3,3'-sulphonyldianiline

Endpoint summary

Description of key information

An OECD 404 study was performed under GLP conditions with the substance and the P.I.I was determined to be 0.

An Bovine Corneal Opacity OECD 437 study was also performed under GLP conditions and the GHC criteria for classification were not met.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

The study was conducted between 01 November 2016 and 04 November 2016

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

See attachment in section 13.

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Version / remarks:

28 July 2015

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Version / remarks:

EC 440/2008

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Strain:

New Zealand White

Remarks:

Hsdlf:NZW strain

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Envigo RMS (UK) Limited, Leicestershire, UK.
- Age at study initiation: 15 - 52 weeks
- Weight at study initiation: 4.09 - 4.11 kg
- Housing: individually housed in suspended cages
- Diet (e.g. ad libitum): ad libitum (2930C Teklad Global Rabbit diet supplied by Envigo RMS (UK) Limited, Oxon, UK)
- Water (e.g. ad libitum): adlibitum
- Acclimation period: >5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 - 23”C
- Humidity (%): 30 - 70%
- Air changes (per hr): >15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 01 November 2016 To: 04 November 2016

Type of coverage:

occlusive

Preparation of test site:

clipped

Remarks:

Clipped free of fur from the dorsal/flank area using veterinary clippers. Only animals with a healthy intact epidermis by gross observation were selected for the study.

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

On the day of the test a suitable test site was selected on the back of each rabbit. At each test site a quantity of 0.5 g of the test item, moistened sufficiently with 0.5 mL of distilled water, was introduced under a 2.5 cm x 2.5 cm cotton gauze patch. The patch was secured in position with a strip of surgical adhesive tape. To prevent the animals interfering with the patches, the trunk of each rabbit was wrapped in an elasticated corset and the animals were returned to their cages for the duration of the exposure period

Duration of treatment / exposure:

4 h

Observation period:

72 h

Number of animals:

2

Details on study design:

Study Design
On the day before the test each of a group of two rabbits was clipped free of fur from the dorsal/flank area using veterinary clippers. Only animals with a healthy intact epidermis by gross observation were selected for the study.
On the day of the test a suitable test site was selected on the back of each rabbit. At each test site a quantity of 0.5 g of the test item, moistened sufficiently with 0.5 mL of distilled water, was introduced under a 2.5 cm x 2.5 cm cotton gauze patch. The patch was secured in position with a strip of surgical adhesive tape. To prevent the animals interfering with the patches, the trunk of each rabbit was wrapped in an elasticated corset and the animals were returned to their cages for the duration of the exposure period.
Four hours after application the corset and patches were removed from each animal and any residual test item removed by gentle swabbing with cotton wool soaked in distilled water.
Immediately following removal of the patches and approximately 1, 24, 48 and 72 hours later, the test sites were examined for evidence of primary irritation and scored according to the scale below (Ta ble 1).:

Any other skin reactions and clinical signs of toxicity, if present, were also recorded.
Individual body weights were recorded on Day 0 (the day of dosing) and at the end of the observation period.

Data Evaluation
The scores for erythema and edema at the 24 and 72 Hour readings were totaled for the two test rabbits (8 values) and this total was divided by 4 to give the primary irritation index of the test item. The test item was classified according to the following scheme devised by Draize, J.H. (1959):
Primary Irritation Index Classification of Irritancy
0 Non-irritant
> 0 to 2 Mild irritant
> 2 to 5 Moderate irritant
> 5 to 8 Severe irritant
If irreversible alteration of the dermal tissue is noted in any rabbit, as judged by the Study Director, which include ulceration and clear necrosis or signs of scar tissue, the test item is classified as corrosive to rabbit skin. Classification according to Draize may, therefore, not be applicable.
The results were also evaluated according to the Globally Harmonized System of Classification and Labelling of Chemicals.

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

animal #1

Time point:

72 h

Score:

<= 0

Max. score:

0

Reversibility:

other: Not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

animal #2

Time point:

72 h

Score:

<= 0

Max. score:

0

Reversibility:

other: Not applicable

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

No evidence of skin irritation was noted during the study

Other effects:

One animal showed body weight loss and the other animal showed expected gain in body weight during the study.

Individual Skin Reactions:

Skin Reaction	Observation Time (following patch removal)	Individual Scores		Total
		75628 Female	75629 Female
	Immediately	0	0	(0)
Erythema/Eschar Formation	1 Hour	0	0	(0)
	24 Hours	0	0	(0)
	48 Hours	0	0	(0)
	72 Hours	0	0	(0)
	Immediately	0	0	(0)
Edema Formation	1 Hours	0	0	(0)
	24 Hours	0	0	(0)
	48 Hours	0	0	(0)
	72 Hours	0	0	(0)

 Sum of 24 and 72 Hour Readings (S) :  0

 Primary Irritation Index (S/4)              :  0/4 = 0.0

 Classification                                    :  MILD IRRITANT    

                    

  Individual Body Weights and Body Weight Changes:

Rabit Number and Sex	Individual Body Weight (kg)		BOdy Weight Change (kg)
	Day 0	Day 3
75628 Female	4.11	4.18	0.07
75269 Female	4.09	4.06	-0.03

Interpretation of results:

GHS criteria not met

Conclusions:

The test item produced a primary irritation index of 0.0 and was classified as non irritant to rabbit skin according to the Draize classification scheme.
The test item does not meet the criteria for classification according to the Globally Harmonized System of Classification and Labelling of Chemicals.

Executive summary:

The study was performed to assess the irritancy potential of the test item to the skin of the New Zealand White rabbit.

Results

A single 4 Hour, semi occluded application of the test item to the intact skin of two rabbits produced no evidence of skin irritation.  

Conclusion

The test item produced a primary irritation index of 0.0 and was classified as non irritant to rabbit skin according to the Draize classification scheme.  

The test item does not meet the criteria for classification according to the Globally Harmonized System of Classification and Labelling of Chemicals.

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:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

Experimental start and completion date: 27 January 2015

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

See attachment in section 13.

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

OECD Guideline 437 (Bovine Corneal Opacity and Permeability Test Method for Identifying Ocular Corrosives and Severe Irritants)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Species:

other: Eyes from adult 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:

other: 20% w/v solution in 0.9% w/v sodium chloride solution.

Controls:

no

Amount / concentration applied:

For the purpose of this study the test item was prepared as a 20% w/v solution in 0.9% w/v sodium chloride solution.

The test item was formulated within two hours of being applied to the test system. It is assumed that the formulation was stable for this duration.

No analysis was conducted to determine the homogeneity, concentration or stability of the test item formulation. This is an exception with regard to GLP compliance statement.

Duration of treatment / exposure:

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.

Observation period (in vivo):

Not applicable

Number of animals or in vitro replicates:

Not applicable

Details on study design:

Study Design
Preparation of Corneas
All eyes were macroscopically examined before and after dissection. Only corneas free of damage were used.
The cornea from each selected eye was removed leaving a 2 to 3 mm rim of sclera to facilitate handling. The iris and lens were peeled away from the cornea. The isolated corneas were immersed (epithelial side uppermost) in a dish containing HBSS until they were mounted in Bovine Corneal Opacity and Permeability (BCOP) holders.
The anterior and posterior chambers of each BCOP holder were filled with complete Eagle’s minimum essential medium (MEM) and plugged. The holders were incubated at 32 ± 1 ºC for 60 minutes. At the end of the incubation period each cornea was examined for defects. Only corneas free of damage were used.


Selection of Corneas and Opacity Reading
The medium from both chambers of each holder was replaced with fresh complete MEM.
A pre treatment opacity reading was taken for each cornea using a calibrated opacitometer. The average opacity for all corneas was calculated.
Three corneas with opacity values close to the median value of all corneas were allocated to the negative control. Three corneas were also allocated to the test item and three corneas to the positive control item.

Treatment of corneas:
The MEM was removed from the anterior chamber of the BCOP holder and 0.75 ml of the test item preparation or control items were applied to the appropriate corneas.
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.
At the end of the exposure period the test item preparation and control items were removed from the anterior chamber and the corne was rinsed three times with fresh complete MEM containing phenol red before a final rinse with complete MEM. The anterior and posterior chambers were refilled with fresh complete MEM. A post treatment opacity reading was taken and each cornea was visually observed.


Preparation of negative and positive control items.
The negative control item, 0.9 % w/v sodium chloride solution, was used as supplied.
The positive control item, Imidazole, was used as a 20% w/v solution in 0.9% w/v sodium chloride solution.

Irritation parameter:

other: Corneal opacity and permeability

Basis:

other: Cornea (average of three)

Score:

0.6

Reversibility:

not specified

Remarks on result:

other: In vitro irritancy score

Irritant / corrosive response data:

The corneas treated with the test item were clear post treatment. The corneas treated with the negative control item were clear post treatment. The corneas treated with the positive control item were cloudy post treatment.

Other effects:

No other effects observed

In Vitro Irritancy Score

TheIn Vitro irritancy scores are summarized as follows:

 

Treatment	In Vitro Irritancy Score
Test Item	0.6
Negative Control	1.1
Positive Control	96.9

 

Criteria for an Acceptable Test

The positive control In VitroIrritancy Score was within the range of 65.9 – 140.8. The positive control acceptance criterion was therefore satisfied.

 

The negative control gave opacity of ≤4.7 and permeability≤0.080. The negative control acceptance criteria were therefore satisfied.

Table1     Individual and Mean Corneal Opacity and Permeability Measurements

Treatment	Cornea Number	Opacity				Permeability (OD)		In VitroIrritancy Score
		Pre-Treatment	Post-Treatment	Post-Treatment-Pre‑Treatment	Corrected Value		Corrected Value
Negative Control	16	2	1	0		0.064
	18	2	2	0		0.067
	19	2	2	0		0.080
				0.0*		0.07 -		1.1
Positive Control	1	1	70	67	67.0	1.759	1.689
	3	1	74	72	72.0	2.199	2.129
	20	2	71	64	64.0	2.100	2.030
					67.7·		1.949·	96.9
Test Item	22	1	2	1	1.0	0.101	0.031
	23	3	2	-1	0.0	0.066	0.000
	24	4	3	-1	0.0	0.099	0.029
					0.3·		0.020·	0.6

 

OD= Optical density            * = Mean of the post-treatment -pre‑treatment values            ¨= Mean permeability                     ·= Mean corrected value

 

 

 

Table2     Corneal Epithelium Condition Post Treatment

 

 

Treatment	Cornea Number	Observation
		Post Treatment
Negative Control	16	clear
	18	clear
	19	clear
Positive Control	1	cloudy
	3	cloudy
	20	cloudy
Test Item	22	clear
	23	clear

Interpretation of results:

GHS criteria not met

Conclusions:

The test item is not classified, no category, not requiring classification to UN GHS or EU CLP.

Executive summary:

Introduction

The purpose of this test was to identify test items that can induce serious eye damage and to identify test items not requiring classification for eye irritation or serious eye damage. The Bovine Corneal Opacity and Permeability (BCOP) test method is an organotypic model that provides short-term maintenance of normal physiological and bioitem function of the bovine corneain vitro. In this test method, damage by the test item is assessed by quantitative measurements of changes in corneal opacity and permeability.

 

The test method can correctly identify test items (both chemicals and mixtures) inducing serious eye damage as well as those not requiring classification for eye irritation or serious eye damage, as defined by the United Nations (UN) Globally Harmonized System of Classification and Labelling of Items (GHS), and it was therefore endorsed as scientifically valid for both purposes. Test items inducing serious eye damage are classified as UN GHS Category 1. Items not classified for eye irritation or serious eye damage are defined as those that do not meet the requirements for classification as UN GHS Category 1 or 2 (2A or 2B), i.e. they are referred to as UN GHS No Category.

 

 

Method

The test item was applied at a concentration of 20% w/v in 0.9% w/v sodium chloride solution for 240 minutes. Negative and positive control items were tested concurrently. The two endpoints, decreased light transmission through the cornea (opacity) and increased passage of sodium fluorescein dye through the cornea (permeability) were combined in an empirically derived formula to generate anIn VitroIrritancy Score (IVIS).

 

 

Interpretation

The test item is classified according to the prediction model below:

 

IVIS	CLASSIFICATION
≤ 3	No category. Not requiring classification to UN GHS or EU CLP
> 3; ≤55	No prediction of eye irritation can be made
> 55	Category 1. UN GHS or EU CLP Causes serious eye damage

 

Results

The In Vitro irritancy scores are summarized as follows:

 

Treatment	In Vitro Irritancy Score
Test Item	0.6
Negative Control	1.1
Positive Control	96.9

Conclusion

No category. Not requiring classification to UN GHS or EU CLP.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Justification for classification or non-classification

Based on the above mentioned results the substance does not need to be classified according to CLP regulation (EC No. 1272/2008) and DSD (Directive 67/548/EEC).