N'-(2-Cyano-5-methoxy-4-nitrophenyl)-N,N-dimethylmethanimid amide

Eye irritation

Administrative data

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

16th November 2011 to 9th February 2012

Reliability:

1 (reliable without restriction)

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 405 (Acute Eye Irritation / Corrosion)

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2400 (Acute Eye Irritation)

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 material

Test material information

Constituent 1

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 / tissue source

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Charles River France, L’Arbresle Cedex, France
- Age at study initiation: between 10-20 weeks old
- Weight at study initiation: between 2-4 kg.
- Housing: Animals were individually housed in labeled cages with perforated floors (Ebeco, Germany, dimensions 67 x 62 x 55 cm) and shelters (Ebeco, Germany, dimensions 40 x 32 x 23 cm).
- Diet: Pelleted diet for rabbits (Global Diet 2030 from Harlan Teklad®, Mucedola, Milanese, Italy) approximately 100 grams per day. Hay (TecniLab-BMI BV, Someren, The Netherlands) and wooden sticks (Swedish aspen wood, Bioservices, Uden, The Netherlands) were available during the study period
- Water: Tap water ad libitum
- Acclimation period: at least 5 days before start of treatment under laboratory conditions.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.2 – 19.9ºC
- Humidity (%): 44 - 65%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 hours artificial fluorescent light and 12 hours darkness per day.

IN-LIFE DATES: From: 28th November 2011 To: 8th December 2011

Test system

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

84.3 mg (range 84.0 - 84.6 mg) of the test substance

Duration of treatment / exposure:

24 hours

Observation period (in vivo):

Observations were made 1, 24, 48 and 72 hours after instillation.

Number of animals or in vitro replicates:

Three rabbits

Details on study design:

Animals were treated by instillation of, on average, 84.3 mg (range 84.0 - 84.6 mg) of the test substance (a volume of approximately 0.1 mL) in the conjunctival sac of one of the eyes after gently pulling the lower lid away from the eyeball. The lids were then gently held together for about one second to prevent loss of the test substance. The other eye remained untreated and served as the reference control.
Immediately after the 24-hour observation, a solution of 2% fluorescein in water (adjusted to pH 7.0) was instilled into both eyes of each animal to quantitatively determine corneal epithelial damage. Any bright green stained area, indicating epithelial damage, was estimated as a percentage of the total corneal area.

Observations
Mortality/Viability: Twice daily.
Toxicity: At least once daily.
Body Weight: Day of treatment (prior to instillation) and after the final observation.
Irritation: The eyes of each animal were examined approximately 1, 24, 48 and 72 hours after instillation of the test substance. The irritation scores and a description of all other (local) effects were recorded.

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Remarks on result:

no indication of irritation

Results 2

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Remarks on result:

no indication of irritation

Results 3

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Remarks on result:

no indication of irritation

Results 4

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Remarks on result:

no indication of irritation

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

Based on these results, PF-05188294 does not have to be classified and has no obligatory labelling requirement for eye irritation according to the:
- Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2011), - Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures.

Executive summary:

Acute eye irritation/corrosion study with PF-05188294 in the rabbit.
The study was carried out based on the guidelines described in:
OECD No.405 (2002) "Acute Eye Irritation / Corrosion" EC No 761/2009 Part B5: "Acute Toxicity: Eye Irritation/Corrosion" EPA, OPPTS 870.2400 (1998): "Acute Eye Irritation" JMAFF guidelines (2011); including the most recent partial revisions.
Single samples of approximately 84 mg of PF-05188294 (a volume of approximately 0.1 mL) were instilled into one eye of each of three rabbits. Observations were made 1, 24, 48 and 72 hours after instillation.
Instillation of the test substance resulted in irritation of the conjunctivae, which consisted of redness and discharge. The irritation had completely resolved within 24 hours in two animals and within 48 hours in the other animal.
Remnants of the test substance were present in the eye and on the outside of the eyelids for all animals on Day 1.
Based on these results, PF-05188294 does not have to be classified and has no obligatory labelling requirement for eye irritation according to the:
- Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2011),
- Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures.