Registration Dossier

Administrative data

Description of key information

For both dermal and eye irritation/corrosion old pre-GLP studies are available. Although not performed according to the current guidelines, the results as presented are robust enough for adequate conclusions regarding classification: o/p-Toluenesulfonamide does not need to be classified for dermal or eye irritation.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1978
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This study was performed pre-GLP and according to a method similar to OECD404. But with deviations.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Qualifier:
according to
Guideline:
other: U.S. FDA (Fed. Reg. 28 (119), 5582, 1963)
Principles of method if other than guideline:
- exposure period 24 hours
- rabbit skin is exposed under occlusion
- the test substance is not moistened to ensure optimal skin contact
- the animal skin is exposed intact and abraded
- it cannot be assessed if/when effects are reversible. Observation were made up to 72 hour after exposure.
- no details on test animals and their accomodation
GLP compliance:
no
Remarks:
pre-GLP
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: no data
- Housing: no data
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

IN-LIFE DATES: no data
Type of coverage:
occlusive
Preparation of test site:
other: clipped
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5g
Duration of treatment / exposure:
24 hours
Observation period:
The skin is evaluated 24 and 72 hours after the start of exposure.
Number of animals:
6 with intact and 6 with abraded skin
Details on study design:
TEST SITE
- Area of exposure: back of the animal
- % coverage: 2.5x2.5 cm
- Type of wrap if used: Surgical patch measuring 1 inch x 1 inch (2.5 x2.5 cm). The patches are fixed to the application site by means of adhesive tape and the entire trunk of the rabbits is wrapped with an impervious material.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): none
- Time after start of exposure: not applicable


SCORING SYSTEM: Draize
Erythema and eschar formation
0 No erythema
1 Very slight erythema (barely perceptible)
2 Well defined erythema
3 Moderate to severe erythema
4 Severe erythema (beet redness) to slight eschar formation (injuries in depth)

Oedema formation
0 No oedema
1 Very slight edema(barely perceptible)
2 Slight edema(edges of the area well defined by definite raising)
3 Moderate edema(raised approximately 1mm)
4 Severe edema( raised more than 1 mm and extending beyond the area of exposure)
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24-72 hours
Score:
0.6
Max. score:
4
Reversibility:
not fully reversible within: 72 hours
Remarks on result:
other: intact + abraded skin
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24-72 hours
Score:
0
Max. score:
4
Remarks on result:
other: intact + abraded skin
Irritant / corrosive response data:
after 24 hours: very slight erythema
after 72 hours: very slight erythema

No difference was observed between intact and abraded skin

Results

Rabbit No and sex

Hours after instillation

Average 24-72 hours:

Intact

Rabbit No and sex

Hours after instillation

Average 24-72 hours:

Abraded

Site

24

72

24

72

7247

erythema

1

1

1

7241

1

1

1

oedema

0

0

0

0

0

0

7248

erythema

D

D

-

7242

1

1

1

oedema

D

D

-

0

0

0

7249

erythema

1

0

0.5

7243

1

0

0.5

oedema

0

0

0

0

0

0

7250

erythema

0

0

0

7244

1

0

0.5

oedema

0

0

0

0

0

0

7251

erythema

0

1

0.5

7245

1

1

1

oedema

0

0

0

0

0

0

7252

erythema

0

1

0.5

7246

1

0

0.5

oedema

0

0

0

0

0

0

D = dead

Conclusions:
The results show that the test substance causes slight erythema which is not fully reversible after 72 hours. But taking into account that these effects are slight it is expected that they are reversible within 14 days. Although this study has many deviations performing a new study is not warranted because it will not provide any new information. With this study it has been shown that the substance is not a skin irritant.
Executive summary:

The primary irritation of Ketjenflex 9R to the skin is measured by a occlussive patch-test technique on the abraded and intact skin of albino rabbits. The study was performed accoding to methods similar to OECD404. but with the following deviations:

- exposure period 24 hours

- rabbit skin is exposed under occlusion

- the test substance is not moistened to ensure optimal skin contact

- the animal skin is exposed intact and abraded

- it cannot be assessed if/when effects are reversible. Observation were made up to 72 hour after exposure.

- no details on test substance identity or composition

- no details on test animals and their accomodation

Twelve healthy adult New Zealand White albino rabbits are used . Twenty four hours prior to applying the materials, the hair is removed from the backs of the animals with an electric clipper in such a way as to avoid abrasions. An amount of 0.5 g is placed on the skin under occlusion for 24 hours. The skin is evaluated 24 and 72 hours after the start of exposure. After 24 hours: slight erythema. After 72 hours: slight erythema. No difference was observed between intact and abraded skin.

The results show that the test substance causes slight erythema which is not fully reversible after 72 hours. Although this study has many deviations performing a new study is not warranted because it will not provide any new information. With this study it has been shown that the substance is not a skin irritant.

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:
1978
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study was performed according to a method similar to OECD 405 and pre-GLP. There is no data on substance indentity or composition. Since observed effects are minor and all other effects were reversible within 7 days it is assumed that the redness will also be reversibel within 21 days.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Qualifier:
according to
Guideline:
other: U.S. FDA (Fed. Reg. 28(119), 5582, 1963)
Principles of method if other than guideline:
The study did not last for 21 days to study reversibility but this would also not be acceptable nowadays for animal welfare reasons.
GLP compliance:
no
Remarks:
pre-GLP
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: no data
- Housing: no data
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

IN-LIFE DATES: no data
Vehicle:
unchanged (no vehicle)
Controls:
other: untreated eye served as the control
Amount / concentration applied:
0.1g
Duration of treatment / exposure:
One single dose is given
Observation period (in vivo):
The eyes are examined at 24, 48, 72 hours and 7 days after instillation of the test material.
Number of animals or in vitro replicates:
6
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): not done
- Time after start of exposure: not applicable

SCORING SYSTEM: Scoring system eye irritation

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

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

Conjunctivae
Redness (refers to palpebral and bulbar conjunctivae cornea and iris)

0 Blood vessels normal
1 Some blood vessels definitely hyperaemic
(injected)
2 Diffuse, crimson colour, individual vessels not easily discernible
3 Diffuse, beefy red

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

TOOL USED TO ASSESS SCORE: Ocular reactions are read using a binocular magnifying glass. The diagnosis of corneal damage is confirmed, if necessary, by staining the eyes of the animals with fluorescein-impregnated papers. After flushing the excess fluorescein solution, the eyes are examined in a dark room under ultraviolet illumination.
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
all animals
Time point:
other: 14-48-72h
Score:
0.1
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 24-48-72 h
Score:
0.05
Max. score:
2
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 24-48-72h
Score:
1.05
Max. score:
3
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: A score of 1 remained in 3 out of 6 animals after 7 days. In the other 3 animals effects were reversible.
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 24-48-72h
Score:
0.4
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Irritant / corrosive response data:
Very slight corneal damage, slight iritis and moderate lesions of the conjunctivae in one out of six rabbits and slight lesions of the conjunctivae in the other five rabbits.

Rabbit No and sex

Region of the eye

Hours after instillation

Average 24-48-72 hours

24

48

72

7 days

13

Cornea

Degree of opacity

0

0

0

0

0

Iris

0

0

0

0

0

Conjunctivae

Redness

1

1

1

1

1

Chemosis

1

1

0

0

0.6

14

Cornea

Degree of opacity

0

0

0

0

0

Iris

0

0

0

0

0

Conjunctivae

Redness

1

1

1

0

1

Chemosis

1

0

0

0

0.3

15

Cornea

Degree of opacity

0

0

0

0

0

Iris

0

0

0

0

0

Conjunctivae

Redness

1

1

0

0

0.6

Chemosis

1

0

0

0

0.3

16

Cornea

Degree of opacity

0

0

0

0

0

Iris

0

0

0

0

0

Conjunctivae

Redness

1

1

1

1

1

Chemosis

1

0

0

0

0.3

17

Cornea

Degree of opacity

1

1

0

0

0.6

Iris

1

0

0

0

0.3

Conjunctivae

Redness

2

1

1

1

1.7

Chemosis

2

1

0

0

3

18

Cornea

Degree of opacity

0

0

0

0

0

Iris

0

0

0

0

0

Conjunctivae

Redness

1

1

1

0

1

Chemosis

1

1

0

0

0.6

Conclusions:
The test substance is not considered as eye irritant according to GHS. The animals were not observed for 21 days and not all effects had dissappeared within 7 days. A score of 1 for redness remained in 3 out of 6 animals after 7 days. In the other 3 animals effects were reversible. Since observed effects are minor and all other effects were reversible within 7 days it is assumed that the redness will also be reversibel within 21 days.
Executive summary:

A study was performed to access the eye irritancy of Ketjenflex 9R. The study was performed pre-GLP. The study is similar to OECD405. 0.1g of the test substance was instilled in the eye of one rabbit. The untreated eye served a sthe control. Observations were made after 24, 48, 72 hours and after 7 days. In these animals very slight corneal damage, slight iritis and moderate lesions of the conjunctivae in one out of six rabbits and slight lesions of the conjunctivae in the other five rabbits. The test substance is not considered as eye irritant according to GHS. The animals were not observed for 21 days and not all effects had dissappeared within 7 days. A score of 1 for redness remained in 3 out of 6 animals after 7 days. In the other 3 animals effects were reversible. Since observed effects are minor and all other effects were reversible within 7 days it is assumed that the redness will also be reversibel within 21 days. Besides, the score of 1 was not considered sufficient as positive reation according to the protocol.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation/corrosion:

The primary irritation of o/p-TSA to the skin is measured by an occlusive patch-test technique on the abraded and intact skin of albino rabbits (TNO, 1978).

Twelve healthy adult New Zealand White albino rabbits are used. Twenty four hours prior to applying the materials, the hair is removed from the backs of the animals with an electric clipper in such a way as to avoid abrasions. An amount of 0.5 g is placed on the skin under occlusion for 24 hours. The skin is evaluated 24 and 72 hours after the start of exposure. After 24 hours: very slight erythema after 72 hours: very slight erythema. No difference was observed between intact and abraded skin. The results show that the test substance causes slight erythema which is not fully reversible after 72 hours. But taking into account that these effects are slight it is expected that they are reversible within 14 days. Although this study has many deviations performing a new study is not warranted because it will not provide any new information. With this study it has been shown that the substance is not a skin irritant.

The study was performed according to methods similar to OECD 404, but with the following relevant deviations from the current guidelines:

-      exposure period 24 hours: this would result to a comparable worst case condition

-      rabbit skin is exposed under occlusion: worst case condition

-      the test substance is not moistened to ensure optimal skin contact: Due to full occlusion and 24 hour rather than 4 hour exposure, this is likely of no consequence.

-      the animal skin is exposed intact and abraded: Abraded would represent worst case condition.

-      it cannot be assessed if/when effects are reversible. Observations were made up to 72 hour after exposure: The highest grades observed only consisted of very slight erythema. This was at 72 hours still visible in 2/11 animals and can be expected to completely resolve.

 

In an additional study (Younger Labs, 1974) of low validity due to limited reporting, 6 New Zealand Albino Rabbits were given 0.5 Gram o/p-TSA applied as finely ground powder moistened with water. Exposure duration was 48 hours. Results: None of the 6 animals showed any signs of erythema or oedema during the 7 days observation period.

 

Eye irritation

A study was performed to access the eye irritancy of o/p-TSA (TNO, 1978). The study was performed pre-GLP. The study is similar to OECD 405. 0.1g of the test substance was instilled in the eye of one rabbit. The untreated eye served as the control. Observations were made after 24, 48, and 72 hours and after 7 days. Results showed very slight corneal damage, slight iritis and moderate lesions of the conjunctivae in one out of six rabbits and slight lesions of the conjunctivae in the other five rabbits. After 72 hours five of the six animals showed slight erythema, and after 7 days still 3 animals showed slight erythema. The observed effects are not severe enough to trigger classification. Probably the observed effects are related to the physical properties of the crystalline solid. Testing of the individual components p-TSA and o-TSA showed even less effects on the eyes indicating that a chemical irritation by the mixture is not likely.

 

This minimal irritation hazards to the eyes is confirmed in an additional study (Younger Labs, 1974) of low validity due to limited reporting. Ten milligrams of finely ground o/p-TSA sample were placed in the conjunctival sac of the right eye of each of three albino rabbits and the resulting redness scored according to Draize et al. The eye was washed out with warm water after 24 hours.

After one hour there was slight erythema and lacrimation with very slight oedema for an average maximum score of 5.3 out of possible 110. Iris and cornea were unaffected. Little change was noted in 24 hours when the remaining compound was washed out of the sac. One animal was free of inflammation in 48 hours and all were given a score zero in 72 hours. Most of the irritation was probably mechanical in nature.

 

Respiratory irritation:

Vp is 0.00004 Pa at 22°C, and the respirable fraction (≤ 4 µm) of the crystalline solid is <1%. Also likelihood of exposures by aerosols from the use of the substance is low (also taking into consideration the low water solubility of 5.1 g/L). Therefore, exposures can be expected to be minimal an in combination of the lack of irritation seen in skin and eye irritation studies, respiratory irritation is not likely to occur.


Justification for selection of skin irritation / corrosion endpoint:
Most valid study available

Justification for selection of eye irritation endpoint:
Most valid study available

Justification for classification or non-classification

The available data indicate that even following 24 hr dermal exposure under occlusive conditions only slight erythema was visible. The substance therefore does not need to be classified for dermal irritation according to GHS.

A study evaluating the irritating effects in rabbit eyes resulted to limited effects that were (considered to be) fully reversible. These results do not trigger classification for GHS classification.

There are no data that that would lead to consider respiratory irritation. Besides, exposure via inhalation does not occur. There is no need to consider classification for STOT-SE Cat.3 regarding respiratory irritation.