Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Justification for type of information:
QSAR prediction: migrated from IUCLID 5.6
Reference:
Composition 0
Qualifier:
according to
Guideline:
other: Given below
Principles of method if other than guideline:
Prediction is done using QSAR Toolbox version 3.3 .
GLP compliance:
not specified
Test material information:
Composition 1
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:

TEST ANIMALS
- Source: Charles River Wiga, D-97633
- Weight at study initiation: Animal No. 1: 2.4 kg, Animal No. 2: 2.2 kg, Animal No. 3: 2.3 kg
- Weith at study termination: Animal No. 1: 2.5 kg, Animal No. 2: 2.3 kg, Animal No. 3: 2.4 kg
- Housing: Optimal hygienic conditions, individual caging in metal wire cages, Ehret GmbH, D-79312 Emmendingen, type KK 016R, 79 cm x 59 cm x 38 cm, with a wooden rest shelf, 15 x 59 cm.
- Diet: Altromin 2023 diet for rabbtis, ad libitum and hay-briquettes (supplied by SSNIFF, D-59494 Soest) were offered additionally as a dietary supplement.
- Water: tap water from an automatical watering system, ad libitum.
- Acclimation period: 5 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): average of 22 °C
- Humidity (%): average of 61 %.
- Air changes (per hr): 12 per hour.
- Photoperiod (hrs dark / hrs light): 12 hrs dark, 12 hrs light.
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
water
Controls:
not required
Amount / concentration applied:
Samples with approximately 0.5 g of the test substance (the weighed amounts of the individual doses were 497, 500 and 500 mg), were moistened
with 1.0 mL deionised water and were placed on cellulose patches) in a size of about 2.5 cm x 2.5 cm and were applied to the test sites.
Duration of treatment / exposure:
4 hours
Observation period:
No data available
Number of animals:
3 females
Irritation parameter:
overall irritation score
Basis:
mean
Remarks on result:
other: not irritating





Estimation method: Takes mode value from the 7 nearest neighbours
Domain  logical expression:Result: In Domain

(((((((((((((("a" and ("b" and ( not "c") )  )  and ("d" and ( not "e") )  )  and ("f" and ( not "g") )  )  and ("h" and ( not "i") )  )  and ("j" and ( not "k") )  )  and ("l" and ( not "m") )  )  and "n" )  and "o" )  and "p" )  and ("q" and ( not "r") )  )  and "s" )  and ("t" and ( not "u") )  )  and ("v" and ( not "w") )  )  and ("x" and "y" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Acylation AND Acylation >> Direct Acylation Involving a Leaving group AND Acylation >> Direct Acylation Involving a Leaving group >> Acetates by Protein binding by OECD

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.3

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Carbamoylation after isocyanate formation OR AN2 >> Carbamoylation after isocyanate formation >> N-Hydroxylamines OR AN2 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds OR AN2 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds >> Four- and Five-Membered Lactones OR AN2 >> Schiff base formation OR AN2 >> Schiff base formation >> Dicarbonyl compounds OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation >> Geminal Polyhaloalkane Derivatives OR AN2 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters OR AN2 >> Shiff base formation for aldehydes OR AN2 >> Shiff base formation for aldehydes >> Geminal Polyhaloalkane Derivatives OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> Coumarins OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide Side Chain OR Non-specific OR Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    OR Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    >> Specific Imine and Thione Derivatives OR Radical OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Coumarins OR Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> N-Hydroxylamines OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitro Azoarenes OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroarenes with Other Active Groups OR Radical >> Radical mechanism via ROS formation (indirect) >> p-Substituted Mononitrobenzenes OR Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines OR Radical >> Radical mechanism via ROS formation (indirect) >> Specific Imine and Thione Derivatives OR SN1 OR SN1 >> Alkylation after metabolically formed carbenium ion species OR SN1 >> Alkylation after metabolically formed carbenium ion species >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN1 >> Nucleophilic attack after carbenium ion formation OR SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters OR SN1 >> Nucleophilic attack after diazonium or carbenium ion formation OR SN1 >> Nucleophilic attack after diazonium or carbenium ion formation >> Nitroarenes with Other Active Groups OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> N-Hydroxylamines OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Single-Ring Substituted Primary Aromatic Amines OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitro Azoarenes OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitroarenes with Other Active Groups OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> p-Substituted Mononitrobenzenes OR SN1 >> Nucleophilic substitution on diazonium ions OR SN1 >> Nucleophilic substitution on diazonium ions >> Specific Imine and Thione Derivatives OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters OR SN2 >> Acylation involving a leaving group  OR SN2 >> Acylation involving a leaving group  >> Geminal Polyhaloalkane Derivatives OR SN2 >> Acylation involving a leaving group after metabolic activation OR SN2 >> Acylation involving a leaving group after metabolic activation >> Geminal Polyhaloalkane Derivatives OR SN2 >> Alkylation, direct acting epoxides and related OR SN2 >> Alkylation, direct acting epoxides and related >> Epoxides and Aziridines OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom >> Sulfonates and Sulfates OR SN2 >> Alkylation, ring opening SN2 reaction OR SN2 >> Alkylation, ring opening SN2 reaction >> Four- and Five-Membered Lactones OR SN2 >> Direct acting epoxides formed after metabolic activation OR SN2 >> Direct acting epoxides formed after metabolic activation >> Coumarins OR SN2 >> Direct acting epoxides formed after metabolic activation >> Quinoline Derivatives OR SN2 >> Direct acylation involving a leaving group OR SN2 >> Direct acylation involving a leaving group >> Acyl Halides OR SN2 >> DNA alkylation OR SN2 >> DNA alkylation >> Vicinal Dihaloalkanes OR SN2 >> Internal SN2 reaction with aziridinium and/or cyclic sulfonium ion formation (enzymatic) OR SN2 >> Internal SN2 reaction with aziridinium and/or cyclic sulfonium ion formation (enzymatic) >> Vicinal Dihaloalkanes OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation >> Geminal Polyhaloalkane Derivatives OR SN2 >> SN2 at an activated carbon atom OR SN2 >> SN2 at an activated carbon atom >> Quinoline Derivatives OR SN2 >> SN2 attack on activated carbon Csp3 or Csp2 OR SN2 >> SN2 attack on activated carbon Csp3 or Csp2 >> Nitroarenes with Other Active Groups by DNA binding by OASIS v.1.3

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OECD

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> P450 Mediated Activation to Isocyanates or Isothiocyanates OR Acylation >> P450 Mediated Activation to Isocyanates or Isothiocyanates >> Formamides OR Michael addition OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Alkyl phenols OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Arenes OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Hydroquinones OR Michael addition >> Polarised Alkenes-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated amides OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated esters OR SN1 OR SN1 >> Carbenium Ion Formation OR SN1 >> Carbenium Ion Formation >> Allyl benzenes OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Aromatic azo OR SN1 >> Nitrenium Ion formation >> Aromatic nitro OR SN1 >> Nitrenium Ion formation >> Aromatic phenylureas OR SN1 >> Nitrenium Ion formation >> Primary (unsaturated) heterocyclic amine OR SN1 >> Nitrenium Ion formation >> Primary aromatic amine OR SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine OR SN1 >> Nitrenium Ion formation >> Unsaturated heterocyclic azo by DNA binding by OECD

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Not possible to classify according to these rules by DPRA Cysteine peptide depletion

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as High reactive OR High reactive >> Activated haloarenes OR High reactive >> Unsaturated acid anhydrides OR Low reactive OR Low reactive >> N-substituted aromatic amides OR Low reactive >> Saturated acid anhydrides OR Moderate reactive OR Moderate reactive >> Five-membered heterocyclic urea by DPRA Cysteine peptide depletion

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Non binder, non cyclic structure OR Strong binder, OH group OR Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Acylation AND Acylation >> Direct Acylation Involving a Leaving group AND Acylation >> Direct Acylation Involving a Leaving group >> Acetates by Protein binding by OECD

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Acylation >> Direct Acylation Involving a Leaving group >> Anhydrides OR Acylation >> Direct Acylation Involving a Leaving group >> Azlactone OR Michael addition OR Michael addition >> Acid imides OR Michael addition >> Acid imides >> Acid imides-MA OR Michael addition >> Polarised Alkenes OR Michael addition >> Polarised Alkenes >> Polarised alkene - amides OR Michael addition >> Polarised Alkenes >> Polarised alkene - ketones OR Michael addition >> Quinones and Quinone-type Chemicals OR Michael addition >> Quinones and Quinone-type Chemicals >> Quinone-imine OR SN2 OR SN2 >> SN2 reaction at sp3 carbon atom OR SN2 >> SN2 reaction at sp3 carbon atom >> Alkyl diazo OR SN2 >> SN2 reaction at sp3 carbon atom >> alpha-Halocarbonyls OR SNAr OR SNAr >> Nucleophilic aromatic substitution OR SNAr >> Nucleophilic aromatic substitution >> Activated halo-benzenes by Protein binding by OECD

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Not possible to classify according to these rules (GSH) by Protein binding potency

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Moderately reactive (GSH) OR Moderately reactive (GSH) >> 2-Chloroacetamides (SN2) OR Moderately reactive (GSH) >> 2-Vinyl carboxamides (MA) by Protein binding potency

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as No superfragment by Superfragments ONLY

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as High (Class III) by Toxic hazard classification by Cramer (original) ONLY

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Class 5 (Not possible to classify according to these rules) by Acute aquatic toxicity classification by Verhaar (Modified) ONLY

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as No alert found by Protein binding alerts for skin sensitization by OASIS v1.3

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct acylation involving a leaving group OR Acylation >> Direct acylation involving a leaving group >> Azlactones and unsaturated lactone derivatives  by Protein binding alerts for skin sensitization by OASIS v1.3

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Alkali Earth AND Non-Metals by Groups of elements

Domain logical expression index: "u"

Referential boundary: The target chemical should be classified as Halogens by Groups of elements

Domain logical expression index: "v"

Referential boundary: The target chemical should be classified as Not categorized by Repeated dose (HESS)

Domain logical expression index: "w"

Referential boundary: The target chemical should be classified as Perhexiline (Hepatotoxicity) Alert OR Thiocarbamates/Sulfides (Hepatotoxicity) No rank by Repeated dose (HESS)

Domain logical expression index: "x"

Parametric boundary:The target chemical should have a value of log Kow which is >= -1.25

Domain logical expression index: "y"

Parametric boundary:The target chemical should have a value of log Kow which is <= 0.302

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The substance disodium 2-(3-oxo-6-oxidoxanthen-9-yl)benzoate is estimated to be not irritating to skin of New Zealand White rabbits.
Executive summary:
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The skin irritation potential for 2-(3-oxo-6-oxidoxanthen-9-yl) benzoate is estimated using OECD QSAR toolbox version 3.3 .The test substance is estimated to be not irritating to skin of New Zealand White rabbits.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Reference:
Composition 0
Qualifier:
according to
Guideline:
other: As mentioned below
Principles of method if other than guideline:
Skin irritation test was conducted for chemical Sodium Fluorescein in human.
GLP compliance:
not specified
Test material information:
Composition 1
Species:
human
Strain:
other: Not applicable
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
Source: Oxford Eye Hospital
Age at study initiation:51 years
Weight at study initiation: Not mentioned
Fasting period before study: Not mentioned
Housing: Not mentioned
Diet (e.g. ad libitum): Not mentioned
Water (e.g. ad libitum): Not mentioned
Acclimation period: Not mentioned
Vehicle:
not specified
Controls:
not specified
Amount / concentration applied:
fluorescein 2% eye drops (Bausch and Lomb Minims®)
Duration of treatment / exposure:
30 seconds
Observation period (in vivo):
48 hour
Number of animals or in vitro replicates:
1 female
Details on study design:
A case of a 51-year-old woman who developed an anaphylactic reaction when she was administered fluorescein sodium 2% eye drops after cataract surgery is reported. This was the second time she had been exposed to fluorescein. She had brittle asthma and a history of anaphylaxis following exposure to a variety of drug and food allergens. She was successfully resuscitated and recovered completely over a period of two days
Irritation parameter:
overall irritation score
Basis:
other: one person
Time point:
other: 30 seconds
Remarks on result:
other: Non irritating
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
A case of a 51-year-old woman who developed an anaphylactic reaction when she was administered fluorescein sodium 2% eye drops after cataract surgery is reported. This was the second time she had been exposed to fluorescein. She had brittle asthma and a history of anaphylaxis following exposure to a variety of drug and food allergens. She was successfully resuscitated and recovered completely over a period of two days.
This is a rare case of anaphylaxis caused after topical application of fluorescein in the eye.
Executive summary:

Almost all patients with ocular problems are exposed to fluorescein in topical form, during routine ocular examination. A case of a 51-year-old woman who developed an anaphylactic reaction when she was administered fluorescein sodium 2% eye drops after cataract surgery is reported.

 

A 51-year-old English woman attended the Oxford Eye Hospital for a postoperative check-up two weeks after uneventful phacoemulsification cataract surgery that was performed under topical anaesthesia. As part of the ophthalmic examination, fluorescein 2% eye drops (Bausch and Lomb Minims®) were administered topically into her operated eye in order to check the corneal wound integrity and measure the intraocular pressure. No other eye drops were instilled into her eye during her outpatient visit. Within 30 seconds of topical fluorescein administration, she developed acute dyspnoea, wheezing and tachycardia. Well-versed with the symptoms of the onset of anaphylaxis, she administered 0.6 mg intramuscular adrenaline from her auto-injector (EpiPen®). Venous access was obtained and the patient was given intravenous chlorpheniramine and oral prednisolone. Despite a good initial response, she deteriorated acutely within 30 minutes, with tongue swelling, airway obstruction, and subsequent loss of consciousness. Following appropriate resuscitation, she was transferred for further observation to the intensive care unit. She was discharged from our hospital after 48 hours.

 

This case illustrates how the administration of a seemingly benign fluorescein 2% eye drop can have serious consequences in a susceptible patient. The absence of an anaphylactic reaction when topical fluorescein is used for the first time does not preclude a life-threatening reaction from its subsequent administration in the same patient.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation

The skin irritation potential for 2-(3-oxo-6-oxidoxanthen-9-yl) benzoate is estimated using OECD QSAR toolbox version 3.3 .The test substance is estimated to be not irritating to skin of New Zealand White rabbits.

In other study by (P.L. Smart, 1984) with 2-(3-oxo-6-oxidoxanthen-9-yl) benzoate was assessed in mammals. The test chemical Sodium Fluorescein was found to be non – irritating to skin.

In other study by (E. Di Leo, 2008) with 2-(3-oxo-6-oxidoxanthen-9-yl) benzoate was assessed in human.A case of fixed drug eruption due to sodium fluorescein diagnosed by a positive patch test was reported. A patch test using Large Finn Chambers on Scanpor tape with 2-day occlusion on the involved site of the previous lesion using sodium fluorescein (Fluoralfa_ 20%; Alfa Intes) undiluted and at 1:10 dilution in preservative- free sterile water was performed. Readings were made on D2, D3, and D4; reactions were first seen on D3 and consisted of violaceous bullous lesions (+++) according to International Contact Dermatitis Research Group criteria. The same tests performed in 10 controls were negative. It was found to be irritating according to the International Contact Dermatitis Research Group criteria.

On the basis of available information for the target and applying weight of evidence approach, the test substance can be considered as not irritating to the skin.

Eye irritation

Eye irritation test was observed by (Humma Shahid, John F Salmon, 2010) with 2-(3-oxo-6-oxidoxanthen-9-yl) benzoate was assessed in human. A 51-year-old English woman attended the Oxford Eye Hospital for a postoperative check-up two weeks after uneventful phacoemulsification cataract surgery that was performed under topical anaesthesia. As part of the ophthalmic examination, fluorescein 2% eye drops (Bausch and Lomb Minims®) were administered topically into her operated eye in order to check the corneal wound integrity and measure the intraocular pressure. No other eye drops were instilled into her eye during her outpatient visit. Within 30 seconds of topical fluorescein administration, she developed acute dyspnoea, wheezing and tachycardia. Well-versed with the symptoms of the onset of anaphylaxis, she administered 0.6 mg intramuscular adrenaline from her auto-injector (EpiPen®). Venous access was obtained and the patient was given intravenous chlorpheniramine and oral prednisolone. Despite a good initial response, she deteriorated acutely within 30 minutes, with tongue swelling, airway obstruction, and subsequent loss of consciousness. Following appropriate resuscitation, she was transferred for further observation to the intensive care unit. She was discharged from our hospital after 48 hours. This case illustrates how the administration of a seemingly benign fluorescein 2% eye drop can have serious consequences in a susceptible patient. The absence of an anaphylactic reaction when topical fluorescein is used for the first time does not preclude a life-threatening reaction from its subsequent administration in the same patient.

 

In other supporting study by (KAIMBO WA KAIMBO D, 2011) with 2-(3-oxo-6-oxidoxanthen-9-yl) benzoate was assessed in human. A 34-year-old Lebanese man presented at our private eye clinic in May 2009 with pain, photophobia, tearing, and decreased vision in the left eye that had appeared a few hours after accidentally being hit with a fingernail by his child in the eye. There was no previous history of ocular trauma, surgery, or ophthalmic disorders, and the visual acuity had always been excellent in both eyes. His visual acuity was 20/20 in the right eye and 20/50 in the left eye. Slit lamp examination of the left eye revealed mild lid swelling and hyperemia of conjunctival vessels. The cornea in the left eye showed corneal defect (epithelial lesions) involving the inferior half with folds in the Descemet membrane and mild edema in the corneal stroma; the anterior chamber was quiet. Examination of the right eye was unremarkable. Two drops of fluorescein (Minims Natriumfluorescein 2%) were administered to stain the corneal defect in the left eye. About 3 minutes after having received two drops of fluorescein, the patient became diaphoretic and pale, developed nausea, sweating, shivering, weakness, dizziness, syncope, apnea and anaphylactic shock. After immediate reanimation (with corticoids,adrenalineand artificial reanimation), the symptoms resolved and the patient regained consciousness. Fortunately, he recovered without any neurologic sequelae. When the patient was specifically questioned, he reported a history of urticaria to the right side of his neck and nose that had developed three months previously. He mentioned no previous sodium fluorescein angiography and no radioconstract media injection. No additional problems occurred after the patient left the eye clinic. Examination on the next day revealed a small inferior corneal abrasion. Topical medications were continued.4 days later, the corneal epithelium had healed. This is a rarecase of anaphylaxis caused after topical application of Fluorescein in the eye.

In other supporting study by (THOMAS E.et al 1993) with 2-(3-oxo-6-oxidoxanthen-9-yl) benzoate was assessed in rabbit.Optimum Fluorescein staining test was conducted to evaluate the staining effects of chemical sodium Fluorescein when exposed to eye of the rabbit. The rabbits were randomly divided into 4 groups of 3 males and 3 females each. The eyes of the rabbits in group 1 were exposed to Fluorescein for I 5 set, in group 2 for 30 set, in group 3 for 1 mitt, and in group 4 for 4 min. Each exposure consisted of instilling 0. 10 ml of 23; 1 Fluorescein sodium’ into the lower conjunctival sac of each eye. After the specified exposure time, the eyes were flushed gently with 20 ml of sterile isotonic saline to remove excess Fluorescein. Intensity of the staining was classified into 4 major categories:

No staining- grade 0;

Slight staining (visible only with cobalt filter and magnification),-grade 1

Moderate staining (visible with normal light and magnification)- grade 2;

Heavy staining (visible without magnification), grade 3.

The eyes were exposed and examined daily, Monday through Friday, for 2 weeks.

None of the normal corneas exposed for 15 set had a staining intensity score greater than grade 1. Staining intensities of grades 2 or 3 occurred 6 times in the group of normal corneas exposed for 30 set, 26 times in those exposed for 1 min. and 32 times in corneas exposed for 4 min. Immediately after injury, the staining of the corneas in all groups was intense. All corneas had healed completely within 48 hr. Except for the epithelial defects, corneas exposed to Fluorescein for 15 set did not stain, but the typical staining of normal corneas was seen in the other exposure groups.  Mildly irritating effects were known in eye staining test of chemical Sodium Fluorescein when exposed to eye of male and female rabbits rabbit exposed for 15 sec, 30 sec, 1 min and 4 min in 4 groups.

In other supporting study by (Hisae Aoshima et al, 2009) with 2-(3-oxo-6-oxidoxanthen-9-yl) benzoate was assessed in rabbit.Eye irritation test was conducted according to all standards Guiding Principles for the Care and Use Of Laboratory Animals of the Japanese Pharmacological Society and the animal care guidelines used in laboratories, as approved by the Tokyo Women's Medical University Ethics Committee on Animal Care and Use. Sodium Fluorescein was instilled in the treated eye and rinsed out with isotonic sodium chloride solution, The cornea was then fully examined for any lesion under UV light (UVL-5 6F;unakoshi Co., Ltd., Tokyo, Japan) 24 hr after instillation. Opacity of the cornea; the area of opacity; defects of the iris and redness, chemosis, and discharge of, the conjunctivae were scored at 1, 24, 48, and 72 hr, and 4 days post treatment. Individual scores of the ocular reactions were determined, coniunctivae redness (score 1) and discharge (score=2) were observed in all animals of the eye-unwashed group (n = 3) at 1 hr after application, but disappeared by 48 hr after application. Cornea epithelial defects were observed in all animals at 24 hr after application, but also disappeared by 48 hr alter application. in the eye-washed group (n = 3), no ocular reactions were observed in any animal.  Mildly irritating effects were known in eye irritation test of chemical Sodium Fluorescein when exposed to eye of rabbit for 24-hrs.

The eye irritation potential for 2-(3-oxo-6-oxidoxanthen-9-yl) benzoate is estimated using OECD QSAR toolbox version 3.3 .The test substance is estimated to be not irritating to eye of New Zealand White rabbits.

On the basis of available information from the majority of target studies, the test substance can be considered as not irritating to the eye.


Justification for selection of skin irritation / corrosion endpoint:
The skin irritation potential for 2-(3-oxo-6-oxidoxanthen-9-yl) benzoate is estimated using OECD QSAR toolbox version 3.3 .The test substance is estimated to be not irritating to skin of New Zealand White rabbits.

Justification for selection of eye irritation endpoint:
A case of a 51-year-old woman who developed an anaphylactic reaction when she was administered fluorescein sodium 2% eye drops after cataract surgery is reported. This was the second time she had been exposed to fluorescein. She had brittle asthma and a history of anaphylaxis following exposure to a variety of drug and food allergens. She was successfully resuscitated and recovered completely over a period of two days.
This is a rare case of anaphylaxis caused after topical application of fluorescein in the eye. No irritation was observed .

Justification for classification or non-classification

The test substance sodium Fluoresceinis considered to be not irritating to both skin and eye.