.beta.-D-Galactopyranoside, ethyl 3-O-[(1S)-1-(cyclohexylmethyl)-2-oxo-2-(phenylmethoxy)ethyl]-1-thio-, 2,4,6-tribenzoate

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

18 August - 04 September 2015

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2015

Report date:

2015

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

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

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

(2S,3R,4S,5S,6R)-5-(benzoyloxy)-6-[(benzoyloxy)methyl]-4-{[(2S)-1-(benzyloxy)-3-cyclohexyl-1-oxopropan-2-yl]oxy}-2-(ethylsulfanyl)oxan-3-yl benzoate

EC Number:

805-702-8

Cas Number:

322761-81-9

Molecular formula:

C45H48O10S

IUPAC Name:

(2S,3R,4S,5S,6R)-5-(benzoyloxy)-6-[(benzoyloxy)methyl]-4-{[(2S)-1-(benzyloxy)-3-cyclohexyl-1-oxopropan-2-yl]oxy}-2-(ethylsulfanyl)oxan-3-yl benzoate

Test material form:

solid: particulate/powder

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 weeks old) were selected.
- Weight at study initiation: Body weight variation did not exceed +/- 20% of the sex mean.
- Fasting period before study: Animals were deprived of food overnight prior to dosing and until 3-4 hours after administration of the test substance. Water was available ad libitum.
- Housing: 6 animals total. Group housing of 3 animals per cage in labeled Makrolon cages (MIV 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: Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
- Water: Free access to tap water.
- Acclimation period: Acclimatization period was at least 5 days before start of treatment under laboratory conditions.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 24°C
- Humidity (%): A relative humidity of 40 to 70%
- Air changes (per hr): At least 10 air changes/hour
- Photoperiod (hrs dark / hrs light): A 12-hour light/12-hour dark cycle

IN-LIFE DATES: From: 18 August 2015 To: 04 September 2015

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

propylene glycol

Details on oral exposure:

VEHICLE
Propylene glycol (specific gravity 1.036)
- Justification for choice of vehicle: The vehicle was selected based on trial preparations performed at WIL Research Europe and on test substance data supplied by the Sponsor.
There was no information available regarding the solubility or stability in vehicle.

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg b.w. for each dose. If practicably impossible, multiple doses will be given within a 24-hour period.

Doses:

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.

No. of animals per sex per dose:

Three females will be dosed with the selected dose level.

Control animals:

no

Details on study design:

Since it is the intention to minimize the number of animals to be used, a starting dose level will be
selected by the Study Director, based on available toxicity data of the test substance. The starting
dose level should be the one that is likely to produce mortality in at least some of the animals and will
be selected from 5 (lowest dose level), 50, 300 and 2000 (highest dose level) mg/kg body weight.
Three females will be dosed with the selected dose level. The absence or presence of mortality of
animals dosed at one step will determine the next step, according to WIL Research Europe Standard
Operating Procedure DIE-H-138, which is based on the test procedure defined in the guidelines. The
time interval between treatment groups will be determined by the onset, duration and severity of the
toxic signs. Treatment of the next group will be delayed until no further mortality is to be expected in
the previously dosed animals.

Statistics:

No statistical analysis was performed (The method used is not intended to
allow the calculation of a precise LD50 value).

Results and discussion

Effect levels

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred.

Clinical signs:

other: Hunched posture, uncoordinated movements and/or piloerection were noted for the animals on Days 1 and/or 2.

Other findings:

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 oral LD50 value of PF-06460246 in Wistar rats was established to exceed 2000 mg/kg body weight.
According to the OECD 423 test guideline, the LD50 cut-off value was considered to exceed 5000 mg/kg body weight.
Based on these results, PF-06460246 does not have to be classified and has no obligatory labelling requirement for acute oral toxicity according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2011) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures (including all amendments).

Executive summary:

PF-06460246 does not have to be classified and has no obligatory labelling requirement for acute oral toxicity.