5-(Acetyl-(3-(acetyl-(3,5-bis(2,3-dihydroxypropylcarbamoyl)-2,4,6-triiodophenyl)amino)-2- hydroxypropyl)amino)-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodobenzene-1,3-dicarboxamide; 5,5'-((2-Hydroxytrimethylene)bis(acetylimino))bis(N,N'-bis(2,3-dihydroxypropyl)-2,4,6- triiodoisophthalamide);

Acute Toxicity: other routes

Administrative data

Endpoint:

acute toxicity: other routes

Type of information:

experimental study

Adequacy of study:

key study

Study period:

September 1984

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study and data are well documented and scientifically acceptable.

Data source

Reference

Reference Type:

other company data

Title:

Unnamed

Year:

1984

Report date:

1984

Materials and methods

Test guideline

Qualifier:

no guideline available

Guideline:

other:

Principles of method if other than guideline:

Iodixanol was injected intravenously into four groups, each of 20 NMRI male mice. The injection rate was 1.2 ml/min. The weight was 18-22 gr. They were marked individually with colour marks immediately after the injection. The mice were fed Ewos rat and mice pellets and they were not deprieved of food and water before the injection. The temperature in the mouse room varied between 18 and 24 and the relative humidity was between 39 and 70. The mice were observed individually at least 2,5 hours, at 24 hours and daily during one week with recording of mortality and behaviour anomalies. Mice which died were necropsied. The results were evaluated with logit transformation and regression calculation.

GLP compliance:

not specified

Test material

Reference

Name:

Unnamed

Type:

Constituent

Test animals

Species:

mouse

Strain:

NMRI

Sex:

male

Administration / exposure

Route of administration:

intravenous

Doses:

14.0; 17.5; 21.0; 24.5

No. of animals per sex per dose:

20; 20; 20; 20

Control animals:

not specified

Results and discussion

Effect levels

Sex:

male

Dose descriptor:

LD50

Effect level:

21 other: gI/kg bw

Applicant's summary and conclusion

Conclusions:

The acute intravenous toxicity in male was found to be low, the LD50 being 21.0 gI/kg.

Executive summary:

Iodixanol was injected intravenously into four groups, each of 20 NMRI male mice. The injection rate was 1.2 ml/min. The behaviour was normal immediately after injection, but animals subsequently became sedate with laboured breathing. Most deaths occurred 1-2 days after injection, although one high dose mouse died two hours post-dose. Before death, animals were lethargic and almost unresponsive to stimulus. In the four groups of 14.0, 17.5, 21.0 or 24.5 gI/kg, the total numbers of deaths were 1, 8, 8 and 14, respectively. From this study a LD50 value of 21.0 gI/kg was calculated. At sacrifice, 7 days after treatment, the surviving

animals in the low dose group showed the greatest weight gain, whereas in the group dosed with 21.0 gI/kg, three of the 12 mice had lost weight. Median body weight gain was decreased 10-12 % in the higher dose groups compared to those in the low dose group. Necropsy was performed on all animals that died, and on all survivors in the two highest dose groups.

Necropsy of the mice that died showed normal lungs without haemorrhage, whereas in the kidney, the cortex was pale and the medulla dark red. One third of the surviving animals in the two highest dose groups also had kidney changes at autopsy, comprising pale cortex and medulla, and some also had haemorrhagic spots in the medulla. The histopathological examination of the kidneys from 10 animals that died and 10 survivors revealed necrotic tubules in the subcortical zone and medulla. From these findings it was concluded that the mice probably died from kidney toxicity.