Registration Dossier

Administrative data

Description of key information

Skin irritation/corrosion:

- not irritating (read-across, OECD 404, GLP, K, rel. 2).

- OASIS TIMES prediction (S, rel. 2): The substance is predicted to be not a skin irritant.


Eye irritation:

- not irritating (read-across, OECD 405, GLP, K, rel. 2).

- OASIS TIMES prediction (S, rel. 2): The substance is predicted to be not an eye irritant.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 1991-07-09 to 1991-07-16
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
age of animals at study initiation not reported
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
age of animals at study initiation not reported
Principles of method if other than guideline:
not applicable
GLP compliance:
yes (incl. certificate)
Remarks:
Inspected on 19 June 1990. Signed on 5 October 1990.
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Ranch Rabbits, Crawley Down, Sussex.
- Age at study initiation: no data
- Weight at study initiation: 2.6-3.0 kg
- Housing: individually in grid bottomed metal cages.
- Diet (e.g. ad libitum): antibiotic free rabbit diet ad libitum (SQC standard rabbits pellets, produced by Special Diets Services, Witham, Essex)
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-23 °C. On 3 occasions the temperature exceeded this range by 1°C.
- Humidity (%): 59-69 % with the exception of one occasion when a value of 76 % relative humidity was recorded.
- Air changes (per hr): no data
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: no data
Type of coverage:
semiocclusive
Preparation of test site:
shaved
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:
4 hours
Observation period:
1, 24, 48, and 72 hours after patch removal. Additional examination on day 7.
Number of animals:
4 animals
Details on study design:
TEST SITE
- Area of exposure: dorsal surface of the trunk
- % coverage: 2.5 cm square (6.25 cm2)
- Type of wrap if used: surgical lint held in position with "Elastoplast" elastic adhesive bandage 7.5 cm wide.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): cotton wool soaked in warm water
- Time after start of exposure: 4 hours

SCORING SYSTEM: Draize scale according to OECD guideline No. 404
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.66
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
erythema score
Basis:
animal #4
Time point:
24/48/72 h
Score:
2.66
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1.33
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.66
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
edema score
Basis:
animal #4
Time point:
24/48/72 h
Score:
1.33
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritant / corrosive response data:
One hour after the end of the dosing period, erythema varying in degree from slight to well defined was apparent in all 4 rabbits and very slight oedema was noted in 2 of the 4 animals.
24 hours after patch removal erythema and oedema were observed in all 4 rabbits.
At the 72 hour assessment, irritation has entirely subsided in 2 animals. Erythema was slight to moderate in the remaining 2 rabbits.
7 days after the dosing, erythema and oedema were no longer apparent in any of the animal although skin thickening was noted in one of them.
Other effects:
none

Table 7.3.1/1: Mean irritant/corrosive response data (4 animals) at each observation time up to removal of animals from the test

 

Score at time point / Reversibility

Erythema

Max. score 4

Edema

Max. score 4

1 h

1.75

0.5

24 h

1.25

1.25

48 h

1.50

0.75

72 h

1.50

0.75

Average 24h, 48h, 72h

1.4

0.9

Reversibility*)

c

c

Average time (day) for reversion**

7 days

7 days

 *) Reversibility: c. = completely reversible; n.c. = not completely reversible; n. = not reversible

**): correspond to the last day for which skin irritation signs in the last animal were observed

Table 7.3.1/2: Irritant/corrosive response data for each animal at each observation time up to removal of animals from the test

Score at time point / Reversibility

Erythema

Max. score 4

Oedema

Max. score 4

24 h

1 / 1 / 1 / 2

2 / 1 / 1 / 1

48 h

2 / 1 / 0 / 3

1 / 1 / 0 / 1

72 h

3 / 0 / 0 / 3

1 / 0 / 0 / 2

Average 24h, 48h and 72h

2 / 0.66 / 0.33 / 2.66

1.33 / 0.66 / 0.33 / 1.33

Reversibility*)

c

c

Average time for reversion

7 days

7 days

 *) Reversibility: c. = completely reversible; n.c. = not completely reversible; n. = not reversible

Interpretation of results:
Category 3 (mild irritant) based on GHS criteria
Conclusions:
Under the test conditions, since a slight irritation being completely reversible within 7 days was observed:
- no additional self-classification is proposed for the registered substance regarding skin irritation according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP)
- the registered substance is classified as Category 3 (slight skin irritation) according to the GHS based on differences betwen the individual scores for each animal within 3 scoring times (24, 48 and 72 h) for erythema (2 / 0.66 / 0.33 / 2.66).
Executive summary:

In a dermal irritation study performed according to the OECD guideline No. 404, and in compliance with GLP, 0.5 mL of undiluted test material was dermally applied on the shaved skin of the dorsal surface of the trunk of 4 New Zealand White rabbits.Test sites were covered with a semi-occlusive dressing for 4 hours. Animals were then observed for up to 7 days for edema and erythema. 

Skin irritation was assessed and scored according to the Draize scale at 1, 24, 48 and 72 hrs after the removal of the patch and on day 7.

The individual scores for each animal within 3 scoring times (24, 48h and 72 hours) were 2 / 0.66 / 0.33 / 2.66 for erythema and 1.33 / 0.66 / 0.33 / 1.33 for oedema.

Under the test conditions, since a slight irritation being completely reversible within 7 days was observed:

- no additional self-classification is proposed for the registered substance regarding skin irritation according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP)

- the registered substance is classified as Category 3 (slight skin irritation) according to the GHS based on differences betwen the individual scores for each animal within 3 scoring times (24, 48 and 72 h) for erythema (2 / 0.66 / 0.33 / 2.66).

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

Endpoint:
skin irritation: in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
[further information is included as attachment to Iuclid section 13]

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across approach is based on the hypothesis that the source and target substances have similar physico-chemical, toxicological and environmental fate properties because of their structural similarity.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The target substance is a mono-constituent substance while the source substance is a multiconstituent.

3. ANALOGUE APPROACH JUSTIFICATION
The study design (OECD 404, GLP) is adequate and reliable for the purpose of the prediction based on read-across. The test material used represents the source substance as described in the hypothesis in terms of purity and impurities. The results of the studies are adequate for the purpose of classification and labelling.
Therefore, based on the considerations above, it can be concluded that the results of the in vivo skin irritation study conducted in the rabbit with the source substance are likely to predict the properties of the target substance and are considered as adequate to fulfil the information requirement of Annex VIII, 8.1.

4. DATA MATRIX
See Iuclid section 13
Reason / purpose:
read-across source
Reason / purpose:
read-across: supporting information
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.66
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
erythema score
Basis:
animal #4
Time point:
24/48/72 h
Score:
2.66
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1.33
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.66
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
edema score
Basis:
animal #4
Time point:
24/48/72 h
Score:
1.33
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritant / corrosive response data:
One hour after the end of the dosing period, erythema varying in degree from slight to well defined was apparent in all 4 rabbits and very slight oedema was noted in 2 of the 4 animals.
24 hours after patch removal erythema and oedema were observed in all 4 rabbits.
At the 72 hour assessment, irritation has entirely subsided in 2 animals. Erythema was slight to moderate in the remaining 2 rabbits.
7 days after the dosing, erythema and oedema were no longer apparent in any of the animal although skin thickening was noted in one of them.
Other effects:
none

Table 7.3.1/1: Mean irritant/corrosive response data (4 animals) at each observation time up to removal of animals from the test

 

Score at time point / Reversibility

Erythema

Max. score 4

Edema

Max. score 4

1 h

1.75

0.5

24 h

1.25

1.25

48 h

1.50

0.75

72 h

1.50

0.75

Average 24h, 48h, 72h

1.4

0.9

Reversibility*)

c

c

Average time (day) for reversion**

7 days

7 days

 *) Reversibility: c. = completely reversible; n.c. = not completely reversible; n. = not reversible

**): correspond to the last day for which skin irritation signs in the last animal were observed

Table 7.3.1/2: Irritant/corrosive response data for each animal at each observation time up to removal of animals from the test

Score at time point / Reversibility

Erythema

Max. score 4

Oedema

Max. score 4

24 h

1 / 1 / 1 / 2

2 / 1 / 1 / 1

48 h

2 / 1 / 0 / 3

1 / 1 / 0 / 1

72 h

3 / 0 / 0 / 3

1 / 0 / 0 / 2

Average 24h, 48h and 72h

2 / 0.66 / 0.33 / 2.66

1.33 / 0.66 / 0.33 / 1.33

Reversibility*)

c

c

Average time for reversion

7 days

7 days

 *) Reversibility: c. = completely reversible; n.c. = not completely reversible; n. = not reversible

Interpretation of results:
Category 3 (mild irritant) based on GHS criteria
Conclusions:
Based on the available data on the analogue substance,:
- no additional self-classification is proposed for the registered substance regarding skin irritation according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP)
- the registered substance is classified as Category 3 (slight skin irritation) according to the GHS based on differences betwen the individual scores for each animal within 3 scoring times (24, 48 and 72 h) for erythema (2 / 0.66 / 0.33 / 2.66).
Executive summary:

In a dermal irritation study performed according to the OECD guideline No. 404, and in compliance with GLP, 0.5 mL of undiluted test material was dermally applied on the shaved skin of the dorsal surface of the trunk of 4 New Zealand White rabbits.Test sites were covered with a semi-occlusive dressing for 4 hours. Animals were then observed for up to 7 days for edema and erythema. 

Skin irritation was assessed and scored according to the Draize scale at 1, 24, 48 and 72 hrs after the removal of the patch and on day 7.

The individual scores for each animal within 3 scoring times (24, 48h and 72 hours) were 2 / 0.66 / 0.33 / 2.66 for erythema and 1.33 / 0.66 / 0.33 / 1.33 for oedema.

Under the test conditions, since a slight irritation being completely reversible within 7 days was observed:

- no additional self-classification is proposed for the registered substance regarding skin irritation according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP)

- the registered substance is classified as Category 3 (slight skin irritation) according to the GHS based on differences betwen the individual scores for each animal within 3 scoring times (24, 48 and 72 h) for erythema (2 / 0.66 / 0.33 / 2.66).

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

Endpoint:
skin irritation / corrosion, other
Type of information:
(Q)SAR
Adequacy of study:
supporting study
Study period:
16 November 2016
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification
Justification for type of information:
1. SOFTWARE
OASIS TIMES v2.27.19.13

2. MODEL (incl. version number)
Skin irritation corrosion v.05 - June 2016

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
O=C1CCCCCCCCCC/C=C\CC1

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See QMRF attached

- Defined endpoint:
Species : Rabbit, Mouse, Rat, Guinea pig and others.
Endpoint : The model predicts the reversible (irritation) and irreversible (corrosion) damage of the skin by using In vivo data.
Endpoint units : The model used the following type of experimental data:
1) Primary irritation index (PII) with four ranges of activity according to UN Globally Harmonized System (GHS) cut-offs, as follows:
- Not irritating - PII <1.5
- Mildly irritating – PII [1.5;2.3]
- Irritating – PII (2.3;4.0]
- Corrosive – PII > 4.0
2) Categories according to UN GHS classification:
- Skin corrosion - categories 1A, 1B and 1C
- Skin irritation – categories 2, 3
3) UN GHS/ H phrases are presented as follows:
- H316 – mildly irritating to skin
- H315- Causes skin irritation
- H314- Causes severe skin burns and eye damage
4) EU DSD*/ R phrases with following type of R phrases for skin irritation/corrosion:
- R38-irritating to skin
- R34- causes burns
- R35- causes severe burns
*EU classification system according to the Dangerous Substance Directive
Dependent variable : Obs. Irritation/Corrosion effect on the skin
Experimental protocol : Draize Skin Test
Endpoint data quality and variability :
1) Experimental data sources:
- Skin irritation database with Primary Skin Irritation (PII) for about 350 chemicals provided by RIVM (National Institute for Public Health and the Environment (RIVM) Netherlands)
2) Internet sources:
- Japanese GHS Inter-ministerial Committee, Trade and Industry (METI) in Japan: http://www.safe.nite.go.jp/english/ghs_index.html
- Occupational agents with respiratory effects according to ACGIH: http://www.eomsociety.org/attachments/ACGIH%20Tabelle_20.11.2012.pdf
- http://www.docstoc.com/docs/128422216/Data-matrix-GHS---CLP-314-FN-_16-12-2010_---For-public-availability
- Joint Research Centre – Institute for Health and Consumer Protection: http://health.cat/open.php?url=http://publications.jrc.ec.europa.eu/repository/bitstream/111111111/5430/1/reqno_jrc52455.pdf
- National Institute of Environmental Research (“NIER”): http://www.safechemicals.net/attachement/pubnotice/5121058_NIER_No.2011-7_April-15-2011.pdf
European List of Notified Chemical Substances Directive 92/32/EEC, the 7th amendment to Directive 67/548/EEC;
- IUCLID Chemical Data Sheets Information (published in JRC website 18.02.2000) http://esis.jrc.ec.europa.eu/index.php?PGM=dat
- Hazardous Substances Information System (HSIS) safe work Australia: http://hsis.safeworkaustralia.gov.au/ConsolidatedLists
- List of harmonised classification and labelling of hazardous substances (Table 3.1 and Table 3.2 of Annex VI to the CLP Regulation), published in JRC website 16.01.2012): http://esis.jrc.ec.europa.eu/index.php?PGM=cla
- ECETOC Technical Report No.66 Skin Irritation and Corrosion – In vivo data from Draize test as Primary Irritation Index ;
- REGULATION (EC) No 1272/2008 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL
- of 16 December 2008 on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006.Official Journal of the European Union,31.12.2008
- Sigma-Aldrich: www.sigmaaldrich.com

- Unambiguous algorithm:
Type of model : QSAR model
Descriptors in the model : For the assessment of the applicability domain, EPI Suite’s KOWWIN and WATERNT are embedded into TIMES platform to providing an automated calculation of log KOW and water solubility.

- Defined domain of applicability:
TIMES platforms utilises a multi-stage applicability domain that has been described by Dimitrov et al. (2005). The applicability domain of Skin irritation/corrosion model contains two layers:
1) General properties requirements. These requirements specify in the domain only those chemicals that fall in the range of variation of physicochemical properties that may affect significantly the quality of the measured endpoint. For Skin I/C model attention is focused on lipophilicity (log KOW), molecular weight (MW) and water solubility (WS). Only correctly predicted chemicals from the training set are used to determine the range of variation of these properties.
2) Structural domain. It determines the maximum structural similarity between the target chemical and chemicals from the training set. The structural neighborhood of atom-centered fragments (ACF) accounting for first neighbours or 3 heteroatoms, atom type, hybridization and attached hydrogen atoms are used to determine this similarity. The target chemical could contain the following types of ACF:
- Fragments present in correctly predicted training chemicals only (i.e. correct fragments),
- Fragments found both in correctly and non-correctly predicted training chemicals (i.e. fuzzy fragments). These fragments are treated as correct fragments,
- Fragments present in non-correctly predicted training chemicals only (i.e. incorrect fragments),
- Fragments not present in the training chemicals (i.e. unknown fragments).
A chemical belongs to the structural domain of the model if it could be partitioned only on correct fragments. The user is able to analyze how important are unknown and incorrect fragments (if present in the target) and to make a decision about their effect on the quality of prediction.
Reliability of the inclusion rules (categories) - ratio between the number of correctly predicted chemicals and the total number of chemicals in the local training set related to reliability of the Model predictions.
- Method used to assess the applicability domain
The approach use to determine and assess the domain is described in:
Dimitrov S, Dimitrova G., Pavlov T., Dimitrova D., Patlevisz G., Niemela J., Mekenyan O., A stepwise approach for defining the applicability domain of SAR and QSAR models, J. Chem. Inf. Model., 45, 839-849 (2005).
- Software name and version for the applicability domain assessment
The LMC software OASIS Domain Manager v1.11 (which is embedded in TIMES platform) is used to determine the applicability domain.
http://oasis-lmc.org/products/software/domain-manager.aspx
- Limits of applicability
1) General properties requirements:
Property* Domain Target chemical
log KOW [-7.5; 19.1] 2.43
MW, Da [26.0; 1329.5] 279.68
WS, mg/l [0.0; 1000000] 125877.41
* KOW and WS were calculated by EPI Suite’s KOWWIN and WATERNT models.
2) Structural domain extracted from 3175 training chemicals contains:
- 5139 correct fragments,
- 643 fuzzy fragments (treated as correct fragments),
- 858 incorrect fragments.
In order to belong to the model applicability domain a target structure must meet the requirements of all the domain layers.

- Appropriate measures of goodness-of-fit and robustness and predictivity:
Availability of the training set : The training set consisting of 3196 chemicals and is embedded in the software implementation of the model.
Cas RN: yes
Chemicals Name: yes
SMILES: yes
Formula: yes
INChi: no
MOL file: no
Available information for the training set : Chemical names, CAS numbers, SMILES, experimental conditions, test duration and references for each of the chemicals in training set are available in the software implementation of the model.

Data for the dependent variable for the training set : Data for the dependent variable for the training set are embedded in the software implementation of the model.
Other information about the training set : The training set of the TIMES Skin irritation/corrosion model v.05 consists of 3196 chemicals used for deriving of structural boundaries represented by following type of experimental data:
- PII values,
- GHS Categories,
- GHS H-Phrases,
- DSD R-Phrases
- HMIS (USA),
- WHMIS (Canada).
Statistics for goodness-of-fit :
Skin irritation/corrosion model containing 3196 training set chemicals, provided performance as follows:
- Correctly prediction for 98 (75%) out of 131 experimentally Not irritating tr.set chemicals
- Correctly prediction for 2004 (88 %) out of 2284 experimentally irritating tr.set chemicals
- Correctly prediction for 759 (97%) out of 781 experimentally corrosive tr.set chemicals
The training set of the model is not well balanced, since from 3196 chemicals 3048 are positive and only 131 are experimentally observed negative (Not irritating/Corrosive chemicals). Hence the model performance is evaluated by the percent of correctly predicted irritants and corrosives (sensitivity) – 90 %. The current specificity of the model is 75%.

- Mechanistic interpretation:
Mechanistic basis of the model
In particular, dermal irritation is defined in OECD TG 404 as “reversible damage of the skin following the application of a test substance for up to 4 hours”.
The irritation could be regarded as a process leading to chemical and physical tissue dysfunctions [1-6].
- Chemical irritation is considered to be similar to skin allergy in terms of covalent interaction with the proteins. Skin irritation depends on the chemical reactivity of the irritant and on its metabolites. The irritation can also be caused by non-covalent interactions with the macromolecules (ionic, reversible denaturation of proteins, etc).
- Physical irritation results in dissolution of skin lipids by low molecular weight organic chemicals.
Corrosion is defined as irreversible skin damage leading to visible necrosis of the epidermis through to the dermis for up to 4 hours [3]. It could be manifested as erosion of the tissues of skin by strong organic acids with pH < 2 and organic bases with pH > 11.5 such as cationic surfactants, quaternary ammonium salts, sulphonium ions, etc.
The model predicts the reversible (irritation) and irreversible (corrosion) damage of the skin following the application of a test substance.
TIMES-Skin irritation/corrosion model v.4 is an expert system based on Inclusion rules. Each of these rules are organized as categories contain one or more alerts. The alert is a structural requirement considered mechanistically, when the chemicals met them were predict as Irritating/Corrosive to skin.

5. APPLICABILITY DOMAIN
See QPRF attached
- Descriptor domain: The chemical fulfils the general properties requirements
- Structural and mechanistic domains: The following ACF are identified:
Fragments in correctly predicted training chemicals – 100.00%
Fragments in non-correctly predicted training chemicals – 0.00%
Fragments not present in the training chemicals – 0.00%
The chemical is in the interpolation structural space
- Similarity with analogues in the training set: not reported. No analogues were identified from the training set (search criteria: common organic functional groups of cycloketone and cycloalkene, similarity > 50%). No additional comments on structural analogues are provided by the author of prediction
- Other considerations (as appropriate): Detailed information about mechanistic basis of the model underpinning the prediction is available in model QMRF, section 8.

6. ADEQUACY OF THE RESULT
OASIS TIMES evaluation showed no alerts for skin irritation. The substance is predicted to be not irritating or corrosive to the skin in vivo. This result fits well with the results of an in vivo test performed on an analogue (Toxicol, 1992, rel 2, see IUCLID section 13 for additional justification).
Reason / purpose:
reference to other study
Reason / purpose:
reference to other study
Principles of method if other than guideline:
The model predicts the reversible (irritation) and irreversible (corrosion) damage of the skin by using In vivo data
GLP compliance:
no

Outcome: No alert found

Conclusion: Not a skin irritant

Applicability domain: The chemical fulfils the general properties requirements.

Fragments in correctly predicted training chemicals – 100.00%

Fragments in non-correctly predicted training chemicals – 0.00%

Fragments not present in the training chemicals – 0.00%

The chemical is in the interpolation structural space.

No analogues were identified from the training set (search criteria: common organic functional groups of cycloketone and cycloalkene, similarity > 50%).

Interpretation of results:
GHS criteria not met
Conclusions:
OASIS TIMES evaluation showed no alerts for skin irritation. The substance is predicted to be not irritating or corrosive to the skin in vivo.
Executive summary:

OASIS TIMES v2.27.19.13 software was used to predict the skin irritation of the substance.

OASIS TIMES evaluation showed no alerts for skin irritation. The substance is predicted to be not irritating or corrosive to the skin in vivo.

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

Eye irritation

Link to relevant study records

Referenceopen allclose all

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 1991-08-20 to 1991-08-30
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
Study performed according to OECD test guideline No. 405 and in compliance with GLP with minor deviations (age of animals at study initiation not reported).
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
age of animals at study initiation not reported
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
age of animals at study initiation not reported
Principles of method if other than guideline:
not applicable
GLP compliance:
yes (incl. certificate)
Remarks:
Inspected on 19 June 1990. Signed on 5 October 1990.
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Ranch Rabbits, Crawley Down, Sussex.
- Age at study initiation: no data
- Weight at study initiation: 2.8-3.2 kg
- Housing: individually in grid bottomed metal cages.
- Diet (e.g. ad libitum): antibiotic free rabbit diet ad libitum (SQC Stanrab, produced by Special Diets Services, Witham, Essex)
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-21 °C.
- Humidity (%): 59-69 % with the exception of one occasion when a value of 76 % relative humidity was recorded.
- Air changes (per hr): no data
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: no data
Vehicle:
unchanged (no vehicle)
Controls:
other: the contralateral eye remained untreated
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL
- Concentration (if solution): not applicable

VEHICLE
Not applicable
Duration of treatment / exposure:
The eye was not rinsed after the instillation of the test item.
Observation period (in vivo):
Examination made 1, 24, 48 and 72 hours following instillation
Number of animals or in vitro replicates:
4 females
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): not applicable
- Time after start of exposure: not applicable

SCORING SYSTEM: Draize scale according to the OECD guideline No. 405

TOOL USED TO ASSESS SCORE: standard light source designed to comply with the requirements of BS 950 Part 1 (Artificial Daylight for the Assessment of Colour)
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
cornea opacity score
Basis:
animal #4
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
iris score
Basis:
animal #4
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.7
Max. score:
3
Reversibility:
fully reversible within: 72h
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.3
Max. score:
3
Reversibility:
fully reversible within: 72h
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
3
Irritation parameter:
conjunctivae score
Basis:
animal #4
Time point:
24/48/72 h
Score:
0.7
Max. score:
3
Reversibility:
fully reversible within: 72h
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.7
Max. score:
4
Reversibility:
fully reversible within: 72h
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
chemosis score
Basis:
animal #4
Time point:
24/48/72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 72h
Irritant / corrosive response data:
One hour after dosing, some discharge and chemosis and definite conjunctival redness (grade 2-3) were noted in all 4 animals. Between 24 and 48 hours the irritation was reduced with only slight chemosis and/or redness in some animals. At 72 hours, no signs of irritation were detected in any animals. No corneal or iridial irritation occurred in any animal during the study.
Other effects:
No other effect

Table 7.3.2/1: Mean irritant/corrosive response data of 4 animals at each observation time up to removal from the test

 

Score at time point / Reversibility

Cornea

Iris

(/2)

Conjunctivae

Opacity

(/4)

Area

(/4)

Redness

(/3)

Chemosis

(/4)

Discharge

(/3)

1 h

0

0

0

2.25

1.50

1.25

24 h

0

0

0

0.75

0.50

0

48 h

0

0

0

0.50

0.25

0

72 h

0

0

0

0.00

0.00

0

Reversibility*)

-

-

-

c.

c.

c.

Average time (unit) for reversion

-

-

-

72 h

72 h

24 h

*) Reversibility: c. = completely reversible; n.c. = not completely reversible; n. = not reversible

Table 7.3.2/2: Individual irritant/corrosive response data at each observation time up to removal from the test

 

Score at time point / Reversibility

Cornea

Iris

(/2)

Conjunctivae

Opacity

(/4)

Area

(/4)

Redness

(/3)

Chemosis

(/4)

Discharge

(/3)

1 h

0 / 0 / 0 / 0

0 / 0 / 0 / 0

0 / 0 / 0 / 0

3 / 2 / 2 / 2

2 / 1 / 1 / 2

1 / 1 / 1 / 2

24 h

0 / 0 / 0 / 0

0 / 0 / 0 / 0

0 / 0 / 0 / 0

1 / 1 / 0 / 1

1 / 0 / 0 / 1

0 / 0 / 0 / 0

48 h

0 / 0 / 0 / 0

0 / 0 / 0 / 0

0 / 0 / 0 / 0

1 / 0 / 0 / 1

1 / 0 / 0 / 0

0 / 0 / 0 / 0

72 h

0 / 0 / 0 / 0

0 / 0 / 0 / 0

0 / 0 / 0 / 0

0 / 0 / 0 / 0

0 / 0 / 0 / 0

0 / 0 / 0 / 0

Average 24h, 48h, 72h

0 / 0 / 0 / 0

0 / 0 / 0 / 0

0 / 0 / 0 / 0

0.7 / 0.3 / 0.0 / 0.7

0.7 / 0.0 / 0.0 / 0.3

0 / 0 / 0 / 0

Reversibility*)

-

-

-

 c.

c. 

c. 

Average time (unit) for reversion

-

-

-

 72 h

72 h 

24 h 

*) Reversibility: c. = completely reversible; n.c. = not completely reversible; n. = not reversible

Interpretation of results:
GHS criteria not met
Conclusions:
Under the test conditions, the test material is not classified as irritating to eyes according to the criteria of the Annex VI of the Regulation (EC) No 1272/2008 (CLP) and of the GHS.
Executive summary:

In an eye irritation study performed according to the OECD guideline No. 405, and in compliance with GLP, 0.1 mL of undiluted test material was instilled into the right eye of 4 female New Zealand White Rabbits. The eyes were not rinsed after the instillation of the test item.The left eye of each rabbit served as control. Animals were observed at 1, 24, 48 and 72 hours after dosing under a standard light source. The reactions in the conjunctiva (redness, chemosis and discharge), the iris and the cornea (opacity and area involved) were scored according to the Draize scale. 

 

The calculated mean score for each individual lesion for all animals within 3 scoring times (24, 48 and 72 hrs) were as follows: 0.3 for chemosis; 0.4 for redness; 0.0 for discharge, iris and corneal lesions.

The calculated mean score for each individual lesion for each individual animal within 3 scoring times (24, 48 and 72 hrs) were as follows: 0.7/0.0/0.0/0.3 for chemosis; 0.7/0.3/0.0/0.7 for redness; 0/0/0/0 for discharge, iris and corneal lesions.

The effects observed were all reversible within 72 hours.

 

Under the test conditions, the test material is not classified as irritating to eyes according to the criteria of the Annex VI of the Regulation (EC) No. 1272/2008 (CLP) and to the GHS.

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

 

Endpoint:
eye irritation: in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
[further information is included as attachment to Iuclid section 13]

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across approach is based on the hypothesis that the source and target substances have similar physico-chemical, toxicological and environmental fate properties because of their structural similarity.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The target substance is a mono-constituent substance while the source substance is a multiconstituent.

3. ANALOGUE APPROACH JUSTIFICATION
The study design (OECD 405, GLP) is adequate and reliable for the purpose of the prediction based on read-across. The test material used represents the source substance as described in the hypothesis in terms of purity and impurities. The results of the studies are adequate for the purpose of classification and labelling.
Therefore, based on the considerations above, it can be concluded that the results of the in vivo eye irritation study conducted in the rabbit with the source substance are likely to predict the properties of the target substance and are considered as adequate to fulfil the information requirement of Annex VIII, 8.2.

4. DATA MATRIX
See Iuclid section 13
Reason / purpose:
read-across source
Reason / purpose:
read-across: supporting information
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
cornea opacity score
Basis:
animal #4
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
iris score
Basis:
animal #4
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.7
Max. score:
3
Reversibility:
fully reversible within: 72h
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.3
Max. score:
3
Reversibility:
fully reversible within: 72h
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
3
Irritation parameter:
conjunctivae score
Basis:
animal #4
Time point:
24/48/72 h
Score:
0.7
Max. score:
3
Reversibility:
fully reversible within: 72h
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.7
Max. score:
4
Reversibility:
fully reversible within: 72h
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
chemosis score
Basis:
animal #4
Time point:
24/48/72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 72h
Irritant / corrosive response data:
One hour after dosing, some discharge and chemosis and definite conjunctival redness (grade 2-3) were noted in all 4 animals. Between 24 and 48 hours the irritation was reduced with only slight chemosis and/or redness in some animals. At 72 hours, no signs of irritation were detected in any animals. No corneal or iridial irritation occurred in any animal during the study.
Other effects:
No other effect

Table 7.3.2/1: Mean irritant/corrosive response data of 4 animals at each observation time up to removal from the test

 

Score at time point / Reversibility

Cornea

Iris

(/2)

Conjunctivae

Opacity

(/4)

Area

(/4)

Redness

(/3)

Chemosis

(/4)

Discharge

(/3)

1 h

0

0

0

2.25

1.50

1.25

24 h

0

0

0

0.75

0.50

0

48 h

0

0

0

0.50

0.25

0

72 h

0

0

0

0.00

0.00

0

Reversibility*)

-

-

-

c.

c.

c.

Average time (unit) for reversion

-

-

-

72 h

72 h

24 h

*) Reversibility: c. = completely reversible; n.c. = not completely reversible; n. = not reversible

Table 7.3.2/2: Individual irritant/corrosive response data at each observation time up to removal from the test

 

Score at time point / Reversibility

Cornea

Iris

(/2)

Conjunctivae

Opacity

(/4)

Area

(/4)

Redness

(/3)

Chemosis

(/4)

Discharge

(/3)

1 h

0 / 0 / 0 / 0

0 / 0 / 0 / 0

0 / 0 / 0 / 0

3 / 2 / 2 / 2

2 / 1 / 1 / 2

1 / 1 / 1 / 2

24 h

0 / 0 / 0 / 0

0 / 0 / 0 / 0

0 / 0 / 0 / 0

1 / 1 / 0 / 1

1 / 0 / 0 / 1

0 / 0 / 0 / 0

48 h

0 / 0 / 0 / 0

0 / 0 / 0 / 0

0 / 0 / 0 / 0

1 / 0 / 0 / 1

1 / 0 / 0 / 0

0 / 0 / 0 / 0

72 h

0 / 0 / 0 / 0

0 / 0 / 0 / 0

0 / 0 / 0 / 0

0 / 0 / 0 / 0

0 / 0 / 0 / 0

0 / 0 / 0 / 0

Average 24h, 48h, 72h

0 / 0 / 0 / 0

0 / 0 / 0 / 0

0 / 0 / 0 / 0

0.7 / 0.3 / 0.0 / 0.7

0.7 / 0.0 / 0.0 / 0.3

0 / 0 / 0 / 0

Reversibility*)

-

-

-

 c.

c. 

c. 

Average time (unit) for reversion

-

-

-

 72 h

72 h 

24 h 

*) Reversibility: c. = completely reversible; n.c. = not completely reversible; n. = not reversible

Interpretation of results:
GHS criteria not met
Conclusions:
Based on the available data on the analogue substance, the registered substance is not classified as irritating to eyes according to the criteria of the Annex VI of the Regulation (EC) No 1272/2008 (CLP) and of the GHS.
Executive summary:

In an eye irritation study performed according to the OECD guideline No. 405, and in compliance with GLP, 0.1 mL of undiluted test material was instilled into the right eye of 4 female New Zealand White Rabbits. The eyes were not rinsed after the instillation of the test item.The left eye of each rabbit served as control. Animals were observed at 1, 24, 48 and 72 hours after dosing under a standard light source. The reactions in the conjunctiva (redness, chemosis and discharge), the iris and the cornea (opacity and area involved) were scored according to the Draize scale. 

 

The calculated mean score for each individual lesion for all animals within 3 scoring times (24, 48 and 72 hrs) were as follows: 0.3 for chemosis; 0.4 for redness; 0.0 for discharge, iris and corneal lesions.

The calculated mean score for each individual lesion for each individual animal within 3 scoring times (24, 48 and 72 hrs) were as follows: 0.7/0.0/0.0/0.3 for chemosis; 0.7/0.3/0.0/0.7 for redness; 0/0/0/0 for discharge, iris and corneal lesions.

The effects observed were all reversible within 72 hours.

 

Based on the available data on the analogue substance, the registered substance is not classified as irritating to eyes according to the criteria of the Annex VI of the Regulation (EC) No 1272/2008 (CLP) and of the GHS.

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

 

Endpoint:
eye irritation, other
Type of information:
(Q)SAR
Adequacy of study:
supporting study
Study period:
16 November 2016
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification
Justification for type of information:
1. SOFTWARE
OASIS TIMES v.2.27.19

2. MODEL (incl. version number)

Eye Irritation v.05

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
O=C1CCCCCCCCCC/C=C\CC1

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See QMRF attached

- Defined endpoint:
Species : Rabbit, Rat
Endpoint : In vivo: eye irritation
Endpoint units : MMAS (modified maximum average score), GHS categories (Category 1, Category 2 and No category) and DSD R- phrases (R36, R41)
Dependent variable : Obs. Eye irritation/corrosion
Experimental protocol : The Draize Eye Test
Endpoint data quality and variability : High quality. Main in the chemicals used in the model possess experimental data modified maximum average score (MMAS) provided by ECETOC (Belgium) and they are publicly available in the Toolbox databases. Database consists also chemicals with GHS categories and DSD R- phrases as experimental data.

- Unambiguous algorithm:
Type of model : (Q)SAR model
Algorithm and descriptor generation : Not applicable

- Defined domain of applicability:
Description of the applicability domain of the model
The applicability domain of the eye irritation model consists of the following layers:
1. General parametric requirements - includes ranges of variation of log KOW and MW. It specifies in the domain only those chemicals that fall in the range of variation of the MW (from 46.10 to 506 Da, in this study) and log Kow (from -7.32 to 9.10, in this study) defined on the bases of the correctly predicted training set chemicals. This layer of the domain is applied only on parent chemicals.
2. Structural domain - it is represented by the list of atom - centered fragments extracted from the chemicals in the training set. The training chemicals were split into two subsets: chemicals correctly predicted by the model and incorrectly predicted chemicals. These two subsets of chemicals were used to extract characteristics determining the "good" and "bad" space of the domain. Extracted characteristics were split into three categories: unique characteristics of correct and incorrect chemicals (presented only in one of the subsets) and fuzzy characteristics presented in both subsets of chemicals. The target structure is also partitioned into atom-centered fragments and when they present in the list of extracted atom-centered fragments from the training set chemicals and satisfy the accepted thresholds the chemical is categorized as belonging to the structural domain. The default thresholds for classifying of chemicals to the structural domain of the current Eye irritation model are:
- All extracted fragments to belong to the "good" domain ("Correct" = 100%)
- All fuzzy fragments are considered as part of the "good" domain
- No fragments belonging to "bad" domain ("Incorrect" = 0%)
- No unique fragment ("Unknown" = 0%)
Structural domain is applied on parent chemicals, only.
Reliability of the inclusion rules (categories) - ratio between the number of correctly predicted chemicals and the total number of chemicals in the local training set, also is accounting in the model.
5.2 Methods used to access the applicability domain
The approach use to determine and assess the domain is described in:
Dimitrov S, Dimitrova G., Pavlov T., Dimitrova D., Patlevisz G., Niemela J., Mekenyan O., A stepwise approach for defining the applicability domain of SAR and QSAR models, J. Chem. Inf. Model., 45, 839-849 (2005).
5.3 Software name and version for applicability domain assessment
Domain Manager v1.11 (which is embedded in TIMES platform and used for determine the model applicability) developed at Laboratory of Mathematical Chemistry, University "Prof. Assen Zlatarov," 1 Yakimov Str., Bourgas 8010, BULGARIA
5.4 Limits of applicability
In order to belong to the model applicability domain a target structure must meet the requirements of all the domain layers.

- Appropriate measures of goodness-of-fit and robustness and predictivity:
Availability of the training set : Yes, but not attached
Available information for the training set : Training set consists of 119 chemicals.
Cas RN: yes
Chemicals Name: yes
SMILES: yes
Formula: yes
INChi: no
MOL file: no
Other information about the training set : The training set of the TIMES Eye irritation model v.05 consists of 147 chemicals represented by three type of data used for deriving of structural boundaries :
- MMAS values,
- GHS Categories,
- DSD R-Phrases.
Statistics for goodness-of-fit : The model performance is evaluated by the percent of correctly predicted irritants (sensitivity) – 84%. The training set of chemicals is not well balanced: from 147 chemicals 128 are positive and only 19 are experimentally observed negative irritants. In this respect, specificity of the model is not defined, given insufficiency of negatives in training set.

- Mechanistic interpretation:
Mechanistic basis of the model
Eye irritation/corrosion is the production of changes (reversible and irreversible) in the eye (abnormal alteration of the cornea, conjunctiva or iris) following the application of test substance to the anterior surface of the eye. Chemical irritation is considered to be similar to skin allergy in terms of covalent interaction with the proteins. The eye irritation is dependent on the chemical reactivity of the irritant and on its metabolites.
The irritation can also be caused by non-covalent interactions with the macromolecules (ionic, reversible denaturation of proteins, etc). Corrosion is defined as irreversible eye damage. It could be manifested as erosion of the tissues of skin and eye by strong organic acids with pH < 2 and organic bases with pH > 11.5 such as cationic surfactants, quaternary ammonium salts, sulphonium ions, etc.

5. APPLICABILITY DOMAIN
See QPRF attached

- Descriptor domain: The chemical fulfils the general properties requirements
- Structural and mechanistic domains: The following ACF are identified:
Fragments in correctly predicted training chemicals – 100.00%
Fragments in non-correctly predicted training chemicals – 0.00%
Fragments not present in the training chemicals – 0.00%
The chemical is in the interpolation structural space
- Similarity with analogues in the training set: not reported. No analogues were identified from the training set (search criteria: common organic functional groups of cycloketone and cycloalkene, similarity > 50%).
No additional comments on structural analogues are provided by the author of prediction
- Other considerations (as appropriate): Detailed information about mechanistic basis of the model underpinning the prediction is available in model QMRF, section 8.

6. ADEQUACY OF THE RESULT
OASIS TIMES evaluation showed no alerts for eye irritation. The substance is predicted to be not irritating or corrosive to the eye in vivo. This result fits well with the results of an in vivo test performed on an analogue (Toxicol, 1992, rel 2, see IUCLID section 13 for additional justification).
Reason / purpose:
reference to other study
Reason / purpose:
reference to other study
Principles of method if other than guideline:
The model predicts the eye irritation potential of organic chemicals. The model consists of categories (Inclusion rules) for eye irritation/corrosion, which are based on empirically derived structural boundaries. An extrapolation step is introduced in Eye irritation model, based on the general assumption that chemicals causing skin irritation/corrosion also damage the eye. This step looks for skin irritation/corrosion alerts when no structural alerts for eye irritation/corrosion are met.
GLP compliance:
no

Outcome: No alert found

Conclusion: Not an eye irritant

Applicability domain:

The chemical fulfils the general properties requirements

Fragments in correctly predicted training chemicals100.00%

Fragments in non-correctly predicted training chemicals0.00%

Fragments not present in the training chemicals0.00%

The chemical is in the interpolation structural space

No analogues were identified from the training set (search criteria: common organic functional groups of cycloketone and cycloalkene, similarity > 50%).

Interpretation of results:
GHS criteria not met
Conclusions:
OASIS TIMES evaluation showed no alerts for eye irritation. The substance is predicted to be not irritating to the eye in vivo.
Executive summary:

OASIS TIMES v2.27.19.13 software was used to predict the eye irritation of the substance.

OASIS TIMES evaluation showed no alerts for eye irritation. The substance is predicted to be not irritating to the eye in vivo.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation/corrosion:

No study was available on the substance itself, therefore a read-across approach was used. The supporting substance is considered adequate for read-across purposes (see IUCLID section 13 for additional justification). A key study was identified on the supporting substance (Toxicol, 1992, rel 2). This dermal irritation study was performed according to the OECD guideline No. 404, and in compliance with GLP. The study was fully reliable (Klimisch score = 1), however the reliability score was lowered to 2 which is the maximum score for read-across.

The individual scores for each animal within 3 scoring times (24, 48h and 72 hours) were 2 / 0.66 / 0.33 / 2.66 for erythema and 1.33 / 0.66 / 0.33 / 1.33 for oedema.

Under the test conditions, the test material induced a slight irritation being largely reversible within 7 days of dosing and therefore does not require classification for skin irritation.

A QSAR prediction was used as a supporting data to conclude on the in skin irritation potential of the substance. OASIS TIMES v2.27.19.13 software was used to predict the skin irritation of the substance (within the applicability domain of the model). OASIS TIMES evaluation showed no alerts for skin irritation. The substance is predicted to be not irritating or corrosive to the skin in vivo.

Eye irritation:

No study was available on the substance itself, therefore a read-across approach was used. The supporting substance is considered adequate for read-across purposes (see IUCLID section 13 for additional justification). A key study was identified on the supporting substance (Toxicol, 1992, rel. 2). This eye irritation study was performed according to the OECD guideline No. 405, and in compliance with GLP. The study was fully reliable (Klimisch score = 1), however the reliability score was lowered to 2 which is the maximum score for read-across.

The calculated mean score for each individual lesion for all 4 animals within 3 scoring times (24, 48 and 72 hrs) were as follows: 0.3 for chemosis; 0.4 for redness; 0.0 for discharge, iris and corneal lesions.

The calculated mean score for each individual lesion for each individual animal within 3 scoring times (24, 48 and 72 hrs) were as follows: 0.7/0.0/0.0/0.3 for chemosis; 0.7/0.3/0.0/0.7 for redness; 0/0/0/0 for discharge, iris and corneal lesions.

The effects observed were all reversible within 72 hours. The test material does not require classification for eye irritation.

A QSAR prediction was used as a supporting data to conclude on the in eye irritation potential of the substance. OASIS TIMES v2.27.19.13 software was used to predict the eye irritation of the substance (within the applicability domain of the model). OASIS TIMES evaluation showed no alerts for eye irritation. The substance is predicted to be not irritating or corrosive to the eye in vivo.

Justification for classification or non-classification

Harmonized classification:

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

Self-classification:

Skin irritation:

Based on the available information on the supporting substance:

- no additional self-classification is proposed for the registered substance regarding skin irritation according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP)

- the registered substance is classified as Category 3 (slight skin irritation) according to the GHS based on differences between the individual scores for each animal within 3 scoring times (24, 48 and 72 h) for erythema (2 / 0.66 / 0.33 / 2.66).

Eye irritation:

Based on the available information on the supporting substance, no additional self-classification is proposed for the registered substance regarding eye irritation according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP) and according to the GHS.

Respiratory irritation:

No data was available regarding respiratory irritation, however the substance not being classified for skin and eye irritation, no classification is expected for respiratory irritation.