2-Hydroxypropyl-β-cyclodextrine ethers

Acute Toxicity: other routes

Administrative data

Endpoint:

acute toxicity: other routes

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1993

Report date:

1993

Materials and methods

Test guideline

Qualifier:

no guideline available

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

420-920-1

EC Name:

-

Cas Number:

128446-35-5

Molecular formula:

Hill formula: (C42H70-nO35)(C3H7O)n; n(mittel)=5,25

IUPAC Name:

5,10,15,25-tetrakis(hydroxymethyl)-40,44,47,49-tetrakis(2-hydroxypropoxy)-20,30,35-tris[(2-hydroxypropoxy)methyl]-2,4,7,9,12,14,17,19,22,24,27,29,32,34-tetradecaoxaoctacyclo[31.2.2.2³,⁶.2⁸,¹¹.2¹³,¹⁶.2¹⁸,²¹.2²³,²⁶.2²⁸,³¹]nonatetracontane-36,37,38,39,41,42,43,45,46,48-decol

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

rat/Sprague-Dawley, Hag: SD/LippischeVersuchstierzucht HAGEMANN GmbH, D-32699 Extertal

Administration / exposure

Route of administration:

intravenous

Vehicle:

physiological saline

Details on exposure:

0.9% NaO-solution on the day before injection the test substance was dissolved in 0.9% NaCl-solution and administered once by i.v. injection at a constant volume of 25.0 ml/kg b.w., adjusted according to the individual body weight recorded on the day of administration; before administration
the pH value and the osmolarity of the prepared solutions were verified

Doses:

1000 mg, 1470 mg, 2150 mg and 3160 mg/kg b.w., once by i.v.. injection

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

Following administration, .observations were made and recorded•. systematically with individual records being maintained for each animal. Observations were performed immediately, 5, 15, 30 and 60 min, as well as 3, 6 and 24 h after administration. All surviving animals were observed for a period of 14 days. Owing this follow-up period changes of skin and fur, eyes and mucous membranes, respiratory and the circulatory, autonomic and central nervous system and somatomotor activity and behaviour pattern were observed and recorded at least twice daily (morning and afternoon) until all symptoms subsided, and thereafter each working day. Attention was also paid to possible tremor, convulsions, salivation, diar-rhoea, lethargy, sleep. and coma. Observations on mortality were made at least twice daily with appropri-ate actions taken to minimize loss of animals during the study. Individual body weights were recorded before administration of the substance and on days 5, 8 and 14. Changes in weight were calculated and recorded as precisely as possible. The LD50 was calculated by regression analysis. The mortality rates at 24 h and 14 d were used.

Results and discussion

Effect levels

Effect levels 1

Sex:

male

Dose descriptor:

LD50

Effect level:

1 499 mg/kg bw

Based on:

test mat.

Effect levels 2

Sex:

female

Dose descriptor:

LD50

Effect level:

2 140 mg/kg bw

Based on:

test mat.

Mortality:

The lowest lethal dose was 1470 mg/kg b.w. for male ·and 2150 mg/kg b.w. for female animals, the no-effect-Ievel was below 1000 mg/kg b.w. .

Gross pathology:

Macroscopic examination showed serverly enlarged kidneys (cherry sized) in 1 of 5 male animals treated with 1470 mg/kg b.w. i.v. One of 5 female animals treated with 2150 mg/kg b.w. showed spotted kidneys with coarse-grained surface. No macroscopic findings were observed in the female animals treated with 3160 mg/kg b.w..

Other findings:

At histopathology tubular nephrosis in the kidneys was regarded as the main substancerelated finding. The lymphatic oedema observed in the lungs· is probably related to a combination of the high volume injected and the test substance. These changes occurred from 1000 mg/kg b.w. . onwards, nearly in all animals examined. These changes were less pronounced at 2150 mg/kg b.w. in the males and at 3160 mg/kg b.w. in the females, but one has to take into consideration, that the animals died within 3 or 4 minutes after dosing. At nearly all dose-levels spontaneous fatty deposits were found in the liver and kidneys as well as congestion in the lungs and in the liver.

Applicant's summary and conclusion

Executive summary:

The aim of this experiment was to establish the acute toxic symptoms and in case of mortality the cause of death of Methyl-beta-cyclodextrin after a single intravenous administration to rats.

Under the present test conditions first intolerance reactions were observed at microscopy at 1000 mg/kg b.w. i.v. In addition reduced motility, ataxia, dyspnoea and muscu1ar hypotonia occurred at 1470 mg/kg b.w. i.v.. The lowest lethal dose was 1470 mg/kg b.w. i.v. for male and 2150 mg/kg b.w. i.v. for female animals, the no-effect-Ievel was below 1000 mg/kg b.w. i.v..

The LD50 was calculated as 1499 mg/kg b.w. i.v. (24 h and 14 d) for males, 2140 mg/kg b.w. i.v.. (24 h) and 2108 mg/kg b.w. i.v. (14 d) for females.

Autopsy

Macroscopic examination showed severely enlarged kidneys (cherry sized) in 1 of 5 male animals treated with 1470 mg/kg b.w. i.v. One of 5 female animals treated with 2150 mg/kg b.w. i.v. showed spotted kidneys with coarse-grained surface. No macroscopic findings were observed in the female animals treated with 3160 mg/kg b.w. i.v..

Histopathology

At histopathology tubular nephrosis in the kidneys was regarded as the main substance related finding. The lymphatic oedema .observed in the lungs is probably related to a combination of the high volume injected and the test substance. These changes occurred from 1000 mg/kg b.w. i.v. onwards, nearly in all animals examined. These changes were less pronounced at 2150 mg/kg b.w. i.v. in the males and at 3160 mg/kg b.w. i.v. in the females, but one has to take into consideration, that the animals died within 3 or 4 minutes after dosing. At nearly all dose-levels spontaneous fatty deposits were found in the liver and kidneys as well as congestion in the lungs and in the liver.