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);

Repeated dose toxicity: other routes

Administrative data

Endpoint:

short-term repeated dose toxicity: other route

Type of information:

experimental study

Adequacy of study:

key study

Study period:

February-June 1988

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: This study was conducted scientifically and in accordance with Good Laboratory Practices.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1989

Materials and methods

Test guideline

Qualifier:

no guideline available

Guideline:

other:

Principles of method if other than guideline:

Rats were given intravenous injections with iodixanol three times a week for 3 weeks. Sixty male and sixty female CD rats were divided into four group. There were four groups; control (saline), 0.5 gI/kg (low dose), 2.0 gI/kg (mid dose) and 4.0 gI/kg (high dose). At the end of the dosing period, ten males and ten females from each group were sacrificed, and the remaining ten animals from the top dose and control male and female groups were maintained without treatment for a further four weeks and then sacrificed.

GLP compliance:

yes

Test material

Reference

Name:

Unnamed

Type:

Constituent

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Administration / exposure

Route of administration:

intravenous

Duration of treatment / exposure:

3 weeks

Frequency of treatment:

3 times a week

Doses / concentrations

Remarks:

Doses / Concentrations:0; 0.5; 2.0; and 4.0 gr I/kg bw)

No. of animals per sex per dose:

0 (gr I/kg bw) 20 animals per sex per dose0.5 (gr I/kg bw) 10 animals per sex per dose2.0 (gr I/kg bw) 10 animals per sex per dose4.0 (gr I/kg bw) 20 animals per sex per dose

Control animals:

yes

Results and discussion

Effect levels

Dose descriptor:

NOAEL

Remarks on result:

not determinable

Remarks:

no NOAEL identified

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Clinical signs associated with treatment were red extremities in all dose groups, and swollen muzzle and feet, gelatinous urine under the cages, and pilo-erection (male rats) at the two highest doses. In addition, high dose animals showed signs of subdued behaviour, collapsed posture, partially closed eyelids and shallow breathing. No treatment related trends were seen in body weight change, food consumption or food utilization. Water consumption was marginally increased in high dose females during week 2, and a marginal reduction was observed in high dose males during the recovery period. Ophthalmoscopy did not reveal any ocular lesions attributable to treatment. There were no effects on haematology and clinical chemistry except for a slight increase in serum albumin levels in high dose animals at week 3, and which was also apparent at the end of the recovery period. During week 3, treated animals tended to have more acidic and concentrated urine than controls. At the end of the recovery period the pH was still slightly lower for the high-dose animals. Kidney weights were increased in mid and high dose animals killed at the end of the treatment period, as well as in the high dose group at the end of the recovery period. At this time, female rats in the high dose group also had elevated liver weights. The kidneys appeared enlarged and pale in some animals in the mid and high dose groups. At the end of the recovery period, this was still apparent in the high dose group. Treatment related cytoplasmic vacuolation was observed in the proximal tubules of the kidneys. This was dose related in the mid and high dose animals, and was more severe in males than in females. Moderate cytoplasmic vacuolation of the proximal tubules was evident in all high dose animals after the four week recovery period. Among low dose animals, the vacuolation was minimal and fine, and was not present in all animals. Cytoplasmic vacuolation in the urothelium of the urinary bladder was also observed in all high dose animals, and in 6/10 males and 4/9 females in the mid dose group at termination. This was not observed in the controls or low dose group. Cytoplasmic vacuolation in the urothelium was also observed in most of the high dose recovery animals. There were no other abnormal findings from the terminal investigations.

Executive summary:

Rats were given intravenous injections with iodixanol three times a week for 3 weeks. There were four groups; control (saline), 0.5 gI/kg (low dose), 2.0 gI/kg (mid dose) and 4.0 gI/kg (high dose). At the end of the dosing period, ten males and ten females from each group were sacrificed, and the remaining ten animals from the top dose and control male and female groups were maintained without treatment for a further four weeks and then sacrificed. Two female animals (one from the high dose and one from the mid dose group) died during the bleeding procedure on day 21, but this was considered to be unrelated to treatment with the test item. Clinical signs associated with treatment were red extremities in all dose groups, and swollen muzzle and feet, gelatinous urine under the cages, and pilo-erection (male rats) at the two highest doses. In addition, high dose animals showed signs of subdued behaviour, collapsed posture, partially closed eyelids and shallow breathing. No treatment related trends were seen in body weight change, food consumption or food utilization. Water consumption was marginally increased in high dose females during week 2, and a marginal reduction was observed in high dose males during the recovery period. Ophthalmoscopy did not reveal any ocular lesions attributable to treatment. There were no effects on haematology and clinical chemistry except for a slight increase in serum albumin levels in high dose animals at week 3, and which was also apparent at the end of the recovery period. During week 3, treated animals tended to have more acidic and concentrated urine than controls. At the end of the recovery period the pH was still slightly lower for the high-dose animals. Kidney weights were increased in mid and high dose animals killed at the end of the treatment period, as well as in the high dose group at the end of the recovery period. At this time, female rats in the high dose group also had elevated liver weights. The kidneys appeared enlarged and pale in some animals in the mid and high dose groups. At the end of the recovery period, this was still apparent in the high dose group. Treatment related cytoplasmic vacuolation was observed in the proximal tubules of the kidneys. This was dose related in the mid and high dose animals, and was more severe in males than in females. Moderate cytoplasmic vacuolation of the proximal tubules was evident in all high dose animals after the four week recovery period.

Among low dose animals, the vacuolation was minimal and fine, and was not present in all animals. Cytoplasmic vacuolation in the urothelium of the urinary bladder was also observed in all high dose animals, and in 6/10 males and 4/9 females in the mid dose group at termination. This was not observed in the controls or low dose group. Cytoplasmic vacuolation in the urothelium was also observed in most of the high dose recovery animals.

There were no other abnormal findings from the terminal investigations.