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

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2010-11-12 - 2010-12-08

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 402 (Acute Dermal Toxicity)

Version / remarks:

Adopted on February 24, 1987

Deviations:

yes

Remarks:

2 dose levels

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1200 (Acute Dermal Toxicity)

Version / remarks:

Adopted in August 1998

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 TG 402

GLP compliance:

yes

Test type:

standard acute 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: 10/0230-2
- Physical state: solid / white
- Analytical purity: 98.2 mol%
- Lot/batch No.: 10109/101006
- 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:

male/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 animals (male animals approx. 8 weeks, female animals approx. 12 weeks). The female animals were nulliparaus and non-pregnant.
- Weight at study initiation: see Table 1; animals of comparable weight (± 20% of the mean weight) were used.
- 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

Type of coverage:

semiocclusive

Vehicle:

olive oil

Remarks:

Olive oil Ph.Eur.

Details on dermal exposure:

TEST SITE
- Area of exposure: about 40 cm2 clipped (ca. 24 hours before administration) epidermis of the dorsal and dorsolateral parts of the trunk.
- % coverage: the area of exposure corresponds to at least 10% of the body surface.
- Type of wrap if used: the test item was covered with an air-permeable dressing and stretch bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): removal of the semi occlusive dressing and rinsing of the application site with warm water.
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit):see below
- Concentration (if solution): 40 g/100 ml in the 2000 mg/kg dose group and 10 g/100 ml in the 500 mg/kg dose group.
- Constant volume or concentration used: yes
- For solids, paste formed: yes (suspension)

VEHICLE
- Amount(s) applied (volume or weight with unit): 5 ml/kg bw (test substance suspension in vehicle).

Duration of exposure:

24 hours

Doses:

500 and 2000 mg/kg bw

No. of animals per sex per dose:

5

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.
- Other examinations performed: for scoring of skin findings (edema and erythema scores) individual readings were performed according to the Draize scoring system 30 - 60 minutes after removal of the semi-occlusive dressing (day 1), weekly thereafter, and on the last day of observation.

Statistics:

The mean body weights were calculated in each treatment group.

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: No mortality occurred and no signs of systemic toxicity were observed up to 2000 mg/kg bw.

Mortality:

No mortality occurred.

Clinical signs:

No signs of systemic toxicity were observed in the animals of the 500 and 2000 mg/kg test groups.

Body weight:

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

Gross pathology:

No macroscopic pathologic abnormalities were noted at necropsy on the last day of observation.

Other findings:

- Other observations: no skin effects were observed in the animals of the 500 and 2000 mg/kg test groups.

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
	Males	Females	Males	Females
0	258.6±7.80	210.6±6.47	236.8±8.44	207.6±3.58
7	275.8±14.81	217.2±12.70	263.6±10.31	212.8±5.63
14	298.6±15.31	225.8±16.15	295.4±11.33	221.6±5.77