Monalazone disodium

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

18.10.2018-07.12.2018

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2018

Report date:

2018

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

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

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Monalazone disodium

EC Number:

262-810-2

EC Name:

Monalazone disodium

Cas Number:

61477-95-0

Molecular formula:

C7H4ClNO4S.2Na

IUPAC Name:

disodium 4-[(chloroazanidyl)sulfonyl]benzoate

Test material form:

solid

Specific details on test material used for the study:

Test Item Name : Monalazone Disodium
CAS No. : Proprietary
Molecular Formula : C7H4ClNNa2O4S
Molecular Weight : 279.602 g/mol
Purity as per COA : >99% excluding water
Physical Appearance : White or Off white powder or crystals
Aqueous pH : 8-10
Lot No. : 72617S
Manufactured Date : 26-07-2017
Expiry date : 01-02-2019
Recommended Storage : Ambient (+18 to +36oC)
Photosensitive : Yes

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Invivo Biosciences, Shed No. 23, Katha No.3169, Assessment No. 154, Kodigehalli Village, Magadi Road, Bangalore-560091, Karnataka, India
- Females (if applicable) nulliparous and non-pregnant
- Age at study initiation: 8 to 9 Weeks
- Weight at study initiation: 165.6 to 192.5 g
- Fasting period before study: overnight (for a maximum of 20 hours) prior to dosing and until 3-4 hours after administration of the test item.
- Housing:Rats were housed individually in standard polysulfone cages (Size: approximately L 425 x B 266 x H 185 mm), with stainless steel top grill having facilities for pelleted food and drinking water in polycarbonate bottle. Additionally, polycarbonate rat huts were placed inside the cage as an enrichment object and were changed along with the cage once a week. Bedding: steam sterilized
- Diet: Ad libitum. Hypro Rat & Mice pellet feed, manufactured by Krishna Valley Agrotech LLP, MIDC Kupwad block, Sangli, Maharashtra, was provided to animals.
- Water: Ad libitum. Deep bore-well water passed through activated charcoal filter and exposed to UV rays in Aquaguard on-line water filter-cum-purifier manufactured by Eureka Forbes Ltd, Mumbai 400 001, India, was provided to animals in polycarbonate bottles with stainless steel sipper tubes.
- Acclimation period: After physical examination for good health and suitability for experiment, the animals were acclimatized 8 days for G1-FTS, 10 days for G1-STS, 12 days for G2-FTS & 12 days for G2-STS, before treatment. Animals were observed once daily during acclimatization period.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 25°C
- Humidity (%): 64 to 68%
- Air changes (per hr): 13.5 air changes per hour
- Photoperiod (hrs dark / hrs light): 12-hour light/12-hour dark

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Justification for choice of vehicle: The test item was checked for solubility / suspendability with Milli-Q water Test item formed suspension in Milli-Q water. Hence Milli-Q water was selected as vehicle and was used to prepare the dose formulations.
- The details of dose formulation
Dose (mg/kg) Concentration(mg/mL) Volume of test item
Suspension (mL) Test item quantity (g)
300 30 20 0.6
300 30 20 0.6
2000 200 15 3.0
2000 200 15 3.0

MAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg bw

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: The dose levels were based on the OECD test guidelines and were selected from the series 5 (lowest dose level), 50, 300 and 2000 (highest dose level) mg/kg body weight. As there was no available toxicology information about this test item, Hence, the study was initiated with the starting dose of 300 mg/kg body weight

Doses:

300 and 2000 (highest dose level) mg/kg body weight

No. of animals per sex per dose:

Group Dose
(mg/kg) No. of Rats Sex
G1 (FTS) 300 3 Female
G1 (STS) 300 3 Female
G2 (FTS) 2000 3 Female
G2 (STS) 2000 3 Female

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were observed five times on test day 1 (day of administration) i.e. at 30 minutes and four times at hourly intervals and once daily during days 2 to 15. The body weights were recorded on test day 1 (pre-administration), day 8 (7 days post administration) and day 15 (14 days post administration).
- Necropsy of survivors performed: yes. Microscopic examination was not carried out as no gross pathological changes were observed.
- Other examinations performed: clinical signs, body weight,gross pathology

Results and discussion

Effect levels

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality was observed during the study.

Clinical signs:

other: G1 - [300 mg/kg body weight - Treatment (FTS & STS)]: There were no clinical signs observed and there was no mortality. G2 - [2000 mg/kg body weight - Treatment (FTS & STS)]: G2-FTS: there were no clinical signs and pre-terminal deaths G2-STS: Clinical

Gross pathology:

There were no gross pathological changes at necropsy.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

The oral LD50 value of Monalazone Disodium 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 be 2500 mg/kg body weight.

Executive summary:

To determine the acute toxicity, a stepwise procedure was employed with the use of three animals of a single sex (female), at each step. Sufficient information was obtained on the acute toxicity of the test item for its classification. The test item was administered orally to a group of experimental animals at one of the defined doses (i.e. 300 mg/kg body weight) as a first step (G1-FTS). All the rats survived at this step, the test was continued with the same dose of 300 mg/kg body weight (G1-STS), all the rats survived at this step. The dosing was continued with the next higher dose of 2000 mg/kg body weight (G2-FTS). All the rats survived at this step, the test was continued with three additional animals with the same dose of 2000 mg/kg body weight (G2-STS). 2 out of 3 rats survived, hence testing was stopped and the LD₅₀cut-off value was arrived.