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Description of key information

No in vitro assessments for skin or eye irritation available.  The in vivo data are limited but give no indication of irritation potential to either skin or eyes.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
7 December 1993 - 14th December 1993
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted according the EU Method B.4. Acute toxicity dermal irritation/corrosion with no deviations and is GLP compliant.
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study
Qualifier:
according to guideline
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
no
Principles of method if other than guideline:
Not relevant
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Froxfield (U .K.) Ltd., Petersfield, Hampshire, England.
- Age at study initiation: 12 to 13 weeks
- Weight at study initiation: 2.7 to 3.1 kg
- Housing: individually in metal cages with perforated floors
- Diet (e.g. ad libitum): A standard laboratory diet SDS Stanrab (P) Rabbit Diet ad libitum
- Water (e.g. ad libitum):ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19°C
- Humidity (%): 30 -70%.
- Air changes (per hr): 19 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours of artificial light in each 24 hours period

IN-LIFE DATES: From: 7 December, 1993 To: 14 December, 1993
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 m1

Duration of treatment / exposure:
4 hours
Observation period:
8 days
Number of animals:
3 animals
Details on study design:
TEST SITE
- Area of exposure: 25 mm x 25 mm
- % coverage: 100%
- Type of wrap if used: gauze pad covered with "Elastoplast" elastic adhesive dressing

REMOVAL OF TEST SUBSTANCE
- Washing (if done): washed with warm water (30° to 40°C) to remove any residual test substance. The treated area was blotted dry with absorbent paper.
- Time after start of exposure: 4 hours

SCORING SYSTEM:
Local dermal irritation was assessed using the standard Draize numerical system:
Erythema and eschar formation:
No erythema 0
Very slight erythema (barely perceptible) 1
Well-defined erythema 2
Moderate to severe erythema 3
Severe erythema (beet redness) to slight eschar formation (injuries in depth) preventing erythema reading 4
Oedema formation:
No oedema 0
Very slight oedema (barely perceptible) 1
Slight oedema (edges of area well-defined by definite raising) 2
Moderate oedema (raised approximately 1 millimetre) 3
Severe oedema (raised more than 1 millimetre and extending beyond the area of exposure) 4
Irritation parameter:
erythema score
Basis:
mean
Time point:
24/48/72 h
Score:
0.89
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
edema score
Basis:
mean
Time point:
24/48/72 h
Score:
0.33
Max. score:
1
Reversibility:
fully reversible
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 72 h
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: reversibility not applicable
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: reversibility not applicable
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: reversibility not applicable
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritant / corrosive response data:
The numerical values given to the dermal reactions elicited by Benzyl acetate are shown in the table below.
Very slight to well-defined with or without very slight oedema developed in two animals. These reactions had resolved by Day 4 or 8.
No dermal reactions were seen in the third animal.
Other effects:
There were no signs of toxicity or ill health in any rabbit during the observation period.

No additional information

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
A single semi-occlusive application of Benzyl acetate to intact rabbit skin for four hours elicited very slight to well-defined dermal reactions. According to Directive 67/548/EEC, no classification is warranted. According to Regulation (EC) No. 1272/2008, no classification is warranted.
The results for benzyl acetate are considered appropriate for use as read-across to hexyl acetate and confirm the potential for slight dermal irritation following skin exposure to these structurally similar materials.
Executive summary:

A study was performed to assess the skin irritation potential of Benzyl acetate to the rabbit. Three rabbits were each administered a single dermal dose of 0.5 ml of the test substance and observed for a maximum of eight days. A single semi-occlusive application of Benzyl acetate to intact rabbit skin for four hours elicited very slight to well-defined dermal reactions. All reactions had resolved by Day 4 or 8. According to Directive 67/548/EEC, no classification is warranted. According to Regulation (EC) No. 1272/2008, no classification is warranted.

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:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
20 December 1993 - 11 January 1994
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Conducted according to GLP and guideline.
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study
Qualifier:
according to guideline
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
no
Principles of method if other than guideline:
Not relevant
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Froxfield (U .K.) Ltd., Petersfield, Hampshire, England.
- Age at study initiation: 11 to 15 weeks
- Weight at study initiation: 2.6 to 3.4 kg
- Housing: individually in plastic cages with perforated floors
- Diet (e.g. ad libitum): A standard laboratory diet SDS Stanrab (P) Rabbit Diet ad libitum
- Water (e.g. ad libitum): ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19°C
- Humidity (%): 30 -70%.
- Air changes (per hr): 19 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours of artificial light in each 24 hours period.

IN-LIFE DATES: From: 20 December 1993 To: 11 January 1994
Vehicle:
unchanged (no vehicle)
Controls:
other: contralateral eye remained untreated
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit):0.1 ml
Duration of treatment / exposure:
no rinsing of the treated eyes
Observation period (in vivo):
7 days
Number of animals or in vitro replicates:
3 animals
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): not done


SCORING SYSTEM:
Ocular irritation was assessed using the prescribed numerical system:
Cornea
Opacity: degree of density (area most dense taken for reading)
No ulceration or opacity 0
Scattered or diffuse areas of opacity (other than slight dulling of normal lustre), details of iris clearly visible 1
Easily discernible translucent areas, details of iris slightly obscured 2
Nacreous areas, no details of iris visible, size of pupil barely discernible 3
Opaque cornea, iris not discernible through the opacity 4
Iris
Normal 0
Markedly deepened rugae, congestion, swelling, moderate circumcorneal hyperaemia or injection, any of these or combination of any thereof, iris still reacting to light (sluggish reaction is positive) 1
No reaction to light, haemorrhage, gross destruction (any or all of these) 2
Conjunctivae
Redness (refers to the most severe reading of palpebral and bulbar conjunctivae, as compared to the control eye)
Blood vessels normal 0
Some blood vessels definitely hyperaemic (injected) 1
Diffuse, crimson colour, individual vessels not easily discernible 2
Diffuse beefy red 3
Chemosis (Iids and/or nictating membranes)
No swelling 0
Any swelling above normal (includes nictating 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

TOOL USED TO ASSESS SCORE: handheld light
Irritation parameter:
cornea opacity score
Basis:
mean
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:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
0.11
Max. score:
1
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:
The numerical values given to the ocular reactions elicited by Benzyl acetate are shown in the table below. No corneal damage or iridial inflammation was observed. Temporary well-defined conjunctival reactions only were seen. The eyes were normal two days after instillation.
Other effects:
There were no signs of toxicity or ill health in any rabbit during the observation period.
OCULAR RESPONSES

Rabbit number and sex

Region of eye

One hour

Day after instillation

1

2

3

4

7

2891 M

Cornea

0

0

0

0

0

0

Iris

0

0

0

0

0

0

Conjunctiva

Redness

2

1

0

0

0

0

Chemosis

1

0

0

0

0

0

2921 M

Cornea

0

0

0

0

0

0

Iris

0

0

0

0

0

0

Conjunctiva

Redness

2

0

0

0

0

0

Chemosis

1

0

0

0

0

0

2922 M

Cornea

0

0

0

0

0

0

Iris

0

0

0

0

0

0

Conjunctiva

Redness

1

0

0

0

0

0

Chemosis

1

0

0

0

0

0

Interpretation of results:
slightly irritating
Remarks:
Migrated information no classification triggered Criteria used for interpretation of results: EU
Conclusions:
Instillation of Benzyl acetate into the rabbit eye elicited transient well-defined conjunctival irritation only. According to Directive 67/548/EEC, no classification is warranted. According to Regulation (EC) No. 1272/2008, no classification is warranted.
Read across to hexyl acetate from benzyl acetate ( and n-butyl actetate) based on results from guideline complant studies, indicates no ocular irritation hazard from hexyl acetate.
Executive summary:

A study was performed to assess the eye irritation potential of Benzyl acetate to the rabbit. Three rabbits were each administered a single ocular dose of 0.1 ml of the test substance and observed for seven days after instillation. A single instillation of Benzyl acetate into the eye of the rabbit elicited transient well-defined conjunctival irritation only. All reactions had resolved two days after instillation.

According to Directive 67/548/EEC, no classification is warranted. According to Regulation (EC) No. 1272/2008, no classification is warranted.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The RIFM Monograph for hexyl acetate summarises the skin irritation study, providing a few more details than the 1973 publication (based on the information from previous publications in the series by Smyth et al).

 Primary skin irritation of the test material was assessed using 5 albino rabbits, by a single unoccluded application of undiluted test material to the clipped belly skin. In some instances, the test material was diluted as a solution in water, propylene glycol or acetone. The volume applied was 0.01 ml. Reactions were graded within 24 hours of the application, using a 1 - 10 scale (grade 1 = no irritation; grade 2 = least visible capillary injection from the undiluted material; grade 6 = necrosis from the undiluted material; and grade 10 = necrosis from a 0.01% solution).  Unless otherwise indicated, the results reflect the use of the undiluted test material.

Based on this information it appears that irritant reactions were observed but no adverse irreversible reactions such as necrosis occurred.

Read-across data from benzyl acetate confirm the severity of irritation observed following dermal application to rabbits to be low and less than EU classification thresholds.

Eye irritation was evaluated using 5 albino rabbits per dose. The test material was applied to the centre of the cornea while the lids are retracted, and approximately 1 minute later, the lids are released. The eye was examined in strong diffuse daylight 18 - 24 hours later, stained with fluorescein, and the injury scored. The vehicle was propylene glycol, water or Deobase. Eye injury was graded according to the following 10-point scale: 1 = 0.5 ml undiluted gives injury of 0 to 1 points; 2 = 0.5 ml undiluted gives injury of over 1 up to 5 points; 3 = 0.1 ml undiluted gives injury of up to 5 points (0.5 ml gives over 5); 4 = 0.02 ml undiluted gives injury of up to 5 points (0.1 ml gives over 5); 5 = 0.005 ml undiluted gives injury of up to 5 points (0.02 ml gives over 5); 6 = Excess of 40% solution gives injury of up to 5 points (0.005 ml gives over 5); 7 = Excess of 15% solution gives injury of up to 5 points (40% gives over 5); 8 = Excess of 5% solution gives injury of up to 5 points (15% gives over 5); 9 = Excess of 1% solution gives injury of up to 5 points (5% gives over 5); 10 = Excess of 1% solution gives injury of over 5 points. The points were equivalent to the following symptoms visible after fluorescein staining: 1 point = necrosis on less than 5% of the cornea; 2 points = necrosis on 5 –12%; 3 points = necrosis on 13 – 37%; 4 points = necrosis on 38 - 62%; 5 points = necrosis on 63 - 87%; and 6 points = 88 - 100%. Grade 1 indicates a very small area of necrosis from 0.5 ml of undiluted material; grade 5 indicates a so-called severe burn from 0.005 ml; and grade 10 indicates a severe burn from 0.5 ml of a 1% solution in water or propylene glycol.

Based on the results of the screening assay for ocular irritation in five rabbits, undiluted hexyl acetate did not elicit adverse ocular reactions indicative of irritation.

Read-across to a guideline compliant eye study for benzyl acetate, confirmed the low level of ocular effects and the absence of adverse effects in rabbits eyes that would require classification

Justification for selection of skin irritation / corrosion endpoint:

Read across data from benzyl acetate provides key indication of some irritation potential but generally only slight effects observed.  This was supported by limited information available from an older non-guideline study. In vivo results confirm absence of any adverse dermal findings in either dermal irritation or dermal toxicity studies.

Justification for selection of eye irritation endpoint:

Limited information available but in vivo results confirm absence of any adverse findings.  The key study is used for read across, supported by one unreliable study for hexyl acetate, both studies tend to show a low ocular hazard for exposure to these similar substances.

Justification for classification or non-classification

The indications from in vivo data demonstrate no potential for skin or eye irritation and consequently no classification is warranted for irritation in accordance with the criteria of the Dangerous Substances Directive or those of the Classification, Labelling and Packaging Regulation (EU) No 1272/2008, 3rd ATP.

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