Registration Dossier

Administrative data

Description of key information

The test item is not irritating (or corrosive) to skin of rabbits.

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:
August 31, 1994 - October 18, 1994
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
Qualifier:
according to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
Animals:
Supplier: Charles River Wiga GmbH, D-97633 Sulzfeld
Number ans sex: 3 females

Animal maintenance:
Room temperature: average of 19.5 °C
Relative humidity: average of 50 %
Air exchange: 12 per hour
Light: artificial light from 6 a.m. to 6 p.m.
Cages: individual caging in metal wire cages. Ehret GmbH, D-79312 Emmendingen, type KK 016R
Feed: Altromin 2023 diet for rabbits, ad libitum
Water: tap water from an automatical watering system, ad libitum
Identification: labelling with felt-tipped pen in the ear
Acclimatization: 6 days
Type of coverage:
occlusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
A cellulose patch with 0.5 g of the test substance, spread over an area of approximately 6x2 cm and soaked with 1.5 ml distilled water, was applied to the test site and held in place by fixing marginally with non irritating tape.
Duration of treatment / exposure:
4 hours
Observation period:
1, 24, 48 and 72 hours after patch removal
Number of animals:
3
Details on study design:
Procedure: Hair was clipped on the dorsal area of the trunk one day before the application of the test substance. The test site was median on the dorsal thoracal region.
A cellulose patch with 0.5 g of the test substance, spread over an area of approximately 6x2 cm and soaked with 1.5 ml distilled water, was applied to the test site and held in place by fixing marginally with non irritating tape. The application site was covered by a dressing.
Access by the animal to the application site was prevented by a plastic collar.
The duration of exposure was 4 hours.
At the end of the exposure period the dressing, the tape with the patch and the collar were removed. Residual test substance was wiped off using wet cellulose tissue.

Clinical examination and scoring:
Animals were examined for erythema/eschar and oedema as well as for other local and systemic signs approximately 1, 24, 48 and 72 hours after patch removal.
No additional examinations were performed.
The skin was examined using a cold light source KL 1500 electronic.
Dermal irritation was scored and recorded.

General examinations: At all observation times the animals were examined for other than local changes.
Irritation parameter:
erythema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
edema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritant / corrosive response data:
Erythema/eschar: In all animals only scores of "0" were noted at reading times.
Oedema: In all animals only scores of "0" were noted at reading times.
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
"7-ACA" does not require the risk phrase "R38 - Irritating to skin".
Executive summary:

A skin irritation study with rabbits was performed. The test item is not irritating (or corrosive) according to EU-regulations.

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:
2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
2017
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Version / remarks:
2017
Deviations:
no
GLP compliance:
yes (incl. certificate)
Specific details on test material used for the study:
Chemical name: (6R,7R)-3-[(acetyloxy)methyl)]-7-amino-8-oxo-5thia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylic acid
Batch No.: B363198
Appearance: white yellowish, weakly odorous powder
CAS Number: 957-68-6
Retest date: May 2018
Storage conditions: in refrigerator: 5±3 °C, protected from light
pH value: 4
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
Source: S & K-LAP Kft. 2173 Kartal, Császár út 135, HUNGARY
Hygienic level during the study: good conventional
Justification of strain: The New Zealand white rabbit is one of the standard animals in acute eye irritation study.
Number of animal: 3 males
Age of animals: adult rabbits, 113 weeks old
Body weight range at the beginning of the study: 3276 - 3556 g
Body weight range at the end of the study: 3460 - 3642 g
Acclimatisation time: 19 days in first animal, 20 days in second and third animals

Housing: Animals were housed individually in metal cage.
Light: 12 hours daily, from 6.00 a.m. to 6.00 p.m.
Temperature: 20 ± 3 °C
Relative humidity: 30-70 %
Ventilation: above 10 air exchanges/hour by central air-condition system
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
0.1 g of the test item was used for the study in undiluted form, as a single dose. The test material was ground to a fine dust.
Duration of treatment / exposure:
The eyes of the test animals were not washed out 24 hour after test item application, because the test item had been removed from the eye of test animal by physiological mechanisms.
Observation period (in vivo):
72 h
Number of animals or in vitro replicates:
3
Details on study design:
Three male animals in acceptable health condition were selected for the test. Care was taken to select only those animals with normal eye condition, any with ocular lesions were rejected.
In the first step an initial test was performed using one animal. The test item was placed into the conjunctival sac of the left eye. The eyelids were held closed gently for about one second to prevent any loss of the test item. The contralateral eye served as control.

In the initial test no irritant effect was observed 24 hours after treatment. The confirmatory test was conducted using a second and third animal.

Topical anesthetics and systemic analgesics:
Approximately sixty minutes prior to test item application systemic analgesics (dose: 0.01 mg/kg) was administered subcutaneously. Approximately five minutes prior to test item application topical ocular anesthetic (dose: one drop) was applied to each eye. The eye of each animal that was not treated with a test item, but which was treated with topical anesthetics, served as a control.

Clinical Observations and Evaluation of Ocular Irritation
The eyes were examined at 1, 24, 48 and 72 hours after the application. The duration of the observation period was sufficient for the statement of reversibility or irreversibility of changes.
Any clinical signs of toxicity or signs of pain and/or distress were recorded at least twice daily, with a minimum of 6 hours between observations.
It was no humane sacrificing connected with severe eye lesions during the study.

The eye irritation scores were evaluated according to the scoring system by Draize (1979) and OECD 405.

The body weights were recorded at the beginning and at the end of the experiment, as well as before each systemic analgesics.
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritant / corrosive response data:
One hour after treatment some hyperemic blood vessels (score 1) were observed in all animals. The swelling of the conjunctivae was different from normal (score 1) in animal No.: 2075 and the amount of discharge of the conjunctivae was different from normal (score 1) in all animals.
24 h, 48 h and 72 h after treatment all animals were free of symptoms.
72 hours after the treatment the study was finished.
During the study the control eyes of animals were symptom-free.
Other effects:
Determined physical-chemical properties of the test item did not reveal potential corrosion effects to the eye.
No systemic toxicity was observed on the day of the treatment and during the 3-day observation period. The body weight of animals corresponded to their species and age. Sign of pain and distress as discharge was observed in all animals on the treatment day at first observation.
Interpretation of results:
GHS criteria not met
Conclusions:
The test item caused slight conjunctival irritant effects which were fully reversible within 24 hours.
Executive summary:

The test item was applied to the rabbits' eye mucosa according to OECD guideline 405. The test item caused slight conjunctival irritant effects which were fully reversible within 24 hours.

According to the EC criteria for classification and labelling requirements for dangerous substances and preparations, the test item 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)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

No classification for skin and eye irritation is derived from the results.