1,4:3,6-dianhydro-2,5-bis-O-(diphenoxyphosphoryl)-D-glucitol

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2011-03-25 - 2011-04-28

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study (GLP)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2011

Report date:

2011

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

Adopted on December 17, 2001

Deviations:

yes

Remarks:

Starting dose at 500 mg/kg bw

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Version / remarks:

Adopted in December 2002

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

other: Japan MAFF Testing Guideline of 12 Nosan No. 8147

Deviations:

yes

Remarks:

as this in line with OECD 423.

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

1,4:3,6-dianhydro-2,5-bis-O-(diphenoxyphosphoryl)-D-glucitol

EC Number:

935-211-5

Cas Number:

1305113-15-8

Molecular formula:

C30H28O10P2

IUPAC Name:

1,4:3,6-dianhydro-2,5-bis-O-(diphenoxyphosphoryl)-D-glucitol

Details on test material:

- Name of test material (as cited in study report): Isosorbid-O,O'-bis(diphenylphosphorsäureester); Lab test item number: 10/0230-4
- Physical state: solid / white
- Analytical purity: 98.5 mol% (NMR-spectroscopy)
- Lot/batch No.: 10264/10/022 B
- Stability under test conditions: the stability under storage conditions over the study period was guaranteed by the sponsor.
- Storage condition of test material: room temperature
- Other: the test item was homogeneous by visual inspection.

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Wistar / Crl:WI (Han) SPF rats from Charles River Wiga GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany.
- Age at study initiation: young adult (approx. 10-11 weeks) nulliparaus and non-pregnant female animals. As suggested by the OECD guideline female animals were used for the test, because there is no indication that male animals are likely to be more sensitive to the acute effects of the test item.
- Weight at study initiation: see Table 1; animals of comparable weight (± 20% of the mean weight) were used.
- Fasting period before study: feed was withdrawn from the animals at least 16 hours before administration, but water was available ad libitum.
- Housing: single housing in Makrolon cage, type 111
- Diet (ad libitum): VRF1 (P); SDS Special Diets Services, 67122 Altrip, Germany)
- Water (ad libitum): tap water
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

olive oil

Remarks:

Olive oil Ph.Eur.

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 40 g/100 ml in the 2000 mg/kg dose group and 10 g/100 ml in the 500 mg/kg dose group.
- Amount of vehicle (if gavage): 5 ml/kg bw (test substance suspension in vehicle).
- Justification for choice of vehicle: good homogeneity of test substance suspension.

MAXIMUM DOSE VOLUME APPLIED: 5 ml/kg bw

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: by the request of the sponsor a starting dose of 500 mg/kg bw was chosen in the first step.

Doses:

500 and 2000 mg/kg bw

No. of animals per sex per dose:

3; 3 female animals were use at the first step and received 500 mg/kg bw test substance in vehicle. As no mortality occurred, 2000 mg/kg bw were administered to 3 additional female rats in the second step. Because no mortality occurred in the second step, 2000 mg/kg bw were administered to another group of 3 female animals in the third step. Because no mortality occurred again the study was terminated

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: recording of clinical signs several times on the day of administration, and at least once daily thereafter each workday for the individual animals. Determination of individual body weights shortly before administration (day 0), weekly thereafter, and on the last day of observation. A check for any dead or moribund animals made at least once each workday.
- Necropsy of survivors performed: yes; necropsy with gross-pathology examination on the last day of the observation period after sacrifice with CO2 in a chamber with increasing concentrations over time.

Statistics:

The mean body weights were calculated in each treatment group.

Results and discussion

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: Interpretation of the results based on the Annex 2 of the OECD TG 423; No mortality occurred and no signs of systemic toxicity were observed up to 2000 mg/kg bw.

Mortality:

No mortality occurred (2000 mg/kg: 6 females evaluated; 500 mg/kg bw 3 females evaluated).

Clinical signs:

No clinical signs were observed during clinical examination.

Body weight:

The mean body weight of the test groups increased throughout the study period within the normal range (see Table 1)

Gross pathology:

There were no macroscopic pathological findings in the animals sacrificed at the end of the observation period.

Any other information on results incl. tables

Table 1: Body weight change

Study day	Mean body weights ± standard deviations at indicated dose levels
	2000 mg/kg bw		500 mg/kg bw
	Second step	Third step	First step
0	188.0±3.46	182.0±2.00	183.3±2.31
7	203.0±4.36	199.7±4.16	201.7±6.43
14	211.7±2.52	205.0±5.29	205.0±4.00