4-[(6-chloro-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile

Endpoint summary

Description of key information

Skin irritation

In a K1 in vivo skin irritation study in New Zealand White Rabbits according to OECD Guideline 404 and EU Method B.4, T002615 was not irritating to the skin based on the criteria of the CLP Regulation (EC) No 1272/2008.

Eye irritation

In a K1 in vivo eye irritation/corrosion study in White Vienna rabbits according to OECD guideline 405 and EU Method B.5, T002615 produced no irritation to eyes and should not be classified for eye irritation or serious eye damage based on the criteria of the CLP regulation (EC) No 1272/2008.

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:

From 2003-02-25 to 2003-04-29

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

GLP study conducted according to OECD Guideline 404 and EU Method B.4 without deviations.

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

: from the Swiss GLP Monitoring Authorities

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 00403487
- Expiration date of the lot/batch: 2003-12-01 (retest date)
- Purity test date: no data

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: in the original container, at room temperature (range of 17-23 °C), away from direct sunlight.
- Stability under test conditions:
- Solubility and stability of the test substance in the solvent/vehicle:
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium:

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: 0.5 g (per animal) of test item was weighed as delivered by the sponsor and then moistened with approximately 0.1 mL of purified water before application.

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: 2 female and 1 male NewZealand White Rabbit, SPF; Elevage Scientifique des Dombes F-014000 Chatillon sur Chalaronne/France
- Age at study initiation: 10 weeks (male), 11 weeks (females)
- Weight at study initiation: 2357-2342 g (females) 2555 g (male)
- Housing:individually in stainless steel cages equipped with feed hoppers and drinking water bowls. Wood blocks (RCC Ltd. Fullinsdorf) and haysticks 4646 (batch no. 0206, Provimi Kliba AG) were provided for gnawing.
- Diet (e.g. ad libitum): pelleted standard Provimi Kliba 3418 rabbit maintenance diet ad libitum (batch no.64/02) provided by Provimi Kliba AG, CH-4303 Kaiseraugust
- Water (e.g. ad libitum): community tap water from Füllinsdorf, ad libitum
- Acclimation period: 5 days (from 2003-02-25 to 2003-03-02), ubder laboratory conditions, after health examination, only animals without any visual signs of illness were used for the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-23
- Humidity (%): 30-70
- Air changes (per hr): air-conditioned with 10-15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hrs dark/ 12 hrs light (music was played during the daytime light period)

IN-LIFE DATES: From: 2003-03-25 To: 2003-03-06

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Controls:

other: untreated skin areas were used as control

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit):0.5 g per animal
- The test item was weighed as delivered by the sponsor and the moistened with approximately 0.1 mL of purified water before application.

Duration of treatment / exposure:

4 hours

Observation period:

72 hours

Number of animals:

3 (one male and two females)

Details on study design:

TEST SITE
- Area of exposure: one flank , clipped free of fur (exposed area of app. 100 cm² =10 cm x 10 cm)
- % coverage: no data
- Type of wrap if used: the test item was placed on a surgical gauze patch (ca.4 cm x 4 cm). This gauze patch was applied to the intact skin of the clipped area. The patch was covered with a semi-occlusive dressing. The dressing was wrapped around the abdomen and anchored with tape.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): the dressig was removed and the skin was flushed with lukewarm tap water to clean the application site so that any reactions (erythema) were clearly visible at that time.
- Time after start of exposure: 4 hours

OBSERVATION TIME POINTS
- Viability/mortality and clinical signs: daily from delivery of the animals to the termination of the test.
- Body weights: at start of acclimatization, on the day of application and at termination of observation
- Skin reactions: 1, 24, 48 and 72 hours after the removal of the dressing, gauze patch and test item

SCORING SYSTEM:
- The skin reaction was assessed according to the numerical scoring system listed in the EEC Commission Directive 92/69/EEC, July 31, 1992 (see scoring table below in any other information on materials and methods).

Irritation parameter:

erythema score

Basis:

mean

Remarks:

3 animals (1 Male+2 Females)

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritation parameter:

edema score

Basis:

mean

Remarks:

3 animals (1 Male +2 Females)

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritant / corrosive response data:

Irritation:
- The test item did not elicit any skin reactions at the application site of any animal at any of the observation times (all scores 0).

Corrosion:
- Neither alterations of the treated skin were observed nor were corrosive effects evident on the skin.

Other effects:

Viability/Mortality/Clinical Signs:
- No clinical signs of systemic toxicity were observed in the animals during the study and no mortality occurred.

Coloration:
- No staining produced by the test item of the treated skin was observed.

Body weights:
- The body weights of all rabbits were considered to be within the normal range of variability.

Interpretation of results:

GHS criteria not met

Conclusions:

Based upon the refered classification criteria (Commission Directive 2001/59/EC of August 06, 2001), T002615 is considered to be "not irritating" to rabbit skin.

Reference 2

Endpoint:

skin irritation: 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

Reference 3

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2003-06-03 to 2003-06-06

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

Study according to OECD Guideline 404 (Acute Dermal Irritation / Corrosion) and EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion); limited information on test material and test system

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

not specified

Qualifier:

according to guideline

Guideline:

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

Deviations:

not specified

GLP compliance:

no

Remarks:

The study was conducted in a facility operating to Good Laboratory Practice within the UK national GLP monitoring programme, but the study report has not been audited by the QA unit. No formal claim of GLP compliance is made for this study.

Specific details on test material used for the study:

no data

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS:
Source: 3 male New Zealand White Rabbits, no further data on test animals

ENVIRONMENTAL CONDITIONS: no data

Type of coverage:

semiocclusive

Preparation of test site:

not specified

Remarks:

intact skin

Vehicle:

not specified

Controls:

other: Untreated skin areas were used as control.

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 g

Duration of treatment / exposure:

4 hours

Observation period:

72 hours

Number of animals:

3

Details on study design:

TEST SITE: no data

REMOVAL OF TEST SUBSTANCE: no data

OBSERVATION TIM POINTS:
- Skin reactions were recorded at 1, 24, 48 and 72 hours after administration

SCORING SYSTEM:
- Primary Irritation Index, scoring based on observations of Erythema/Eschar formation and Oedema formation. [scoring index: 0= non-irritant, >0-2= mild irritant, >2-5= moderate irritant, >5-8= severe irritant]

Irritation parameter:

erythema score

Basis:

mean

Remarks:

animals number 42, 43, 45

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable - score 0

Irritation parameter:

edema score

Basis:

mean

Remarks:

animals number 42, 43, 45

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable - score 0

Irritant / corrosive response data:

No evidence of skin irritation was noted.

Skin Reaction	Observation Time	Individual Scores – Rabbit Number and Sex			Total
		42 Male	43 Male	45 Male
Erythema/Eschar Formation	1 Hour	0	0	0	(0)
	24 Hour	0	0	0	0
	48 Hour	0	0	0	(0)
	72 Hour	0	0	0	0
Oedema Formation	1 Hour	0	0	0	(0)
	24 Hour	0	0	0	0
	48 Hour	0	0	0	(0)
	72 Hour	0	0	0	0
Sum of 24 and 72 Hour Readings (S)					3
Primary Irritation Index (S/6) and Classification					0.0
					Non-Irritant

( ) = Total values not used for calculation of primary irritation index

Interpretation of results:

GHS criteria not met

Conclusions:

No evidence of skin irritation was noted. The test material did not meet the criteria for classification as irritant or corrosive according to EU labelling regulations Commission Directive 2001/59/EC. No symbol and risk phrase are required.

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:

2003-03-18 to 2003-05-08

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

GLP study performed according to OECD Guideline 405 and EU Method B.5 without deviations.

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

: from the Swiss GLP Monitoring Authorities.

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 00403487
- Expiration date of the lot/batch: 2003-12-01 (retest date)
- Purity test date: no data

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: in the original container, at room temperature (range of 17-23 deg C), away from direct sunlight.
- Stability under test conditions: no data

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: not applicable, 0.1 g (per animal) was weighed and applied undiluted as it was delivered by the sponsor

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: 1 male and 2 female New Zealdn White rabbits, SPF; Elevage Scientifique des Dombes, F-01400 Chatillon sur Chalaronne, France.
- Age at study initiation: 12 weeks (male); 11 weeks (females)
- Weight at study initiation: male 2025 g; 2221 - 2278 g (females)
- Housing: Individually in stainless steel cages equipped with feed hoppers, drinking water bowls, with wood and haysticks for gnawing.
- Diet (e.g. ad libitum): Pelleted standard Provimi Kliba 3418 rabbit maintenance diet ad libitum (batch no. 02/03) and results of analysis are archived by RCC Ltd., Itingen.
- Water (e.g. ad libitum): Community tap water from Füllinsdorf, ad libitum.
- Acclimation period: 6 days (2003-03-18 to 2003-03-23), under laboratory conditions after health examination, only animals without any visual signs of illness were used for the study.

ENVIRONMENTAL CONDITIONS
- Temperature (deg C): 17-23 °C
- Humidity (%): 30-70 %
- Air changes (per hr): 10-15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hrs dark / 12 hrs, music was played during the daylight period.

IN-LIFE DATES: From: 2003-03-24 To 2003-03-27

Vehicle:

unchanged (no vehicle)

Controls:

other: The right eye remained untreaded and served as the reference control

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 g (left eye only)

Duration of treatment / exposure:

single application

Observation period (in vivo):

75 hours

Number of animals or in vitro replicates:

3 animals (one male and two females)

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no

OBSERVATION TIME POINTS
- Viability/mortality and clinical signs: daily from delivery of the animals to termination of test.
- Body weights: at start of acclimatization, on the day of application and at termination of observation.
- Ocular reaction: 1, 24, 48 and 75 hours after test substance application.

SCORING SYSTEM:
The ocular reaction was assessed according to the numerical scoring system listed in the EEC Commission directive 92/69/EEC at approximately 1, 24, 48 and 72 h, as well as 7, 14 and 21 days after administration. When present, corrosion of and/or staining of sclera and cornea by the test article were recorded and reported. Eye examinations were made with Varta Cliptrix diagnostic lamp (Roth AG, CH-41-4153 Reinach/Switzerland).

Cornea: Opacity degree of density (area most dense taken for reading)
0 = No ulceration or opacity
1 = Scattered or diffuse areas of opacity (other than slight dulling of normal luster), details of iris clearly visible
2 = Easily discernible translucent area, details of iris slightly obscured
3 = Nacreous area, no details of iris visible, size of pupil barely discernible
4 = Opaque cornea, iris not discernible through the opacity

Area of cornea involved:
0 = Zero
1 = One quarter (or less), but not zero
2 =Greater than one quarter, but less than half
3 = Greater than half, but less than three quarters
4 = Greater than three quarters, up to whole area

Iris:
0 = Normal
1 = Markedly deepened rugae, congestion, swelling moderate circumcorneal hyperemia, or injection, any of these or combination of any thereof, iris still reacting to light (sluggish reaction is positive)
2 = No reaction to light, hemorrhage, gross destruction (any or all of these)

Conjunctivae:
Redness (refers to most severe reading of palpebral and bulbar conjunctivae when compared with control eye; excluding cornea and iris)
0 = Blood vessels normal
1 = Some blood vessels definitely hyperemic (injected)
2 = Diffuse crimson color, individual vessels not easily discernible
3 = Diffuse beefy red

Chemosis: lids and/or nictitating membranes
0 = No swelling
1 = Some swelling above normal (including nictitating membranes)
2 = Obvious swelling, with partial eversion of lids
3 = Swelling, with lids about half closed
4 = Swelling, with lids more than half closed

Discharge:
0=No discharge
1=Any amount different to normal (does not include small amount observed in inner canthus of normal animal)
2=Discharge with moistening of the lids anad hairs just adjacent to the lids
3=Discharge with moistening of the lids and hairs, and a considerable area around the eye (running)

Irritation parameter:

cornea opacity score

Basis:

mean

Remarks:

3 animals

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritation parameter:

iris score

Basis:

mean

Remarks:

3 animals

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: not applicable

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #1

Time point:

24/48/72 h

Score:

0.33

Max. score:

3

Reversibility:

fully reversible within: 48 hours

Irritation parameter:

chemosis score

Remarks:

chemosis

Basis:

mean

Remarks:

3 animals

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.33

Max. score:

4

Reversibility:

not fully reversible within: 48 hours

Irritant / corrosive response data:

-Irritation: no abnormal findings were observed in the cornea or iris of any animal at any of the measurement intervals; slight to moderate reddening of the conjunctivae was observed in all animals at 1-hour reading. Slight reddening of the conjunctivae was observed in 2/3 animals 24 hours after treatment. Slight swelling was noted in 2/3 animals at the 1-hour examination. Slight to moderate reddening of the sclerae was observed in 3/3 animals at 1-hour reading. Slight occular discharge was present in 1/3 animals at 1 hour after treatment.
-Corrosion: no corrosion of the cornea was observed at any of the reading times

Other effects:

-viability/mortality and clinical signs; no clinical signs of systematic toxicity were observed in the animals during the study and no mortality occured
-coloration: no staining of the treated eyes produced vy the test item was observed. Beige remnants of the test item were observed in the eye or conjunctival sac of all animals 1 hour after treatment.
- body weights: the body weights were considered to be within the normal range of variability.

Interpretation of results:

GHS criteria not met

Conclusions:

Based on the referred classification criteria (EEC Commission Directive 2001/59/EC of August 06, 2001), T002615 is considered to be "not irritating" to the rabbit eye.

Reference 3

Endpoint:

eye irritation: in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2003-05-23 to 2003-05-23

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

Only a study summary was available for review which provided limited details on the test substance and methodology; however, sufficient information was provided to deem the study reliable with restrictions.

Qualifier:

no guideline followed

Principles of method if other than guideline:

The ocular irritancy potential of the test material was assessed using the rabbit enucleated eye test (REET). This method involved the application of the test material onto the cornea of the enucleated eye.

GLP compliance:

no

Remarks:

The study was conducted in a facility operating to Good Laboratory Practice within the UK national GLP monitoring programme, but the study report had not been audited by the QA Unit. No formal claim of GLP compliance was made for the study.

Specific details on test material used for the study:

no data

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

SOURCE OF COLLECTED EYES
- Source: 5 enucleated eyes,, obtained from the New Zealand White strain of rabbits
- Characteristics of donor animals (e.g. age, sex, weight): no data
- Storage, temperature and transport conditions of ocular tissue (e.g. transport time, transport media and temperature, and other conditions): the eyes were maintained at a temperature of 32°C ± 1.5°C within the superfusion apparatus
- Time interval prior to initiating testing: no data
- indication of any existing defects or lesions in ocular tissue samples: no data
- Indication of any antibiotics used: no data

Vehicle:

not specified

Controls:

yes, concurrent negative control

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL
- Concentration (if solution): no data

NEGATIVE CONTROL
- Amount(s) applied (volume or weight with unit): no data
- Concentration (if solution): 0.9%

Duration of treatment / exposure:

single application

Number of animals or in vitro replicates:

3 enucleated eyes were treated with the test item, 2 enucleated eyes were treated as control

Details on study design:

REMOVAL OF TEST SUBSTANCE:
- washing: no

OBSERVATION TIME POINTS:
- corneal opacity and corneal epithelium condition: 60, 120, 180 and 240 min post dosing
- fluorescein uptake: 240 min post dosing
- corneal swelling: 60, 120 and 240 min post dosing

SCORING SYSTEM:
- CORNEA
The scoring scheme measures the severity of corneal cloudiness and the area of the cornea involved. Severity of
corneal cloudiness is graded as follows:
0 = Normal cornea. Appears with the slit-lamp as having a bright grey line on the epithelial surface and a
bright grey appearance of the stroma.
1 = Some loss of transparency. Only the anterior half of the stroma is involved as observed with an optical
section of the slit-lamp. The underlying structures are clearly visible with diffuse illumination, although
some cloudiness can be readily apparent with diffuse illumination.
2 = Moderate loss of transparency. In addition to involving the anterior stroma, the cloudiness extends all
the way to the endothelium. The stroma has lost its marble-like appearance and is homogeneously white.
With diffuse, illumination, underlying structures are clearly visible.
3 = Involvement of the entire thickness of the stroma. With optical section, the endothelial surface is still
visible. However, with diffuse illumination the underlying structures are just visible.
4 = Involvement of the entire thickness of the stroma. With the optical section cannot clearly visualise the
endothelium. With diffuse illumination, the underlying structures cannot be seen.
5
The surface of the cornea relative to the area of cloudiness is divided into five grades from 0 to 4.

0 = Normal cornea with no area of cloudiness
1 = 1 to 25% area of stromal cloudiness
2 = 26 to 50% area of stromal cloudiness
3 = 51 to 75% area of stromal cloudiness
4 = 76 to 100% area of stromal cloudiness

- FLUORESCEIN
The use of fluorescein is a valuable aid in defining epithelial damage for fluorescein staining. The area can be
judged as a 0 to 4 scale using the same terminology as for corneal cloudiness. The intensity of fluorescein
staining can be divided into a 0 to 4 scale.
0 = Absence of fluorescein staining
1 = Slight fluorescein staining confined to a small focus. With diffuse illumination the underlying structures
are clearly visible, although there is some loss of detail.
2 = Moderate fluorescein staining confined to a small focus. With diffuse illumination the underlying
structures are clearly visible, although there is some loss of detail.
3 = Marked fluorescein staining. Staining may involve a larger portion of the cornea. With diffuse
illumination underlying structures are barely visible but are not completely obliterated.
4 = Extreme fluorescein staining. With diffuse illumination the underlying structures cannot be seen.

TOOL USED TO ASSESS SCORE:
- Slit-Lamp

Irritation parameter:

cornea opacity score

Remarks:

mean of 3 eyes

Run / experiment:

1

Value:

0

Vehicle controls validity:

not applicable

Negative controls validity:

valid

Positive controls validity:

not applicable

Remarks on result:

no indication of irritation

Remarks:

all scores were 0

Irritation parameter:

fluorescein retention score

Remarks:

mean of 3 eyes

Run / experiment:

1

Value:

0

Vehicle controls validity:

not applicable

Negative controls validity:

valid

Positive controls validity:

not applicable

Remarks on result:

other:

Remarks:

all scores were 0

Irritation parameter:

percent corneal swelling

Remarks:

mean of 3 eyes 60 min post dosing

Run / experiment:

1

Value:

4.3

Vehicle controls validity:

not applicable

Negative controls validity:

valid

Positive controls validity:

not applicable

Irritation parameter:

percent corneal swelling

Remarks:

mean of 3 eyes 120 min post dosing

Run / experiment:

1

Value:

2.1

Vehicle controls validity:

not applicable

Negative controls validity:

valid

Positive controls validity:

not applicable

Irritation parameter:

percent corneal swelling

Remarks:

mean of 3 eyes 240 min post dosing

Run / experiment:

1

Value:

1.2

Vehicle controls validity:

not applicable

Negative controls validity:

valid

Positive controls validity:

not applicable

Other effects / acceptance of results:

negative control eyes:
- corneal opacity: 0 (mean of 2 eyes)
- corneal epithelium condition: normal (2 eyes)
- fluorescein uptake: 0 (mean of 2 eyes)
- corneal swelling: 0.4 at 60 min post dosing, 0.0 at 120 minutes post dosing and 0.0 at 240 minutes post dosing

Corneal epithelium condition was normal at all timepoints for all treated eyes.

Interpretation of results:

GHS criteria not met

Conclusions:

The test material is considered unlikely to have the potential to cause severe ocular irritancy in vivo.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation:

Arcelin (2003) investigated acute dermal irritation of T002615 in 2 females and 1 male New Zealand White rabbits after 4 hours of exposure to 0.5 g of test item. Skin reactions were recorded 24, 48 and 72 hours after administration. Under the conditions of this study, no evidence of skin irritation was noted. The test item does not meet the criteria for classification as irritant or corrosive according to the criteria of the CLP regulation (EC) No 1272/2008.

In addition, Sanders (2004) investigated acute dermal irritation of T002615 in 3 male New Zealand White rabbits after 4 hours of exposure to 0.5 g of test item. Skin reactions were recorded 24, 48 and 72 hours after administration. Under the conditions of this study, no evidence of skin irritation was noted. The test item does not meet the criteria for classification as irritant or corrosive according to the criteria of the CLP regulation (EC) No 1272/2008

The GLP in vivo skin irritation study of 2003 is considered the key result for assessing the skin irritation endpoint, since the in vivo skin irritation study performed in 2004 was non-GLP compliant and limited information is available. As the result of the non-GLP in vivo skin irritation study of 2004 was negative, this study was added to the dossier as supporting evidence and the GLP compliant in vivo skin irritation study of 2003 is selected as key study for classification purposes.

An in vitro skin irritation study was waived based on the justification that adequate data from an in vivo skin irritation study are available.

Eye irritation

Arcelin (2003) investigated eye irritation in an in vivo acute eye irritation/corrosion study in 3 New Zealand White rabbits. 0.1 g/animal of T002615 was applied to the left eye. Eye irritation (cornea score, iris score, conjunctivae score and chemosis score) was scored according to Draize. The observation period last up to 75 hours (reading was performed at 1, 24, 48 and 72 hours and 7, 14 and 21 days after instillation). The mean conjunctivae score for animal #1 and animal #3 was 0.33, 0.33, respectively at the 24/48/72 hour observation, and was fully reversible within 48 hours for animal #1, but not fully reversible within 48 hours for animal #3. Based on the results of the study, the test item produced no ocular irritation. Based on the criteria of the CLP regulation (EC) 1272/2008, the test item should not be classified for eye irritation or serious eye damage. 

 

In addition, a rabbit enucleated eye test (REET) was performed by Sanders (2004) to assess the ocular irritancy potential of T002615. Three enucleated eyes, obtained from the New Zealand White strain of rabbit, were treated with 0.1 mL of test item T002615. Corneal opacity (60, 120, 180 and 240 minutes after application), corneal swelling (60, 120 and 240 minutes after application) and fluorescein uptake (240 minutes after application) were observed and scored. No indication of irritation was noted. The test item was not considered to have the potential to cause severe ocular irritancy in vivo.

The in vivo acute eye irritation/corrosion study is considered the key result for assessing the eye irritation endpoint. According to Chapter R.7a: Endpoint specific guidance Version 6.0 - July 2017 (R.7.2.11.2), data obtained from non-validated suitable in vitro tests can only be used according to the criteria set out in section 1.4 of Annex XI to the REACH Regulation, i.e. only positive results can be accepted in a weight of evidence approach. As the result of the non-validated REET test was negative, this study was added to the dossier as supporting evidence and the validated in vivo acute eye irritation/corrosion study was selected as key study for classification purposes.

 

An in vitro eye irritation study was waived based on the justification that adequate data from an in vivo eye irritation study are available.

Justification for classification or non-classification

Skin irritation:

According to the in vivo acute dermal irritation study of 2003, no skin irritation was noted for T002615. The test item did not meet the criteria for classification as irritant or corrosive according to the criteria of the CLP regulation (EC) No 1272/2008.

 

Eye irritation:

According to the in vivo acute eye irritation/corrosion study test, T002615 induced no ocular irritation. No classification is required for eye irritation or serious eye damage according to the criteria of the CLP regulation (EC) No 1272/2008.