4'-Butyl-4-ethoxy-2,3-difluoro-1,1'-biphenyl

Eye irritation

Administrative data

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

Sep 30, 2019 - May 14, 2020

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

The study was conducted for a registration in a non-EU country.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2020

Report date:

2020

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Version / remarks:

2017

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

EC No 440/2008

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: JMAFF Guidelines

Version / remarks:

2000

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

4'-butyl-4-ethoxy-2,3-difluoro-1,1'-biphenyl

EC Number:

695-755-1

Cas Number:

1229661-51-1

Molecular formula:

C18H2F2O

IUPAC Name:

4'-butyl-4-ethoxy-2,3-difluoro-1,1'-biphenyl

Test material form:

solid: particulate/powder

Test animals / tissue source

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Charles River France, L’Arbresle, France
- Age at study initiation: approximately 15-24 weeks old
- Weight at study initiation: 3267 to 3874 g.
- Housing: individually
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20
- Humidity (%): 54 - 61
- Air changes (per hr): >10
- Photoperiod (hrs dark / hrs light): 12/12

Test system

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

Animals were treated by instillation of about 78 mg (range 0.0643 - 0.0783 mg) of the test item (a volume of approximately 0.1 mL),

Duration of treatment / exposure:

The lids were gently held together for about one second to prevent loss of the test item and the test item was washed out after completion of the 1 and 24 hour examination.

Observation period (in vivo):

1, 24, 48, 72 h

Number of animals or in vitro replicates:

3

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Yes
- Time after start of exposure: 24 hours

SCORING SYSTEM:

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.

TOOL USED TO ASSESS SCORE: fluorescein

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Results 2

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

no indication of irritation

Results 3

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Results 4

Irritation parameter:

conjunctivae score

Remarks:

Redness

Basis:

animal #1

Time point:

24/48/72 h

Score:

0.3

Max. score:

3

Reversibility:

fully reversible within: 48 h

Remarks on result:

no indication of irritation

Results 5

Irritation parameter:

conjunctivae score

Remarks:

Redness

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

3

Remarks on result:

no indication of irritation

Results 6

Irritation parameter:

conjunctivae score

Remarks:

Redness

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.3

Max. score:

3

Reversibility:

fully reversible within: 48 h

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

Instillation of the test item (a volume of approximately 0.1 mL) into one eye of each of three rabbits resulted in very slight irritation of the conjunctivae, which consisted of redness and chemosis in all animals and discharge in two out of three animals. The irritation had completely resolved within 24 hours in one animal and within 48 hours in the other two animals.
No iridial irritation or corneal opacity was observed, and treatment of the eyes with 2% fluorescein 24 hours after test item instillation revealed no corneal epithelial damage.

Other effects:

No staining of (peri) ocular tissues 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.

Any other information on results incl. tables

Individual Eye Irritation Scores

Animal	Timepoint after Dosing	Cornea			Iris	Conjunctivae			Comments
		Opacity (0-4)	Area (0-4)	Fluor Area / [%]^2	(0-2)	Redness (0-4)	Chemosis (0-4)	Discharge (0-4)
450^1	1 hour	0	0	n.a.	0	1	1	1	-
	24 hours	0	0	0	0	1	0	0	-
	48 hours	0	0	n.a.	0	0	0	0	-
	72 hours	0	0	n.a.	0	0	0	0	-
458	1 hour	0	0	n.a.	0	1	1	0	-
	24 hours	0	0	0	0	0	0	0	-
	48 hours	0	0	n.a.	0	0	0	0	-
	72 hours	0	0	n.a.	0	0	0	0	-
459	1 hour	0	0	n.a.	0	1	1	1	-
	24 hours	0	0	0	0	1	0	0	-
	48 hours	0	0	n.a.	0	0	0	0	-
	72 hours	0	0	n.a.	0	0	0	0	-

1 Sentinel
²Green staining after fluorescein treatment (% of total corneal area) indicating corneal epithelial damage
n.a. not applicable
-  No comments

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

Based on these results, the test material 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 (2017) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments).

Executive summary:

The objective of this acute eye irritation study was to assess the possible irritation or corrosion potential when a single dose of the test material was placed in the conjunctival sac of the rabbit eye.

Single samples of approximately 0.05 mg of the test material (a volume of approximately 0.1 mL) were instilled into one eye of each of three rabbits. Observations were made 1, 24, 48 and 72 hours after instillation. Instillation of the test item resulted in irritation of the conjunctivae, which consisted of redness and discharge in all animals and chemosis in one animal only. The irritation had completely resolved within 24 hours in one animal and within 48 hours in the other two animals. No iridial irritation or corneal opacity was observed and treatment of the eyes with 2% fluorescein 24 hours after test item instillation revealed no corneal epithelial damage.

Remnants of the test item were present in the eye at one hour after instillation in all animals. Based on these results, the test material 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 (2017) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments).