Registration Dossier

Administrative data

Description of key information

Skin / eye irritation / corrosion in vitro: Data waiving, in vivo studies are available.

Skin irritation in vivo: not irritating, rabbits, 0.5ml undiluted, semiocclusive (OECD 404, GLP)

Eye irritation in vivo: not irritating, rabbits, 0.1ml undiluted, semiocclusive ( US EPA FIFRA Guideline § 81-4, GLP)

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
Peer-reviewed assessment report (attached in section 13)
Reference:
Composition 0
Qualifier:
according to
Guideline:
EPA OPP 81-5 (Acute Dermal Irritation)
Version / remarks:
US EPA FIFRA § 81-5
Deviations:
yes
Remarks:
Purity of the test compound was not determined by the laboratory prior to conduct of the test.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
not applicable
GLP compliance:
yes
Remarks:
self-certified to US EPA regulations at 40 CFR Parts 160 and 792
Test material information:
Composition 1
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazleton Research Products, Inc. Denver PA USA
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 ml
Duration of treatment / exposure:
4h
Observation period:
≥ 7d
Number of animals:
6
Details on study design:
TEST SITE
- Area of exposure:
- % coverage:
- Type of wrap if used: semi-occlusive dressings / bandages

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes
- Time after start of exposure: 4h

OBSERVATION TIME POINTS
Application sites were evaluated in accordance with the method of Draize at approximately 30 - 60 minutes and 24, 48 and 72 hours after patch removal and daily thereafter through Day 7 since erythema still persisted in few animals at 72 hours.

SCORING SYSTEM:
- Method of calculation: Draize / according to OECD 404
Irritation parameter:
erythema score
Basis:
mean
Time point:
24/48/72 h
Score:
0.333
Max. score:
1
Reversibility:
fully reversible within: 4 days or earlier
Irritation parameter:
edema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
other: not applicable
Irritant / corrosive response data:
The test material induced very slight erythema on five animals. Desquamation was noted on two sites. There were no edema or other dermal findings. With the exception of desquamation on two sites, all dermal irritation completely subsided by Day 4 or earlier.
Other effects:
There were no deaths during the study. There were no remarkable body weight changes during the study period.

Table Individual and mean skin irritation scores according to Draize

 

Erythema

Edema

Animal No.

708

712

715

725

735

742

708

712

715

725

735

742

After 1h

1

1

0

0

1

1

0

0

0

0

0

0

After 24h

0

1

1

0

1

0

0

0

0

0

0

0

After 48h

0

0

0

0

1

0

0

0

0

0

0

0

After 72h

0

0

1 d

0

1 d

0

0

0

0

0

0

0

Mean score 24-72h

0.333

0.0

Additional criteria specified in Directive 93/21/EEC Point 3.2.6.1 fulfilled: No

d = Desquamation

Interpretation of results:
GHS criteria not met
Conclusions:
As information was provided via a peer-reviewed assessment report, it can be considered as sufficiently reliable to assess the skin irritation potential of ethoxyquin in rabbits. Based on the observations after 24, 48 and 72 hours, the overall mean scores for erythema, eschar formation and edema were 0.33, 0.0 and 0.0, respectively. One hour after patch removal, erythema (but no edema) was seen in four out of six rabbits. If this observation time point is included, primary irritation index would be 0.4. Perhaps because of this calculation, classification by the notifier was “slightly irritating”. However, in fact, no classification according to Dir 67/548/EEC is required.
According to Regulation 1272/2008, classification as Skin irritation category 2 is triggered if:
(1) Mean value of ≥ 2,3 - ≤ 4,0 for erythema/ eschar or for oedema in at least 2 of 3 tested animals from gradings at 24, 48 and 72 hours after patch removal or, if reactions are delayed, from grades on 3 consecutive days after the onset of skin reactions; or
(2) Inflammation that persists to the end of the observation period normally 14 days in at least 2 animals, particularly taking into account alopecia (limited area), hyperkeratosis, hyperplasia, and scaling; or
(3) In some cases where there is pronounced variability of response among animals, with very definite positive effects related to chemical exposure in a single animal but less than the criteria above.
Based on the available results, this is not the case, so classification as skin irritant is also not triggered according to Regulation 1272/2008.
Executive summary:

In a primary dermal irritation study (US EPA FIFRA § 81-5, equivalent to OECD 404), six New Zealand White rabbits were dermally exposed to 0.5 ml of neat ethoxyquin for 4 hours.  Animals then were observed for ≥ 7 days.  Irritation was scored by the method of Draize.

There were no deaths during the study. The test material induced very slight erythema on five animals. Desquamation was noted on two sites. There were no edema or other dermal findings. With the exception of desquamation on two sites, all dermal irritation completely subsided by Day 4 or earlier. There were no remarkable body weight changes during the study period.

In this study, ethoxyquin is not a dermal irritant, no classification is triggered.

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)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
Peer-reviewed assessment report (attached in section 13)
Reference:
Composition 0
Qualifier:
according to
Guideline:
EPA OPP 81-4 (Acute Eye Irritation)
Version / remarks:
US EPA FIFRA Guideline § 81-4
Deviations:
yes
Remarks:
Purity of the test compound was not determined by the laboratory prior to conduct of the test.
GLP compliance:
yes
Remarks:
self-certified to US EPA regulations at 40 CFR Parts 160, 792
Test material information:
Composition 1
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Hazleton Research Products, Inc. Denver PA USA
Vehicle:
unchanged (no vehicle)
Controls:
other: Left eyes were manipulated in a similar manner as the right eyes and served as contralateral controls.
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 ml
- Concentration (if solution): undiluted
Duration of treatment / exposure:
The eyes of all rabbits remained unwashed.
Observation period (in vivo):
96 h
Number of animals or in vitro replicates:
6
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): The eyes of all rabbits remained unwashed.

SCORING SYSTEM: The eyes were examined for ocular reactions in accordance with the method of Draize at approximately 1, 24, 48 and 72 hours, and, since conjunctival redness was still noted after 72 hours, on Day 4.

TOOL USED TO ASSESS SCORE: fluorescein; Sodium fluorescein was used to aid in revealing corneal damage at 72 hours.
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
other: not applicable
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
other: not applicable
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Remarks:
conjunctive - redness
Basis:
mean
Time point:
24/48/72 h
Score:
0.444
Max. score:
2
Reversibility:
fully reversible within: 96h
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
0.167
Max. score:
1
Reversibility:
fully reversible within: 72h
Irritant / corrosive response data:
The left (control) eyes of all rabbits were free of evidence of ocular irritation and other findings for the duration of the study. The right (test) eye for one rabbit exhibited a positive conjunctival reaction and all animals had minor conjunctival irritation. There was no evidence of any damage to the iris or the cornea. All ocular irritation was reversible and completely subsided by Day 4 or earlier. There were no remarkable changes or differences observed in body weights during the study period. The maximum average score for ethoxyquin was 3.7 and was observed at one hour postinstillation.
Other effects:
There were no deaths during the study.

Table Eye irritation scores according to the Draize scheme - unwashed eyes

 

Cornea

Iris

Conjunctiva - Redness

Conjunctiva - Chemosis

Time / rabbit No.

1

2

3

4

5

6

1

2

3

4

5

6

1

2

3

4

5

6

1

2

3

4

5

6

1 h

0

0

0

0

0

0

0

0

0

0

0

0

1

1

1

2

1

1

1

0

1

1

0

1

24 h

0

0

0

0

0

0

0

0

0

0

0

0

1

1

1

1

0

1

0

0

1

1

0

0

48 h

0

0

0

0

0

0

0

0

0

0

0

0

0

1

0

1

0

0

0

0

0

1

0

0

72h

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1

0

0

0

0

0

0

0

0

Mean scores 24-72 h

0.0

0.0

0.444

0.167

Additional criteria in Directive 93/21/EEC Point 3.2.6.2 fulfilled: No

Interpretation of results:
GHS criteria not met
Conclusions:
As information was provided via a peer-reviewed assessment report, it can be considered as sufficiently reliable to assess the eye irritation potential of ethoxyquin in rabbits.
The “Primary Eye Irritation Score” for each observation time is calculated as the sum of all individual irritation scores at that time divided by the number of animals in the group. Taking these values for the 24-, 48- and 72-hour observations into account, overall mean scores for corneal opacity, iris lesions, redness of the conjunctivae and edema of the conjunctivae (chemosis) will result. In this study, only conjunctival redness and chemosis were observed and for these findings, low mean scores of 0.44 and 0.17 were calculated.
If the 1-hour values for conjunctiva redness and conjunctiva chemosis are included in that calculation, mean scores would augment to 0.624 and 0.289, respectively.
Based on these results and in accordance with Annex VI of Commission Directive 2001/59/EC, ethoxyquin shall not be classified as an eye irritant.
According to Regulation 1272/2008, a substance must be classified as Irritating to eyes (Category 2), if, when applied to the eye of an animal, a substance produces:
— at least in 2 of 3 tested animals, a positive response of:
— corneal opacity ≥ 1 and/or
— iritis ≥ 1, and/or
— conjunctival redness ≥ 2 and/or
— conjunctival oedema (chemosis) ≥ 2
— calculated as the mean scores following grading at 24, 48 and 72 hours after installation of the test material, and which fully reverses within an observation period of 21 days.
In the present study, ethoxyquin was tested on six rabbits. In none of the tested animals the above-mentioned scores met or exceeded the scores triggering classification, so also according to Regulation 1272/2008, ethoxyquin does not need to be classified as eye irritant.
Executive summary:

In a primary eye irritation study [US EPA FIFRA Guideline § 81-4], 0.1 ml of undiluted ethoxyquin was instilled into the conjunctival sac of the right eye of six New Zealand white rabbits.  Eyes were not washed.  Animals then were observed for ≥ 4 days.  Irritation was scored by the method of Draize.

There were no deaths during the study. The left (control) eyes of all rabbits were free of evidence of ocular irritation. The right (test) eye for one rabbit exhibited a positive conjunctival reaction and all animals had minor conjunctival irritation. There was no evidence of any damage to the iris or the cornea. All ocular irritation was reversible and completely subsided by Day 4 or earlier. There were no remarkable changes or differences observed in body weights during the study period. The maximum average score for ethoxyquin was 3.7 and was observed at one hour postinstillation.

In this study, ethoxyquin is not an eye irritant and does not need to be classified.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

According to Regulation 1272/2008, classification as Skin irritation category 2 is triggered if:

(1) Mean value of2,3 -4,0 for erythema/ eschar or for oedema in at least 2 of 3 tested animals from gradings at 24, 48 and 72 hours after patch removal or, if reactions are delayed, from grades on 3 consecutive days after the onset of skin reactions; or

(2) Inflammation that persists to the end of the observation period normally 14 days in at least 2 animals, particularly taking into account alopecia (limited area), hyperkeratosis, hyperplasia, and scaling; or

(3) In some cases where there is pronounced variability of response among animals, with very definite positive effects related to chemical exposure in a single animal but less than the criteria above.

Based on the observations made in the study according to US EPA FIFRA § 81-5 after 24, 48 and 72 hours, the overall mean scores for erythema, eschar formation and edema were 0.33, 0.0 and 0.0, respectively. One hour after patch removal, erythema (but no edema) was seen in four out of six rabbits. If this observation time point is included, primary irritation index would be 0.4. Perhaps because of this calculation, classification by the notifier was “slightly irritating”. However, in fact, no classification according to Dir 67/548/EEC is required.

 

According to Regulation (EC) No. 1272/2008, a substance must be classified as eye irritant category 2, if, when applied to the eye of an animal, a substance produces:

— at least in 2 of 3 tested animals, a positive response of:

— corneal opacity1 and/or

— iritis1, and/or

— conjunctival redness2 and/or

— conjunctival oedema (chemosis)2

— calculated as the mean scores following grading at 24, 48 and 72 hours after installation of the test material, and which fully reverses within an observation period of 21 days

In the study according to US EPA FIFRA Guideline § 81-4 in none of the tested animals the above-mentioned scores met or exceeded the scores triggering classification, so also according to Regulation 1272/2008, ethoxyquin does not need to be classified as eye irritant.