Benzenemethanol, 2,6-dichloro-3-fluoro-.alpha.-methyl-, (.alpha.S)-

Endpoint summary

Description of key information

Acute dermal toxicity: A primary dermal toxicity study (Beerens-Heijnen, 2010) was available which is key study.

This study showed that the dermal LD50 value of test substance is established to be in the range of 1000-2000 mg/kg body weight.

Key value for chemical safety assessment

Acute toxicity: via dermal route

Link to relevant study records

Reference

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

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

Batch: E010010678 (PFI-09-01-097)
Purity: 100.0 %

Species:

rat

Strain:

other: Wistar strain, Crl:WI (Han) (outbred, SPF-Quality)

Sex:

male/female

Details on test animals or test system 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

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

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:

other: 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 postur

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

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.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 000 mg/kg bw

Quality of whole database:

1 (reliable without restriction)

Additional information

Acute dermal toxicity:

A primary dermal toxicity study was conducted according to OECD 402 using rat (Beerens-Heijnen, 2010). Key study.

This study showed that the dermal LD50 value of test substance is established to be in the range of 1000-2000 mg/kg body weight.

Justification for selection of acute toxicity – dermal endpoint

Study run to a method comparable with current guidelines and to GLP

Justification for classification or non-classification

Dermal LD50>1000 -<=2000 mg/kg (actual range>1000 -<=2000 mg/kg)

Therefore in accordance with Regulation (EC) No. 1272/2008 Table 3.1.1 the substance is classified for Category 4 H312.