Registration Dossier

Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 16 Sep to 03 Nov 2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study run to a method comparable with current guidelines and to GLP

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2010
Report Date:
2010

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Specific details on test material used for the study:
Batch: E010010678 (PFI-09-01-097)
Purity: 100.0 %

Test animals

Species:
rat
Strain:
other: Wistar strain, Crl:WI (Han) (outbred, SPF-Quality)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany.
- Age at study initiation: Approx. 10 weeks old
- Weight at study initiation: Bodyweight variation was within +/- 20% of the sex mean.
- Fasting period before study:
- Housing: Individually housed in labeled Macrolon cages (MIII type, height 18 cm.) containing sterilized sawdust as bedding material and paper as cage-enrichment.
- Diet (e.g. ad libitum): Free access to pelleted rodent diet.
- Water (e.g. ad libitum): Free access to tap water.
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.0 ± 3.0ºC (actual range: 19.5 - 21.6ºC)
- Humidity (%): A relative humidity of 40-70% (actual range: 40 - 73%)
- Air changes (per hr): 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours artificial fluorescent light and 12 hours darkness per day

IN-LIFE DATES: From: 16 September 2010 To: 03 November 2010

Administration / exposure

Type of coverage:
occlusive
Vehicle:
propylene glycol
Details on dermal exposure:
TEST SITE
- Area of exposure: Approx. 25 cm² for males and 18 cm² for females
- % coverage: 10%
- Type of wrap if used: A surgical gauze patch (Surgy 1D), successively covered with aluminum foil and Coban elastic bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The skin cleaned of residual test substance using tap water.
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 10 mL/kg
- Concentration (if solution):
- Constant volume or concentration used: yes
- For solids, paste formed: yes/no
Duration of exposure:
24 hours, after which dressings were removed and the skin cleaned of residual test substance using tap water. (Animals at 2000 mg/kg had an application period of 22 hours.)
Doses:
Dose level (volume) 2000 mg/kg (10 mL/kg) body weight
1000 mg/kg (10 mL/kg) body weight
No. of animals per sex per dose:
2000 mg/kg (10 mL/kg) body weight five males and five females
1000 mg/kg (10 mL/kg) body weight five males and five females
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Mortality/Viability: Twice daily.
Body weights: 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.
- Necropsy of survivors performed: yes. The moribund animals and/or animals surviving to the end of the observation period were sacrificed by an oxygen/carbon dioxide procedure. All animals assigned to the study were subjected to necropsy and descriptions of all internal macroscopic abnormalities recorded.
Statistics:
none stated

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
1 000 - 2 000 mg/kg bw
Based on:
act. ingr.
Mortality:
All animals at 2000 mg/kg were sacrificed in moribund condition within 24 hours of dosing. No mortality occurred at 1000 mg/kg.
Clinical signs:
Animals at 2000 mg/kg showed lethargy (grade 3), flat posture, slow breathing, watery discharge of the eyes, ptosis and/or hypothermia on Day 2. Piloerection was noted on Days 1 and 2 in these animals. Restless behavior, lethargy (grade 1), hunched posture, uncoordinated movements, shallow respiration, piloerection, chromodacryorrhoea and/or ptosis were noted in animals treated at 1000 mg/kg. White discoloration of the treated skin was noted in two animals at 2000 mg/kg on Day 2. General erythema and/or scales of the treated skin and/or in general were note in all females and one male at 1000 mg/kg.
Body weight:
The changes noted in body weight gain in surviving males and females were within the range expected for rats used in this type of study and were therefore considered not indicative of toxicity.
Gross pathology:
Pelvic dilation, many dark red foci in the glandular mucosa and/or pale discolouration of the liver were noted in one male and two females at 2000 mg/kg. No abnormalities were found at macroscopic post mortem examination of the animals at 1000 mg/kg.
Other findings:
none stated

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The dermal LD50 value of this substance in Wistar rats was established to be in the range of 1000-2000 mg/kg body weight.
Executive summary:

Assessment of acute dermal toxicity with PF-00968603 in the rat.

The study was carried out based on the guidelines described in:  OECD No.402 (1987) "Acute Dermal Toxicity" Commission Regulation (EC) No 440/2008, B3: "Acute Toxicity (Dermal)" EPA, OPPTS 870.1200 (1998), "Acute Dermal Toxicity"  JMAFF Guidelines (2000), including the most recent revisions.

Initially, PF-00968603 was administered to five rats of each sex by dermal application at 2000 mg/kg body weight for 22 hours. In addition PF-00968603 was administered to five rats of each sex by dermal application at 1000 mg/kg body weight for 24 hours in a stepwise manner. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed on the day of death or after terminal sacrifice (Day 15).

All animals at 2000 mg/kg were sacrificed in moribund condition within 24 hours of dosing. No mortality occurred at 1000 mg/kg.

Animals at 2000 mg/kg showed lethargy (grade 3), flat posture, slow breathing, watery discharge of the eyes, ptosis and/or hypothermia on Day 2. Piloerection was noted on Days 1 and 2 in these animals.

Restless behavior, lethargy (grade 1), hunched posture, uncoordinated movements, shallow respiration, piloerection, chromodacryorrhoea and/or ptosis were noted in animals treated at 1000 mg/kg.

White discoloration of the treated skin was noted in two animals at 2000 mg/kg on Day 2. General erythema and/or scales of the treated skin and/or in general were note in all females and one male at 1000 mg/kg.

The changes noted in body weight gain in surviving males and females were within the range expected for rats used in this type of study and were therefore considered not indicative of toxicity.

Pelvic dilation, many dark red foci in the glandular mucosa and/or pale discolouration of the liver were noted in one male and two females at 2000 mg/kg. No abnormalities were found at macroscopic post mortem examination of the animals at 1000 mg/kg.

The dermal LD50 value of PF-00968603 in Wistar rats was established to be in the range of 1000-2000 mg/kg body weight.

Based on these results: According to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2007),  PF-00968603 S should be classified as: harmful in contact with skin (Category 4) for acute toxicity by the dermal route. According to the Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures, PF-00968603 should be classified as Category 4 and should be labeled as H312: Harmful in contact with skin.