6H-Furo[2',3':4,5]oxazolo[3,2-a]pyrimidin-6-one, 2,3,3a,9a-tetrahydro-3-hydroxy-2-(hydroxymethyl)-7-methyl-, (2S,3S,3aR,9aS)-

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

24 September - 08 October 2008

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2008

Report date:

2008

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1200 (Acute Dermal Toxicity)

Deviations:

no

Test guideline 4

Qualifier:

according to guideline

Guideline:

other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nousan, Notification No 8147, November 2000; including the most recent partial revisions.

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

(2S,3S,3aR,9aS)-3-hydroxy-2-(hydroxymethyl)-7-methyl-2,3,3a,9a-tertryhydro-6H-furo[2’,3’:4,5][1,3]oxazolo [3,2-a]pyrimidin-6-one

EC Number:

700-330-1

Cas Number:

433733-92-7

Molecular formula:

C10H12N2O5

IUPAC Name:

(2S,3S,3aR,9aS)-3-hydroxy-2-(hydroxymethyl)-7-methyl-2,3,3a,9a-tertryhydro-6H-furo[2’,3’:4,5][1,3]oxazolo [3,2-a]pyrimidin-6-one

Test material form:

solid: bulk

Details on test material:

- Name of test material (as cited in study report): Anhydrothymidine
- Substance type: White powder
- Physical state: powder
- Analytical purity: 99.7%
- Purity test date: not stated
- Lot/batch No.: 073904/05
- Expiration date of the lot/batch: 11 December 2008
- Stability under test conditions: stable
- Storage condition of test material: At room temperature in the dark

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
-Strain: Wistar strain, Crl:WI (Han) (outbred, SPF-Quality)
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approx. 10 weeks old
- Weight at study initiation:
- Fasting period before study: nor applicable
- Housing: Individually housed in labeled Macrolon cages (MIII type, height 18 cm.) containing sterilized sawdust as bedding material and paper as cage-enrichment.
- Diet: Free access to pelleted rodent diet
- Water: Free access to tap water.
- Acclimation period: was at least 5 days before start of treatment under laboratory conditions. During the acclimatization period the animals were group housed in Macrolon cages (MIV type).


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.5 – 21.2
- Humidity (%): 43 - 74
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Type of coverage:

occlusive

Vehicle:

water

Details on dermal exposure:

TEST SITE
- Area of exposure: approx. on the back of the animal, 10% of the total body surface, i.e. approx. 25 cm² for males and 18 cm² for females
- % coverage: 100
- Type of wrap if used: surgical gauze patch (Surgy 1D)*, successively covered with aluminum foil and Coban elastic bandage*. A piece of Micropore tape* was additionally used for fixation of the bandages in females only.


REMOVAL OF TEST SUBSTANCE
- Washing (if done): skin cleaned of residual test substance using tap water.
- Time after start of exposure: 24h


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg (10 mL/kg) body weight
- Constant volume or concentration used: yes

Duration of exposure:

24 h

Doses:

2000 mg/kg (10 mL/kg) body weight.

No. of animals per sex per dose:

5

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality/Viability - Twice daily
Body weights- Days 1 (pre-administration), 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred.

Clinical signs:

Flat posture and piloerection were noted in the majority of animals between Days 1 and 3. Scales and focal erythema in the treated skin-area were noted among the animals between Days 4 and 14 and on Days 2 and 3 respectively.

Chromodacryorrhoea was noted in the majority of animals on Days 1 and 2.

Body weight:

The body weight gain during the observation period was within the range expected for rats used in this type of study.

Gross pathology:

No abnormalities were found at macroscopic post mortem examination of the animals.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

The dermal LD50 value of the test substance in Wistar rats was established to exceed 2000 mg/kg body weight.