Registration Dossier

Data platform availability banner - registered substances factsheets

Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

repeated dose toxicity: oral, other
7 Day
Type of information:
experimental study
Adequacy of study:
key study
Study period:
19 October - 27 October 2015
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guidelineopen allclose all
according to guideline
other: EC 440/2008, B.7 Repeated Dose (28 days) Toxicity (oral), 2008.
according to guideline
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
GLP compliance:
Limit test:

Test material

Constituent 1
Chemical structure
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:
Cas Number:
Molecular formula:
(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

Wistar Han
Details on test animals or test system and environmental conditions:
- Source: Charles River Deutschland, Sulzfeld, Germany.
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at study initiation: Approximately 9 weeks.
- Housing: 12 males and 12 females. Group housing of 3 animals per sex in Makrolon cages (MIV type, height 18 cm) with 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. Lilico & 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: At least 5 days before the start of treatment under laboratory 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): 12-hour light/12-hour dark cycle

IN-LIFE DATES: 19 October - 27 October 2015

Administration / exposure

Route of administration:
oral: gavage
Details on route of administration:
Oral gavage, using a plastic feeding tube. Formulations were placed on a magnetic stirrer during dosing.
propylene glycol
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: Formulations (w/w) were prepared daily within 5 hours prior to dosing, and were homogenized to visually acceptable levels. Adjustment was made for specific gravity of the vehicle. No correction was made for the purity of the test substance.

- Justification for use and choice of vehicle: Based on trial formulations performed at WIL Research Europe and on information provided by the Sponsor.
- Concentration in vehicle: Specific gravity 1.036
- Amount of vehicle (if gavage): 5 mL/kg
Analytical verification of doses or concentrations:
Duration of treatment / exposure:
7 days
Frequency of treatment:
Once daily for up to 7 consecutive days, approximately the same time each day with a maximum of 6 hours difference between the earliest and latest dose. Animals were dosed up to the day prior to necropsy.
Doses / concentrationsopen allclose all
Dose / conc.:
150 mg/kg bw (total dose)
Dose / conc.:
300 mg/kg bw (total dose)
Dose / conc.:
1 000 mg/kg bw (total dose)
No. of animals per sex per dose:
3 males and 3 females per dose
Control animals:
yes, concurrent vehicle
Details on study design:
Male and female Wistar Han rats, approximately 9 weeks of age on study Day 1, were
administered PF-06460246 via oral gavage daily for at least 7 consecutive days.
Group Number Dose level (mg/kg/day) Number of animals (Males) (Females) Animal numbers (Males) (Females)
1 0 (vehicle)a 3 3 1-3 13-15
2 150 3 3 4-6 16-18
3 300 3 3 7-9 19-21
4 1000 3 3 10-12 22-24
a = The vehicle was propylene glycol, specific gravity 1.036.


Observations and examinations performed and frequency:
Mortality / Viability: At least twice daily.
Clinical signs: At least once daily from start of treatment onwards, detailed clinical
observations were made in all animals. The time of onset, grade and
duration of any observed signs were recorded. Signs were graded for
severity and the maximum grade was predefined at 3 or 4. Grades were
coded as slight (grade 1), moderate (grade 2), severe (grade 3) and very
severe (grade 4). For certain signs, only its presence (grade 1) or
absence (grade 0) was scored. In the data tables, the scored grades are
reported, as well as the percentage of animals affected in summary
Body weights: On Days 1, 4 and 7.
Food consumption: Over Days 1-4 and 4-7.
Water consumption: Subjective appraisal was maintained during the study, but no quantitative
investigation introduced as no effect was suspected.
Sacrifice and pathology:
Animals showing pain, distress or discomfort, which is considered not transient in nature or is likely to become more severe, will be sacrificed for humane reasons based on OECD guidance
document on humane endpoints (ENV/JM/MONO/ 2000/7). The time of death will be recorded as precisely as possible.

Animals surviving to the end of the observation period and all moribund animals will be deeply anaesthetized using isoflurane. Blood samples for clinical laboratory investigations will be drawn from
the retro-orbital sinus of all rats/sex/group (for details see par 4.7.) immediately prior to sacrifice.

All organ and tissue samples, as defined under Histopathology (following), were processed, embedded in paraffin wax (Klinipath, Duiven, The Netherlands) and cut at a thickness of 2-4 micrometers and stained with haematoxylin and eosin (Klinipath, Duiven, The Netherlands).
A descriptive statistical analysis was performed (mean, SD and/or median).

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
No clinical signs of toxicity were noted during the observation period.
no mortality observed
Description (incidence):
No mortality occurred during the study period.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Body weights and body weight gain of male animals remained in the same range as controls over the study period.
Slight weight loss was observed for one high dose male and one low dose and two high dose females. Based on this low incidence and severity and the absence of a clear dose relation, this finding was considered to be of no toxicological significance.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Food consumption before or after allowance for body weight was similar between treated and control animals.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
Haematological parameters of treated rats were considered not to have been affected by treatment.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
Clinical biochemistry parameters of treated rats were considered not to have been affected by treatment.
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
Test item-related absolute and relative lower adrenal glands weights (22 and 21% decrease compared to mean control values, respectively) were noted in males at 1000 mg/kg. Since no macro- or
microscopic correlates were noted in these animals, this was considered to be a non-adverse finding.
There were no other test item-related organ weight changes.
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Description (incidence and severity):
Macroscopic examination: Necropsy did not reveal any toxicologically relevant alterations.
Microscopic examination: There were no microscopic findings recorded which could be attributed to treatment with the test
substance. All microscopic findings were within the range of background pathology encountered in Wistar rats of
this age and strain and occurred at similar incidences and severity in both control and treated rats.
Details on results:
No toxicologically relevant changes were noted in clinical appearance, functional observations, body
weight, food consumption, clinical laboratory investigations, organ weights, macroscopic examination
and microscopic examination.

Effect levels

Key result
Dose descriptor:
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
behaviour (functional findings)
body weight and weight gain
clinical biochemistry
clinical signs
dermal irritation
food consumption and compound intake
food efficiency
gross pathology
histopathology: neoplastic
histopathology: non-neoplastic
ophthalmological examination
organ weights and organ / body weight ratios
water consumption and compound intake
Remarks on result:
not determinable due to absence of adverse toxic effects

Target system / organ toxicity

Key result
Critical effects observed:

Applicant's summary and conclusion

From the results presented in this report it was concluded that PF-06460246 has no toxic potential when administered to rats by daily oral gavage for a period of up to 7 consecutive days up to 1000 mg/kg.