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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.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

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
23rd August 2011 to 13th February 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 guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Qualifier:
according to guideline
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
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

Constituent 1
Chemical structure
Reference substance name:
N'-(2-Cyano-5-methoxy-4-nitrophenyl)-N,N-dimethylimidoformamide
EC Number:
813-618-8
Cas Number:
1269400-04-5
Molecular formula:
C11H12N4O3
IUPAC Name:
N'-(2-Cyano-5-methoxy-4-nitrophenyl)-N,N-dimethylimidoformamide
Test material form:
solid

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: approx. 8-12 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 - 60%
- 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: 28 December 2011

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
propylene glycol
Remarks:
(Merck, Darmstadt, Germany) (specific gravity 1.036).
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.
50 mg/kg (10 mL/kg) body weight.
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.
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 dead/moribund animals were recorded manually).

Results and discussion

Effect levels
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
200 mg/kg bw
Based on:
test mat.
Mortality:
All animals at 2000 mg/kg were found dead on Day 2. Four animals at 300 mg/kg were found dead on Day 2, 4 or 5 and one animal at 300 mg/kg was sacrificed in moribund condition on Day 7.
One animal at 300 mg/kg and all animals at 50 mg/kg survived the observation period.
Clinical signs:
bodyweight loss
irregular respiration
lethargy (hypoactivity)
observations of tremors
Body weight:
other body weight observations
Remarks:
All animals that were found dead or sacrificed in moribund condition showed body weight loss. The body weight gain shown by the surviving animal at 300 mg/kg and all animals at 50 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 at 2000 mg/kg revealed spleens that appeared reduced in size. The animal at 300 mg/kg that was sacrificed in moribund condition showed several, dark red foci on the glandular mucosa of the stomach and three animals at 300 mg/kg that were found dead showed advanced autolysis.
No abnormalities were found at macroscopic post mortem examination of the remaining two animals at 300 mg/kg and all animals at 50 mg/kg.

Applicant's summary and conclusion

Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
The oral LD50 value of PF-05188294 in Wistar rats was established to be within the range of 50-300 mg/kg body weight.
According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 200 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 (2011), PF-05188294 should be classified as: Toxic if swallowed (Category 3) 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-05188294 should be classified as Category 3 and should be labeled as H301: Toxic if swallowed.
Executive summary:

Assessment of acute oral toxicity with PF-05188294 in the rat (Acute Toxic Class Method).
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-05188294 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 and two additional groups of females were dosed at 50 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 at 2000 mg/kg were found dead on Day 2. Four animals at 300 mg/kg were found dead on Day 2, 4 or 5 and one animal at 300 mg/kg was sacrificed in moribund condition on Day 7. One animal at 300 mg/kg and all animals at 50 mg/kg survived the observation period.
Clinical signs observed during the study period were as follows:
Dose level                      Clinical signs
2000 mg/kg                   Lethargy, general tremor, hunched posture, shallow respiration, piloerection and watery discharge from the eyes were observed for all animals on Day 1.
300 mg/kg                     Lethargy, general tremor, hunched posture, uncoordinated movements, piloerection and/or chromodacryorrhoea were observed for all animals. The animal that survived the observation period had recovered from all clinical signs by Day 9.
50 mg/kg                       Lethargy, hunched posture, uncoordinated movements, shallow respiration, piloerection and/or chromodacryorrhoea were observed for all animals. The animals had recovered from all clinical signs by Day 4.
All animals that were found dead or sacrificed in moribund condition showed body weight loss.
The body weight gain shown by the surviving animal at 300 mg/kg and all animals at 50 mg/kg over the study period was considered to be normal. Macroscopic post mortem examination of the animals at 2000 mg/kg revealed spleens that appeared reduced in size. The animal at 300 mg/kg that was sacrificed in moribund condition showed several, dark red foci on the glandular mucosa of the stomach and three animals at 300 mg/kg that were found dead showed advanced autolysis. No abnormalities were found at macroscopic post mortem examination of the remaining two animals at 300 mg/kg and all animals at 50 mg/kg.
The oral LD50 value of PF-05188294 in Wistar rats was established to be within the range of 50-300 mg/kg body weight.
According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 200 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 (2011), PF-05188294 should be classified as: Toxic if swallowed (Category 3) 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-05188294 should be classified as Category 3 and should be labeled as H301: Toxic if swallowed.