Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Skin irritation:
Two studies are available:
1) An acute dermal irritation study (Latour J.E.H.M., MSc., 2016) is available which is key study. This study showed that the test substance is not irritating.
2) An in vitro skin corrosion study (Eurlings I.M.J., PhD., 2016) is available which is supporting study. This study showed that the test substance is not corrosive.
Eye irritation:

Two studies are availible:
1) In vitro study is available (Eurlings I.M.J., PhD., 2016) which is key study. This study showed that the test substance is not corrosive and not irritating to bovine eyes.

2) In vivo study (Latour J.E.H.M, MSc., 2016) is available which is a key study. This study demonstrated that the test substance is not irritating to rabbit eyes, meeting no GHS criteria for classification as an eye irritant.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 09 to 18 Feb 2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Specific details on test material used for the study:
Batch No.: E010016692Purity: 99.3%
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS- Source: Charles River France, L’Arbresle, France- Age at study initiation: between 12 and 24 weeks old- Weight at study initiation: at least 1.5 kg- Housing: Animals were individually housed in labeled cages with perforated floors and shelters.- Diet (e.g. ad libitum): Pelleted diet for rabbits approximately 100 grams per day. Hay and wooden sticks were available during the study period.- Water (e.g. ad libitum): Free access to tap water.- Acclimation period: at least 5 days before start of treatmentENVIRONMENTAL CONDITIONS- Temperature (°C): 18 to 24- Humidity (%): 40 to 70- Air changes (per hr): at least 10 air changes/hour- Photoperiod (hrs dark / hrs light): a 12-hour light/12-hour dark cycle
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
water
Controls:
yes, concurrent no treatment
Amount / concentration applied:
TEST MATERIAL- Amount(s) applied (volume or weight with unit): 0.5 grams of the test substanceVEHICLE- Amount(s) applied (volume or weight with unit): 0.3 mL
Duration of treatment / exposure:
4 h
Observation period:
72 h
Number of animals:
1 male and 2 females
Details on study design:
TEST SITE- Area of exposure: 2x3 cm- Type of wrap if used: metalline patch mounted on Micropore tape, which was wrapped around the abdomen and secured with Coban elastic bandage.REMOVAL OF TEST SUBSTANCE- Washing (if done): tap water- Time after start of exposure: Four hoursOBSERVATION:-Mortality/Viability: Twice daily. -Toxicity: At least once daily. -Body Weight: Day of treatment (prior to application) and on the day of the final observation-Irritation: The skin reactions were assessed at approximately 1, 24, 48 and 72 hours after the removal of the dressings and test item.The irritationscores and a description of all other (local) effects were recorded. Adjacent areas of the untreated skin of each animal served as controls.-Necropsy: No necropsy was performed according to study plan.SCORING SYSTEM: Draize
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
fully reversible
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
fully reversible
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
fully reversible
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
fully reversible
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
fully reversible
Irritant / corrosive response data:
No skin irritation was caused by 4 hours exposure to test substance.There was no evidence of a corrosive effect on the skin.
Other effects:
No staining of the treated skin by the test item was observed and no test item remnants were seen.No signs of systemic toxicity were observed in the animals during the test period and no mortality occurred.

Individual skin irritation scores:

Animal

6

15

16

Time after exposure

Erythema

(0-4)

Oedema

(0-4)

Erythema

(0-4)

Oedema

(0-4)

Erythema

(0-4)

Oedema

(0-4)

1 hour

0

0

0

0

0

0

24 hours

0

0

0

0

0

0

48 hours

0

0

0

0

0

0

72 hours

0

0

0

0

0

0

 

Interpretation of results:
GHS criteria not met
Conclusions:
Based on these results the test substance 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 (2015) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments).
Endpoint:
skin corrosion: in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
From 25 to 29 Jan 2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 431 (In Vitro Skin Corrosion: Human Skin Model Test)
Deviations:
no
GLP compliance:
yes
Specific details on test material used for the study:
Batch No.: E010016692Purity: 99.3%
Test system:
human skin model
Source species:
human
Details on animal used as source of test system:
TEST ANIMALS- Source: MatTek Corporation, Ashland MA, U.S.A.ENVIRONMENTAL CONDITIONSAll incubations, with the exception of the test item incubation of 3 minutes at room temperature, were carried out in a controlled environment, in which optimal conditions were a humid atmosphere of 80 - 100% (actual range 79 - 90%), containing 5.0 ± 0.5% CO2 in air in the dark at 37.0 ± 1.0°C (actual range 36.5 - 36.7°C). Temperature and humidity were continuously monitored throughout the experiment. The CO2 percentage was monitored once on each working day. Temporary deviations from the temperature, humidity and CO2 percentage may occur due to opening and closing of the incubator door. Based on laboratory historical data these deviations are considered not to affect the study integrity.
Justification for test system used:
Recommended test system in international guidelines (OECD and EC).
Vehicle:
unchanged (no vehicle)
Details on test system:
RECONSTRUCTED HUMAN EPIDERMIS (RHE) TISSUE- Model used: EpiDerm Skin Model- Tissue batch number(s): 23297 kit M and N- Production date:- Shipping date:- Delivery date:- Date of initiation of testing: 25 Jan 2016TEMPERATURE USED FOR TEST SYSTEM- Temperature used during treatment / exposure: All incubations, with the exception of the test item incubation of 3 minutes at room temperature, were carried out in the dark at 37.0 ± 1.0°C (actual range 36.5 - 36.7°C).- Temperature of post-treatment incubation (if applicable):REMOVAL OF TEST MATERIAL AND CONTROLS-Volume and number of washing steps: After the exposure period, the tissues were washed with phosphate buffered saline to remove residual test item. Rinsed tissues were kept in 24 well plates on 300 μL DMEM medium until 6 tissues (= one application time) were dosed and rinsed.- Observable damage in the tissue due to washing:- Modifications to validated SOP:MTT DYE USED TO MEASURE TISSUE VIABILITY AFTER TREATMENT / EXPOSURE- MTT concentration: 1 mg/mL- Incubation time: 3 hours- Spectrophotometer: TECAN Infinite® M200 Pro Plate Reader- Wavelength: 570 nm- Filter:- Filter bandwidth:- Linear OD range of spectrophotometer:FUNCTIONAL MODEL CONDITIONS WITH REFERENCE TO HISTORICAL DATA- Viability:- Barrier function:- Morphology:- Contamination:- Reproducibility:NUMBER OF REPLICATE TISSUES: 2CONTROL TISSUES USED IN CASE OF MTT DIRECT INTERFERENCE- Fresh tissues- Procedure used to prepare the killed tissues (if applicable):- N. of replicates : 1- Method of calculation used:NUMBER OF INDEPENDENT TEST SEQUENCES / EXPERIMENTS TO DERIVE FINAL PREDICTION:PREDICTION MODEL / DECISION CRITERIA (choose relevant statement)- The test substance is considered to be corrosive to skin if the viability after 3 minutes exposure is less than 50%.- The test substance is considered to be non-corrosive to skin if the viability after 3 minutes exposure is greater than or equal to 50% and the viability after 1 hour exposure is greater than or equal to 15%.- Justification for the selection of the cut-off point(s) if different than recommended in TG 431 and 439:
Control samples:
yes, concurrent negative control
yes, concurrent positive control
Amount/concentration applied:
TEST MATERIAL- Amount(s) applied (volume or weight with unit): 35.0 to 40.6 mg
Duration of treatment / exposure:
3, 60 minutes
Number of replicates:
2 each group
Irritation / corrosion parameter:
% tissue viability
Value:
84
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
no indication of irritation
Remarks:
The exposure period is 3 mins.
Irritation / corrosion parameter:
% tissue viability
Value:
89
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
no indication of irritation
Remarks:
The exposure period is 60 mins.
Other effects / acceptance of results:
Skin corrosion is expressed as the remaining cell viability after exposure to the test item. The relative mean tissue viability obtained after the 3-minute and 1-hour treatments with test substance compared to the negative control tissues was 84% and 89% respectively. Because the mean relative tissue viability for test substance was not below 50% after 3 minutes treatment and not below 15% after 1 hour treatment test substance is considered to be not corrosive.The absolute mean OD570 (optical density at 570 nm) of the negative control tissues was within the laboratory historical control data range. The mean relative tissue viability following 3-minute exposure to the positive control was 5%.The maximum inter-tissue variability in viability between two tissues treated identically was less than 18% and the maximum difference in percentage between the mean viability of two tissues and one of the two tissues was less than 10% for the negative control and test item. For the positive control, the maximum inter-tissue variability in viability between two tissues treated identically was less than 35% and the maximum difference in percentage between the mean viability of two tissues and one of the two tissues was less than 21%, however since the viabilities were below 20% the acceptability criteria were met. It was therefore concluded that the test system functioned properly.Test substance was checked for colour interference in aqueous conditions and possible direct MTT reduction by adding the test item to MTT medium. Because the solutions did not turn blue / purple nor a blue / purple precipitate was observed it was concluded that test substance did not interfere with the MTT endpoint.
Interpretation of results:
GHS criteria not met
Conclusions:
Finally, it is concluded that this test is valid and that test substance is not corrosive in the in vitro skin corrosion test under the experimental conditions described in this report.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Referenceopen allclose all

Endpoint:
eye irritation: in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 18 to 19 Jan 2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 437 (Bovine Corneal Opacity and Permeability Test Method for Identifying Ocular Corrosives and Severe Irritants)
Deviations:
no
GLP compliance:
yes
Specific details on test material used for the study:
Batch No.: E010016692Purity: 99.3%
Species:
other: cattle
Strain:
not specified
Details on test animals or tissues and environmental conditions:
TEST ANIMALS- Source: Bovine eyes from young cattle were obtained from the slaughterhouse (Vitelco, -'s Hertogenbosch, The Netherlands), where the eyes were excised by a slaughterhouse employee as soon as possible after slaughter.-Transport: Eyes were collected and transported in physiological saline in a suitable container under cooled conditions.
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent positive control
yes, concurrent negative control
Amount / concentration applied:
TEST MATERIAL- Amount(s) applied (volume or weight with unit): 315.6 to 365.5 mg
Duration of treatment / exposure:
240±10 minutes
Duration of post- treatment incubation (in vitro):
1 hour
Number of animals or in vitro replicates:
Three eyes each group
Details on study design:
SELECTION AND PREPARATION OF CORNEASThe eyes were checked for unacceptable defects, such as opacity, scratches, pigmentation and neovascularization by removing them from the physiological saline and holding them in the light. Those exhibiting defects were discarded.The isolated corneas were stored in a petri dish with cMEM (Eagle’s Minimum Essential Medium (Life Technologies, Bleiswijk, The Netherlands) containing 1% (v/v) L-glutamine (Life Technologies) and 1% (v/v) Foetal Bovine Serum (Life Technologies)). The isolated corneas were mounted in a corneal holder (one cornea per holder) of BASF (Ludwigshafen, Germany) with the endothelial side against the O-ring of the posterior half of the holder. The anterior half of the holder was positioned on top of the cornea and tightened with screws. The compartments of the corneal holder were filled with cMEM of 32 ± 1°C. The corneas were incubated for the minimum of 1 hour at 32 ± 1°C.QUALITY CHECK OF THE ISOLATED CORNEASAfter the incubation period, the medium was removed from both compartments and replaced with fresh cMEM. Opacity determinations were performed on each of the corneas using an opacitometer (BASF-OP3.0, BASF, Ludwigshafen, Germany). The opacity of each cornea was read against a cMEM filled chamber, and the initial opacity reading thus determined was recorded. Corneas that had an initial opacity reading higher than 7 were not used. NUMBER OF REPLICATESThree corneas were selected at random for each treatment group.NEGATIVE CONTROL USEDphysiological salineSOLVENT CONTROL USED (if applicable)POSITIVE CONTROL USED20% (w/v) ImidazoleAPPLICATION DOSE AND EXPOSURE TIMEThe medium from the anterior compartment was removed and 750 μl of the negative control and 20% (w/v) Imidazole solution (positive control) were introduced onto the epithelium of the cornea. Test substance was weighed in a bottle and applied directly on the corneas in such a way that the cornea was completely covered (315.6 to 365.5 mg).The holder was slightly rotated, with the corneas maintained in a horizontal position, to ensure uniform distribution of the solutions over the entire cornea. Corneas were incubated in a horizontal position for 240 ± 10 minutes at 32 ± 1°C.TREATMENT METHOD: [closed chamber / open chamber]POST-INCUBATION PERIOD: no.REMOVAL OF TEST SUBSTANCE- Number of washing steps after exposure period: After the incubation the solutions and the test compound were removed and the epithelium was washed at least three times with MEM with phenol red.- POST-EXPOSURE INCUBATION:METHODS FOR MEASURED ENDPOINTS: - Corneal opacity: The opacity of a cornea was measured by the diminution of light passing through the cornea.- Corneal permeability: passage of sodium fluorescein dye measured with the aid of microtiter plate reader (OD490)- Others: Possible pH effects of the test item on the corneas were recorded. Each cornea was inspected visually for dissimilar opacity patterns.SCORING SYSTEM: In Vitro Irritancy Score (IVIS)DECISION CRITERIA: please specify if the decision criteria as indicated in the TG was used.
Irritation parameter:
in vitro irritation score
Value:
-0.2 - 1.3
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
no indication of irritation
Other effects / acceptance of results:
The individual in vitro irritancy scores for the negative controls ranged from -0.1 to 0.9. The individual positive control in vitro irritancy scores ranged from 101 to 154. The corneas treated with the positive control were turbid after the 240 minutes of treatment.The corneas treated with the test substance showed opacity values ranging from -0.3 to 1.2 and permeability values ranging from 0.003 to 0.022. The corneas were clear after the 240 minutes of treatment with test substance. No pH effect of the test item was observed on the rinsing medium. Hence, the in vitro irritancy scores ranged from -0.2 to 1.3 after 240 minutes of treatment with test substance.
Interpretation of results:
GHS criteria not met
Conclusions:
The test substance did not induce ocular irritation through both endpoints, resulting in a mean in vitro irritancy score of 0.8 after 240 minutes of treatment.Since test substance induced an IVIS ≤ 3, no classification is required for eye irritation or serious eye damage.
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
09 March 2016 - 14 March 2016
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:
Organization for Economic Co-operation and Development (OECD), OECD Guidelines for Testing of Chemicals, Section 4, Health Effects, No.405, "Acute Eye Irritation / Corrosion", Paris Cedex, 2012.
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2400 (Acute Eye Irritation)
Version / remarks:
United States Environmental Protection Agency (EPA). Health Effects Test Guidelines, OPPTS 870.2400, Acute Eye Irritation. Office of Prevention, Pesticides and Toxic Items (7101), EPA 712- C-98-195, August 1998.
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Version / remarks:
Commission Regulation (EC) No 440/2008 Part B: Methods for the Determination of Toxicity and other Health Effects; B5: "Acute Toxicity: Eye Irritation/Corrosion". Official Journal of the European Union No. L142, May 2008, including most recent amendments.
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: JMAFF 8147
Version / remarks:
Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nousan, Notification No 8147, November 2000; including the most recent partial revisions.
GLP compliance:
yes
Specific details on test material used for the study:
Purity 100% (HPLC %area)
Species:
rabbit
Strain:
New Zealand White
Remarks:
SPF-Quality
Details on test animals or tissues and environmental conditions:
Age and body weight: At start of dosing, the animals were between 12 and 24 weeks old and
body weights were at least 1.5 kg.

Identification: Earmark.

Health inspection At least prior to dosing. It was ensured that the animals were healthy and
that eyes were free from any abnormality.

Conditions
Environmental controls for the animal room were set to maintain 18 to 24°C, a relative humidity of 40 to 70%, at least 10 air changes/hour, and a 12-hour light/12-hour dark cycle. Any variations to these conditions were maintained in the raw data and had no effect on the outcome of the study.

Accommodation
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). Acclimatization period was at least 5 days before start of treatment under laboratory conditions.

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) wereavailable during the study period.

Water
Free access to tap water.

Diet, water, bedding and cage enrichment evaluation for contaminants and/or nutrients was performed according to facility standard procedures. There were no findings that could interfere with the study.
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
On average, 86.1 mg (range 85.6 - 86.4 mg) of the test item (avolume of approximately 0.1 mL).
Duration of treatment / exposure:
1 second
Observation period (in vivo):
72 hours
Number of animals or in vitro replicates:
3 females
Details on study design:
The eyes of each animal were examined approximately 1, 24, 48 and 72 hours after instillation of the test item. The irritation scores and a description of all other (local) effects were recorded.
The irritation was assessed according to the following numerical scoring system. At each observation, the highest scores given were recorded:

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

Area of cornea involved:
No ulceration or opacity 0
One quarter or less but not zero 1
Greater than one quarter, but less than half 2
Greater than half, but less than three quarters 3
Greater than three quarters, up to whole area 4

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

CONJUNCTIVAL IRRITATION
Redness (refers to palpebrae and sclera, excluding cornea and iris):
Blood vessels normal 0
Some blood vessels definitely hyperaemic (injected) 1
Diffuse, crimson color, individual vessels not easily discernible 2
Diffuse beefy red 3

Chemosis (refers to lids and/or nictitating membranes):
No swelling 0
Any swelling above normal (includes nictitating membranes) 1
Obvious swelling with partial eversion of lids 2
Swelling with lids about half closed 3
Swelling with lids more than half closed 4

Discharge:
No discharge (may include small amounts observed in inner canthus of normal animals) 0
Any amount different from normal and/or lacrimation 1
Discharge with moistening of the lids and hairs just adjacent to lids 2
Discharge with moistening of the lids and hairs (considerable area around the eye) 3

Where standard lighting was considered inadequate for observing minor effects, eye examinations were performed using an
ophthalmic examination lamp.
Irritation parameter:
conjunctivae score
Basis:
animal: 28
Time point:
24/48/72 h
Score:
0.3
Max. score:
1
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal: 31
Time point:
24/48/72 h
Score:
0.3
Max. score:
0.3
Reversibility:
fully reversible
Irritation parameter:
conjunctivae score
Basis:
animal: 32
Time point:
24/48/72 h
Score:
0.7
Max. score:
0.7
Reversibility:
fully reversible
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
fully reversible
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
fully reversible
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
fully reversible
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
fully reversible
Irritant / corrosive response data:
IRRITATION:
Instillation of approximately 86 mg of PF-06811569 (a volume of approximately 0.1 mL) into one eye of each of three rabbits resulted in irritation of the conjunctivae, which consisted of redness, chemosis and discharge. The irritation had completely resolved within 48 hours in two animals and within 72 hours in the other animal.
No iris irritation or corneal opacity were observed, and treatment of the eyes with 2% fluorescein 24 hours after test item instillation revealed no corneal epithelial damage.

CORROSION:
There was no evidence of ocular corrosion.

Table 1: Individual Eye Irritation Scores

Cornea Iris Conjunctivae

Animal Time after Opacity Area Fluor area Redness Chemosis Discharge Comments dosing (0-4) (0-4) (%)2 (0-2) (0-3) (0-4) (0-3)


281

1 hour

0

0


0


1

1


24 hours

0

0

0

0

1

0

0


48 hours

0

0


0

0

0

0


72 hours

0

0


0

0

0

0


31


1 hour


0


0



0



1


1


24 hours

0

0

0

0

1

0

0


48 hours

0

0


0

0

0

0


72 hours

0

0


0

0

0

0


32


1 hour


0


0



0



1



24 hours

0

0

0

0


0

1


48 hours

0

0


0

1

0

0


72 hours

0

0


0

0

0

0


1 Sentinel, 2 Green staining after fluorescein treatment (percentage of total corneal area)


Table 2: Mean Value Eye Irritation Scores



Animal Corneal

Mean 24, 48 and 72 hours


Iris Conjunctivae



opacity




Redness


Chemosis

28



0.0



0.0



0.3



0.0

31


0.0


0.0


0.3


0.0

32


0.0


0.0


0.7


0.0


Table 3: Animal Specifications


Animal

Sex


(weeks)


prior to application


at termination


28

Cjl

24

3929

3992


31

Cjl

20

3693

3710


32

Cjl

20

3864

3906


Age at start Body weights (grams)


Table 4: Draize Score Calculation


Animal Tissue Time after application



1 hr

24 hrs

48 hrs

72 hrs

28

Cornea

(x5)

0

0

0

0


Iris

(x5)

0

0

0

0


Conjunctivae

(x2)

6

2

0

0


Subtotal


6

2

0

0

31

Cornea

(x5)

0

0

0

0


Iris

(x5)

0

0

0

0


Conjunctivae

(x2)

6

2

0

0


Subtotal


6

2

0

0

32

Cornea

(x5)

0

0

0

0


Iris

(x5)

0

0

0

0


Conjunctivae

(x2)

6

4

2

0

Subtotal 6 4 2 0

Total

(max 110)

18

8

2

0

Mean total


6.0

2.7

0.7

0

Interpretation of results:
GHS criteria not met
Conclusions:
Based on these results, PF-06811569 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 (2015) (including all amendments) and EC criteria for classification and labelling requirements for dangerous items and preparations (Council Directive 67/548/EEC) (including all amendments).
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation/corrosion

Two studies are available:

1) An acute dermal irritation study was conducted according to OECD 404 using rabbits (Latour J.E.H.M., MSc., 2016). Key study.

This study showed that the test substance is not irritating.

2) An in vitro skin corrosion study was conducted according to OECD 431 using a human skin model (Eurlings I.M.J., PhD., 2016). Supporting study.

This study showed that the test substance is not corrosive.

Eye irritation:

Two studies are available:

One in vitro study is available which was conducted according to OECD Guideline 437 under GLP (Eurlings I.M.J., PhD., 2016). Key study.

This study showed that the test substance is not corrosive and not irritating to bovine eyes.

One in vivo study is available which was conducted according to OECD Guideline 405 under GLP (Paris Cedex, 2012)

Justification for classification or non-classification

Skin irritation/corrosion: Mean scores at 24, 48 and 72 hours for erythema were < 2.3 (actual value 0) and for edema were < 2.3 (actual value 0).

 

Serious eye damage/eye irritation: An in vitro study data is available with IVIS <3 (actual value 0.8).

An in vivo study is availible with fully reversible conjunctivae score < 1 over 72 hours (actual values of 0.3,0.3, and 0.7).

Therefore in accordance with Regulation (EC) No. 1272/2008 Table 3.2.2 and section 3.3.2, this substance should not be classified for skin irritation/corrosion and serious eye damage endpoint.