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Description of key information

Skin irritation: not irritating (OECD 404, GLP, K, Rel.1)


Eye irritation: not irritating (OECD 405, GLP, K, Rel.1)

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
Study period:
8 to 22 January, 2019
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
GLP study conducted according to OECD Guideline 404 without deviations
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
2015
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Version / remarks:
Council Regulation (EC) No. 440/2008
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2500 (Acute Dermal Irritation)
Version / remarks:
1998
Deviations:
no
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Received from Robinson Services, Inc. on December 28, 2018 and January 9, 2019.
- Age: Young adult of 10-13 weeks
- Weight at study initiation: 2.118-2.506 kg
- Housing: Each animal was singly housed in suspended stainless steel caging. Enrichment (e.g., toy) was placed in each cage. Litter paper was placed beneath the cage and was changed at least
three times per week.
- Diet: Certified RSI 5025 High Fiber Rabbit Diet (Rowe Nutrition, LLC). A designated amount of diet (approximately 150 grams/day) and Alfalfa Timothy Hay Cubes (Standlee Premium Western Forage) were available to each rabbit.
- Water: Filtered tap water was supplied ad libitum.
- Acclimation period: 6-11 days

ENVIRONMENTAL CONDITIONS
- Temperature: 19-23 °C
- Humidity: 39-69 %
- Air Changes/Hour: 13
- Photoperiod: 12-hour light/dark cycle
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
not specified
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL
- Concentration (if solution): The test substance was applied as received and mixed well prior to use.
Duration of treatment / exposure:
3 minutes, 1 hour and 4 hours.
Observation period:
0,5 h, 1 hour and then 24, 48, 72 hours and Days 7 after removal of the patch.
Number of animals:
3 females
Details on study design:
TEST SITE
- Area of exposure and type of wrap: Three dose sites, each approximately 6-cm², were delineated on this rabbit. Five tenths of a milliliter of the test substance was applied to the skin of each dose site and covered with a 1-inch x 1-inch, 4-ply gauze pad. The pads and entire trunk of the animal were then wrapped with semi-occlusive 3-inch Micropore™ tape to avoid dislocation of the patches.

REMOVAL OF TEST SUBSTANCE
- Time after start of exposure: The pads were removed at the appropriate intervals (3 minutes, 1hour, and 4 hours).

OBSERVATION TIME POINTS
- Skin reactions were appreciated 30 minutes, 1 hour and then 24, 48, 72 hours and Days 7 after removal of the patch.

SCORING SYSTEM:
Individual dose sites were scored according to the Draize scoring system (Draize et al., 1944) at approximately 30-60 minutes, 24, 48, and 72 hours and at 7 days after patch removal
in addition to evaluation for corrosion at these intervals for the first animal only.
The classification of irritancy was obtained by adding the average erythema and edema scores for the 30-60 minute, 24, 48, and 72-hour scoring intervals and dividing by the number of evaluation
intervals. The resulting Primary Dermal Irritation Index (PDII) was classified as follows:

PDII: Classification:
0 Non-irritating
> 0 - 2.0 Slightly irritating
2.1 - 5.0 Moderately irritating
> 5.0 Severely irritating
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Remarks on result:
probability of weak irritation
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1.3
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
probability of weak irritation
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Remarks on result:
probability of weak irritation
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Time point:
other: 30, 60 minutes, 24, 48 and 72 hours
Score:
0.9
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
probability of weak irritation
Irritant / corrosive response data:
Very slight erythema was observed at the 3-minute exposure site 30-60 minutes following patch removal which resolved by Day 7 for the first animal.
Very slight erythema was observed at the 1-hour exposure site 30-60 minutes following patch removal which resolved by 24 hours for the first animal.
Within 24 hours after patch removal, all three treated sites exhibited very slight to well-defined erythema and one treated site exhibited very slight edema. The overall incidence and severity of
irritation decreased gradually with time. All animals were free of dermal irritation by Day 7 (study termination).
No visible necrosis (corrosion) of the skin tissue was observed at the 3-minute, 1-hour and 4-hour dose sites during the study.
The Primary Dermal Irritation Index for the test item is 0.9.
See Table 7.3.1/1: Individual and average scores after 4 h exposure.
Other effects:
All animals appeared active and healthy and gained body weight during the study. Apart from the dermal irritation noted, there were no other signs of gross toxicity, adverse clinical effects, or abnormal behavior.

Table 7.3.1/1: Individual and average scores after 4 h exposure

Observations Scores
Skin reactions Observation time Animal No. 3501 Animal No. 3502 Animal No. 3503
Erythema 1h 1 2 1
24h 1 2 1
48h 0 1 0
72h 0 1 0
Day 7 0  0  0
Mean 24/48/72h 0.3 1.3 0.3
Oedema 1h 0 1 0
24h 0 0 0
48h 0 0 0
72h 0 0 0
Day 7 0 0 0
Mean 24/48/72h 0 0 0
Interpretation of results:
GHS criteria not met
Conclusions:
Under the test conditions, the test substance is classified as slightly irritating to the skin according to the criteria of the Primary Dermal Irritation Index but the test substance is not classified according to the criteria of the Draize score system, the Regulation EC No. 1272/2008 (CLP) and to the GHS.
This study is considered as acceptable and satisfies the requirement for skin irritation endpoint.
Executive summary:

In a dermal irritation study performed according to the OECD Guideline No. 404, and in compliance with GLP, undiluted test substance was applied at the dose of 0.5 mL, under semiocclusive dressing during 4 hours on a clipped dorsal area of 3 females rabbits. Skin irritation was assessed and scored according to the Draize scale at 1, 24, 48, 72 h and Day 7 after the removal of the patch.

 

Within 24 hours after patch removal, all three treated sites exhibited very slight to well-defined erythema and one treated site exhibited very slight edema. The overall incidence and severity of irritation decreased gradually with time. All animals were free of dermal irritation by Day 7 (study termination).

The individual scores for each animal within 3 scoring times (24, 48 and 72 h) were 0.3 / 1.3 / 0.3 for erythema and 0.0 / 0.0 / 0.0 for oedema. 

The Primary Dermal Irritation Index (PDII) calculated for this test substance was 0.9.

Under the test conditions, the test substance is classified as slightly irritating to the skin according to the criteria of the Primary Dermal Irritation Index but the test substance is not classified according to the criteria of the Draize score system, the Regulation EC No. 1272/2008 (CLP) and to the GHS.

This study is considered as acceptable and satisfies the requirement for skin irritation endpoint.

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
Study period:
21 to 24 January 2019
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
GLP study conducted according to OECD Guideline 405 without deviations
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
2017
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Version / remarks:
Commission regulation (EU) No. 2017/735
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2400 (Acute Eye Irritation)
Version / remarks:
1998
Deviations:
no
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Received from Robinson Services, Inc. on January 9, 2019.
- Age: Young adult of 11 weeks
- Weight at study initiation: 2.149-2.598 kg
- Housing: Each animal was singly housed in suspended stainless steel caging. Enrichment (e.g., toy) was placed in each cage. Litter paper was placed beneath the cage and was changed at least
three times per week.
- Diet: Certified RSI 5025 High Fiber Rabbit Diet (Rowe Nutrition, LLC). A designated amount of diet (approximately 150 grams/day) and Alfalfa Timothy Hay Cubes (Standlee Premium Western Forage) were available to each rabbit.
- Water: Filtered tap water was supplied ad libitum.
- Acclimation period: 6-11 days

ENVIRONMENTAL CONDITIONS
- Temperature: 19-23 °C
- Humidity: 48-69 %
- Air Changes/Hour: 13
- Photoperiod: 12-hour light/dark cycle
Vehicle:
unchanged (no vehicle)
Controls:
other: untreated eye serving as control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL
- Concentration (if solution): Undiluted
Duration of treatment / exposure:
No washing was done
Observation period (in vivo):
Ocular examinations were performed on both right and left eyes 1, 24, 48, 72 h following treatment, according with the Draize method of scoring (Draize et al., 1944).
Number of animals or in vitro replicates:
3 females
Details on study design:
TREATMENT
Prior to instillation, 1-2 drops of ocular anesthetic (Tetracaine Hydrochloride Ophthalmic Solution USP, 0.5%) were placed into both the treated and control eye of each animal. One-tenth of a milliliter of the test substance was then instilled into the conjunctival sac of the right eye of each rabbit by pulling the lower lid away from the eyeball. The upper and lower lids were then gently held together for about one second before releasing to minimize loss of the test substance.
The other eye of each rabbit remained untreated with the test substance and served as a control.
The rabbits were then returned to their designated cages.

REMOVAL OF TEST SUBSTANCE
- Washing: No

SCORING SYSTEM:
According to OECD guideline 405, ocular irritation was evaluated using a white light source in accordance with the Draize method of scoring (Draize et al., 1944).
The time interval with the highest mean score (Maximum Mean Total Score - MMTS) for all rabbits was used to classify the test substance by the system of Kay and Calandra (Kay & Calandra, 1962).

MMTS Irritation classification Requirement For Maintenance of Classification
0.0 - 0.5 Non Up to 0.5 at 1 hour with zeros at 24 hours; otherwise, increase one 0.0 - 0.5 non level
0.6 - 2.5 practically non with zeros at 24 hours; otherwise, increase one level
2.6- 15.0 minimally with zeros at 48 hours; otherwise, increase one level
15.1 -25.0 mildly with zeros at 96 hours; otherwise, increase one level
25.1 - 50.0 moderately with 7 day mean <=20 and individual total scores <=10 in at least 60% of the rabbits with no total score >30; otherwise, increase one level
50.1 - 80.0 severely with 7 day mean <=40 and individual total scores <=30 in at least 60% of the rabbits with no total score >60; otherwise, increase one level
80.1 - 100.0 extremely with 7 day mean <=80 and individual total scores <=60 in at least 60% of the rabbits with no total score >100; otherwise, increase one level
100.1 - 110 maximally with 7 day mean >80 and individual total scores >60 in at least 60% of the rabbits; otherwise, decrease one level
Irritation parameter:
cornea opacity score
Basis:
other:
Remarks:
animal #1, animal #2 and animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
other:
Remarks:
animal #1, animal #2 and animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
2
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.3
Max. score:
3
Reversibility:
fully reversible within: 48 hours
Remarks on result:
probability of weak irritation
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.6
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Remarks on result:
probability of weak irritation
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.3
Max. score:
3
Reversibility:
fully reversible within: 48 hours
Remarks on result:
probability of mild irritation
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.6
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Remarks on result:
probability of weak irritation
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.3
Max. score:
3
Reversibility:
fully reversible within: 48 hours
Remarks on result:
probability of weak irritation
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.6
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Remarks on result:
probability of weak irritation
Irritation parameter:
maximum mean total score (MMTS)
Basis:
mean
Time point:
24/48/72 h
Score:
6
Max. score:
110
Reversibility:
fully reversible within: 72 hours
Remarks on result:
probability of weak irritation
Irritant / corrosive response data:
One hour after test substance instillation, minimal conjunctivitis was noted for all three treated eyes. There was no corneal opacity or iritis observed in any treated eye during this study. The
overall incidence and severity of irritation decreased with time. All animals were free of ocular irritation by 72 hours (study termination).
The Maximum Mean Total Score (MMTS) of of test material is 6.0.
See Table 7.3.2/1: Individual and mean scores of conjunctivae, iris and cornea.
Other effects:
All animals appeared active and healthy and gained body weight during the study. Apart from the eye irritation noted, there were no other signs of gross toxicity, adverse clinical effects,
or abnormal behavior.

Table 7.3.2/1: Individual and mean scores of conjunctivae, iris and cornea

 

Time / Animal

 

Cornea

 

Iris

 

Conjunctivae

 

redness

 

chemosis

 

1 (3401)

2 (3402)

3 (3403)

1 (3401)

2 (3402)

3 (3403)

1 (3401)

2 (3402)

3 (3403)

1 (3401)

2 (3402)

3 (3403)

1 h

0

0

0

0

0

0

1

1

1

1

1

1

24 h

0

0

0

0

0

0

1

1

1

1

1

1

48 h

0

0

0

0

0

0

0

0

0

1

1

1

72 h

0

0

0

0

0

0

0

0

0

0

0

0

 Mean 24/48/72 h  0  0  0  0  0  0 0.3  0.3  0.3  0.6  0.6  0.6
Interpretation of results:
GHS criteria not met
Conclusions:
Under the test conditions, the test substance is classified as mildly irritating to the eye according with the time interval with the highest mean score (Maximum Mean Total Score - MMTS) for all
rabbits using to classify the test substance by the system of Kay and Calandra.
However, the test substance is not classified according to the criteria of the Draize score system, the Regulation EC No. 1272/2008 (CLP) and to the GHS.
This study is considered as acceptable and satisfies the requirement for skin irritation endpoint.
Executive summary:

In an eye irritation study conducted according to OECD 405 Guideline and in compliance with GLP, test substance was instilled as supplied, into the eye of 3 New Zealand rabbits at the dose of 0.1 mL, the other eye remained untreated serving as control. The lids were then gently held together for about one second in order to prevent loss of the test substance. The eyes were examined and the changes were observed at 1, 24, 48 and 72 h after treatment and graded according to the Draize method and by the system of Kay and Calandra.

 

All animals appeared active and healthy and gained body weight during the study. Apart from the eye irritation noted below, there were no other signs of gross toxicity, adverse clinical effects, or abnormal behavior. One hour after test substance instillation, minimal conjunctivitis was noted for all three treated eyes. There was no corneal opacity or iritis observed in any treated eye during this study. The overall incidence and severity of irritation decreased with time. All animals were free of ocular irritation by 72 hours (study termination).

Mean individual scores at 24, 48 and 72 h after exposure for the 3 animals were 0.0, 0.0, 0.0 for cornea score; 0.0, 0.0, 0.0 for iris score; 1.0, 0.0, 0.0 for conjunctivae score and 1.0, 1.0, 0.0 for chemosis score. The Maximum Mean Total Score (MMTS) of of test material is 6.0.

Under the test conditions, the test substance is classified as mildly irritating to the eye according with the time interval with the highest mean score (Maximum Mean Total Score - MMTS) for all rabbits using to classify the test substance by the system of Kay and Calandra.

However, the test substance is not classified according to the criteria of the Draize score system, the Regulation EC No. 1272/2008 (CLP) and to the GHS.

This study is considered as acceptable and satisfies the requirement for skin irritation endpoint.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation:


A key study was identified (PSL, 2020).


In a dermal irritation study performed according to the OECD Guideline No. 404, and in compliance with GLP, undiluted test substance was applied at the dose of 0.5 mL, under semiocclusive dressing during 4 hours on a clipped dorsal area of 3 females rabbits. Skin irritation was assessed and scored according to the Draize scale at 1, 24, 48, 72 h and Day 7 after the removal of the patch.


Within 24 hours after patch removal, all three treated sites exhibited very slight to well-defined erythema and one treated site exhibited very slight edema. The overall incidence and severity of irritation decreased gradually with time. All animals were free of dermal irritation by Day 7 (study termination).


The individual scores for each animal within 3 scoring times (24, 48 and 72 h) were 0.3 / 1.3 / 0.3 for erythema and 0.0 / 0.0 / 0.0 for oedema. 


The Primary Dermal Irritation Index (PDII) calculated for this test substance was 0.9.


The test substance is not classified according to the criteria of the Draize score system, the Regulation EC No. 1272/2008 (CLP) and to the GHS.


 


Eye irritation:


In an eye irritation study conducted according to OECD 405 Guideline and in compliance with GLP, test substance was instilled as supplied, into the eye of 3 New Zealand rabbits at the dose of 0.1 mL, the other eye remained untreated serving as control. The lids were then gently held together for about one second in order to prevent loss of the test substance. The eyes were examined and the changes were observed at 1, 24, 48 and 72 h after treatment and graded according to the Draize method and by the system of Kay and Calandra.


All animals appeared active and healthy and gained body weight during the study. Apart from the eye irritation noted below, there were no other signs of gross toxicity, adverse clinical effects, or abnormal behavior. One hour after test substance instillation, minimal conjunctivitis was noted for all three treated eyes. There was no corneal opacity or iritis observed in any treated eye during this study. The overall incidence and severity of irritation decreased with time. All animals were free of ocular irritation by 72 hours (study termination).


Mean individual scores at 24, 48 and 72 h after exposure for the 3 animals were 0.0, 0.0, 0.0 for cornea score; 0.0, 0.0, 0.0 for iris score; 1.0, 0.0, 0.0 for conjunctivae score and 1.0, 1.0, 0.0 for chemosis score. The Maximum Mean Total Score (MMTS) of of test material is 6.0.


The test substance is not classified according to the criteria of the Draize score system, the Regulation EC No. 1272/2008 (CLP) and to the GHS.

Justification for classification or non-classification

Harmonized classification:


The substance has no harmonized classification according to the Regulation (EC) No. 1272/2008 (CLP).


 


Self classification:


Based on the available data:


No additional self-classification is proposed regarding skin and eye irritation and the test substance is not classified according to the criteria of the Regulation EC No. 1272/2008 (CLP) and to the GHS.


- No data was available regarding respiratory irritation.

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