Diphenyl sulphone

Endpoint summary

Description of key information

Skin and eye irritation studies were conducted with diphenyl sulphone in New Zealand White rabbits according to OECD 404/405 methods. There were no signs of irritation and corrosion in both studies. 

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation / corrosion, other

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2001

Reliability:

1 (reliable without restriction)

Justification for type of information:

The DPS dossier containsold in vivo studies, which are not allowed today. Therefore a justification needs to be added in the end point data summary. The new legal requirements (21 June 2016) require an in vitro skin irritation study.However the previous data requirements were met with an in vivo study during the dossier compilation for the 100-1000 T/Y tonnage band. Therefore there is no need to repeat the study using the alternatiuve test method.

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Qualifier:

according to guideline

Guideline:

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

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Kisslegg, Germany
- Age at study initiation: 6 weeks
- Weight at study initiation: between 1.0 and 3.5 kg
- Housing: Individually in labelled cages with perforated floors (Scanbur, Denmark, dimensions 53.5*63*38.5 cm).
- Diet (e.g. ad libitum): Standard laboratory rabbit diet (Charles River Breeding and Maintenance Diet for Rabbits, Altromin, Germany) approx. 100g per day. Certificates of analysis were examined and retained in the NOTOX archives. In addition, hay (BMI, Helmond, the Netherlands) was provided twice a week.
- Water (e.g. ad libitum): Free acces to tap-water. Certificates of quarterly analysis were examined and retained in the NOTOX archives.
- Acclimation period: at least 5 days before start of treatment under laboratory conditions.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21+-3°c
- Humidity (%): 30-70%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light):12 hours artificial fluorescent light and 12 h dark per day.


IN-LIFE DATES: From: To:

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

water

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5g
- Concentration (if solution):


VEHICLE
- Amount(s) applied (volume or weight with unit):0.5g
- Concentration (if solution):
- Lot/batch no. (if required):
- Purity:

Duration of treatment / exposure:

4 hours

Observation period:

The skin reactions were assessed at approximately 1, 24, 48 and 72 hours after the removal of the dressing and test substance

Number of animals:

3 animals of one sex

Details on study design:

TEST SITE
- Area of exposure: 150 square centimeters (10*15 cm²)
- % coverage:
- Type of wrap if used: metalline patch (supplier: Lohmann GmbH, Neuwied, Germany) of 2*3 cm. The patch was mounted on Micropore tape (supplier: 3M, St. Paul, Minnesota, USA), which was wrapped around the abdomen and securied with Coban elastic bandage (supplier: 3M, St. Paul, Minnesota, USA).


REMOVAL OF TEST SUBSTANCE
- Washing (if done): the dressing was removed and the skin cleaned of residual test substance using water
- Time after start of exposure: four hours after the application


SCORING SYSTEM:
The irritation was assessed according to the following numerical scoring system. At each observation, the highest scores given was recorded:

ERYTHEMA AND ESCHAR FORMATION:
No erythema......................................................................................0
Very slight erythema (barely perceptible).....................................1
Well-defined erythema.....................................................................2
Moderate to severe erythema..........................................................3
Severe erythema (beet redness)*....................................................4
(* Where signs of necrosis or corrosion (injuries in depth) prevent erythema scoring, the maximum grade for erythema (=4) is given.)

OEDEMA FORMATION:
No oedema........................................................................................................................................................0
Very slight oedema (barely perceptible).......................................................................................................1
Slight oedema (edges of area well-defined by definite raising)................................................................2
Moderate oedema (raised approximately 1 millimeter)..............................................................................3
Severe oedema (raised more than 1 millimeter and extending beyond the area of exposure)...........4

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 24,48,72h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 24,48,72 h

Score:

0

Max. score:

4

Irritant / corrosive response data:

IRRITATION: No skin irritation was caused by 4 hours exposure to DPS.
CORROSION: There was no evidence of a corrosive effect on the skin.
COLOURATION: No staining of the treated skin by the test substance was observed.
TOXICITY / MORTALITY: No symptoms of systematic toxicity were observed in the animals during the test period and no mortality occured

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Based on the results and according to the EC criteria for classification and labelling requirements for dangerous substances and preparations (Guidelines in Commission Directive 93/21/EEC), diphenylsulfon (DPS) does not have to be classified and has no obligatory labelling requirement for skin irritation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation, other

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2001

Reliability:

1 (reliable without restriction)

Justification for type of information:

The DPS dossier containsold in vivo studies, which are not allowed today. Therefore a justification needs to be added in the end point data summary. The new legal requirements (21 June 2016) require an in vitro eye irritation study.However the previous data requirements were met with an in vivo study during the dossier compilation for the 100-1000 T/Y tonnage band. Therefore there is no need to repeat the study using the alternatiuve test method.

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Kissleg, Germany
- Age at study initiation: at least 6 weeks old
- Weight at study initiation: body weights between 1.0 and 3.5 kg
- Housing: Individually in labelled cages with perforated floors (Scanbur, Denmark, dimensions 53.5*63*38.5 cm).
- Diet (e.g. ad libitum): Standard laboratory rabbit diet (Charles River Breeding and Maintenance Diet for Rabbits, Altromin, Germany) approx. 100g per day. Certificates of analysis were examined and retained in the NOTOX archives. In addition, hay (BMI, Helmond, the Netherlands) was provided twice a week.
- Water (e.g. ad libitum): Free acces to tap-water. Certificates of quarterly analysis were examined and retained in the NOTOX archives.
- Acclimation period: At least 5 days before start of treatment under laboratory conditions.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 +- 3°c
- Humidity (%): 30-70%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 hours artificial fluorescent light and 12 hours dark per day

Vehicle:

unchanged (no vehicle)

Controls:

other: The other eye remained untreated and served as the reference control.

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit):71.4 +- 0.6 mg (a volume of approximately 0.1 ml).
- Concentration (if solution):


VEHICLE
- Amount(s) applied (volume or weight with unit):
- Concentration (if solution):
- Lot/batch no. (if required):
- Purity:

Duration of treatment / exposure:

24 h

Observation period (in vivo):

The eyes of each animal were examined approximately 1, 24, 48 and 72 hours after instillation of the test substance.

Number of animals or in vitro replicates:

3

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Immediately after the 24 hour observation, a solution of 2 % fluorescein in water (adjusted to pH 7.0) was instilled into both eyes of each animal to quantitatively determine corneal epithelial damage.
- Time after start of exposure: 24h


SCORING SYSTEM:
The irritation will be assessed according to the following numerical scoring system. At each observation, the highest scores given will be recorded:

CORNEAL IRRITATION:
Opacity: degree of density (area most dense taken for reading)
No ulceration or opacity (may include slight dulling of normal lustre).................................................0
Scattered or diffuse areas of opacity, details of iris clearly visible.........................................................1
Easily discernible translucent area, details of iris, slightly obscured.....................................................2
Nacreous area, no details of iris visible, size of pupil barely discernible...............................................3
Opaque cornea, iris not discernible through the opacity.........................................................................4

Area of cornea involved:
No ulceration or opacity..................................................................................................................................0
One quarter or less but not zero....................................................................................................................1
Greater than one quarter, but less than half................................................................................................2
Greater than half, but less than three quarters............................................................................................3
Greater than three quarers, up the whole area.............................................................................................4

IRIS
Normal..................................................................................................................................................................0
Markedly deepened rugae, congestion, swelling, moderate circumcorneal hyperaemia,
or injection, any of these or combination thereof, iris still reacting to light
(sluggish reaction is positive)...........................................................................................................................1
No reaction to light, hemorrhage, gross destruction (any or all of these)................................................2

CONJUNCTIVAL IRRITATION
Redness (refers to palpebrae and sclera, excluding cornea and iris):
Blood vessels normal:..........................................................................................................................................0
Some blood vessels definitely hyperaemic (injected).....................................................................................1
Diffuse, crimson color, individual vesses not easily discernible..................................................................2
Diffuse beefy red..................................................................................................................................................3

Chemosis (refers to lids and/or nictitating membranes):
No swelling.............................................................................................................................................................0
Any swelling above normal (includes nictitating membranes)......................................................................1
Obvious swelling with partial eversion of lids..................................................................................................2
Swelling with lids about half closed....................................................................................................................3
Swelling with lids more than half closed............................................................................................................4

Discharge:
No discharge (may include small amounts observed in inner canthus of normal animals).......................0
Any amount different from normal and/or lacrimation...................................................................................1
Discharge with moistening of the lids and hairs just adjacent to lids............................................................2
Discharge with moistening of the lids and hairs (considerable area around the eye).................................3


TOOL USED TO ASSESS SCORE: fluorescein
Where standard lighting is considered inadequate for observing minor effects, eye examinations will be performed using an ophthalmic examination lamp.
In cases of equivocal results when comparing the threated and untreated eyes, the illustrated guide from the Consumer Product Safety Commission, Washington, D.C. 20207 will be used for additional control purposes.

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

other: 48h

Score:

ca. 0

Max. score:

1

Reversibility:

fully reversible within: 48 h

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

other: 24 h

Score:

ca. 0

Max. score:

0

Reversibility:

fully reversible

Irritation parameter:

iris score

Basis:

mean

Time point:

other: 24h

Score:

ca. 0

Max. score:

1

Reversibility:

fully reversible within: 24 h

Irritant / corrosive response data:

IRRITATION:
Instillation of approximately 71 mg of the test substance into one eye of each of three rabbits resulted in effects on the iris and conjunctivae. One eye of each of three rabbits resulted in effects on the iris and conjunctivae. Iridial irritation (grade 1) was observed in all animals and had resolved within 24 hours. Irritation of the conjunctivae was seen as redness, chemosis and discarge, which had completely resolved within 48 hours in all animals.

No corneal opacity was observed, and treatment of the eyes with 2% fluorescein, 24 hours after test substance instillation revealed no corneal epithelial damage in any of the animals.

CORROSION
There was no evidence of ocular corrosion

COLOURATION:
No staining of (peri) ocular tissues by the test substance was observed. Remnants of the test substance were present in the eyes of all animals on day 1.

TOXICITY / MORTALITY
No symptoms of systemic toxicity were observed in the animals during the test period and no mortality occurred

Individual eye irritation scores:

Time after dosing	Opacity (cornea)	area (cornea)	fluor area (%) (cornea)	Iris	redness (conjunctivae)	chemosis (conjunctivae)	discharge (conjunctivae)	Comments
♂892
1 h	0	0		1	1	1	1	b
24 h	0	0	0	0	1	0	0	/
48h	0	0		0	0	0	0	/
72 h	0	0		0	0	0	0	/
♂893
1 h	0	0		1	1	1	1	b
24 h	0	0	0	0	1	0	0	/
48 h	0	0		0	0	0	0	/
72 h	0	0		0	0	0	0	/
♂ 894
1 h	0	0		1	1	1	1	b
24 h	0	0	0	0	1	0	0	/
48 h	0	0		0	0	0	0	/
72 h	0	0		0	0	0	0	/

(Fluor area (%): green staining (percentage of total corneal area) after fluorescein treatment.)

Comments: b: remnants of the test substance in the eye.

mean value eye irritation scores

( # animal, mean 24 -72 hours)

animal#	Corneal opacity	Iris	redness (conjunctivae)	chemosis (conjunctivae)
892	0	0	0.3	0
893	0	0	0.3	0
894	0	0	0.3	0

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Based on these results and according to the EC criteria for classification and labelling requirements for dangerous substances and preparations (Guidelines in Commission Directive 93/21/EEC), diphenylsulfon (DPS) does not have to be classified and has no obligatory labelling requirement for eye irritation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Additional information

A key study for dermal irritation was conducted in vivo by semi-occlusive testing of diphenyl sulphone in New Zealand White rabbits according to OECD 404 method (Notox, 2001b). Application of 0.5 mg during 4 hours demonstrated that the substance was not irritating or corrosive to the skin up to 14 days after application and no staining was observed.

A key study for eye irritation was conducted in vivo by ocular testing of diphenyl sulphone in New Zealand White rabbits according to OECD 405 method (Notox, 2001c). Application of 0.1 mg demonstrated that the substance was not irritating or corrosive to the eye up to 14 days after application.

Justification for selection of skin irritation / corrosion endpoint:
Key study

Justification for selection of eye irritation endpoint:
Key study

Justification for classification or non-classification

Based on the results and according to the EC criteria for classification and labelling requirements for dangerous substances and preparations (Guidelines in Commission Directive 93/21/EEC) and CLP regulation (EC No. 1272/2008 of 16 December 2008), diphenyl sulphone does not have to be classified and has no obligatory labelling requirement for skin irritation and eye irritation.