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Diss Factsheets

Administrative data

Description of key information

No irritating or corrosive effects

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:
1982
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study without GLP
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: HOECHST AG, Kastengrund, konventionelle Zucht
- Age at study initiation: -
- Weight at study initiation: 2 - 3.1 kg
- Housing: single
- Diet (e.g. ad libitum): Alleinfutter für Zuchtkaninchen ERKA Z 6000 (Futtermittelwerke Robert Koch oHG, Hamm/Westfalen), ad libitum
- Water (e.g. ad libitum): deionisiertes; gechlortes Wasser aus automatischen Tränken, ad libitum
- Acclimation period: NA

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 30 - 70
- Air changes (per hr): -
- Photoperiod (hrs dark / hrs light): 12/12

In-life date: 12. to 15. October 1982
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
physiological saline
Remarks:
0.15 mL to form a paste
Controls:
yes, concurrent no treatment
Amount / concentration applied:
500 mg on 2.5 cm x 2.5 cm gauze pads
Duration of treatment / exposure:
4 hours
Observation period:
up to 72 hours
Number of animals:
3
Details on study design:
TEST SITE
- Area of exposure shaved skin: 2.5x2.5 cm
- Type of wrap if used: Hansamed Wundpflaster and semi-occlusive wrapping

REMOVAL OF TEST SUBSTANCE
- Time after start of exposure: 4 hours


SCORING SYSTEM: OECD guideline

Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24 - 72 h
Score:
0.6
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24 - 72 h
Score:
0
Max. score:
4
Irritant / corrosive response data:
Nach Einwirkung der angeteigten Substanz (4 Stunden Exposition) wurde aufgrund der Befunde der Erythem- und Oedembildung (1, 24, 48, 72 h) ein Reizindex von 0,8 ermittelt. Zusätzlich zu den in den Reizindex eingegangenen Symptomen waren die behandelten Hautstellen nach 30 Minuten großflächig gelb verfärbt Alle Reizerscheinungen waren bis auf eine leichte kaum wahrnehmbare Rötung bei einem Tier bereits innerhalb 48 Stunden nach Entfernung des Patch reversibel.

Unter den beschriebenen Versuchsbedingungen nach der OECO-Richtlinie zur Prüfung auf akute dermale Reizwirkung / Ätzwirkung ist die Substanz Remazol-Goldgelb RNL somit als leicht hautreizend zu bezeichnen.
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The test item was tested according to OECD 404 for skin irritation properties. The evaluation of the erythema and edema scores at the 24, 48, and 72 hour time points showed that the test item is not irritating to skin according to GHS and CLP evaluation schemes.
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:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
03 November 2011 to 24 November 2011
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted to OECD, EU and US test guidance in compliance with GLP and reported with a valid GLP certificate
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2400 (Acute Eye Irritation)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
EXPERIMENTAL ANIMALS

Species and strain: New Zealand White rabbits
Source: S&K-LAP Kft. 2173 Kartal, Császár út 135, Hungary
Justification of strain: The New Zealand White rabbit is one of the standard strains used for acute irritation toxicity studies.
Animal health: Only animals in acceptable health condition were used for the test. Both eyes of each animal provisionally selected for testing were examined approximately one hour before starting the study. Animals showing eye irritation, ocular defects or pre-existing corneal injury were not used.
Number of animals: 3 animals
Age of animals at treatment: ~11 weeks old (adult)
Sex: Male
Body weight range at the beginning of the life phase: 2933 – 3023 g, end of the life phase: 3689 – 3700 g
Date of receipt: 26 October 2011
Acclimatization time: 8 days
Animal identification: The individual identification was by engraved ear tag. The cages were marked with individual identity cards with information about study code, sex, dose group, cage number and individual animal number.

HUSBANDRY

Animal health: Only healthy animals were used for the test. The veterinarian certified health status.
Number of animal room: 607
Light: 12 hours daily, from 6.00 a.m. to 6.00 p.m.
Temperature: 20 ± 3°C
Relative humidity: 28 - 65 %
Housing/Enrichment: Rabbits were individually housed in AAALAC approved metal wire rabbit cages. Cages were of an open wire structure and cages were placed together to allow some social interaction with rabbit(s) in adjoining cages
Ventilation: 15-20 air exchanges/hour
The environmental parameters were recorded twice daily during the study. Minor variations from the target humidity (min. 28%) range were observed during the study. These deviations were considered to have no impact on the animal health, as certified by the Clinical Veterinarian, or on the outcome of the study and interpretation of the results.

FOOD AND FEEDING

Animal received PURINA Base – Lap gr. diet for rabbits produced by AGRIBRANDS Europe Hungary PLC, H-5300 Karcag, Madarasi road, Hungary, ad libitum.

WATER SUPPLY AND QUALITY CONTROL OF WATER

The animals received municipal tap water, as for human consumption, ad libitum, from an automatic system.
The quality control analysis is performed once every three months and microbiological assessment is performed monthly, by Veszprém County Institute of State Public Health and Medical Officer Service (ÁNTSZ, H-8201 Veszprém, József A.u.36., Hungary). The quality control results are retained in the archives of CiToxLAB Hungary Ltd.
Vehicle:
unchanged (no vehicle)
Controls:
other: contralateral eye served as the control
Amount / concentration applied:
A single dose of 0.1 g of the solid test item was administered to each animal.

Duration of treatment / exposure:
The eyes of the test animals were washed out at 1 hour after application of test item.
Observation period (in vivo):
The eyes were examined at 1, 24, 48, 72 hours and 1, 2 and 3 weeks after treatment.
Number of animals or in vitro replicates:
3 male
Details on study design:
Application of the Test Item

Three male animals in acceptable health condition were selected for the test. Care was taken to select only those animals that had a normal eye condition and any with ocular lesions were rejected.

For ethical reasons, since data on pain response with this test item is available, the animals were analgised using by Butorphanole (0.3-0.4 mg/ kg bw im) administered approximately 15 - 20 minutes before treatment. This procedure follows the principals of the draft OECD 405 guideline.
The test item was instilled into the conjunctival sac of the left eye. The eyelids were held closed for several seconds to prevent the loss of the test item. The contralateral eye served as the control.

After consideration of the ocular responses produced in the first animal, two additional animals were treated.

Clinical Observations

The eyes were examined at 1, 24, 48, 72 hours and 1, 2 and 3 weeks after treatment. The duration of the observation period was sufficient to identify reversibility or irreversibility of changes. Any clinical signs of toxicity or signs of ill- health during the study were recorded.

At the end of the observation period, each animal was sacrificed by intramuscular injections of CP-Ketamin 10% and CP-Xylazin 2% followed by i.v. Euthasol® 40% anaesthesia. Death was verified by checking pupil and corneal reflex and the absence of respiration.

Scoring and Assessment of Local Reaction

The eye irritation scores were evaluated according to the scoring system by Draize (1977) and OECD 405 (24 April 2002).
Irritation parameter:
cornea opacity score
Basis:
animal #1
Remarks:
(mean)
Time point:
other: Overall at 24, 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
other: Not applicable
Irritation parameter:
cornea opacity score
Basis:
animal #2
Remarks:
(mean)
Time point:
other: Overall at 24, 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
other: Not applicable
Irritation parameter:
cornea opacity score
Basis:
animal #3
Remarks:
(mean)
Time point:
other: Overall at 24, 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
other: Not applicable
Irritation parameter:
iris score
Basis:
animal #1
Remarks:
(mean)
Time point:
other: Overall at 24, 48 and 72 hours
Score:
0
Max. score:
2
Reversibility:
other: Not applicable
Irritation parameter:
iris score
Basis:
animal #2
Remarks:
(mean)
Time point:
other: Overall at 24, 48 and 72 hours
Score:
0
Max. score:
2
Reversibility:
other: Not applicable
Irritation parameter:
iris score
Basis:
animal #3
Remarks:
(mean)
Time point:
other: Overall at 24, 48 and 72 hours
Score:
0
Max. score:
2
Reversibility:
other: Not applicable
Irritation parameter:
conjunctivae score
Basis:
animal #1
Remarks:
(mean)
Time point:
other: Overall at 24, 48 and 72 hours
Score:
0.33
Max. score:
3
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
conjunctivae score
Basis:
animal #2
Remarks:
(mean)
Time point:
other: Overall at 24, 48 and 72 hours
Score:
0
Max. score:
3
Reversibility:
other: Not applicable
Irritation parameter:
conjunctivae score
Basis:
animal #3
Remarks:
(mean)
Time point:
other: Overall at 24, 48 and 72 hours
Score:
0
Max. score:
3
Reversibility:
other: Not applicable
Irritation parameter:
chemosis score
Basis:
animal #1
Remarks:
(mean)
Time point:
other: Overall at 24, 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
other: Not applicable
Irritation parameter:
chemosis score
Basis:
animal #2
Remarks:
(mean)
Time point:
other: Overall at 24, 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
other: Not applicable
Irritation parameter:
chemosis score
Basis:
animal #3
Remarks:
(mean)
Time point:
other: Overall at 24, 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
other: Not applicable
Irritation parameter:
other: Discharge
Basis:
animal #1
Remarks:
(mean)
Time point:
other: Overall at 24, 48 and 72 hours
Score:
0
Max. score:
3
Reversibility:
other: Not applicable
Irritation parameter:
other: Discharge
Basis:
animal #2
Remarks:
(mean)
Time point:
other: Overall at 24, 48 and 72 hours
Score:
0
Max. score:
3
Reversibility:
other: Not applicable
Irritation parameter:
other: Discharge
Basis:
animal #3
Remarks:
(mean)
Time point:
other: Overall at 24, 48 and 72 hours
Score:
0
Max. score:
3
Reversibility:
other: Not applicable
Irritant / corrosive response data:
The eyes were examined at 1, 24, 48, 72 hours and 1, 2 and 3 weeks after the application.

During the study, no signs of eye irritation were observed in the control eye of animals.

One hour after the application:
Conjunctival redness (score 1) was found in all rabbits, conjunctival chemosis (score 1) were observed in one animal and all rabbits showed conjunctival discharge (score 3 or 2).

At 24 hours after treatment:
Conjunctival redness (score 1) was found in 1 rabbit.

At 48 and 72 hours after treatment:
No signs of eye irritation or other clinical signs were observed.
Other effects:
The surface of the cornea was coloured by the test item. The discoloration of the cornea was fully reversible within 1 week in two animals, and within 2 weeks in one animal.

The conjunctivae were coloured by the test item during the study up to and including the 3-week observation. The study was terminated after the 3-week observation.
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The test item, applied to rabbit eye mucosa, caused conjunctival irritant effects at one hour which were reduced at 24 hours after application. There were no corneal irritation effects observed at any timepoint, all conjunctival irritation effects were completely reversed after the 48 hours observation period. Discoloration of the cornea was fully reversible within 2 weeks. Some discoloration of the conjuctivae remained at the observation period of 3 weeks, but this is not considered as a classifiable effect under CLP or GHS guidelines.
The test substance is hence “not classified” according to Regulation (EC) No 1272/2008.
Executive summary:

An acute eye irritation study of the test item was performed in New Zealand White rabbits. The irritation effects of the test item were evaluated according to the Draize method (OECD No.: 405, 2002).

The test item was placed into the conjunctival sac of the left eye of each animal. The untreated right eye served as control. An amount of 0.1 g of the test item was administered as a single dose.

Individual body weight was recorded at the beginning and end of the study. Morbidity and clinical signs of toxicity were checked daily. The eyes were examined at 1, 24, 48, 72 hours and 1, 2 and 3 weeks after the application.

No adverse effects on body weight development were noted during the study period. The general state and behaviour of animals were normal throughout the study period.

Eye examination:

During the study, no signs of eye irritation were observed in the control eye of animals.

Initial Pain Reaction (IPR) (score 2 or 3) was observed in all animals after test item administration.

One hour after the application:

Conjunctival redness (score 1) was found in all rabbits, conjunctival chemosis (score 1) were observed in one animal and all rabbits showed conjunctival discharge (score 3 or 2).

At 24 hours after treatment:

Conjunctival redness (score 1) was found in 1 rabbit.

At 48 and 72 hours after treatment:

No signs of eye irritation or other clinical signs were observed.

At 1, 2 and 3 weeks after treatment:

No signs of eye irritation or other clinical signs were observed.

The surface of the cornea was coloured by the test item. The discoloration of the cornea was fully reversible within 1 week in two animals, and within 2 weeks in one animal.

The conjunctivae were coloured by the test item during the study up to and including the 3-week observation. The study was terminated after the 3-week observation.

The animal’s individual mean scores (considering readings at 24, 48 and 72 hours after the treatment) were as follows:

Animal Number

Cornea Opacity

Iris

Conjunctivae

Redness

Chemosis

Discharge

00832

0.00

0.00

0.33

0.00

0.00

00838

0.00

0.00

0.00

0.00

0.00

00843

0.00

0.00

0.00

0.00

0.00

 

The test item applied to rabbit eye mucosa, caused conjunctival irritant effects at one hour which were reduced at 24 hours after application. There were no corneal irritation effects observed at any timepoint, all conjunctival irritation effects were completely reversed after the 48 hours observation period. Discoloration of the cornea was fully reversible within 2 weeks. Some discoloration of the conjuctivae remained at the observation period of 3 weeks, but this is not considered as a classifiable effect under CLP or GHS guidelines.

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

Respiratory irritation

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

Additional information

Skin irritation / Corrosion

The test item was tested according to OECD 404 for skin irritation properties. The evaluation of the erythema and edema scores at the 24, 48, and 72 hour time points showed that the test item is not irritating to skin according to GHS and CLP evaluation schemes.

Eye irritation

The effects on rabbit eyes observed up to 72 hours (chemosis and/or reddening) do not result in any classification. However, staining of the cornea was still present at the end of the 7-day observation period. As the observation period does not extend over the requested 21-day period, it is assumed in accordance with the structural analogue that the staining of the cornea is not longer present after 21 days.

The acute eye irritation study with the structural analogue was performed in New Zealand White rabbits. The irritation effects of the test item were evaluated according to the Draize method (OECD No.: 405, 2002). The test item, applied to rabbit eye mucosa, caused conjunctival irritant effects at one hour, which were reduced at 24 hours after application. There were no corneal irritation effects observed at any timepoint; all conjunctival irritation effects were completely reversed after the 48 hours observation period. Discolouration of the cornea was fully reversible within 2 weeks. Some discolouration of the conjuctivae remained at the observation period of 3 weeks, but this is not considered as a classifiable effect under the CLP Regulation.

Respiratory irritation

Respiratory irritation was not assessed; however no effects on the animals were noted in any associated studies.


Justification for selection of eye irritation endpoint:
The observation period in the study with the test substance is only 7 days.

Justification for classification or non-classification

The above studies have all been ranked reliability 1 or 2 according to the Klimisch et al system. This ranking was deemed appropriate because the studies were conducted in compliance with agreed protocols.

The above results triggered no classification under the Dangerous Substance Directive (67/548/EEC) and the CLP Regulation (EC No 1272/2008).