Registration Dossier

Administrative data

Description of key information

Skin irritation/corrosion: not irritating

Eye irritation: irritating

Respiratory irritation: inconclusive database

 

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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Lot/batch No.of test material: PK 95/222

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: refrigerated
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Dr. K. Thomae GmbH, Biberach
- Age at study initiation: Young adult animals
- Housing: Single housing in fully air-conditioned rooms.
- Diet (ad libitum): Kliba-Labordiaet 341 (Klingentakmuehle AG, Kaiseraugst, Switzerland), about 130 g per animal per day.
- Water (ad libitum): tap water, about 250 mL per animal per day.
- Acclimation period: for at least 1 week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12 h/12 h
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
other: untreated skin sites of the same animal.
Amount / concentration applied:
The test patch (2.5 cm x 2.5 cm) was moistened with a dose of 0.5 mL of the unchanged liquid test substance.
Duration of treatment / exposure:
4 h
Observation period:
72 h
Number of animals:
6
Details on study design:
TEST SITE
- Area of exposure: Upper third of the back or flanks
- Type of wrap: The test substance was covered with a test patch (Idealbinde, Pfaelzische Verbandstoff-Fabrik, kaiserslautern) and fixomull stretch (adhesive fleece), Beiersdorf AG.

REMOVAL OF TEST SUBSTANCE
- Washing: The substance was removed at the end of the exposure with lutrol and lutrol/water (1:1)

READING TIME POINTS
- at 1, 24, 48 and 72 hours after removal of the dressing.

SCORING SYSTEM
- As recommended by OECD Guideline 404, the Draize scoring system was used.
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:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
No local effects were observed in any of the treated animals. Therefore, the study was terminated at 72 hours after removal of the patches. Under the test conditions, the test substance did not give indications of an irritant property to the skin.
Other effects:
No clinical symptoms were observed in any of the treated animals.
Interpretation of results:
GHS criteria not met
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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Lot/batch No.of test material: PK 95/222

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: refrigerated
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Dr. K. Thomae GmbH, Biberach
- Age at study initiation: Young adult animals
- Housing: Single housing in fully air-conditioned rooms.
- Diet (ad libitum): Kliba-Labordiaet 341 (Klingentakmuehle AG, Kaiseraugst, Switzerland), about 130 g per animal per day.
- Water (ad libitum): tap water, about 250 ml per animal per day.
- Acclimation period: for at least 1 week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12 h/12 h
Vehicle:
unchanged (no vehicle)
Controls:
other: untreated left eye.
Amount / concentration applied:
Each animal received a single application of 0.1 mL of undiluted test substance into the conjunctival sac of the right eye.
Duration of treatment / exposure:
24 h
Observation period (in vivo):
15 d and 21 d for animal 01
Number of animals or in vitro replicates:
6
Details on study design:
Prior to treatment, both eyes of the animals were examined for signs of pre-existing irritation, reaction or abnormality which would prevent it from being used on the study.

REMOVAL OF TEST SUBSTANCE
- Washing: with tap water
- Time after start of exposure: 24 hours

SCORING SYSTEM: The assessment and scoring of the findings was based on the OECD Guideline 405 (adopted Feb. 24, 1987) and EEC L 383A, B.5 (Dec. 29, 1992).
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 24-48-72 h
Score:
0.4
Max. score:
4
Reversibility:
fully reversible within: 15 or 21 d
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 24-48-72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 15 or 21 d
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 24-48-72- h
Score:
2.1
Max. score:
3
Reversibility:
fully reversible within: 15 or 21 d
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 24-48-72 h
Score:
1.7
Max. score:
4
Reversibility:
fully reversible within: 15 or 21 d
Irritant / corrosive response data:
The average score (24 to 72 h) for irritation was calculated to be 0.4 for corneal opacity, 1.0 for iris, 2.1 for conjunctivae redness and 1.7 for chemosis. The findings were reversible in all animals within 15 or 21 days after application, thus the study was terminated.

The mean values were calculated according to 93/21/EEC criteria (Apr. 27, 1993).

Please refer to "Any other information on results incl. tables" for individual scores.

The following table summarizes the individual observations

Animal

Readings

(hours)

Cornea

Iris

Conjunctivae

Symptoms

Redness

Chemosis

01

24

1

1

2

3

S, PC, DB, LC

48

1

1

2

3

SR, S, PC DB, LC

72

1

1

2

2

SR, S, PC DB, LC

Mean score

1.0

1.0

2.0

2.7

 

02

24

0

1

2

2

 

48

0

1

2

2

PC, DB

72

0

1

2

1

PC, DB

Mean score

0.0

1.0

2.0

1.7

 

03

24

1

1

2

2

 

48

1

1

2

2

PC, DB

72

1

1

3

2

PC, DB

Mean score

1.0

1.0

2.3

2.0

 

04

24

0

1

2

1

 

48

0

1

2

1

PC, DB

72

0

1

2

1

DB

Mean score

0.0

1.0

2.0

1.0

 

05

24

0

1

2

1

 

48

0

1

2

1

PC

72

0

1

2

1

PC

Mean score

0.0

1.0

2.0

1.0

 

06

24

0

1

2

2

 

48

1

1

2

2

PC, DB

72

1

1

2

2

PC

Mean score

0.7

1.0

2.0

2.0

 

SR: Small retraction in the eyelids

S: Suppuration

PC: Pupil contracted

DB: Dischrage of blood

LC: Loss of corneal tissue

Slight iritis observed in all rabbits was reversible within 8 days. No eye lesions remained in any animal at the end of the 3-week observation period.

Interpretation of results:
Category 2 (irritating to eyes) based on GHS criteria
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Additional information

Skin irritation/corrosion:

In vitro, in EpiDerm Skin Corrosion and EpiDerm Skin Irritation Tests according to OECD guidelines and in compliance with GLP, the substance was tested to be not corrosive but was considered to be irritating to the skin (L.A.C.S.A., 2015). In vivo, however, the substancewas evaluated to be not irritating to the skin:

The key study was performed according to OECD TG 404 in compliance with GLP (BASF AG, 1997). The test substance showed no evidence of elicitation of erythematous or oedematous reactions when applied to intact rabbit skin. Therefore, the test-substance was evaluated to be non-irritating to the skin.

This result is further supported by a study conducted with 5 nude mice (BASF, 1973). The test substance was applied daily for 14 days on the intact skin via brush. No irritating reaction was observed.Furthermore, only very slight erythema and edema were observed on rabbit skin at one hour post-dose which were fully reversible within 24 hours (Siglin, 1992).

 

Eye irritation:

The key study was performed according to OECD TG 405 in compliance with GLP (BASF AG, 1997). In this study with six rabbits, unrinsed treated eyes (with undiluted test substance) showed signs of corneal and iridial lesions and conjunctival irritation. However, the degree of reaction was only slight to moderate and recovery was generally apparent within 15 days. Other ocular reactions observed within 3-4 days after instillation included small retraction in the eyelids, suppuration, contraction of the pupil, discharge of blood and loss of corneal cells. All effects were reversible, and the substance was evaluated to be slightly irritating to the eye.

This result is supported by another in vivo eye irritation study in rabbits according to OECD guideline 405 in compliance with GLP (L.A.C.S.A, 2015). In this study, the test material was evaulated to be irritating to the eye according to GHS criteria.

A study conducted with New Zealand rabbits further supports that the regsitered substance is irritating to the eye (BASF, 1977). In this study, the test substance was diluted (1:10) with water and several drops were applied into the conjunctival sac of the rabbits. According to Draize et al. the substance caused severe redness of the conjunctiva which was reversible within three days.

In contrast, in another GLP guideline study (Rhodia, 1984) undiluted test substance was instilled in a single dose of 0.1 ml into the conjunctival sac of the right eye of six New Zealand White rabbits (sex unspecified). The left eye remained untreated and served as a control. The eyes were not rinsed. Ocular examinations were performed 1, 24, 48 and 72 hours after the instillation. Translucent corneal opacity (grade 2) had developed in all rabbits at the 24 hour reading. An increase in severity was seen at the subsequent readings. By the 72 hour reading nacreous opacity or areas of complete opacification (grade 3-4) were observed in all six animals. Iritis (grade 1) was observed in all six rabbits throughout the 72-hour observation period. A diffuse, beefy-red colouration of the conjunctivae (grade 3), accompanied by considerable swelling with the eye almost closed (grade 4), together with copious discharge, had developed in all six rabbits by the 24-hour reading. This level of reaction persisted throughout the 72 hours observation period, accompanied in some rabbits by blood-stained discharge and in all six rabbits by necrosis and haemorrhage on the conjunctivae and nictitating membrane. The mean scores calculated over the 24-48-72 hour period were 2.89 for corneal opacity, 1.0 for iris inflammation, 3.0 for conjunctival redness, and 4.0 for chemosis. Due to the severity of the reactions at 72 hours, all animals were killed following this reading.

In conclusion, the test substance produced positive ocular irritation in 6/6 rabbits. In addition, all rabbits showed evidence of permanent damage to the eye. Only a study summary was available for assessment, and documentation was insufficient for assessment (especially concerning the identity and purity of the test material).

Because of these contradictory results, the potential of the test substance to cause serious damage to the eyes was assessed by a single topical application of 750 μL of the undiluted test substance to the epithelial surface of isolated bovine corneas (BASF SE, 2012). The test was conducted according to OECD guideline 437 in compliance with GLP.

Three corneas were treated with the test substance for 10 minutes followed by a 2-hours post-incubation period. Corneal opacity was measured quantitatively as the amount of light transmission through the cornea. Permeability was measured quantitatively as the amount of sodium fluorescein dye that passes across the full thickness of the cornea. Both measurements were used to calculate an In Vitro Irritancy Score of the test substance relative to the control corneas. Based on the observed results and applying the evaluation criteria it was concluded, that the test substance does not cause serious eye damage in the Bovine Corneal Opacity and Permeability Test (BCOP Test) under the test conditions chosen. This conclusion is supported by the results of a second BCOP test (L.A.C.S.A., 2014).

Based on available infromation it is concluded that the regsitered substance is irritating to the eyes.

Respiratory irritation:

The respiratory effects of two synthetic metalworking fluids and their components were evaluated in two inhalation studies (Krystofiak and Schaper, 1996; Detwiler-Okabayashi and Schape, 1996). The test substance was identified as an irritating component in both fluids. Male Swiss-Webster mice exposed to the test substance at 112 - 351 mg/m³ exhibited signs of both sensory and pulmonary irritation during the 3-hour exposure. In both studies, the test substance resulted in delayed deaths of mice at 24 to 72 hours post exposure. The concentrations of the test substance capable of evoking a 50 percent decrease in mean respiratory frequency based on pulmonary irritation (RD50) were calculated as 137 mg/m³ in the study by Krystofiak and Schaper (1996) and as 190 mg/m³ in the study by Detwiler-Okabayashi and Schaper (1996). However, this information is insufficient to make a final assessment of the respiratory irritation potential of the substance (inconclusive database).

Justification for classification or non-classification

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008.

The test substance was not irritating to the skin in vivo and is not classified as a skin irritant according to annex VI of Directive 1272/2008 (EU GHS, CLP).

The test substance classified as eye irritating cat. 2 (H319) under Regulation (EC) No 1272/2008, as amended for the ninth time in Regulation (EU) No 2016/ 1179.