Hydrogen (glycinato-N,O)[sulphato(2-)-O,O']ferrate(1-)

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

2019-07-26 to 2019-10-31

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2019

Report date:

2019

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)

Version / remarks:

Federal Law No. 61–FZ “On the Circulation of Medicinal Products” of 12 April 2010 (as amended);Federal Law No. 323–FZ “On the Basics of Health Protection of the Citizens in the Russian Federation” of 21 November 2011 (as amended)

GLP compliance:

yes

Test type:

up-and-down procedure

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Diiron tris(sulphate)

EC Number:

233-072-9

EC Name:

Diiron tris(sulphate)

Cas Number:

10028-22-5

Molecular formula:

Fe.3/2H2O4S

IUPAC Name:

diiron tris(sulphate)

Constituent 2

Reference substance name:

DL-lysine

EC Number:

200-740-6

EC Name:

DL-lysine

Cas Number:

70-54-2

Molecular formula:

C6H14N2O2

IUPAC Name:

DL-Lysine

Test animals

Species:

rat

Strain:

not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: NPO House of Pharmacy (inhouse bred)
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 8-12 weeks
- Fasting period before study: 16h
- Housing: individually in standard transparent plastic cages. Wood pellets were used as bedding.
- Diet (e.g. ad libitum): Feed for laboratory animals PK-120-1 prepared in accordance with GOST R50258-92 "Compound Feeds for Laboratory Animals. Specifications” was given ad libitum
- Water (e.g. ad libitum): purified water normalized in respect of organoleptic properties, pH, solids, reducing substances, carbon dioxide, nitrates and nitrites, ammonia, chlorides, sulphates, calcium and heavy metals in accordance with SanPiN 2.1.4.1074-01 "Drinking Water. Hygienic Requirements for the Quality of Water from Centralized Drinking Water Supply Systems. Quality Control". Water in standard drinking bowls with steel nose caps was given ad libitum.
- Acclimation period: 5 days
- Method of randomisation in assigning animals to test and control groups: Randomization was not expected in this study, since dosing occurred in stages and individually. The main criterion for including an animal in the experiment was its body weight.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-26 °C
- Humidity (%): 30-70%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From:
No. 2.0-31.05/19 of 31 May 2019
No. 2.0-30.06/19 of 01 July 2019

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: 1% starch solution

Details on oral exposure:

VEHICLE
- Concentration in vehicle: Before administration, suspensions of the test article was prepared with concentrations of ≈ 29.2 mg/mL for 175 mg/kg, ≈ 91.7 mg/ml for 550 mg/kg and 333.3 mg/ml for 2000 mg/kg.
- Amount of vehicle (if gavage): 1.5 mL per 250g rat
- Lot/batch no. (if required): М-4.38/19

MAXIMUM DOSE VOLUME APPLIED: 333.3 mg/mL

CLASS METHOD
- Rationale for the selection of the starting dose:since the test article is presumably a low toxicity substance, 175 mg/kg was selected as the starting dose for a single intragastric administration to one male and one female rat.

Doses:

175, 550, 2000 mg/kg bw

No. of animals per sex per dose:

175 mg/kg bw: 1 animal; 550 mg/kg bw: 1 animal; 2000 mg/kg bw 3 animals

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: On day 1, 2, 7 and 15
- Necropsy of survivors performed: yes
- Clinical signs: daily
- Other examinations performed: other:Clinical examination on day 2, 7, 14 and local tolerance evaluation on day 15

Statistics:

Calculation of LD50 with confidence intervals was performed using the AOT 425 StatPgm program (Westat, USA).

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No deaths were observed

Clinical signs:

other: No clinical signs of intoxication were observed.

Gross pathology:

No gross abnormalities in the internal organs were identified at the scheduled necropsy in experimental animals treated with a single intragastric dose

Other findings:

The test article, ferrous monolysinate sulfate, at 175 mg/kg (in 1 male) and at 2000 mg/kg (in 1 male and 1 female) following single-dose intragastric administration had a moderate local irritant effect, which was manifested as catarrhal gastritis detected by a histological examination of the stomach tissues.

Applicant's summary and conclusion

Interpretation of results:

other: According to Regulation (EU) No. 1272/2008 (CLP) the substance does not need to be classified as acutely toxic by oral route

Conclusions:

LD50 for ferrous monolysinate sulfate is > 2000 mg/kg following single-dose intragastric administration to male and female rats. Ferrous monolysinate sulfate can be classified as toxicity category 5 according to the international GHS classification.

Executive summary:

In an acute oral toxicity study according to OECD guideline 425, fasted, 8-12 weeks old Sprague Dawley strain rats were given a single oral dose of ferrous monolysinate sulfate in 1% starch solution by gavage at a dose of 175 mg/kg bw: 1 animal; 550 mg/kg bw: 1 animal; 2000 mg/kg bw 3 animals and were observed for 14 days.

None of the animals died. No clinical signs were observed in the treated animals. No gross abnormalities in the internal organs were identified at the scheduled necropsy in experimental animals treated with a single intragastric dose. The test article, at 175 mg/kg (in 1 male) and at 2000 mg/kg (in 1 male and 1 female) following single-dose intragastric administration had a moderate local irritant effect, which was manifested as catarrhal gastritis detected by a histological examination of the stomach tissues.

 

Oral LD50 (rat, females/males) > 2000  mg/kg bw