1-[([[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]oxy]carbonyl)oxy]pyrrolidine-2,5-dione

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2018-11-19 - 2019-03-14

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2019

Report date:

2019

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

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:

1-[([[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]oxy]carbonyl)oxy]pyrrolidine-2,5-dione

EC Number:

813-811-7

Cas Number:

253265-97-3

Molecular formula:

C11H13NO7

IUPAC Name:

1-[([[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]oxy]carbonyl)oxy]pyrrolidine-2,5-dione

Test material form:

solid: particulate/powder

Details on test material:

- Physical state: powder
- Appearance: white powder

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: I18IB2522
- Expiration date of the lot/batch: 2019-03-19 (retest date)
- Purity test date: 2018-09-20
- Appearance: White powder

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: In refrigerator (2-8°C)
- Stability under test conditions: No data
- Solubility and stability of the test substance in the solvent/vehicle: Stable for 6 hours in propylene glycol

OTHER SPECIFICS:
- Correction factor: 1

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany.
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: Young adult animals (approx. 10-12 weeks old)
- Weight at study initiation: 183 - 209 g; Body weight variation did not exceed +/- 20% of the mean.
- Fasting period before study: no data
- Housing: Individually housed in labeled Makrolon cages (MIII type, height 18 cm.) containing sterilized sawdust as bedding material (Lignocel S 8-15, JRS - J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) and paper as cage-enrichment (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom).
- Diet (e.g. ad libitum): ad libitum, free access to pelleted rodent diet
- Water (e.g. ad libitum): ad libitum, free access to tap water
Diet, water, bedding and cage enrichment evaluation for contaminants and/or nutrients was performed according to facility standard procedures. There were no findings that could interfere with the study. - Acclimation period: at least 5 days before start of treatment under laboratory conditions. During the acclimatization period the animals were group housed in Makrolon cages (MIV type, height 18 cm).
- Health inspection: At least prior to dosing. It was ensured that the animals were healthy and that the skin to be treated was intact and free from any abnormality.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 24°C
- Humidity (%): 40 to 70%,
- Air changes (per hr): at least 10 air changes/hour
- Photoperiod (hrs dark / hrs light): 12-hour light/12-hour dark cycle
- Any variations to these conditions were maintained in the raw data and had no effect on the outcome of the study.

IN-LIFE DATES: From: 2018-11-19 To:2018-12-17

Administration / exposure

Type of coverage:

semiocclusive

Vehicle:

polyethylene glycol

Remarks:

specific gravity 1.036

Details on dermal exposure:

TEST SITE
- Area of exposure: the back of each animal
- % coverage: approx. 10% of the total body surface i.e. approx. 18 cm² for females
- 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.
- One day before exposure (Day -1) an area of approximately 5x7cm on the back of each animal was clipped.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): 24 hours, after which dressings were removed and the skin cleaned of residual test item using tap water
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg (10 mL/kg) body weight
- Concentration: 200 mg/mL
- Constant volume or concentration used: yes

VEHICLE
- propylene glycol

PREPARATION OF FORMULATION
- The preparations (w/w) were kept at room temperature and dosed within 4 hours after adding the vehicle to the test item. Homogeneity was assessed by visual inspection of the solutions and the formulations were stirred during dosing, which ensures homogeneity sufficiently for these kinds of studies. Adjustment was made for specific gravity of the vehicle. No correction was made for purity of the test item as the correction factor is 1.
- Test item preparation was stirred on a magnetic stirrer during application.

Duration of exposure:

24 hours

Doses:

2000 mg/kg body weight

No. of animals per sex per dose:

3 females

Control animals:

not required

Details on study design:

- Duration of observation period following administration: until day 15 after treatment

Observations
- Mortality/viability: Twice daily
- Weighing: Days 1 (pre-administration), 8 and 15 and at death.
- Clinical signs: at periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15. The time of onset, degree and duration were recorded and the symptoms graded according to fixed scales:
Maximum grade 4: grading slight (1) to very severe (4)
Maximum grade 3: grading slight (1) to severe (3)
Maximum grade 1: presence is scored (1).
- Necropsy: At the end of the observation period, all animals were sacrificed by oxygen/carbon dioxide procedure and subjected to necropsy. Descriptions of all internal macroscopic abnormalities were recorded.

Statistics:

No statistical analysis was performed.

Results and discussion

Effect levels

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

No mortality occurred.

Clinical signs:

other: Chromodacryorrhoea of the snout was noted for two animals on Day 1 and hunched posture was noted for the other animal on Day 2. No further clinical signs were noted

Gross pathology:

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

Other findings:

Irritation:
- no test item related erythema and edema was noted for the treated skin between Days 2 and 4
- Focal erythema, scales and scabs of the treated skin and scales and scabs of the right flank were seen in the animals during the observation period. The focal erythema was considered to be due to the dosing procedure rather than to be test item related, as test itel related erythema would show as general erythema of the treated skin area.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

The dermal LD50 value of JNJ-26144612-AAA (T002632) in Wistar Han rats was established to exceed 2000 mg/kg body weight.
Based on these results, JNJ-26144612-AAA (T002632) does not have to be classified and has no obligatory labelling requirement for acute dermal toxicity according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2017) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures (including all amendments).