Registration Dossier

Administrative data

Description of key information

To assess eye irritation an invitro study was conducted first which resulted in no prediction therefore an in vivo study was required. Final classification is based on the in vivo study.

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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
according to
Guideline:
other: OECD principles of GLP, Annex 2, C (8) 30
Qualifier:
according to
Guideline:
other: U.S Environmental Protection Agency's Good Laboratory Practice Standards, 40 CFR 160
GLP compliance:
yes
Specific details on test material used for the study:
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature
Justification for test system used:
Historically, the New Zealand White albino rabbit has been the animal of choice for evaluating the effect of chemicals on the skin
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
SOURCE ANIMAL
- Sex: Male
- Weight at study initiation: 2010 - 2620g
- Housing: Individually in screen-bottom cages in temperature- and humidity-controlled quarters
- Water (e.g. ad libitum): ad libitum
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
physiological saline
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5g

REMOVAL OF TEST MATERIAL AND CONTROLS
- Observable damage in the tissue due to washing: Material was removed from the test site as throughly as possible without irritating the skin
Duration of treatment / exposure:
4 hours
Observation period:
72 hours
Number of animals:
6
Details on study design:
TEST ANIMALS
- Weight at study initiation: 2010 - 2620g
- Housing: Individually in screen-bottom cages in temperature- and humidity-controlled quarters
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 69 -78 °F
- Humidity (%): 61 - 74 %RH
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: 4 hours
Score:
0
Max. score:
0
Reversibility:
not specified
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
not specified
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: 4 hours
Score:
0
Max. score:
0
Reversibility:
not specified
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
not specified
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: 4 hours
Score:
0
Max. score:
0
Reversibility:
not specified
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
not specified
Irritation parameter:
erythema score
Basis:
animal #4
Time point:
other: 4 hours
Score:
0
Max. score:
0
Reversibility:
not specified
Irritation parameter:
erythema score
Basis:
animal #4
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
not specified
Irritation parameter:
erythema score
Basis:
animal #5
Time point:
other: 4 hours
Score:
0
Max. score:
0
Reversibility:
not specified
Irritation parameter:
erythema score
Basis:
animal #5
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
not specified
Irritation parameter:
erythema score
Basis:
animal #6
Time point:
other: 4 hours
Score:
0
Max. score:
0
Reversibility:
not specified
Irritation parameter:
erythema score
Basis:
animal #6
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
not specified
Irritation parameter:
edema score
Basis:
animal #1
Time point:
other: 4 hours
Score:
0
Max. score:
0
Reversibility:
not specified
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
not specified
Irritation parameter:
edema score
Basis:
animal #2
Time point:
other: 4 hours
Score:
0
Max. score:
0
Reversibility:
not specified
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
not specified
Irritation parameter:
edema score
Basis:
animal #3
Time point:
other: 4 hours
Score:
0
Max. score:
0
Reversibility:
not specified
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
not specified
Irritation parameter:
edema score
Basis:
animal #4
Time point:
other: 4 hours
Score:
0
Max. score:
0
Reversibility:
not specified
Irritation parameter:
edema score
Basis:
animal #4
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
not specified
Irritation parameter:
edema score
Basis:
animal #5
Time point:
other: 4 hours
Score:
0
Max. score:
0
Reversibility:
not specified
Irritation parameter:
edema score
Basis:
animal #5
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
not specified
Irritation parameter:
edema score
Basis:
animal #6
Time point:
other: 4 hours
Score:
0
Max. score:
0
Reversibility:
not specified
Irritation parameter:
edema score
Basis:
animal #6
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
not specified
Interpretation of results:
GHS criteria not met
Conclusions:
The test material, ADK STAB L-63P, produced no irritation when applied to the skin of six albino rabbits under 4-hour semiccluded conditions.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Referenceopen allclose all

Endpoint:
eye irritation: in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
05 Oct 2016 - 20 Jun 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 437 (Bovine Corneal Opacity and Permeability Test Method for Identifying i) Chemicals Inducing Serious Eye Damage and ii) Chemicals Not Requiring Classification for Eye Irritation or Serious Eye Damage)
Deviations:
no
Qualifier:
according to
Guideline:
EU method B.47 (Bovine corneal opacity and permeability test method for identifying ocular corrosives and severe irritants)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Specific details on test material used for the study:
- Batch: 112Z5
- Purity: 100%
- Physical state/Appearance: white powder
- Expiry Date: 30 June 2017
- Storage Conditions: room temperature in the dark
Species:
cattle
Details on test animals or tissues and environmental conditions:
SOURCE OF COLLECTED EYES
- Source: local abattoir

- Number of animals: 3 per control group

- Characteristics of donor animals - age: 12 - 60 months

- Storage, temperature and transport conditions of ocular tissue (e.g. transport time, transport media and temperature, and other conditions): The eyes were excised and were placed in Hanks’ Balanced Salt Solution (HBSS) supplemented with penicillin at 100 IU/mL and streptomycin at 100 μg/mL. Transported to the test facility over ice packs on the same day of slaughter. The corneas were prepared immediately on arrival.
Vehicle:
physiological saline
Controls:
yes, concurrent positive control
yes, concurrent negative control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.75mL
- Concentration (if solution): 20% w/v solution

VEHICLE
- Concentration (if solution): 0.9% w/v sodium chloride solution
Duration of treatment / exposure:
240 min
Duration of post- treatment incubation (in vitro):
240 minutes.
Number of animals or in vitro replicates:
3 per control group
Details on study design:
SELECTION AND PREPARATION OF CORNEAS -
All eyes were macroscopically examined before and after dissection.
Only corneas free of damage were used.
The isolated corneas were immersed in a dish containing HBSS until they were mounted in Bovine Corneal Opacity and Permeability (BCOP) holders.
The anterior and posterior chambers of each BCOP holder were filled with complete Eagle’s Minimum Essential Medium (EMEM) without phenol red and plugged.
The holders were incubated at 32 ± 1 ºC for 65 minutes.
At the end of the incubation period each cornea was examined for defects.
Only corneas free of damage were used.

NUMBER OF REPLICATES
3 per control group

NEGATIVE CONTROL USED
- Sodium chloride 0.9% w/v
- Batch: 3011542
- Purity: 0.9%
- Expiry Date: 01 Mar 2017
- Storage Conditions: Room temperature in the dark

POSITIVE CONTROL USED
- Imidazole
- Batch: 1420882
- Purity: 100%
- Expiry Date: 28 February 2021
- Storage Conditions: Room temperature in the dark

APPLICATION DOSE AND EXPOSURE TIME
0.75mL of 20% w/v solution in 0.9% w/v sodium chloride solution. at 32 ± 1 ºC for 240 minutes.

REMOVAL OF TEST SUBSTANCE
- Number of washing steps after exposure period: 3 with fresh Eagle’s Minimum Essential Medium (EMEM)

METHODS FOR MEASURED ENDPOINTS:
- Corneal opacity:
- Corneal permeability: passage of sodium fluorescein dye measured with the aid of [UV/VIS spectrophotometry / microtiter plate reader] (OD490)
- Others (e.g, pertinent visual observations, histopathology): (please specify)

SCORING SYSTEM: In Vitro Irritancy Score (IVIS)
The following formula was used to determine the In Vitro Irritancy Score:
In Vitro Irritancy Score = mean opacity value + (15 x mean permeability OD492 value)
IVIS Classification
≤ 3 No category. Not requiring classification to UN GHS or EU CLP
> 3; ≤55 No prediction of eye irritation can be made
> 55 Category 1. UN GHS or EU CLP Causes serious eye damage

DECISION CRITERIA: please specify if the decision criteria as indicated in the TG was used.


















Irritation parameter:
in vitro irritation score
Value:
13.2
Vehicle controls validity:
not applicable
Negative controls validity:
valid
Positive controls validity:
valid
Irritation parameter:
cornea opacity score
Run / experiment:
mean
Value:
12.7
Vehicle controls validity:
not applicable
Negative controls validity:
valid
Positive controls validity:
valid
Irritation parameter:
other: Permeability
Run / experiment:
mean
Value:
0.038
Vehicle controls validity:
not applicable
Negative controls validity:
valid
Positive controls validity:
valid
Interpretation of results:
GHS criteria not met
Conclusions:
No prediction of eye irritation can be made
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
23 Jan 2017 - 09 Feb 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
The rabbit is the preferred species of choice as historically used for irritation studies and is specified in the appropriate test guidelines.
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 1125
- Expiration date of the lot/batch: 30 Jun 2017
- Purity: 100%
- Physical state/ Appearance: white powder
- Storage condition: room temperature in the dark
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Envigo RMS (UK) Limited, Leicestershire, UK
- Age at study initiation: 12 - 52 weeks old
- Weight at study initiation: 2.31 - 2.67 kg
- Housing: suspended housing
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 - 23
- Humidity (%): 30 - 70
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/ 12
Vehicle:
unchanged (no vehicle)
Controls:
yes
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 70mg (or 0.1mL)
Duration of treatment / exposure:
1 hour
Observation period (in vivo):
1, 24, 48 and 72 h
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): Not specified
- Time after start of exposure:Not specified

SCORING SYSTEM: Kay and Calandra Classification system

TOOL USED TO ASSESS SCORE: Light source from a standard opthalmoscope.
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
not specified
Remarks on result:
no indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
not specified
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
not specified
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
not specified
Remarks on result:
no indication of irritation
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 1h
Score:
15
Max. score:
15
Irritation parameter:
conjunctivae score
Basis:
animal: 1 and 2
Time point:
24 h
Score:
2
Max. score:
2
Reversibility:
fully reversible within: 48 Hours
Remarks on result:
probability of mild irritation
Irritation parameter:
conjunctivae score
Basis:
animal: 1 and 2
Time point:
48 h
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 24 hours
Remarks on result:
probability of mild irritation
Irritation parameter:
conjunctivae score
Basis:
animal: 1 and 2
Time point:
72 h
Score:
0
Max. score:
0
Reversibility:
not specified
Remarks on result:
no indication of irritation
Irritation parameter:
chemosis score
Basis:
animal: 1 and 2
Time point:
24 h
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 48 hours
Remarks on result:
probability of mild irritation
Irritation parameter:
chemosis score
Basis:
animal: 1 and 2
Time point:
48 h
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 24 Hours
Remarks on result:
probability of mild irritation
Irritation parameter:
chemosis score
Basis:
animal: 1 and 2
Time point:
72 h
Score:
0
Max. score:
0
Reversibility:
not specified
Remarks on result:
no indication of irritation
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
24 h
Score:
7
Max. score:
8
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
48 h
Score:
4
Max. score:
4
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
72 h
Score:
0
Other effects:
No corneal effects were noted during the study.

Iridial inflammation was noted in both treated eyes 1 hour after treatment.

Moderate conjunctival irritation was noted in both eyes 1 hour after treatment.
Moderate conjunctival irritation was noted in one treated eye and minimal conjunctival irritation was noted in the other treated eye at the 24 hours observation with minimal conjunctival irritation noted in both eyes at the eyes at the 48 hours observation.

Both treated eyes appeared normal at the 72 hours observation.
Interpretation of results:
Category 2 (irritating to eyes) based on GHS criteria
Conclusions:
The test item produced a maximum group score of 15.0 and was classified as a mild irritant (Class 4 on a 1 to 8 scale) to the rabbit eye according to a modified Kay and Calandra classification system.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Additional information

Justification for classification or non-classification

The skin irritiation study resulted in no adverse effects therefor LA-63P is not classified for Skin irritation.

The in vivo eye irritation study resulted in adverse effects which were fully reversible within 72 hours therefore according to the CLP criteria LA-63P is classified as Category 2- Irritating to eyes. H319- Causes serious Eye irritation.