2-Propenamide, N-[4-[[(4,6-dimethyl-2-pyrimidinyl)amino]sulfonyl]phenyl]-2-methyl-

Endpoint summary

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Reference 1

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2006

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Version / remarks:

2002

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Version / remarks:

2004

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2500 (Acute Dermal Irritation)

Version / remarks:

1998

Qualifier:

according to guideline

Guideline:

other: JMAFF Guidelines: Acute Dermal Irritation

Version / remarks:

2000

GLP compliance:

yes

Specific details on test material used for the study:

Since the test substance did not mix with water, the powdery test substance was moistened with watery ethanol (50% w/v) (water, Milli-U, Millipore Corporation, Bedford, USA, ethanol, Merck, Darmstadt, Germany), immediately before application, to ensure close contact with the animal's skin.

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

Animals used within the study were at least 6 weeks old and body weights were at least 1.0 kg.
Identification: Earmark.
A health inspection was performed prior to the commencement of treatment, to ensure that the animals were in a good state of health. Special attention was paid to the skin to be treated, which was intact and free from abnormalities,

Conditions
Animals were housed in a controlled environment, in which optimal conditions were considered to be approximately 15 air changes per hour, a temperature of 21.0 +- 3.0°C (actual range: 20.8 - 22.4°C), a relative humidity of 30-70% (actual range: 46 - 59%) and 12 hours artificial fluorescent light and 12 hours darkness per day.
Accommodation
Individually in labelled cages with perforated floors (Scanbur, Denmark, dimensions 56x44x37.5cm). Acclimatisation period was at least 5 days before start of treatment under laboratory conditions.
Diet
Standard laboratory rabbit diet (Charles River Breeding and Maintenance Diet for Rabbits, Altromin, Lage, Germany) approx. 100 g. per day, Hay (TecniLab-BMI BV, Someren, The Netherlands) was provided at least three times a week.
Water
Free access to tap water.
Results of analysis for each batch of diet (nutrients) and results of quarterly analysis of diet (contaminants) and water were assessed and did not reveal any findings that were considered to have affected the study integrity. All certificates and results of analysis are retained in the NOTOX archives.

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Remarks:

Approximately 24 hours before treatment, the dorsal fur was clipped with electric clippers, exposing an area of approximately 150 cm2 (10x15 cm). To facilitate scoring, treated skin areas were re-clipped at least 3 hours before the observations.

Vehicle:

other: watery ethanol (50% v/v)

Remarks:

ince the test substance did not mix with water, the powdery test substance was moistened with watery ethanol (50% w/v), immediately before application, to ensure close contact with the animal's skin.

Amount / concentration applied:

Each animal was treated by dermal application of 0.5 grams of the test substance. The test substance was moistened with 0.7 ml of the vehicle and applied to the skin of one flank, using a metalline patch" of 2x3 cm. The patch was mounted on Micropore tape", which was wrapped around the abdomen and secured with Coban elastic bandage".

Duration of treatment / exposure:

4 hours

Observation period:

72 hours

Number of animals:

3 males

Details on study design:

In the interest of animal welfare and to minimize any testing likely to produce severe responses in animals, a weight of evidence analysis was performed, prior to the start of this in-vivo skin irritation study in rabbit. As recommended in the test guidelines, all available information was evaluated (e.g. existing human and animal data, literature, substance data supplied by the sponsor, analysis of structure activity relationships (SAR), physicochemical properties and reactivity (pH, buffering capacity) and in-vitro, ex-vivo tests and in-vivo tests) to determine the need for in-vivo skin testing. It was concluded that there is need to perform this in-vivo skin irritation study in rabbit in order to establish the possible skin irritating properties of the test substance.

The study was performed in a stepwise manner and was started by treatment of a single rabbit (sentinel). The two other animals were treated in a similar manner three weeks later, after considering the degree of skin irritation observed in the first animal.

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not relevant

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not relevant

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

none

Other effects:

none

Interpretation of results:

GHS criteria not met

Conclusions:

Based on these results v123109 does not have to be classified and has no obligatory labelling requirement for skin irritation according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (New York and Geneva, 2003) and EC criteria for classification and labelling requirements for dangerous substances and preparations (Council Directive 671548/EEC).

Reference 2

Endpoint:

skin corrosion: in vitro / ex vivo

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

an in vitro skin irritation study does not need to be conducted because adequate data from an in vivo skin irritation study are available

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Reference 1

Endpoint:

eye irritation: in vitro / ex vivo

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

an in vitro eye irritation study does not need to be conducted because adequate data from an in vivo eye irritation study are available

Reference 2

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2006

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Version / remarks:

2002

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

2004

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2400 (Acute Eye Irritation)

Version / remarks:

1998

Qualifier:

according to guideline

Guideline:

other: JMAFF guidelines: 'Acute Eye Irritation"

Version / remarks:

2000, inclusing the most recent partial revisions

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Remarks:

Source: Charles River Deutschland, Kissler, Germany

Details on test animals or tissues and environmental conditions:

Age and body weight: Animals used within the study were at least 6 weeks old and body weights were at least 1.0 kg.
Identification: Earmark.

Conditions
Animals were housed in a controlled environment, in which optimal conditions were considered to be approximately 15 air changes per hour, a temperature of 21.0 +- 3.0°C (actual range: 21.0 —22.4°C), a relative humidity of 30-70% (actual range: 47% - 59%) and 12 hours artificial fluorescent light and 12 hours darkness per day.

Accommodation
Individually in labelled cages with perforated floors (Scanbur, Denmark, dimensions 56x44x37.5 cm).
Acclimatisation period was at least 5 days before start of treatment under laboratory conditions.

Diet
Standard laboratory rabbit diet (Charles River Breeding and Maintenance Diet for Rabbits, Altromin, Lage, Germany) approx. 100 g. per day. In addition, hay (TecniLab-BMI BV, Someren, The Netherlands) was provided at least three times weekly.

Water
Free access to tap-water.

Results of analysis for each batch of diet (nutrients) and results of quarterly analysis of diet (contaminants) and water were assessed and did not reveal any findings that were considered to have affected study integrity. All certificates and results of analysis are retained in the NOTOX archives.

Vehicle:

other: The powdery test substance was instilled as delivered by the sponsor.

Amount / concentration applied:

instillation of on average 35.1 (range 35.0-35.3 mg) of test substance (volume of approximately 0.1 ml ) i

Observation period (in vivo):

1, 24, 48 and 72 hours after instillation

Number of animals or in vitro replicates:

3

Details on study design:

The study was performed in a stepwise manner and was started by treatment of a single rabbit (sentinel). The two other animals were treated in a similar manner three weeks later, after considering the degree of eye irritation observed in the first animal.

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not relevant

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

<= 1

Max. score:

1

Reversibility:

fully reversible within:

Remarks:

24 hours

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

<= 1

Max. score:

1

Reversibility:

fully reversible within:

Remarks:

24 hours

Irritation parameter:

conjunctivae score

Remarks:

Redness

Basis:

mean

Time point:

24/48/72 h

Score:

<= 1

Max. score:

1

Reversibility:

fully reversible within:

Remarks:

48 hours

Irritation parameter:

conjunctivae score

Remarks:

Discharge

Time point:

24/48/72 h

Score:

<= 1

Max. score:

1

Reversibility:

fully reversible within:

Remarks:

24 hours

Irritant / corrosive response data:

Instillation of approximately 35 mg of v123109 (a volume of approximately 0.1 ml) into one eye of each of three rabbits resulted in effects on the iris and conjunctivae.
lrldial irritation grade 1 was observed in two animals and had resolved within 24 hours.
The irritation of the conjunctivae consisted of redness, chemosis and discharge and had completely resolved within 48 hours.
No corneal opacity was observed, and treatment of the eyes with 2% fluorescein, 24 hours after test substance instillation revealed no corneal epithelial damage.

There was no evidence of ocular corrosion.

Other effects:

Colouration I Remnants
Remnants of the test substance were present in the eye of one animal on day 1.
Toxicity I Mortality
No symptoms of systemic toxicity were observed in the animals during the test period and no mortality occurred

Interpretation of results:

GHS criteria not met

Conclusions:

Based on these results v123109 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 (New York and Geneva, 2003) and EC criteria for classification and labelling requirements for dangerous substances and preparations (Council Directive 67/548/EEC).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)