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Diss Factsheets

Administrative data

Description of key information

Skin irritation/corrosion rabbit (according to OECD 404 of 2002):
Mean irritation score 24, 48 and 72 h for each of 3 animals: 0.0 for erythema, 0.0 for oedema; No signs of irritation at any observation time point of the study.
Eye irritation, rabbit (according to OECD 405 of 2002:
Mean irritation score 24, 48 and 72 h for each of 3 animals:
0.0 for corneal opacity; 0.0 for iris lesion; 0.0 to 0.3 for redness of conjunctivae; 0.0 for oedema of conjunctivae (chemosis); Minor findings (conjunctival redness grade 1) at 1 h post dosing were not relevant.

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:
other: Well documented and reported study fully adequate for assessment. The study was conducted according to internationally accepted technical guidelines and in compliance with GLP in a recognized contract research organization.
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
of 2002
Deviations:
no
Remarks:
Inadvertently 14 h artificial light per 24 h, instead of 12 h per 24 h did not compromise the study results
Qualifier:
according to guideline
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Version / remarks:
of 2008
Deviations:
no
Remarks:
Inadvertently 14 h artificial light per 24 h, instead of 12 h per 24 h did not compromise the study results
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2500 (Acute Dermal Irritation)
Version / remarks:
of 1998
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Japanese MAFF Test Data for Registration of Agricultural Chemicals, Skin Irritation (2-1-4), 12 Nohsan No. 8147, Agricultural Production Bureau, November 24, 2000.
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS

- Stock supply of healthy adult rabbits
- Number and Sex: 3 females
- Age on day of dosing (Day 1): 40 - 45 weeks
- Weight prior to dosing (Day 1): Minimum 3.83 kg, maximum 4.25 kg
- Housing: Individual housing in plastic cages with peforated floor
- Environmental enrichment: Small soft white untreated wood blocks
- Diet : Standard laboratory rabbit diet (125 g/animal/day). In addition, dietary supplement of hay.
- Water: Drinking water, ad libitum
- Acclimation period: 22 to 26 weeks prior to study start under laboratory conditions.

Routine analysis of the batch of diet used for nutrients, possible contaminants and microorganisms and of the drinking water were conducted or available at the testing facility.


ENVIRONMENTAL CONDITIONS

Air conditioned animal room set at:
- Temperature (°C): 18 ± 2°C
- Relative Humidity (%): 40 to 70%
- Photoperiod: 14 hrs artificial light per 24 hrs

Type of coverage:
semiocclusive
Preparation of test site:
other: On the day before exposure removal of hair from the dorsolumbar region by use of clippers
Vehicle:
unchanged (no vehicle)
Remarks:
Treatment site was moistened with 0.5 mL reverse osmosis water
Controls:
not required
Amount / concentration applied:
ca. 0.5 g of the test material per 2.5 cm x 2.5 cm clipped intact skin per animal.
Duration of treatment / exposure:
Animal # 3 (sentinel animal): Three exposures of 3 minutes, 1 hour or 4 hours in sequential order to act as a preliminary screen.
Animals # 1 & 2: 4 hours
Observation period:
72 hours post patch removal
Number of animals:
3 females
Details on study design:
TEST SITE PREPARATION:
On the day before treatment, hair was removed with clippers from the dorsolumbar region of each animal. The neat test substance was administered under a 2-ply 25 mm x 25 mm porous gauze pad secured with 'blenderm' surgical tape to intact skin sites moistened with 0.5 mL reverse osmosis water. For exposures of one hour or more each treatment site was covered additionally with cotton wool and "Tubigrip" elasticated bandage dressing for the duration of the exposure period.

On each animal an additional site was similarly treated with the exception of test substance and acted as a control.

TREATMENT PERIOD AND REMOVAL OF TEST SUBSTANCE
At the end of the exposure period, the semi-occlusive dressing and gauze pad were removed and the treatment site was washed with lukewarm water (30-40°C) to remove any residual test substance. The treated area was blotted dry with absorbent paper.

SKIN EVALUATION:
The treated skin patches were evaluated immediately after patch removal (for 3 minute and 1 hour exposures) and at 1, 24, 48 and 72 h afterwards, whereby only the data for the 4 hour exposures were reported. The scoring system for the grading of skin reactions is listed in Table 1 (next field below).
Irritation parameter:
erythema score
Remarks:
as defined in Table 1
Basis:
mean
Remarks:
over 3 animals and 3 time points
Time point:
other: 24, 48, 72 h
Score:
0
Max. score:
4
Reversibility:
other: erythema or eschar formation was not evident
Irritation parameter:
edema score
Remarks:
as defined in Table 1
Basis:
mean
Remarks:
over 3 animals and 3 time points
Time point:
other: 24, 48, 72 h
Score:
0
Max. score:
4
Reversibility:
other: edema formation was not evident
Irritant / corrosive response data:
In each animal, erythema, eschar or edema formation or any other skin reactions were not evident at any observation time point of the study, i.e. not evident at 1, 24, 48 or 72 hours after the end of administration.
Other effects:
Signs of systemic toxicity or ill health were not evident.
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
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:
other: Well documented and reported study fully adequate for assessment. The study was conducted according to internationally accepted technical guidelines and in compliance with GLP in a recognized contract research organization.
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
of 2002
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Version / remarks:
of 2008
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2400 (Acute Eye Irritation)
Version / remarks:
of 1998
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Japanese MAFF Test Data for Registration of Agricultural Chemicals, Eye Irritation (2-1-5), 12 Nohsan No. 8147, Agricultural Production Bureau, November 24, 2000.
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS

- Stock supply of healthy adult rabbits
- Number and Sex: 3 females
- Age on day of dosing (Day 1): 39 or 40 weeks
- Weight prior to dosing (Day 1): Minimum 4.04 kg, maximum 4.63 kg
- Housing: Individual housing in plastic cages with peforated floor
- Environmental enrichment: Small soft white untreated wood blocks
- Diet : Standard laboratory rabbit diet (125 g/animal/day). In addition, dietary supplement of hay
replaced by a supplement of wholemeal bread as from 2 days prior to dose instillation.
- Water: Drinking water, ad libitum
- Acclimation period: 20 to 21 weeks prior to study start under laboratory conditions.

Routine analysis of the batch of diet used for nutrients, possible contaminants and microorganisms and of the drinking water were conducted or available at the testing facility.


ENVIRONMENTAL CONDITIONS

Air conditioned animal room set at:
- Temperature (°C): 18 ± 2°C (as an exception on a single day up to 28°C) *
- Relative Humidity (%): 40 to 70% (as an exception on a single day up to 79%) *
- Photoperiod: 12 hrs artificial light per 24 hrs

* The excursion from the target limits of animal room temperature and relative humidity on a single day was transient and had no impact on the wellbeing of the animals, and thus was considered to have had no impact on the study results.
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
0.1 mL (weighing ca. 98 mg) of the test material was instilled into the conjunctival sac of one eye per rabbit (right eye).
Immediately after instillation upper and lower eyelids were held together for about 1 second to prevent loss of test material.
The contralateral eye (left eye) remained untreated to serve as a control.
Duration of treatment / exposure:
Eyes were not rinsed after treatment with the test substance. Consequently the treatment/exposure period was equivalent to the entire observation period following instillation, which was 72 hours, or lasted until removal of the test material by physiological mechanisms, whichever happened sooner.
Observation period (in vivo):
72 hours post instillation
Number of animals or in vitro replicates:
3
Details on study design:
EYE EVALUATION:

Before treatment start both eyes of each animal were investigated to ensure that there was no pre-existing corneal damage, iridial inflammation or conjunctival irritation.

One animal (the sentinel) was initially treated and in the absence of a severe effect the remaining two animals were committed to the study.

Eyes were evaluated in all animals at approximately 1, 24, 48 and 72 hours after test substance instillation adopting the numerical scoring system listed in Table 1 in the field below. Grades attained at 24, 48 and 72 hours after instillation were included in the mean gradings of ocular lesions and used for evaluation of the necessity of eye irritation/corrosion classification. Additional checks of the animals at appropriate intervals ensured that no severe injury passed unnoticed.

Equipment used for eye evaluation: Ophthalmoscope or pencil beam torch
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
over 3 animals and 3 time points
Time point:
other: 24, 48, 72 h
Score:
0
Max. score:
4
Reversibility:
other: Corneal ulceration or opacity were not evident
Irritation parameter:
other: Area of corneal opacity
Basis:
mean
Remarks:
over 3 animals and 3 time points
Time point:
other: 24, 48, 72 h
Score:
0
Max. score:
4
Reversibility:
other: Corneal ulceration or opacity were not evident
Irritation parameter:
iris score
Basis:
mean
Remarks:
over 3 animals and 3 time points
Time point:
other: 24, 48, 72 h
Score:
0
Max. score:
2
Reversibility:
other: Iridic changes were not evident
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
mean
Remarks:
over 3 animals and 3 time points
Time point:
other: 24, 48, 72 h
Score:
0.1
Max. score:
3
Reversibility:
fully reversible within: 48 h
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #1
Remarks:
mean over 3 time points
Time point:
other: 24, 48, 72 h
Score:
0.3
Max. score:
3
Reversibility:
fully reversible within: 48 h
Remarks on result:
other: In addition, score 1 at 1 hour post instillation
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #2
Remarks:
mean over 3 time points
Time point:
other: 24, 48, 72 h
Score:
0
Max. score:
3
Reversibility:
fully reversible within: 24 h
Remarks on result:
other: Score 1 at 1 hour post instillation
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #3
Remarks:
mean over 3 time points
Time point:
other: 24, 48, 72 h
Score:
0
Max. score:
3
Reversibility:
fully reversible within: 24 h
Remarks on result:
other: Score 1 at 1 hour post instillation
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
over 3 animals and 3 time points
Time point:
other: 24, 48, 72 h
Score:
0
Max. score:
4
Reversibility:
other: Chemosis was not evident
Irritation parameter:
other: Discharge
Basis:
mean
Remarks:
over 3 animals and 3 time points
Time point:
other: 24, 48, 72 h
Score:
0
Max. score:
4
Reversibility:
other: Discharge was not evident
Remarks on result:
other: Residual test material was seen around the treated eye of one animal (#3) at 1 hour post instillation
Irritant / corrosive response data:
Corneal and iridic lesions, chemosis and conjunctival discharge were not evident throughout the study. Conjunctival redness, grade 1 (injection of conjunctival blood vessels), was seen in all treated eyes at 1 and/or 24 hours after instillation having completely disappeared in two animals by 24 hours after instillation and in the other animal by 48 hours after instillation. Throughout the study no other signs of ocular irritation were evident.
Other effects:
Observation of the animals for defined behavioural criteria led to the conclusion that instillation of the test substance induced practically no or a slight initial pain response. Any other signs, of systemic toxicity or ill health were not evident.
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The outcome of the present study does not necessitate any labelling regarding eye irritation according to EU classification rules [DIRECTIVE 67/548/EEC and REGULATION (EC) 1272/2008]. The minor findings noted at 1 and/or 24 hours post instillation are within the category “not irritating to eyes”. They were fully reversible.
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

In view of the absence of any effects during the skin irritation study and the absence of relevant effects during the eye irritation study, the attained results do not necessitate any classification and labelling regarding skin or eye irritation according to EU classification rules [DIRECTIVE 67/548/EEC and REGULATION (EC) 1272/2008].