3β-hydroxyandrost-5-en-17-one acetate

Endpoint summary

Description of key information

Acute toxicity: Oral

In an acute oral toxicity study in female Wistar rats, following the acute toxic class method in accordance with the OECD Guideline 423, the LD50 was established to be greater than 2000 mg/kg (van Sas 2018).

Acute toxicity: Inhalation

In addition to the oral route of exposure, for substances other than gases, the information mentioned under REACH section 8.5.2 to 8.5.3 shall be provided for at least one other exposure route (REACH Regulation, column 2 adaptation of Annex VIII). For this substance, a study was considered however not deemed scientifically justified for the dermal route of exposure due to its low potential for a significant rate of absorption through the skin. Based on the fact that the inhalation route of exposure is not considered relevant in the risk assessment for human exposure and the addition of a waiver for the acute dermal toxicity testing, an acute inhalation toxicity study will not be performed.

 Acute toxicity: Dermal

In addition to the oral route of exposure, for substances other than gases, the information mentioned under REACH section 8.5.2 to 8.5.3 shall be provided for at least one other exposure route (REACH Regulation, column 2 adaptation of Annex VIII). For this substance, an acute dermal toxicity study was considered. However, this can be waived based on the fact that the substance does not meet the criteria for classification for acute toxicity or STOT SE by the oral route, and no systemic toxicity is observed in in vivo studies with dermal exposure.

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 2017-10-25 to 2017-11-16

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

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: (JMAFF) No 8147

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Janssen Pharmaceutica N.V.; M16GB2547
- Expiration date of the lot/batch: 2018-07-01 (retest date)
- Purity/composition correction factor: 1

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature
- Solubility and stability of the test substance in the solvent/vehicle: no data

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: The preparations (w/w) were kept at room temperature and were dosed within 4 hours after adding the vehicle to the test item. Homogeneity was assessed by visual inspection of the solutions and the formulations were stirred during dosing, which ensures homogeneity sufficiently for these kinds of studies. Adjustment was made for specific gravity of the vehicle. No correction was made for purity of the test item as the correction factor is 1.

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Wistar strain Crl:WI (Han) (outbred, SPF-Quality), Charles River Deutschland, Sulzfeld, Germany.
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: approx. 8-9 weeks
- Weight at study initiation: 153-176 grams
- Fasting period before study: Animals were deprived of food overnight prior to dosing and until 3-4 hours after administration of the test item. Water was available ad libitum.
- Housing: Group housing of 3 animals per cage in labeled Makrolon cages (MIV type; height 18 cm.) containing sterilized sawdust as bedding material (Lignocel S 8-15, JRS - J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) and paper as cage enrichment (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom).
- Diet (e.g. ad libitum): Free access to pelleted rodent diet
- Water (e.g. ad libitum): Free access to tap water.
- Acclimation period: At least 5 days before start of treatment under laboratory conditions.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 24°C
- Humidity (%): 40 to 70%
- Air changes (per hr): 10 air changes/hour
- Photoperiod (hrs dark / hrs light): 12-hour light/12- hour dark cycle.

Route of administration:

oral: gavage

Vehicle:

propylene glycol

Remarks:

(specific gravity 1.036)

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200 mg/mL)
- Amount of vehicle (if gavage): 2000 mg/kg (10 mL/kg) body weight
- Justification for choice of vehicle: The vehicle was selected based on trial preparations performed at Charles River Den Bosch and on test item data supplied by the Sponsor. The vehicle was chosen from (in order of preference): water (Elix) (test item did not dissolve), 1% aq. carboxymethyl cellulose (test item did not dissolve), propylene glycol (spec.gravity 1.036) (turbid solution), polyethylene glycol 400 (spec. gravity 1.125) (turbid solution) and corn oil (spec. gravity 0.92) (test item did not dissolve).
There was no information available regarding the solubility or stability in vehicle.

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg

The toxicity of the test item was assessed by stepwise treatment of groups of 3 females. The first group was treated at a dose level of 2000 mg/kg.
The absence or presence of mortality of animals dosed at one step determined the next step, based on the test procedure defined in the guidelines. The onset, duration and severity of the signs of toxicity were taken into account for determination of the time interval between the dose groups. Based on the results, a second group was treated at a dose level of 2000 mg/kg.

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

3 females per group

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality/viability: twice daily.
Body weights: Days 1 (pre-administration), 8 and 15 and at death
Clinical signs: at periodic intervals on the day of dosing (day 1) and once daily thereafter, until day 15. The signs were graded according to fixed scales and the time of onset, degree and duration were recorded: maximum grade 4: grading slight (1) to very severe (4); maximum grade 3: grading slight (1) to severe (3); maximum grade 1: presence is scored (1).
- Necropsy of survivors performed: yes, at the end of the observation period all animals were sacrificed by oxygen/carbon dioxide procedure. All animals assigned to the study were subjected to necropsy and descriptions of all internal macroscopic abnormalities recorded.

Statistics:

No statistical analysis was performed

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred.

Clinical signs:

other: Hunched posture, uncoordinated movements and piloerection were noted for the animals on Days 1 and/or 2.

Gross pathology:

No abnormalities were found at macroscopic post mortem examination of all animals.

Interpretation of results:

GHS criteria not met

Conclusions:

The oral LD50 value of T008506 in Wistar rats was established to exceed 2000 mg/kg body weight.
According to the OECD 423 test guideline, the LD50 cut-off value was considered to exceed 5000 mg/kg body weight.

Based on these results, T008506 does not have to be classified and has no obligatory labelling requirement for acute oral toxicity according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2015) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures (including all amendments).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute Oral Toxicity:

An acute oral toxicity study with T008506 according to the acute toxic class method in female Wistar rats (OECD guideline 423) was performed (van Sas 2018). The test item was administered by oral gavage to two subsequent groups of three female rats at 2000 mg/kg body weight. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (Day 15).

No mortality occurred. Hunched posture, uncoordinated movements and piloerection were noted for all animals on Day 1 and/or 2. The mean body weight gain shown by the animals over the study period was considered to be normal. No abnormalities were found at macroscopic post mortem examination of all animals.

The oral LD50 value of T008506 in Wistar rats was established to exceed 2000 mg/kg body weight. According to the OECD 423 test guideline, the LD50 cut-off value was considered to exceed 5000 mg/kg body weight.

Acute toxicity: Inhalation

In addition to the oral route of exposure, for substances other than gases, the information mentioned under REACH section 8.5.2 to 8.5.3 shall be provided for at least one other exposure route (REACH Regulation, column 2 adaptation of Annex VIII). For this substance, a study was considered however not deemed scientifically justified for the dermal route of exposure due to its low potential for a significant rate of absorption through the skin. Based on the fact that the inhalation route of exposure is not considered relevant in the risk assessment for human exposure and the addition of a waiver for the acute dermal toxicity testing, an acute inhalation toxicity study will not be performed.

 Acute toxicity: Dermal

In addition to the oral route of exposure, for substances other than gases, the information mentioned under REACH section 8.5.2 to 8.5.3 shall be provided for at least one other exposure route (REACH Regulation, column 2 adaptation of Annex VIII). For this substance, an acute dermal toxicity study was considered. However, this can be waived based on the fact that the substance does not meet the criteria for classification for acute toxicity or STOT SE by the oral route, and no systemic toxicity is observed in in vivo studies with dermal exposure.

Justification for classification or non-classification

Acute Oral classification:

Based on the available data, T008506 does not have to be classified and has no obligatory labelling requirement for acute oral toxicity according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2015) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures (including all amendments).

Acute Inhalation classification:

No data were available to decide on the classification for the inhalation route.

Acute Dermal classification:

No data were available to decide on the classification for the dermal route.