3-chloro-4-fluoroaniline

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

23rd August 2011 to 23rd January 2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2012

Report date:

2012

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)

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Test guideline 4

Qualifier:

according to guideline

Guideline:

other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nohsan, Notification No. 8147, April 2011; including the most recent partial revisions.

GLP compliance:

yes

Test type:

acute toxic class method

Test material

Test material information

Constituent 1

Reference substance name:

3-chloro-4-fluoroaniline

EC Number:

206-682-8

EC Name:

3-chloro-4-fluoroaniline

Cas Number:

367-21-5

Molecular formula:

C6H5ClFN

IUPAC Name:

3-chloro-4-fluoroaniline

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: nulliparous and non-pregnant
-- Age at study initiation: 9 or 12 weeks old
- 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.
- Housing: Group housing of 3 animals per cage in labeled Makrolon cages (MIV type; height 18cm.) containing sterilized sawdust as bedding material (Litalabo, S.P.P.S., Argenteuil, France) 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): 19.3 – 21.9ºC
- Humidity (%): 40 - 59%
- Air changes (per hr): 15
- Photoperiod:12 hours artificial fluorescent light and 12 hours darkness per day.

IN-LIFE DATES: From: 09 November 2011 To: 30 November 2011

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

propylene glycol

Details on oral exposure:

The formulations (w/w) were prepared within 4 hours prior to dosing.
Homogeneity was accomplished to a visually acceptable level.
Adjustment was made for specific gravity of the vehicle. No correction was made for purity of the test substance. The concentration of the test substance in vehicle was varied to allow constant dosage volume in terms of mL/kg body weight.

MAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg (10 mL/kg) body weight.

Doses:

2000 mg/kg (10 mL/kg) body weight.
300 mg/kg (10 mL/kg) body weight.

Single dosage on Day 1

No. of animals per sex per dose:

3 females

Details on study design:

Observations
Mortality/Viability Twice daily. Animals showing pain, distress or discomfort, which was considered not transient in nature or was likely to become more severe, were sacrificed for humane reasons based on OECD guidance document on humane endpoints (ENV/JM/MONO/ 2000/7). The time of death was recorded as precisely as possible.
Body weights Days 1 (pre-administration), 8 and 15 and at death (for the sacrificed animal on Day 2).
Clinical signs At periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15. The symptoms were graded according to fixed scales and the time of onset, degree and duration were recorded:
Maximum grade 4: grading slight (1) to very severe (4)
Maximum grade 3: grading slight (1) to severe (3)
Maximum grade 1: presence is scored (1).
Necropsy: The moribund animal and animals surviving to the end of the observation period were sacrificed by oxygen/carbon dioxide procedure. All animals assigned to the study were subjected to necropsy and descriptions of all internal macroscopic abnormalities recorded.

Statistics:

Observations/measurements in the study were recorded electronically using the following programme(s):
REES Centron Environmental Monitoring system version SQL 2.0 (REES scientific, Trenton, NJ, USA); TOXDATA version 8.0 (NOTOX B.V., ‘s-Hertogenbosch, The Netherlands): Clinical signs, Body weights. (Body weight of the moribund animal on Day 2 was recorded manually).

Results and discussion

Effect levels

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

500 mg/kg bw

Based on:

test mat.

Mortality:

All animals treated at 2000 mg/kg were found dead within one or two hours after dosing.
One animal treated at 300 mg/kg was sacrificed in moribund condition on Day 2. No further mortality occurred among the animals treated at 300 mg/kg.

Clinical signs:

irregular respiration

lethargy (hypoactivity)

other: Uncoordinated movements

Body weight:

other body weight observations

Remarks:

The animal at 300 mg/kg that was sacrificed in moribund condition on Day 2 showed body weight loss. The body weight gain shown by the surviving animals at 300 mg/kg over the study period was considered to be similar to that expected of normal untreated animals of the same age and strain.

Gross pathology:

Macroscopic post mortem examination of the animals that were found dead or sacrificed in moribund condition revealed tan discolouration of the lungs. Many tan foci on the lungs were also observed for one animal at 300 mg/kg that survived until the scheduled necropsy.
Two animals showed pelvic dilation of the right kidney and another animal showed diaphragmatic hernia of the median lobes of the liver. These findings are occasionally seen among rats of this age and strain and were therefore considered not toxicologically significant.

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The oral LD50 value of PF-01458762 in Wistar rats was established to be within the range of 300- 2000 mg/kg body weight.
According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 500 mg/kg body weight.
- according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2007), PF-01458762 should be classified as: harmful if swallowed (Category 4) for acute toxicity by the oral route.
- according to the Regulation (EC) No 1272/2008 on classification, labelling and packaging of
substances and mixtures, PF-01458762 should be classified as Category 4 and should be labeled as H302: Harmful if swallowed.

Executive summary:

The study was carried out based on the guidelines described in:
OECD No.423 (2001) "Acute Oral Toxicity, Acute Toxic Class Method" Commission Regulation (EC) No 440/2008, B1 tris: "Acute Oral Toxicity, Acute Toxic Class Method" EPA, OPPTS 870.1100 (2002), "Acute Oral Toxicity" JMAFF guidelines (2011) including the most recent partial revisions.
Initially, PF-01458762 was administered by oral gavage to three female Wistar rats at 2000 mg/kg body weight. In a stepwise procedure, two additional groups of females were dosed at 300 mg/kg body weight. All 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 treated at 2000 mg/kg were found dead within one or two hours after dosing.
One animal treated at 300 mg/kg was sacrificed in moribund condition on Day 2. No further mortality occurred among the animals treated at 300 mg/kg.
Clinical signs observed during the study period were as follows:
Dose level          Clinical signs
2000 mg/kg       Uncoordinated movements and shallow respiration.
300 mg/kg         Lethargy, hunched or flat posture, uncoordinated movements, slow breathing, shallow respiration, piloerection, watery discharge from the eyes and/or ptosis.
The surviving animals at 300 mg/kg had recovered from all symptoms between Days 5 and 7.
The animal at 300 mg/kg that was sacrificed in moribund condition on Day 2 showed body weight loss.
The body weight gain shown by the surviving animals at 300 mg/kg over the study period was considered to be similar to that expected of normal untreated animals of the same age and strain.
Macroscopic post mortem examination of the animals that were found dead or sacrificed in moribund condition revealed tan discolouration of the lungs. Many tan foci on the lungs were also observed for one animal at 300 mg/kg that survived until the scheduled necropsy.
The oral LD50 value of PF-01458762 in Wistar rats was established to be within the range of 300-2000 mg/kg body weight.
According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 500 mg/kg body weight.
- according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2007), PF-01458762 should be classified as: harmful if swallowed (Category 4) for acute toxicity by the oral route.
- according to the Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures, PF-01458762 should be classified as Category 4 and should be labeled as H302: Harmful if swallowed.