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Administrative data

Description of key information

4,4`-sulphonyldiphenol is not irritating to skin and not irritating to eye.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin irritation: in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2010-03-15 to 2010-04-14
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Qualifier:
according to
Guideline:
OECD Guideline 431 (In Vitro Skin Corrosion: Human Skin Model Test)
Version / remarks:
April 13, 2004
Deviations:
no
Qualifier:
according to
Guideline:
other: OECD: Draft proposal for a new guideline on in vitro skin irritation: Human skin model test of 06-06-2008
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test system:
human skin model
Source species:
human
Cell type:
non-transformed keratinocytes
Vehicle:
unchanged (no vehicle)
Details on test system:
The EpiDermTM model consists of normal, human-derived epidermal keratinocytes which have been cultured to form a multi layered, highly differentiated model of the human epidermis. It consists of organized basal, spinous and granular layers, and a multi-layered stratum corneum containing intercellular lamellar lipid layers arranged in patterns analogous to those found in vivo. The EpiDermTM tissues (surface 0.6 cm²) are cultured on specially prepared cell culture inserts (MILLICELLs®, 10 mm ∅) and commercially available as kits (EpiDerm™ 200), containing 24 tissues on shipping agarose. Based on the results of ECVAM (European Center for Validation of Alternative Methods) funded validation studies, it was concluded by the ECVAM Scientific Advisory Committee that the EpiDerm™ human epidermis model is suitable to be used for distinguishing between corrosive and non-corrosive chemicals (ECVAM: ESAC statement on the application of the EpidermTM human skin model for skin corrosivity testing of 14-15 Mar 2000) as well as between irritant and non-irritant chemicals.
Control samples:
yes, concurrent no treatment
Amount/concentration applied:
25 µL bulk volume (about 15 mg) of test substance
Duration of treatment / exposure:
Exposure times (Corrosion test):
1. 3 minutes
2. 1 hour

Exposure times (Irritation test):
1. 1 hour
2. 42-h post incubation period
Number of replicates:
2 Tissues each for 3 min and 1 hour exposure times (corrosion test); 3 tissues for 1 hour exposure times
Details on study design:
TEST SITE
-Corrosion test:
From the day of arrival in the laboratory, tissues were kept in the refrigerator. At least 1 hour but not more than 1.5 hours before test-substance application, tissues were transferred to 6- well plates with 0.9 mL assay medium and preconditioned in the incubator at 37°C. The preincubation
medium was replaced with fresh medium immediately before application.
Two tissues per exposure time (3 minutes at room temperature or 1 hour in the incubator, as a rule) and test group (test material, negative control and positive control; 12 tissues per test) were used.
For the solid test substance, 25 μL highly de-ionized water was applied first. Thereafter, a bulk volume of 25 μL of the test material was applied with a sharp spoon and homogeneously distributed with the water.
Control tissues were concurrently applied with 50 μL of highly de-ionized water (negative control, NC) or with 50 μL of 8 n potassium hydroxide (positive control, PC).
The tissues were washed with PBS to remove residual test material 3 minutes or 1 hour after start of the application treatment. Rinsed tissues were kept in 24-well plates (holding plates) at room temperature on assay medium until all tissues per application time were dosed and rinsed. The assay medium was then replaced by MTT solution and tissues were incubated for 3 hours.
After incubation, tissues were washed with PBS and the formazan produced by the tissues was extracted with isopropanol over night at room temperature. The optical density at a wavelength of 570 nm (OD570) of the extracts was determined spectrophotometrically. Blank values were established of 6 microtiter wells filled with isopropanol for each microtiter plate.

-Irritation test:
On the day of arrival in the laboratory, the tissues were transferred to sterile 6-well plates with 0.9 mL assay medium and preconditioned in the incubator at 37°C. After 1 hour the preincubation medium was replaced with fresh medium and preconditioning continued for 18 ± 3 hours.
Three tissues were treated with the test substance, the PC and NC, respectively.
For the solid test substance, 25 μL sterile PBS was applied first. Thereafter, a bulk volume of 25 μL of the test material was applied with a sharp spoon and homogeneously distributed together with the fluid.
Control tissues were concurrently applied with 30 μL of sterile PBS (negative control, NC) or with 30 μL of 5% SDS (positive control, PC). A nylon mesh was placed carefully onto the tissue surface afterwards.
The tissues were kept under the laminar flow hood at room temperature for 25 minutes overall and for 35 minutes in the incubator.
The tissues were washed with sterile PBS to remove residual test material 1 hour after start of application. Rinsed tissues were blotted on sterile absorbent paper and transferred into new 6-well plates, pre-filled with 0.9 mL fresh medium. When all tissues were rinsed, the surface of each tissue was carefully dried with a sterile cotton swab. Subsequently, the tissues were incubated in the incubator at 37°C for 24 ± 2 hours.
After 24 ± 2 hours the tissues were transferred into new 6-well plates pre-filled with 0.9 mL of fresh medium and placed into the incubator for additional 18 ± 2 hours post-incubation period.
After the post-incubation period, the assay medium was replaced by 0.3 mL MTT solution and the tissues were incubated in the incubator for 3 hours. After incubation, the tissues were washed with PBS to stop the MTT-incubation.
The formazan that was metabolically produced by the tissues was extracted by incubation of the tissues in isopropanol for at least 2 hours at room temperature on a plate shaker. The optical density at a wavelength of 570 nm (OD570) of the extracts was determined spectrophotometrically. Blank values were established of 6 microtiter wells filled with isopropanol for each microtiter plate.
Irritation / corrosion parameter:
% tissue viability
Run / experiment:
mean, 3 min exposure
Value:
112
Irritation / corrosion parameter:
% tissue viability
Run / experiment:
mean, 1 hour exposure
Value:
105
Irritation / corrosion parameter:
% tissue viability
Run / experiment:
mean, 1 hour exposure
Value:
106
Interpretation of results:
GHS criteria not met
Conclusions:
Based on the results, it was concluded, that 4,4`-sulphonyldiphenol does not show a skin irritation potential in the EpiDermTM skin corrosion/irritation test.
Executive summary:

4,4`-sulphonyldiphenol was tested by a single topical application of 25 μL bulk volume (about 15 mg) of the test substance to a reconstructed three dimensional human epidermis model (EpiDerm™). For the corrosion test two EpiDerm™ tissue samples were incubated with the test substance for 3 minutes and 1 hour, respectively. The irritation test was performed with three EpiDerm™ tissue samples, which were incubated with the test substance for 1 hour followed by a 42-hours post-incubation period.

Tissue destruction was determined by measuring the metabolic activity of the tissue after exposure/post-incubation using a colorimetric test. The reduction of mitochondrial dehydrogenase activity, measured by reduced formazan production after incubation with a tetrazolium salt (MTT) was chosen as suitable endpoint. The formazan production of the test substance treated epidermal tissues is compared to that of negative control tissues. The quotient of the values indicates the relative tissue viability.

The EpiDerm™ skin corrosivity/irritation test showed the following results:

The test substance is not able to reduce MTT directly.

Corrosion test:

The mean viability of the test-substance treated tissues determined after an exposure period of 3 minutes was 112%, and it was 105% after an exposure period of 1 hour.

Irritation test:

The mean viability of the test-substance treated tissues determined after an exposure period of 1 hour with about 42 hours post-incubation was 106%.

Based on the results, it was concluded, that 4,4`-sulphonyldiphenol does not show a skin irritation potential in the EpiDermTM skin corrosion/irritation test.

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1984-03-02 to 1984-03-09
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
May 12, 1981
Deviations:
no
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Kleintierfarm Madoerin AG, CH-4414 Fuellinsdorf
- Age at study initiation: 12 - 14 weeks
- Weight at study initiation: 1870-1970 g
- Housing: Animals were housed individually in metal cages.
- Diet (e.g. ad libitum): Rabbit food, NAFAG, No. 814 Tox, NAFAG AG, Gossau, SG (Switzerland), ad libitum.
- Water (e.g. ad libitum): water were provided ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 3 °C
- Humidity (%): 30-70%
- Air changes (per hr): approximately 15 air changes/h
- Photoperiod (hrs dark / hrs light): 12 hours light/day
Type of coverage:
occlusive
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 g
Duration of treatment / exposure:
one application; exposure duration was 4 hours
Observation period:
1, 24, 48, 72 hours
Number of animals:
3 male animal
Details on study design:
TEST SITE
- Area of exposure: at least 6 cm2
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Other effects:
The animals showed a normal body weight development.
Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of the present experiment, 4,4`-sulphonyldiphenol was found to be non irritant and not corrosive when applied to rabbit skin.
Executive summary:

4,4`-sulphonyldiphenol was tested in an acute dermal irritation/corrosion study in rabbits according to OECD guideline 404. Not less than 24 hours before treatment on the back of the experimental animal an area was shaven of at least 6 cm2, by means of an electric clipper. A gauze patch bearing 0.5 g of the test substance was applied to the skin and loosely held in place by adhesive but non irritating tape . The substance was water moistened before application. After removal of the dressings the skin reaction was assessed on the basis of an evaluation scheme, after 1, 24, 48, 72 hours and during the following observation period. The score obtained is defined as the "index of primary cutaneous irritation". The animals showed a normal body weight development.

It can be concluded, that 4,4`-sulphonyldiphenol is non irritant and not corrosive when applied to the rabbit skin; the animals were free of findings at the 1 hour scoring. The test was finished after 3 observation days.

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

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1984-03-02 to 1984-03-13
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Kleintierfarm Madoerin AG, CH-4414 Fuellinsdorf
- Age at study initiation: 12-14 weeks
- Weight at study initiation: 2090 - 2260 g
- Housing: individually in metal cages
- Diet (e.g. ad libitum): rabbit food NAFAG No. 814, NAFAG AG, Gossau SG (Switzerland); ad libitum
- Water (e.g. ad libitum): water ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 3°C
- Humidity (%): 30-70 %
- Air changes (per hr): 15 air changes/h
- Photoperiod (hrs dark / hrs light): 12 hours light/day
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 g of the test substance
Duration of treatment / exposure:
one application
Observation period (in vivo):
1, 24, 48 and 72 hours
Number of animals or in vitro replicates:
3 female rabbits
Details on study design:
The ocular reactions were examined 1, 24, 48 and 72 hours after substance instillation and again during the following observation period by means of a slit-lamp.
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 72 h
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 72h
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
2
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
2
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
2
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
2
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1.33
Max. score:
3
Reversibility:
fully reversible within: 72 h
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1.33
Max. score:
3
Reversibility:
fully reversible within: 72 h
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
2
Max. score:
3
Reversibility:
fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
1.55
Max. score:
3
Reversibility:
fully reversible within: 7 days
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1.33
Max. score:
4
Reversibility:
fully reversible within: 72 h
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1.33
Max. score:
4
Reversibility:
fully reversible within: 72 h
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1.33
Max. score:
4
Reversibility:
fully reversible within: 72 h
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
1.33
Max. score:
4
Reversibility:
fully reversible within: 72 h
Other effects:
The animals showed a normal body weight development.
Interpretation of results:
GHS criteria not met
Conclusions:
Based on the scores obtained, 4,4`-sulphonyldiphenol has not to be classified as irritant and corrosive when applied to rabbit eye mucosa The animals had recovered at the end of the observation period of 7 days.
Executive summary:

4,4`-sulphonyldiphenol was tested in an acute eye irritation/corrosion study in New Zealand White rabbits according to OECD guideline 405. 0.1 g of 4,4`-sulphonyldipenol was placed into the conjunctival sac of the right eye of each animal, after gently pulling away the lower lid from eyeball. The lids were then held together for about one second in order to prevent loss of the test material. The left eye remained untreated and served as a control. Based on the scores obtained, 4,4`-sulphonyldiphenol has not to be classified as irritant and corrosive when applied to rabbit eye mucosa The animals had recovered at the end of the observation period of 7 days.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation:

In the first key study (BASF, 2010), 4,4`-sulphonyldiphenol was tested by a single topical application of 25 μL bulk volume (about 15 mg) of the test substance to a reconstructed three dimensional human epidermis model (EpiDerm™) according OECD guideline 431. For the corrosion test two EpiDerm™ tissue samples were incubated with the test substance for 3 minutes and 1 hour, respectively. The irritation test was performed with three EpiDerm™ tissue samples, which were incubated with the test substance for 1 hour followed by a 42-hours post-incubation period.

Corrosion test: The mean viability of the test-substance treated tissues determined after an exposure period of 3 minutes was 112%, and it was 105% after an exposure period of 1 hour. Irritation test: The mean viability of the test-substance treated tissues determined after an exposure period of 1 hour with about 42 hours post-incubation was 106%. Based on the results, it was concluded, that 4,4`-sulphonyldiphenol does not show a skin irritation potential in the EpiDermTM skin corrosion/irritation test.

In the second key study (CIBA-Geigy LTD., 1984), 4,4`-sulphonyldiphenol was tested in an acute dermal irritation/corrosion study in rabbits according to OECD guideline 404. Not less than 24 hours before treatment on the back of the experimental animal an area was shaven of at least 6 sq. cm, by means of an electric clipper. A gauze patch bearing 0.5 g of the test substance was applied to the skin and loosely held in place by adhesive but non irritating tape. The substance was water moistened before application. After removal of the dressings the skin reaction was assessed on the basis of an evaluation scheme, after 1, 24, 48, 72 hours and during the following observation period. The animals showed a normal body weight development. It can be concluded, that 4,4`-sulphonyldiphenol is non irritant and not corrosive when applied to the rabbit skin; all animals were free of findings at all scorings. The test was finished after 3 observation days.

The supporting study for skin irritation (Monsanto, 1961) was performed similar to the OECD guideline with occlusive coverage. No edema or erythema developed on any of the application sites as a result of the 24 h exposure (Draize score = 0).

Slight skin irritation was observed in 5 guinea pigs with occlusive coverage of the test substance for 24 hours (Eastman-Kodak, 1983). However, no individual scores are reported in order to evaluate the relevance for classification but based on the information available the effects noted were most likely marginal even under these harsh test conditions (24 h occlusive patch). Additionally, no irritation responses were observed in the skin tissue of the ear of rabbits after application of the test substance for 24 h (Bayer, 1979).

Combining the available animal data, 4,4`-sulphonyldiphenol is not a skin irritant.

Based on the results of the two key studies and the one supporting study, no classification is required according to EU and GHS standards.

Eye irritation:

In the key study (CIBA-Geigy, 1984), 4,4`-sulphonyldiphenol was tested in an acute eye irritation/corrosion study in New Zealand White rabbits (3 females) according to OECD guideline 405. 4,4`-sulphonyldipenol was placed into the conjunctival sac of the right eye of each animal, after gently pulling away the lower lid from eyeball. The lids were then held together for about one second in order to prevent loss of the test material. The left eye remained untreated and served as a control.

4,4`-sulphonyldiphenol showed slighly irritant effects, which were fully reversible within 7 days when applied to rabbit eye mucosa. No corrosive effects were observed. The mean scores for cornea (0.33), iris (0), conjunctivae (1.55) and chemosis (1.33) were below the threshold values defined by DSD and GHS and are well known observations following ocular application of solid test substances with a low solubility.

The supporting study for eye irritation was performed similar to the OECD guideline 405 though only 50 mg of test substance were applied (Bayer, 1979). The test substance was applied to the conjunctival sac of the eyes of 2 rabbits (1 male and 1 female) and observed for 7 days. No irritation responses were observed (Draize score = 0, except for conjunctivae = 0.17; time points 24, 48 and 72 hours).

Slight irritation was observed in the eyes of 3 rabbits after application of several crystals of the chemical and the eye returned to normal at approximately 48 hours after application but no scores were given that allow an assessment according to DSD and GHS criteria (Eastman-Kodak, 1983).

Similarly, mild eye irritation was observed after application of the test substance for 24 h (Monsanto, 1961). Individual Draize scores of each irritation parameter were also not reported in this study, but the general description (mild effects) fits to the key study and other studies at hand and supports the overall conclusion that based on all data available no classification with regard to eye irritation is needed.

Justification for classification or non-classification

Skin:

Based on the results, 4,4`-sulphonyldiphenol is classified as not irritating according to EU Directive 67/548/EC (DSD) and Regulation No 1272/2008 (CLP ,GHS).

Eye:

Based on the results, 4,4`-sulphonyldiphenol is classified as not irritating according to EU Directive 67/548/EC (DSD) and Regulation No 1272/2008 (CLP ,GHS).