Methyl (1R,3S,4R,5R)-3-amino-5-({2,4,6-tri-O-benzoyl-3-O-[(2S)-1-(benzyloxy)-3-cyclohexyl-1-oxopropan-2-yl]-β-D-galactopyranosyl}oxy)-4-[(2,3,4-tri-O-benzyl-6-deoxy-α -L-galactopyranosyl)oxy]cyclohexanecarboxylate hydrochloride

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

18 August to 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

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Methyl (1R,3S,4R,5R)-3-amino-5-({2,4,6-tri-O-benzoyl-3-O-[(2S)-1-(benzyloxy)-3-cyclohexyl-1-oxopropan-2-yl]-β-D-galactopyranosyl}oxy)-4-[(2,3,4-tri-O-benzyl-6-deoxy-α -L-galactopyranosyl)oxy]cyclohexanecarboxylate hydrochloride

EC Number:

945-311-0

Molecular formula:

C78H85NO18 HCl

IUPAC Name:

Methyl (1R,3S,4R,5R)-3-amino-5-({2,4,6-tri-O-benzoyl-3-O-[(2S)-1-(benzyloxy)-3-cyclohexyl-1-oxopropan-2-yl]-β-D-galactopyranosyl}oxy)-4-[(2,3,4-tri-O-benzyl-6-deoxy-α -L-galactopyranosyl)oxy]cyclohexanecarboxylate hydrochloride

Details on test material:

- State of aggregation: white solid powder

Test animals

Species:

rat

Strain:

Wistar

Remarks:

Crl:WI (Han) (outbred, SPF-Quality)

Sex:

female

Details on test animals or test system and environmental conditions:

Source: Charles River Deutschland, Sulzfeld, Germany.
6 Females (nulliparous and non-pregnant). Each dose group consisted of
3 animals. Young adult animals (approx. 10 weeks old) were selected. Body weight variation did not exceed +/- 20% of the sex mean.

Environmental controls for the animal room were set to maintain 18 to 24°C, a relative humidity of 40 to 70%, at least 10 air changes/hour, and a 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.

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 & Sohne GmbH + CO. KG, Rosenberg, Germany) and paper as cage-enrichment (Enviro-dri, Wm. Lillico & Son (Wenham Mill Ltd), Surrey, United Kingdom).
Acclimatization period was at least 5 days before start of treatment under laboratory conditions.

Diet
Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiaten GmbH, Soest, Germany).

Water
Free access to tap water.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

propylene glycol

Remarks:

Propylene glycol (Merck, Darmstadt, Germany)

Doses:

Single doase on Day 1: 2000mg/kg body weight

No. of animals per sex per dose:

3

Control animals:

not specified

Details on study design:

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.

Statistics:

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

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, piloerection, abnormal gait and/or uncoordinated movements were noted for the animals between Days 1 and 3.

Other findings:

Macroscopic 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-06460259-01 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-06460259-01 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).