5,7-Di-t-butyl-3-[3,5-dimethyl-4-[(1,3,7,9-tetra-t-butyl-5-methyl-5H-benzo[d][1,3,2]benzodioxaphosphocin-11-yl)oxy]phenyl]-3H-benzofuran-2-one

Eye irritation

Administrative data

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2016-06-08 to 2016-09-20

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2016

Report date:

2016

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Version / remarks:

2012

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

2008

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2400 (Acute Eye Irritation)

Version / remarks:

1998

Deviations:

no

Test guideline 4

Qualifier:

according to guideline

Guideline:

other: Japan/MAFF 8147

Version / remarks:

2000

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

5,7-Di-t-butyl-3-[3,5-dimethyl-4-[(1,3,7,9-tetra-t-butyl-5-methyl-5H-benzo[d][1,3,2]benzodioxaphosphocin-11-yl)oxy]phenyl]-3H-benzofuran-2-one

EC Number:

817-187-7

Cas Number:

1803088-15-4

Molecular formula:

C54 H73 O5 P

IUPAC Name:

5,7-Di-t-butyl-3-[3,5-dimethyl-4-[(1,3,7,9-tetra-t-butyl-5-methyl-5H-benzo[d][1,3,2]benzodioxaphosphocin-11-yl)oxy]phenyl]-3H-benzofuran-2-one

Details on test material:

- State of aggregation: Solid / white
- Storage Condition: room temperature under light exclusion

Specific details on test material used for the study:

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature; under light exclusion ; no direct sunlight

Test animals / tissue source

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Envigo CRS (Switzerland) Limited
- Age at study initiation: approx. 3 months
- Weight at study initiation: 2.49 - 2.81 kg
- Housing: individual housing
- Diet: STANRAB (P) SQC; SDS Special Diets Services, 67122 Altrip, Germany, ad libitum
- Water: Tap water ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 20 +/- 3 °C
- Humidity: 30 - 70 %
- Air changes: approx. 10 per hr
- Photoperiod: 12 / 12 hrs dark / hrs light

Test system

Vehicle:

unchanged (no vehicle)

Controls:

yes

Amount / concentration applied:

TEST MATERIAL
- Amount applied: 0.1 mL (about 17 mg of the comminuted test item)

Duration of treatment / exposure:

24 h

Observation period (in vivo):

approx. 1, 24, 48, 72 and 96 h after application

Number of animals or in vitro replicates:

3

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing: rinsing with 3 to 6 mL of lukewarm tap water for 1 to 2 minutes using a syringe with a blunt probe
- Time after start of exposure: 24 h

SCORING SYSTEM: according to guidelines and, in addition, evaluations were made of discharge from the eye and the area of cornea affected by the lesions:
Area of cornea involved (ar) Grading:
1 > 0 ≤ ¼
2 > ¼ < ½
3 > ½ < ¾
4 > ¾

Discharge (di) Grading:
0 No discharge
1 Slight: any amount different from normal (does not include small amounts observed in inner canthus of normal animals)
2 Obvious: discharge with moistening of the lids and hairs just adjacent to lids
3 Severe: discharge with moistening of the lids and hairs, and considerable area around the eye


TOOL USED TO ASSESS SCORE: hand-slit lamp, otoscope lamp and fluorescein

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Results 2

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Results 3

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Results 4

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

2

Results 5

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

2

Results 6

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

2

Results 7

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0.3

Max. score:

3

Reversibility:

fully reversible within: 48 h

Results 8

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0.3

Max. score:

3

Reversibility:

fully reversible within: 48 h

Results 9

Irritation parameter:

conjunctivae score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.3

Max. score:

3

Reversibility:

fully reversible within: 48 h

Results 10

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Results 11

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Results 12

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritant / corrosive response data:

No corneal lesions were noted in any animal at any examination time point. Even after instillation of a fluorescein solution no corneal lesions were detectable after 24 and 48 hours. Moderate iritis (grade 1) was observed in one animal 1 hour after application only. Slight conjunctival redness (grade1) was noted in all animals from 1 hour until hour 24 after application. Slight conjunctival chemosis (grade 1) was noted in two animals 1 hour after application. Additional findings like injected scleral vessels in a circumscribed or circular area were noted within 48 hours after application. The ocular reactions were reversible in all animals within 48 hours after application.

Other effects:

- Lesions and clinical observations: none
- Ophthalmoscopic findings: none
- Histopathological findings: not performed
- Effects of rinsing or washing: none

Any other information on results incl. tables

Table 1. Irritant response, data for each individual animal at each observation time as well as calculation of the mean

		Cornea		Iris	Conjunctiva
Readings	Animal No.	Opacity	Area of cornea involved		Redness	Chemosis	Discharge
1 h	1	0	0	0	1	0	0
	2	0	0	1	1	1	0
	3	0	0	0	1	1	0
24 h	1	0	0	0	1	0	0
	2	0	0	0	1	0	0
	3	0	0	0	1	0	0
48 h	1	0	0	0	0	0	0
	2	0	0	0	0	0	0
	3	0	0	0	0	0	0
72 h	1	0	0	0	0	0	0
	2	0	0	0	0	0	0
	3	0	0	0	0	0	0
96 h	1	0	0	0	0	0	0
	2	0	0	0	0	0	0
	3	0	0	0	0	0	0
Mean 24 h- 72h	1	0.0	-	0.0	0.3	0.0	-
	2	0.0	-	0.0	0.3	0.0	-
	3	0.0	-	0.0	0.3	0.0	-
Mean	-	0.0	-	0.0	0.3	0.0	-

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

Considering the described ocular reactions as well as the average score for irritation, the test item does not show an eye irritating potential under the test conditions chosen.

Executive summary:

The potential of the test item to cause damage to the conjunctiva, iris or cornea was assessed by a single ocular application of 0.1 mL bulk volume (about 17 mg) of the undiluted test item to one eye of three New Zealand White rabbits (stepwise procedure starting with one animal and supplementing two additional animals). About, and not less than 24 hours after application the eye was rinsed with tap water. The ocular reactions were assessed approximately 1, 24, 48, 72 and 96 hours after application. Additional eye examinations were performed at 24 and 48 h after application with the instillation of a fluorescein solution. Due to absence of detectable lesions following fluorescein instillation, all subsequent readings were performed without the aid of fluorescein. No corneal lesions were noted in any animal at any examination time point. Even after instillation of a fluorescein solution no corneal lesions were detectable after 24 and 48 hours. The following test item-related clinical observations were recorded during the course of the study: Moderate iritis (grade 1), slight conjunctival redness (grade 1) and slight conjunctival chemosis (grade 1). Additional findings like injected scleral vessels in a circumscribed or circular area were noted in the animals within the first 48 hours. The ocular reactions were reversible in all animals within 48 hours after application. Mean scores calculated for each animal over 24, 48 and 72 hours were 0.0, 0.0 and 0.0 for corneal opacity and for iris lesions, 0.3, 0.3 and 0.3 for redness of the conjunctiva and 0.0, 0.0 and 0.0 for chemosis. Considering the described ocular reactions as well as the average score for irritation, the test article does not show an eye irritating potential under the test conditions chosen.