2-{3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-4-methyl-1,3-thiazol-3-ium-5-yl}ethyl hydrogen phosphate

Repeated dose toxicity: other routes

Administrative data

Endpoint:

sub-chronic toxicity: other route

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Chronic toxicity and teratological test of thiamine monophosphate disulfide

Author:

Hori et al.

Year:

1965

Bibliographic source:

J Vitaminol 12:42-48

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Principle of test: The test substance was administered intraperitoneally for 6 months to male Wistar rats.
- Parameters analysed / observed: Body weight, organ weights, food intake, clinical signs, haematological findings and gross pathology

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

disulfanediylbis[(2Z)-2-{[(4-amino-2-methylpyrimidin-5-yl)methyl](formyl)amino}pent-2-ene-3,5-diyl] bis[dihydrogen (phosphate)]

Cas Number:

992-46-1

Molecular formula:

C24H36N8O10P2S2

IUPAC Name:

disulfanediylbis[(2Z)-2-{[(4-amino-2-methylpyrimidin-5-yl)methyl](formyl)amino}pent-2-ene-3,5-diyl] bis[dihydrogen (phosphate)]

Test animals

Species:

rat

Strain:

Wistar

Remarks:

Wistar-King

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: Approximately 110 g
- Housing: Animals were indiviudally housed.
- Diet: Solid diet of CA-1 (Central Laboratories for Experimental Animals, Tokyo, Japan), ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 1
- Humidity (%): 55 - 60

Administration / exposure

Route of administration:

intraperitoneal

Vehicle:

other: 1.5% sodium bicarbonate in water

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

6 months

Frequency of treatment:

daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

50 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

100 mg/kg bw/day (nominal)

No. of animals per sex per dose:

20

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Based on an acute toxicity study in mice a LD50 of 6 g/kg bw was determined after intravenous administration, thus it was suggested that the toxicity was very low.

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes

BODY WEIGHT: Yes
- Time schedule for examinations: Twice a week

FOOD CONSUMPTION: Yes, for 6 days once a month

HAEMATOLOGY: Yes
- Parameters checked: Number of erythrocytes, number of leucocytes and haemoglobin value

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
Organs checked and weighed: Liver, heart, spleen, kidney, adrenal gland and testes

HISTOPATHOLOGY: Yes

Results and discussion

Results of examinations

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

4/20, 3/20 and 4/20 animals of the control, low- and high-dose group, respectively, that died, had lusterless hair and a bloody nose. According to the authors the animals died of pneumonia.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

Control: 4/20 animals died of pneumonia
50 mg/kg bw/day: 3/20 died of pneumonia and 1/20 animals died due to an error during dosing by injection
100 mg/kg bw/day 4/20 died of pneumonia and 1/20 animals died due to an error during dosing by injection

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

The animals that died, had a reduced body weight (no further details were given).

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

A parasitic infection by Cysticerus fasciolaris and the pathological change due to pneumonia were observed in all dose groups including control group. According to the authors, the high percentage of blood aborption in the lymph sinus of the mesenteric lymph-node was considered to be caused by the bleeding following intraperitoneal injection due to the hemorrage. This effect was not considered to be toxicologically relevant (please refer to Table 1 under "any other information on results incl. tables").

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

A case of hypertrophy in the perihepatic membrane was seen in the high-dose group, but no degeneration of hepatic parenchyma was found. According to the authors this effect was considered to be caused by minor irritation and the physical stimulation during the injection (please refer to Table 2 under "any other information on results incl. tables").

Histopathological findings: neoplastic:

no effects observed

Effect levels

Key result

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: No adverse effects observed up to and including the highest tested dose of 100 mg/kg bw/day

Target system / organ toxicity

Key result

Critical effects observed:

no

Any other information on results incl. tables

Table 1: Pathological findigns

Dose level (mg/kg bw/day)	Pathological findings	Number of pathological cases / Number of animals
Control	Parasitism of Cysticercus	2/16
Control	Partial change of pulmonary lobe	1/16
50	Parasitism of Cysticercus	3/16
50	Partial change of pulmonary lobe	1/16
100	Parasitism of Cysticercus	4/15
100	Partial change of pulmonary lobe	2/15
100	Congestion of the adrenal medulla	1/15
100	Partial fibrin sedimentation of hepatic capsula	1/15

Table 2: Histopathological findings

Dose level (mg/kg bw/day)	Histopathological findings	Number of histopathological cases / Number of animals
Control	Blood absorption in mesenteric lymphnodes	10/16
Control	Infiltration of lympho- and monocytes in heart interstitium	1/16
Control	Infiltration of lympho- and monocytes in hepatic Glisson sheath	1/16
Control	Mild fatty infiltration in the liver	1/16
Control	Infiltration of lympho- and monocytes in kidney	1/16
Control	Atrophy of splenic medulla	1/16
Control	Mild catarrhal pneumonia	3/16
50	Blood absorption in mesenteric lymphnodes	12/16
50	Mild catarrhal pneumonia	2/16
50	Infiltration of lympho- and monocytes below the pericardium	1/16
50	Infiltration of lympho- and monocytes in hepatic Glisson sheath	2/16
50	Mild fatty infiltration in the liver	1/16
100	Blood absorption in mesenteric lymphnodes	12/15
100	Infiltration of lympho- and monocytes in mycocardium	1/15
100	Infiltration of lympho- and monocytes in hepatic Glisson sheath	1/15
100	Hypertrophy of hepatic capsule	2/15
100	Mild fatty infiltration in the liver	2/15
100	Mild catarrhal pneumonia	2/15