Registration Dossier

Administrative data

Description of key information

Skin irritation/corrosion: not irritating (OECD 439, GLP, K, rel. 1).

Eye irritation: not irritating (read-across, OECD 405, GLP, K, rel. 2 and ToxTree prediction, S, rel. 4)

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 16 to 21 September 2015
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 439 (In Vitro Skin Irritation: Reconstructed Human Epidermis Test Method)
Version / remarks:
Adopted 28 July 2015
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.46 (In Vitro Skin Irritation: Reconstructed Human Epidermis Model Test)
Deviations:
no
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes (incl. certificate)
Remarks:
UK GLP Compliance Program (inspected on June 17, 2015 / Signed on September 24, 2015)
Specific details on test material used for the study:
Storage condition of test material: Room temperature in the dark
Test system:
human skin model
Source species:
human
Cell type:
non-transformed keratinocytes
Justification for test system used:
Following the REACH bottom-up strategy, the EPISKIN™ Reconstructed Human Epidermis Model method was used to assess skin irritation as recommended in the OECD test guideline No. 439.
Vehicle:
unchanged (no vehicle)
Details on test system:
RECONSTRUCTED HUMAN EPIDERMIS (RHE) TISSUE
- Model used: EPISKIN™ Reconstructed Human Epidermis Model Kit, SkinEthic Laboratories, Lyon, France
- Tissue batch number(s): 15-EKIN-037
- Production date: not reported
- Shipping date: 15 September 2015
- Delivery date: 15 September 2015
- Expiry date: 21 September 2015
- Date of initiation of testing: 16 September 2015

TEMPERATURE USED FOR TEST SYSTEM
- Temperature used during treatment / exposure: room temperature
- Temperature of post-treatment incubation (if applicable): 37°C

REMOVAL OF TEST MATERIAL AND CONTROLS
- Volume and number of washing steps: not reported. At the end of the treatment period, each tissue was rinsed with Dulbeccos Phosphate Buffered Saline (DPBS) with Ca++ and Mg++ to remove any residual test or control items and then incubated in 2mL maintenance medium for 42 h at 37 °C, 5 % CO2 in air.
- Observable damage in the tissue due to washing: none reported
- Modifications to validated SOP: none reported

MTT DYE USED TO MEASURE TISSUE VIABILITY AFTER TREATMENT / EXPOSURE
- MTT concentration: 0.3 mg/mL
- Incubation time: 3 hours
- Spectrophotometer: Anthos 2001 microplate reader
- Wavelength: 562 nm (without a reference filter)
- Filter: not appicable
- Filter bandwidth: not applicable
- Linear OD range of spectrophotometer: no data reported

FUNCTIONAL MODEL CONDITIONS WITH REFERENCE TO HISTORICAL DATA
- Viability: negative control OD values: 0.722, 0.732 and 0.702 (mean historical OD of the negative control was 0.854 ± 0.148)
- Barrier function: IC50 = 1.9 mg/ml ( ≥ 1.5 mg/ml)
- Morphology: Well-differenciated epidermis consisting of a basal layer, several spinous and granular layers and a thinck stratum corneum
- Contamination: absence of bacteria, fungus and mycoplasma
- Reproducibility: For the previous 28 experiments conducted between 09 March 2015 and 14 September 2015 using this test method, the mean OD of the positive control was 0.091 ± 0.037 and the mean percentage viability was 10.5 ± 4.8 (The assay establishes the acceptance criterion for an acceptable test if the relative mean tissue viability for the positive control treated tissues was ≤40% relative to the negative control treated tissues, and the standard deviation value of the percentage viability is ≤18%). In this same period the mean OD of the negative control was 0.854 ± 0.148 (The assay establishes the acceptance criterion for an acceptable test if the mean OD 562 for the negative control treated tissues was ≥0.6 and ≤1.5).

CONTROL TISSUES USED IN CASE OF MTT DIRECT INTERFERENCE: not applicable

NUMBER OF INDEPENDENT TEST SEQUENCES / EXPERIMENTS TO DERIVE FINAL PREDICTION: 1

PREDICTION MODEL / DECISION CRITERIA (choose relevant statement)
- The test substance is considered to be irritating to skin if relative mean tissue viability is ≤ 50% after 15 minutes of exposure.
- The test substance is considered to be non-irritating to skin if relative mean tissue viability is > 50% after 15 minutes of exposure.
Control samples:
yes, concurrent negative control
yes, concurrent positive control
Amount/concentration applied:
TEST MATERIAL
- The test item was used as supplied (undiluted).
- Amount(s) applied (volume or weight with unit): 10 µL (26.3 µL /cm2) of the test item was applied to the epidermis surface.

NEGATIVE CONTROL
- Amount(s) applied (volume or weight): 10 µL

POSITIVE CONTROL
- Amount(s) applied (volume or weight): 10 µL
- Concentration (if solution): Sodium Dodecyl Sulphate (SDS) at a 5% (w/v) aqueous solution
Duration of treatment / exposure:
The EpiSkin™ human epidermis skin constructs were treated with the undiluted test item for an exposure period of 15 minutes.
Duration of post-treatment incubation (if applicable):
At the end of the exposure period, tissues were rinsed and incubated at 37 °C, 5% CO2 in air for 42 h.
Number of replicates:
Triplicate tissues for test item, negative and positive controls
Irritation / corrosion parameter:
% tissue viability
Run / experiment:
15 minute exposure period and 42 h post-exposure incubation period
Value:
104
Vehicle controls validity:
not applicable
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
no indication of irritation
Other effects / acceptance of results:
- OTHER EFFECTS:
- Visible damage on test system: no
- Direct-MTT reduction: no
- Colour interference with MTT: no

DEMONSTRATION OF TECHNICAL PROFICIENCY: yes

ACCEPTANCE OF RESULTS:
- Acceptance criteria met for negative control: yes
- Acceptance criteria met for positive control: yes
- Acceptance criteria met for variability between replicate measurements: yes

Direct MTT Reduction: The MTT solution containing the test item did not turn blue which indicated that the test item did not directly reduce MTT.

 

Assessment of Color Interference with the MTT endpoint: The solution containing the test item was colorless. It was therefore unnecessary to run color correction tissues.

 

Table 7.3.1/1: Mean OD562Values and Percentage Viabilities for the Negative Control Item, Positive Control Item and Test Item 

 

Item

OD562 of tissues

Mean OD562 of triplicate tissues

±SD of OD562

Relative individual tissue viability (%)

Relative mean viability (%)

± SD of Relative mean viability (%)

Negative Control Item

0.722

0.719

0.015

100.4

100*

2.1

0.732

101.8

0.702

97.6

Positive Control Item

0.085

0.082

0.006

11.8

11.4

0.9

0.075

10.4

0.087

12.1

Test Item

0.751

0.748

0.021

104.5

104.0

2.9

0.768

106.8

0.726

101.0

 

SD=Standard deviation; *= The mean viability of the negative control tissues is set at 100%; OD562= Optical Density

 

Assay validity

The relative mean tissue viability for the positive control treated tissues was 11.4% relative to the negative control treated tissues and the standard deviation value of the viability was 0.9%. The positive control acceptance criteria were therefore satisfied.

The mean OD562 for the negative control treated tissues was 0.719 and the standard deviation value of the viability was 2.1%. The negative control acceptance criteria were therefore satisfied.

The standard deviation calculated from individual tissue viabilities of the three identically test item treated tissues was 2.9%. The test item acceptance criterion was therefore satisfied.

Interpretation of results:
GHS criteria not met
Conclusions:
Under the test conditions, the test item is not classified as a skin irritant according to Regulation (EC) No. 1272/2008 (CLP) and to the GHS.
Executive summary:

An in vitro skin irritation study was performed according to the OECD Guideline 439 and in compliance with GLP, using the EPISKINTM reconstructed human epidermis model. The principle of the assay is based on the measurement of cytotoxicity in reconstructed human epidermal cultures following topical exposure to the test item.  Triplicate tissues were treated with 10 μL (26.3 μL/cm2) of the undiluted test item for an exposure period of 15 minutes. At the end of the exposure period each tissue was rinsed before incubating for 42 h. The cell viability was determined by mitochondrial dehydrogenase activity, assessed by the reduction of MTT (3-(4,5-dimethylthiazol-2-yl)-2, 5‑diphenyltetrazolium bromide) to a soluble, coloured, formazan product. The prediction model uses the percentage viability values (compared to negative control viability) to identify irritant and non-irritant substances.

 

This assay was valid with negative and positive controls showing results within the acceptable range.

The test substance with a mean tissue viability of 104.0 ± 2.9 %, was predicted as non-irritant to the skin. The quality criteria required for acceptance of results in the test were satisfied.

 

Under the experimental conditions of this study, the test item is not classified as a skin irritant according to 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

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:
conjunctivae score
Remarks:
(redness)
Basis:
mean
Remarks:
(4 animals)
Time point:
24/48/72 h
Score:
0.4
Max. score:
3
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: 0.7/0.3/0.0/0.7
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
(4 animals)
Time point:
24/48/72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: 0.7/0.0/0.0/0.3
Irritation parameter:
other: discharge
Basis:
mean
Remarks:
(4 animals)
Time point:
24/48/72 h
Score:
0
Max. score:
3
Irritation parameter:
cornea opacity score
Remarks:
(opacity)
Basis:
mean
Remarks:
(4 animals)
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
cornea opacity score
Remarks:
(area)
Basis:
mean
Remarks:
(4 animals)
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
mean
Remarks:
(4 animals)
Time point:
24/48/72 h
Score:
0
Max. score:
2
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

Average 24h, 48h, 72h

0

0

0

0.31

0.25

0

Reversibility*)

-

-

-

c.

c.

-

Average time 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 substance 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 substances while the source substance 1 is a multi-constituent.

3. ANALOGUE APPROACH JUSTIFICATION
The source 1 substance is expected to be a worst-case compared to the target substance considering the respective physico-chemical and toxicological properties.
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 1 substance are likely to predict the properties of the target substance and are considered as adequate to fulfil the information requirement of Annex VIII, 8.6.2.

4. DATA MATRIX
See Iuclid section 13
Reason / purpose:
read-across source
Reason / purpose:
read-across: supporting information
Irritation parameter:
conjunctivae score
Remarks:
(redness)
Basis:
mean
Remarks:
(4 animals)
Time point:
24/48/72 h
Score:
0.4
Max. score:
3
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: 0.7/0.3/0.0/0.7
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
(4 animals)
Time point:
24/48/72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: 0.7/0.0/0.0/0.3
Irritation parameter:
other: discharge
Basis:
mean
Remarks:
(4 animals)
Time point:
24/48/72 h
Score:
0
Max. score:
3
Irritation parameter:
cornea opacity score
Remarks:
(opacity)
Basis:
mean
Remarks:
(4 animals)
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
cornea opacity score
Remarks:
(area)
Basis:
mean
Remarks:
(4 animals)
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
mean
Remarks:
(4 animals)
Time point:
24/48/72 h
Score:
0
Max. score:
2
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

Average 24h, 48h, 72h

0

0

0

0.31

0.25

0

Reversibility*)

-

-

-

c.

c.

-

Average time 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 source 1 substance, the target 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 source 1 substance 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 source 1 substance, the target 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:
02 February 2017
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
results derived from a (Q)SAR model, with limited documentation / justification
Remarks:
Regulatory accepted model for assessment of chemical substances
Justification for type of information:
1. SOFTWARE
Toxtree ((Estimation of Toxic Hazard –A Decision Tree Approach)

2. MODEL (incl. version number)
Version 2.6.13

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
CC1CCCCCCCCCCCCC(=O)C1

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See QPRF attached. The corresponding QMRF was not available
- Defined endpoint: Eye irritation and corrosion. Estimates eye irritation and corrosion potential by physicochemical property ranges and structural rules.
- Unambiguous algorithm: Toxtree ((Estimation of Toxic Hazard –A Decision Tree Approach) Version 2.6.13. Based on Gerner, I., Liebsch, M., Spielmann, H. (2005). Assessment of the eye irritating properties of chemicals by applying alternatives to the Draize rabbit eye test: the use of QSARs and in vitro tests for the classification of eye irritation. Alternatives to Laboratory Animals 33, 215-237.
- Defined domain of applicability: Not applicable
- Appropriate measures of goodness-of-fit and robustness and predictivity: not applicable
- Mechanistic interpretation: not available

5. APPLICABILITY DOMAIN
See QMRF attached
- Descriptor domain: Based on Gerner, I., Liebsch, M., Spielmann, H. (2005). Assessment of the eye irritating properties of chemicals by applying alternatives to the Draize rabbit eye test: the use of QSARs and in vitro tests for the classification of eye irritation. Alternatives to Laboratory Animals 33, 215-237.
- Structural and mechanistic domains: The chemical has a simple structure and do not contain fragments that are not represented in the model training set.
- Similarity with analogues in the training set: Not available
- Other considerations (as appropriate): None

6. ADEQUACY OF THE RESULT
ToxTree evaluation showed no alerts for eye irritation. The substance is predicted to be not irritating or corrosive to the eye. 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 decision logic is based on Eye irritation Alerts: Assessment of the eye irritating properties of chemicals by applying alternatives to the Draize rabbit eye test: the use of QSARs and in vitro tests for the classification of eye irritation (Gerner et al., 2005)
The model estimates eye irritation and corrosion potential by physicochemical property ranges and structural rules.
GLP compliance:
no

Eye irritation or damage alerts:

-       Melting Point [℃] > 200: No  

-       LogP > 9.0: No  

-       LogP -3.1: No  

-       Lipid Solubility 0.01: No  

-       Water Solubility: 5.0 E-6 Yes. Class NOT eye irritating

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

Toxtree ((Estimation of Toxic Hazard –A Decision Tree Approach) Version 2.6.13 software was used to predict the eye irritation of the substance.

ToxTree evaluation showed no alerts for eye irritation. The substance is predicted to be not irritating to the eye.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation/corrosion:

Since no key study was identified on the registered substance, the testing and assessment strategy, as described in ECHA R.7a Endpoint specific guidance (December 2016), was used to evaluate the skin corrosion/irritation potential of the registered substance:

 

Element

Information

Conclusion

Comments

Existing data on physico
- chemical properties

1a

Is the substance spontaneously flammable in contact with air (pyrophoric) or water at room temperature?

NO

 

1b

Is the substance an organic hydroperoxide or an organic peroxide?

NO

 

1c

Is the pH of the substance ≤ 2.0 or ≥ 11.5?

NO

 

1d

Are there other physical or chemical properties that
indicate that the substance is corrosive/irritant?

NO

 

Existing human data

2

Are there adequate existing human data which provide evidence that the substance is a corrosive
or irritant?

NO

No irritation was observed in the existing human patch test. However, the substance was not applied undiluted, and therefore these results were not considered adequate

Existing animal data from corrosion/irritation studies

3

Are there data from existing studies on corrosion and irritation in laboratory animals, which provide sound conclusive evidence that the substance is a corrosive, irritant or non-irritant?

NO

 

Existing data from general toxicity studies via the dermal route and from sensitisation studies

4a

Is the substance classified as fatal in contact with skin (LD50 ≤ 50 mg/kg bw, CLP hazard statement
H310)

NO

Dermal LD50 > 5000 mg/kg bw

4b

Has the substance proven to be a corrosive, irritant or non-irritant in a suitable acute dermal toxicity test?

NO

Dermal irritation was reported in the acute dermal toxicity test, but scores were not reported, therefore a conclusion was not possible

4c

Has the substance proven to be a corrosive or an irritant in sensitisation studies or after repeated
exposure?

NO

 

Existing/new (Q)SAR data and read
-across

5a

Are there structurally related substances (suitable “read-across” or grouping), which are classified as corrosive to the skin (Skin Corrosive Cat. 1), or do suitable (Q)SAR methods indicate corrosion
potential of the substance?

NO

 

5b

Are there structurally related substances (suitable “read-across” or grouping), which are classified as irritant to the skin (Skin Irritant Cat. 2), or indicating that the substance is non-irritant, or do suitable (Q)SAR methods indicate irritant or non-irritant potential of the substance?

NO

Predicted to be "not irritating to Skin" using Toxtree (v2.6.6)

Existing in vitro data

6a

Has the substance demonstrated corrosive properties in an EU/OECD adopted in vitro test?
Data from in vitro test methods that have been validated and are considered scientifically valid but
are not yet adopted by EU and/or OECD may also be used if the provisions defined in Annex XI are met

NO

 

6b

Has the substance demonstrated irritant or non-irritant properties in an EU/OECD adopted
in vitro test?
Data from in vitro test methods that have been validated and are considered scientifically valid but
are not yet adopted by EU and/or OECD may also be used if the provisions defined in Annex XI are
met.

NO

(at the initiation of the dossier, no test was available)

6c

Are there data from a non-validated suitable in vitro test(s), which provide sound conclusive evidence that the substance is corrosive/ irritant?

NO

 

Weight-of- Evidence analysis

7

The “elements” described above may be arranged as appropriate. Taking all available existing and
relevant data mentioned above (Elements 1-6) into account, is there sufficient information to make a decision on whether classification/labelling is necessary, and –if so –how to classify and label?

NO

 

New in vitro test for corrosivity

8

Does the substance demonstrate corrosive properties in (an) EU/OECD adopted in vitro test(s) for skin corrosion?

NO

Based on all available data, the substance is not considered as a skin corrosive => a skin corrosion assay was not required

New in vitro test for irritation

9

Does the substance demonstrate irritating or non-irritating properties in (an) EU/OECD adopted in vitro test(s) for skin irritation?

YES

 => an Episkin test for irritation was initiated.
The conclusion of this Episkin test is sufficient to conclude on C&L (viability = 104% <=> Not a skin irritant)

New in vivo test for corrosion/irritation

10

To be used only as a last resort

NO

In vivo testing should not be conducted in this case since the substance falls under the scope of the specific in vitro tests performed, and there are no substance-specific limitations on use of those tests.

The purpose of the newly performed in vitro test (Envigo, 2016, rel.1) was to evaluate the skin irritation potential of the test item using the EPISKIN reconstructed human epidermis model after a treatment period of 15 minutes followed by a post-exposure incubation period of 42 hours.

This test was performed in compliance with GLP. The quality criteria required for acceptance of results in the test were satisfied. The relative mean viability of the test item-treated tissues was 104.0 ± 2.9 %, after the 15‑minute exposure period. With a tissue viability > 50%, the registered substance was considered to be non-irritating to skin.

Eye irritation:

No study was available on the substance itself, therefore a read-across approach was used. The source substance is considered adequate for read-across purposes (see IUCLID section 13 for additional justification). A key study was identified on the source 1 substance (Toxicol, 1992, rel. 1). 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.

The QSAR ToxTree did not show any alert for eye irritation with the substance.

Based on the whole data, it can be concluded that the substance is not expected to be an eye irritant.

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, 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). Based on the irritation observed in an acute dermal toxicity study, the substance is classified as a worst-case in Category 3 (mild skin irritation) according to the GHS.

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, however the substance not being classified for skin and eye irritation, no classification is expected for respiratory irritation.