal administration of a microcristalline suspension of gestonorone caproate (ZK 5623) to male and female mice at a dose of 4000 mg/kg caused transient clinical signs (apathy) immediately after administration. All animals were without compound-related clinical signs from Day 2 onwards. One female animal (1/10) died on Day 10. No compound-related macroscopic pathological signs were observed. The acute i.p. toxicity of ZK 5623 in male mice is above 4000 mg/kg body weight. (Günzel 1968; Günzel 1968)

The single intraperitoneal administration of a microcristalline suspension of gestonorone caproate (ZK 5623) to male mice revealed a LD50 of 6000 mg/kg. Animals died on Days 2 to 3 after administration. Clinical signs in moribund animals were apathy and prone position. (Anonymous 1965)

The single intraperitoneal administration of a microcristalline suspension of gestonorone caproate (ZK 5623) to male rats revealed a LD50 of 7000 mg/kg. Animals died on Days 2 to 4 after administration. Clinical signs in moribund animals were apathy. (Anonymous 1965)

The single intramuscular administration of a microcristalline suspension of gestonorone caproate (ZK 5623) to female Beagle dogs at a maximum dose of appr. 150 mg/kg caused transient local intolerance reactions at the application site up to Day 10 after administration and secondary effects on general condition in one animal at the high dose (increased body temperature, apathy and anorexia). All animals survived the observation period. No necropsy was performed. The acute toxicity of ZK 5623 after intramuscular administration in Beagle dogs is above approximately 150 mg/kg (2000 g/dog). (Anonymous 1966)

Justification for classification or non-classification

Based on the results there is no classification required according to Regulation (EC) 1272/2008 (CLP).