Registration Dossier

Administrative data

Description of key information

LD50 oral (rat): > 2000 mg/kg bw [Ihara 2004]
LD50 dermal (rat): > 2000 mg/kg bw [Ihara 2004]

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:
from January to February 2003
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
other: Jcl:SD
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: CLEA Japan, Inc.
- Age at study initiation: 4-5 weeks
- Weight at study initiation: 84-92 g (males), 97-98 g (females)
- Fasting period before study: 19 hours
- Housing: 1 animal/cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 50 +/- 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
oral: gavage
Vehicle:
other: 0.085% Myrj® 53 + 0.9% NaCl in water
Details on oral exposure:
- Application volume: 2.0 ml/100g bw
- Application concentration: 100 mg/ml
- Rationale for the selection of the starting dose:
Dose levels of 2000, 200 and 25 mg/kg were set in accordance with the acute toxic class method
(OECD guideline no. 423). The LD50 in rats after oral administration of dienogest, the final
product of ZK 67026, is >2000 mg/kg. The LD50 of ZK 5397 (4-Estrene-3,17-dione) the
structure of which resembles that of ZK 67026, is between 200 mg/kg and 2000 mg/kg (probably
near 2000 mg/kg). Since the toxic potential of ZK 67026 is supposed to be not high, in Step I,
2000 mg/kg was administered in males. In Step II, 2000 mg/kg was administered in females
since there were no deaths in males after administration. The lower doses were not administered,
since no deaths were observed in either males or females at 2000 mg/kg.
Doses:
2000 mg/kg
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: at least once daily (clinical signs, mortality) or once weekly (weighing)
- Necropsy of survivors performed: yes
Statistics:
none (limit test)
Sex:
male/female
Dose descriptor:
other: LD50 cut-off
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No animals died.
Clinical signs:
No compound-related findings were observed in any of the animals.
Body weight:
No compound-related effects were observed.
Gross pathology:
No compound-related findings were found out.
Executive summary:

A single oral administration of the test substance by gavage to male and female rats at the limit-dose 2000 mg/kg was tolerated without mortalities, clinical findings, effects on body weight gain and gross pathological findings. According to OECD TG 423 the oral LD50 of the test substance is therefore > 2000 mg/kg body weight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw
Quality of whole database:
This study is GLP compliant and is of high quality (Klimisch Score = 1).

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:
from March to April 2003
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose for cross-reference:
reference to same study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
- 3 instead of 5 animals/sex used
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Jcl:SD
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: CLEA Japan, Inc.
- Age at study initiation: 7 weeks (male), 10-11 weeks (female)
- Weight at study initiation: 257-288 g (male), 264-272 g (female)
- Housing: 1 animal/cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.7-22.8
- Humidity (%): 42-57
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
occlusive
Vehicle:
other: liquid paraffin
Details on dermal exposure:
TEST SITE
- Area of exposure: 4 x 9 cm
- % coverage: 10% of body surface
- Type of wrap: gauze pad

REMOVAL OF TEST SUBSTANCE
- Washing: rinsed out with lukewarm water
- Time after start of exposure: 24 hours

TEST MATERIAL
- For solids, paste formed: yes

VEHICLE
- Amount applied: 1 ml/animal
- Lot no.: 2Y28
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: at least once daily (clinical signs, mortality) or once weekly (weighing)
- Necropsy of survivors performed: yes

Statistics:
none (limit test)
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No animals died in the course of the study.
Clinical signs:
No compound-related findings were observed.
Body weight:
No compound-related effects were observed.
Gross pathology:
No compound-related findings were observed.
Executive summary:

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.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw
Quality of whole database:
This study is GLP compliant and is of high quality (Klimisch Score = 1).

Additional information

A single oral administration of the test substance by gavage to male and female rats at the limit-dose 2000 mg/kg was tolerated without mortalities, clinical findings, effects on body weight gain and gross pathological findings (Ihara 2004). According to OECD TG 423 the oral LD50 of the test substance is therefore > 2000 mg/kg body weight.

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 (Ihara 2004). According to OECD TG 402 the dermal LD50 of the test substance is therefore > 2000 mg/kg body weight.


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

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

Justification for classification or non-classification

Based on the study results a classification according to Regulation (EC) No. 1272/2008 (CLP) is not required.