2-{2-[(2R,4R,6R)-4,6-dihydroxytetrahydro-2H-pyran-2-yl]ethyl}-1H-isoindole-1,3(2H)-dione

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

09 January 2008 to 29 January 2008

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP study conducted to apropriate OECD, EU and other Guidelines

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 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

no

Test guideline 4

Qualifier:

according to guideline

Guideline:

other: JMAFF guidelines (2000) including the most recent partial revisions

Deviations:

no

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

2-{2-[(2R,4R,6R)-4,6-dihydroxyoxan-2-yl]ethyl}-2,3-dihydro-1H-isoindole-1,3-dione

EC Number:

700-188-0

Cas Number:

1333481-90-5

Molecular formula:

C15H17NO5

IUPAC Name:

2-{2-[(2R,4R,6R)-4,6-dihydroxyoxan-2-yl]ethyl}-2,3-dihydro-1H-isoindole-1,3-dione

Constituent 2

Reference substance name:

Lactol

IUPAC Name:

Lactol

Constituent 3

Reference substance name:

Phthalamido Lactol

IUPAC Name:

Phthalamido Lactol

Details on test material:

- Name of test material (as cited in study report): Lactol
- Physical state: White powder
- Analytical purity: Not indicated but treated as 100%
- Impurities (identity and concentrations): None reported
- Purity test date: Not reported
- Lot/batch No.: PDC-010-194
- Expiration date of the lot/batch: 13 December 2008 (allocated by NOTOX, 1 year after receipt of test substance
- Stability under test conditions: Not reported
- Storage condition of test material: At room temperature in the dark
- Other:

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.
- Age at study initiation: ca. 10 weeks
- Weight at study initiation: 163 to 189 grams
- Fasting period before study: 20 hours
- Housing: Group housing of 3 animals per cage in labelled Macrolon cages (MIV type; height 18 cm.) containing sterilised sawdust as bedding
material (Litalabo, S.P.P.S., Argenteuil, France) and paper as cage-enrichment (Enviro-dri, Wm. Lillico &Son (Wonham Mill Ltd), Surrey, U.K).
- Diet (e.g. ad libitum): ad libitum, pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiaten GmbH, Soest, Germany).

- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.0±3.0°C (actual range: 19.8 - 22.2°C)
- Humidity (%): 30-70% (actual range: 30-66%)
- Air changes (per hr): 15/hr
- Photoperiod (hrs dark / hrs light): 12 hours


IN-LIFE DATES: From: 09 January 2008 To: 29 January 2008

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200mg/kg
- Amount of vehicle (if gavage): 10ml/kg
- Justification for choice of vehicle: trial formulations performed at NOTOX and on test substance data supplied by the Sponsor
- Lot/batch no. (if required): Not reported
- Purity: Not reported


MAXIMUM DOSE VOLUME APPLIED:
2000mg/kg

DOSAGE PREPARATION (if unusual):


CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose:
The toxicity of the test substance was assessed by stepwise treatment of groups of 3 females.
The first group was treated at a dose level of 2000 mg/kg. The absence or presence of mortality
of animals dosed at one step determined the next step, based on the test procedure defined in
the guidelines. The onset, duration and severity of the signs of toxicity were taken into account
for determination of the time interval between the dose groups.

Doses:

First set of females: 2000 mg/kg Second set of females: 2000 mg/kg

No. of animals per sex per dose:

6 females/per dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observed for mortalities twice daily; Body weights days 1, 8 and 15
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs: At periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15.

Statistics:

No statistical analyses were performed

Results and discussion

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

There were no mortalities during the study

Clinical signs:

other: Hunched posture, piloerection and salivation were noted among the animals on Days 1 and 2.

Gross pathology:

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

Other findings:

N/A

Applicant's summary and conclusion

Interpretation of results:

practically nontoxic

Remarks:

Migrated information Criteria used for interpretation of results: other: EU and GHS

Conclusions:

The oral LD50 value of LACTOL in Wistar rats was established to exceed 2000 mg/kg body weight.

Executive summary:

A study was conducted at NOTOX, The Netherlands, on behalf of Pfizer Ireland Pharmaceuticals Ltd., to assess the acute toxicity of the test substance Lactol, when administered in a single oral dose to female rats at one or more defined dosages. The study was conducted to GLP and to OECD 423 and EU B.1., as well as to EPA and JMAFF guidelines. Lactol was administered by oral gavage to two subsequent groups of three female Wistar rats at 2000 mg/kg body weight. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (Day 15). Hunched posture, piloerection and salivation were noted among the animals on Days 1 and 2 but no mortalities occurred during the study. The body weight gain shown by the animals over the study period was considered to be normal. No abnormalities were found at macroscopic post mortem examination of the animals. The oral LD50 value of Lactol in Wistar rats was established to exceed 2000 mg/kg body weight.