Registration Dossier

Administrative data

Description of key information

GLP-compliant studies were performed to investigate to determine the potential of the registered substance to be corrosive or irritant to the skin, using the OECD Testing Guidelines 431 and 439, respectively. The test substance did not meet the criteria for classification as corrosive or irritant to the skin according to Regulation (EC) No.1272/2008.

A GLP-compliant study was performed to investigate to determine the potential of the registered substance to be damaging or irritant to the eye, using the OECD Testing Guidelines 437. The test substance did not meet the criteria for classification as damaging or irritant to the eye according to Regulation (EC) No.1272/2008.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin corrosion: in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 29 January 2019 to 6 February 2019
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 431 (In Vitro Skin Corrosion: Reconstructed Human Epidermis (RHE) Test Method)
Version / remarks:
OECD Test Guideline 431 (reconstructed human epidermis
(RHE) Test Method)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test system:
human skin model
Source species:
human
Cell type:
non-transformed keratinocytes
Details on animal used as source of test system:
N/A
Justification for test system used:
The EpiDerm TM skin model and assay for skin corrosion testing is endorsed by OECD TG 431.
Vehicle:
unchanged (no vehicle)
Details on test system:
RECONSTRUCTED HUMAN EPIDERMIS (RHE) TISSUE
- Model used: EpiDermTM (EPI-200) Reconstructed Human Epidermis
- Tissue batch number(s): 28682
- Delivery date: 05/02/2019
- Date of initiation of testing: 05/02/2019

TEMPERATURE USED FOR TEST SYSTEM
- Temperature used during treatment / exposure: 37°C

MTT DYE USED TO MEASURE TISSUE VIABILITY AFTER TREATMENT / EXPOSURE
- MTT concentration: not specified
- Incubation time: pre-incubated at 37°C for 1 hour
- Spectrophotometer: BMG LabTech FluoStar Optima
- Wavelength: 570 nm (no reference filter)

FUNCTIONAL MODEL CONDITIONS WITH REFERENCE TO HISTORICAL DATA
- Viability: 2.049 ± 0.023 OD. PASS.
- Barrier function: 5.3hrs. PASS.
- Morphology: 12 layers present, 101.2 µm tissue thickness. PASS.
- Contamination: No contamination. PASS.

NUMBER OF REPLICATE TISSUES: n=3

CONTROL TISSUES USED IN CASE OF MTT DIRECT INTERFERENCE
- Prior to the assay, the test item was checked for interference (water colouration or MTT interference) and found not to interfere.

NUMBER OF INDEPENDENT TEST SEQUENCES / EXPERIMENTS TO DERIVE FINAL PREDICTION: 3

PREDICTION MODEL / DECISION CRITERIA (choose relevant statement)
- The test substance is considered to be corrosive to skin if the viability after 3 minutes exposure is less than 50%, or if the viability after 3 minutes exposure is greater than or equal to 50 % and the viability after 1 hour exposure is less than 15%.
- Justification for the selection of the cut-off point(s) if different than recommended in TG 430: In accordance with TG 431.
Control samples:
yes, concurrent negative control
yes, concurrent positive control
Amount/concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 25 mg
- Concentration (if solution): neat
- Application: push-pin applicator

NEGATIVE CONTROL
- Amount(s) applied (volume or weight): 50 µl
- Concentration (if solution): neat

POSITIVE CONTROL
- Amount(s) applied (volume or weight): 50 µl
- Concentration (if solution): 8.0N
Duration of treatment / exposure:
3 and 60 minutes
Number of replicates:
3
Irritation / corrosion parameter:
% tissue viability
Run / experiment:
3 minutes
Value:
111.3
Vehicle controls validity:
not applicable
Negative controls validity:
valid
Positive controls validity:
valid
Irritation / corrosion parameter:
% tissue viability
Run / experiment:
60 minutes
Value:
95.24
Vehicle controls validity:
not applicable
Negative controls validity:
valid
Positive controls validity:
valid
Other effects / acceptance of results:
- OTHER EFFECTS:
- Colour interference with MTT: Checked, no interference.

ACCEPTANCE OF RESULTS:
- Acceptance criteria met for negative control: mean OD570 must be >0.8. - PASSED
- Acceptance criteria met for positive control: mean of the positive control relative percentage viability, after 1hour exposure must be < 15% of the mean of the negative control. - PASSED
- Acceptance criteria met for variability between replicate measurements: In the range between 20% and 100% viability, the coefficient of variation (CV) is an additional acceptance criterion. It should not exceed 0.3 (30%). - PASSED

see attached background documents.

Interpretation of results:
GHS criteria not met
Conclusions:
4,4’-isopropylidenediphenol, reaction products with 1-chloro-2,3-epoxypropane, mono, di and triesters with acrylic acid was evaluated for skin corrosion. The substance did not meet the criteria for classification as corrosive to the skin.
Executive summary:

A GLP-compliant in-vitro skin corrosion study was carried out on 4,4’-isopropylidenediphenol, reaction products with 1-chloro-2,3-epoxypropane, mono, di and triesters with acrylic acid using the EpiDermTM Reconstructed Human Epidermis (RHE) tissue model. The study was performed following OECD Guideline 431 (In Vitro Skin Corrosion: Human Skin Model Test). The aim of the test was establish whether 4,4’-isopropylidenediphenol, reaction products with 1-chloro-2,3-epoxypropane, mono, di and triesters with acrylic acid has or does not have a corrosive effect on skin, and to what extent. This was done for the purposes of providing a rational basis for a risk assessment.

A single topical application of 25mg of neat test item and 50µl of each reference item were applied to the surface of the EpiDermTM skin models using push-pin applicators. This was left for 3 and 60 minutes under the following conditions: 37°C, 5% CO2, ≥95% Relative Humidity. Three tissues were used per condition.

The results were that the mean tissue viability of the reconstructed human epidermis remained above 50% at 3 minutes (111.30%) and 15% at 60 minutes (95.24%). The substance did not meet the criteria for classification as corrosive to the skin in accordance with Regulation (EC) No.1272/2008.

Endpoint:
skin irritation: in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
15 May 2019 - 27 May 2019
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 439 (In Vitro Skin Irritation: Reconstructed Human Epidermis Test Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.46 (In Vitro Skin Irritation: Reconstructed Human Epidermis Model Test)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test system:
human skin model
Remarks:
EPISKIN™ Reconstructed Human Epidermis Model Kit
Source species:
human
Cell type:
non-transformed keratinocytes
Vehicle:
unchanged (no vehicle)
Details on test system:
RECONSTRUCTED HUMAN EPIDERMIS (RHE) TISSUE
- Model used: EPISKIN™ Reconstructed Human Epidermis Model Kit
- Tissue batch number(s): 19-EKIN-021
- Delivery date: 21 May 2019

TEMPERATURE USED FOR TEST SYSTEM
- Temperature used during treatment / exposure: 37°C

REMOVAL OF TEST MATERIAL AND CONTROLS
- Observable damage in the tissue due to washing: none reported

MTT DYE USED TO MEASURE TISSUE VIABILITY AFTER TREATMENT / EXPOSURE
- MTT concentration: 0.3 mg/mL MTT solution
- Incubation time: 42-Hour post-exposure incubation
- Spectrophotometer: Labtech LT-4500 microplate reader
- Wavelength: 570 nm
- Filter bandwidth: filter band pass 10 nm

FUNCTIONAL MODEL CONDITIONS WITH REFERENCE TO HISTORICAL DATA
- Viability: Pass
- Barrier function: Pass
- Morphology: Pass
- Contamination: Pass
- Reproducibility: Pass

NUMBER OF REPLICATE TISSUES: Triplicate
Control samples:
yes, concurrent negative control
yes, concurrent positive control
Amount/concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 10 mg

NEGATIVE CONTROL
- Amount(s) applied (volume or weight): 10 μL
- Concentration (if solution): >98%

POSITIVE CONTROL
- Amount(s) applied (volume or weight): 10 μL
- Concentration (if solution): 99.5%
Duration of treatment / exposure:
15 minutes
Duration of post-treatment incubation (if applicable):
42-Hour post-exposure incubation
Number of replicates:
Triplicate
Irritation / corrosion parameter:
% tissue viability
Run / experiment:
Mean value
Value:
104.2
Vehicle controls validity:
not applicable
Negative controls validity:
valid
Positive controls validity:
valid
Other effects / acceptance of results:
- OTHER EFFECTS:
- Visible damage on test system: None reported
- Direct-MTT reduction: The test item did not directly reduce MTT
- Colour interference with MTT: Colourless test item

ACCEPTANCE OF RESULTS:
- Acceptance criteria met for negative control: Pass
- Acceptance criteria met for positive control: Pass
- Acceptance criteria met for variability between replicate measurements: Pass
- Range of historical values if different from the ones specified in the test guideline: Pass
Interpretation of results:
GHS criteria not met
Conclusions:
4,4’-isopropylidenediphenol, reaction products with 1-chloro-2,3-epoxypropane, mono, di and triesters with acrylic acid (EC 948-054-2) does not meet the criteria for classification as irritant to the skin according to Regulation (EC) No.1272/2008.
Executive summary:

The in vitro skin irritation of 4,4’-isopropylidenediphenol, reaction products with 1-chloro-2,3-epoxypropane, mono, di and triesters with acrylic acid (EC 948-054-2) was determined in accordance with the OECD Guideline for Testing of Chemicals 439 during a GLP-compliant study. This in vitro risk assessment assay predicts the Skin irritation potential of a chemical by measurement of its cytotoxic effect on the EpiSkin™ tissue model.

Prior to testing, the test substance was checked for interference with water and/or MTT. No interference was identified.

Skin irritation of the test substance and controls was evaluated in triplicate. After 15 minutes exposure on the surface of the EpiSkin™ reconstructed human epidermis and a 42 post-exposure incubation time, viability of the tissues was assessed and compared to the negative control.

The percentage of viability obtained with 4,4’-isopropylidenediphenol, reaction products with 1-chloro-2,3-epoxypropane, mono, di and triesters with acrylic acid (EC 948-054-2) was 104.2%, therefore it was considered as non-irritant to the skin according to the criteria laid down in the OECD Guideline for Testing of Chemicals 439.

The test item did not meet the criteria for classification as irritant to the skin according to Regulation (EC) No.1272/2008 on the Classification, Labelling and Packaging of Substances and Mixtures.

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

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
18 April 2019
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 437 (Bovine Corneal Opacity and Permeability Test Method for Identifying i) Chemicals Inducing Serious Eye Damage and ii) Chemicals Not Requiring Classification for Eye Irritation or Serious Eye Damage)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU method B.47 (Bovine corneal opacity and permeability test method for identifying ocular corrosives and severe irritants)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Species:
cattle
Strain:
not specified
Details on test animals or tissues and environmental conditions:
Eyes from adult cattle (typically 12 to 60 months old) were obtained from a local abattoir as a by-product from freshly slaughtered animals. The eyes were excised by an abattoir employee after slaughter, and were placed in Hanks’ Balanced Salt Solution (HBSS) supplemented with antibiotics (penicillin at 100 IU/mL and streptomycin at 100 μg/mL). They were transported to the test facility over ice packs on the same day of slaughter. The corneas were prepared immediately on arrival.
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent positive control
yes, concurrent negative control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.4554 g
Duration of treatment / exposure:
240 minutes
Number of animals or in vitro replicates:
Three corneas
Details on study design:
SELECTION AND PREPARATION OF CORNEAS
The medium from both chambers of each holder was replaced with fresh complete EMEM. A pretreatment opacity reading was taken for each cornea using a calibrated opacitometer. Three corneas were randomly allocated to the negative control. Three corneas were also allocated to the test item and three corneas to the positive control item.

NUMBER OF REPLICATES
Triplicate

NEGATIVE CONTROL USED
Sodium chloride 0.9% w/v

POSITIVE CONTROL USED
Imidazole

APPLICATION DOSE AND EXPOSURE TIME
The EMEM was removed from the anterior chamber of the BCOP holder and the test item or control items were applied to the cornea. Approximately 0.4554 g of the solid test item was found to adequately cover the corneal surface. The holders were gently tilted back and forth to ensure a uniform application of the item over the entire cornea. Each holder was incubated, anterior chamber uppermost, at 32 ± 1 ºC for 240 minutes.

POST-INCUBATION PERIOD: no.

REMOVAL OF TEST SUBSTANCE
- Number of washing steps after exposure period: At least three.

METHODS FOR MEASURED ENDPOINTS:
- Corneal opacity: A post-treatment opacity reading was taken and each cornea was visually observed.
- Corneal permeability: passage of sodium fluorescein dye measured with the aid of microtiter plate reader (OD492)

SCORING SYSTEM: In Vitro Irritancy Score (IVIS)

DECISION CRITERIA: Decision criteria as indicated in the TG.
Irritation parameter:
in vitro irritation score
Run / experiment:
Mean value
Value:
2.3
Vehicle controls validity:
not applicable
Negative controls validity:
valid
Positive controls validity:
valid
Other effects / acceptance of results:
OTHER EFFECTS:
- Visible damage on test system: None reported

ACCEPTANCE OF RESULTS:
- Acceptance criteria met for negative control: Pass
- Acceptance criteria met for positive control: Pass
- Range of historical values if different from the ones specified in the test guideline: Pass
Interpretation of results:
GHS criteria not met
Conclusions:
4,4’-isopropylidenediphenol, reaction products with 1-chloro-2,3-epoxypropane, mono, di and triesters with acrylic acid (EC 948-054-2) produced an IVIS of 2.3 during an in vitro eye irritation study. The test substance does not meet the criteria for classification as irritant to the eye according to Regulation (EC) No.1272/2008.
Executive summary:

An in vitro Bovine Corneal Opacity and Permeability (BCOP) assay was performed in line with OECD Testing Guideline 437 (Bovine Corneal Opacity and Permeability Test Method) to determine the capacity of 4,4’-isopropylidenediphenol, reaction products with 1-chloro-2,3-epoxypropane, mono, di and triesters with acrylic acid to be irritant or damaging to the eye. The study was GLP-compliant.

0.4554 g of test material in was applied to three cattle corneas obtained from an abattoir, after which each cornea was incubated at 32±1°C for 240 minutes. Opacity and permeability of corneas were measured following exposition.

Negative and positive controls were performed and considered as valid.

An In Vitro Irritation Score (IVIS) of 2.3 was calculated for 4,4’-isopropylidenediphenol, reaction products with 1-chloro-2,3-epoxypropane, mono, di and triesters with acrylic acid from corneal opacity and permeability measurements. Therefore it does not meet the criteria for classification as irritant or damaging to the eye in accordance with Regulation (EC) No.1272/2008.

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

Additional information

Justification for classification or non-classification

In vitro testing was undertaken to investigate the potential of 4,4’-isopropylidenediphenol, reaction products with 1-chloro-2,3-epoxypropane, mono, di and triesters with acrylic acid (EC 948-054-2) to be corrosive or irritant to the skin, and damaging or irritant to the eye, using appropriate OECD Testing Guidelines. It was concluded that the substance did not meet the criteria for classification for these endpoints according to Regulation (EC) No.1272/2008.