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Administrative data

Description of key information

Skin irritation: Not irritating (Read-across, OECD 404 in rabbits, GLP, Rel.2, K).
Eye irritation: Not irritating (Read-across, OECD 405 in rabbits, GLP, Rel. 2, K).

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
From 18 to 21 April 1995
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
OECD Guideline study performed according to GLP. The study was fully reliable (Klimisch score = 1), however the reliability score was lowered to 2 which is the maximum score for read-across. The supporting substance is considered adequate for read-across purpose as data relates to a mixture of cis- and trans-isomers whereas the registered substance is the pure cis-isomer (see Iuclid section 13 for additional justification).
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
no
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Conelli S.n.c., Via Milano 61, 28041 ARONA (Novara) - ITALY
- Age at study initiation: ca. 4 months
- Weight at study initiation: 2-3 kg
- Housing: metal cages measuring 62x47.5x38h cm with stainless steel feeders.
- Diet (e.g. ad libitum): ad libitum (produced by Charles River), periodically analyzed
- Water (e.g. ad libitum): ad libitum, periodically analyzed
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 °C ± 2
- Humidity (%): 50 % ± 15
- Air changes (per hr): ca. 15 per hour filtered on HEPA 99.97%
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
occlusive
Preparation of test site:
abraded
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL
Duration of treatment / exposure:
4 hours
Observation period:
72 hours
Number of animals:
3
Details on study design:
TEST SITE
- Area of exposure: ca. 6 cm2
- Type of wrap if used: gauze patch loosely held in contact with the skin by an impermeable, non-irritant, hypoallergenic tape (Blenderm3M Italia)

SCORING SYSTEM:

- Erythema and Escar formation (maximum score possible: 4):
0: No erythema
1: Very slight erythema (barely perceptible)
2: Well-defined erythema
3: Moderate to severe erythema
4: Severe erythema (beef redness) to slight eschar formation (injuries in depth)

- Oedema formation (maximum score possible: 4):
0: No edema
1: Very slight oedema (barely perceptible)
2: Slight oedema (edges of area well defined by definite raising)
3: Moderate oedema (raised approximately 1 mm)
4: Severe oedema (raised more than 1 mm and extending beyond area ofexposure)
Irritation parameter:
erythema score
Basis:
animal: # 1, #2 and #3
Time point:
other: mean 24, 48 and 72 hours
Score:
0
Max. score:
4
Remarks on result:
other: No erythema was observed at any time
Irritation parameter:
edema score
Basis:
animal: #1, #2 and #3
Time point:
other: mean 24, 48 and 72 hours
Score:
0
Max. score:
4
Remarks on result:
other: No oedema were observed at any time
Irritant / corrosive response data:
See Table 1 in "Any other information on results incl. tables"
Other effects:
None (no animal died during the study, no clinical signs or behavioural alterations were observed during the study in any rabbits).

Table 1: Dermal reactions observed

 

Time of observation

Animal n°

1

2

3

Erythema and Eschar

3 min

60 min

24 hours

48 hours

72 hours

0

0

0

0

0

-

0

0

0

0

-

0

0

0

0

Oedema

3 min

60 min

24 hours

48 hours

72 hours

0

0

0

0

0

-

0

0

0

0

-

0

0

0

0

 

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
At the application sites, no signs of dermal irritancy were noted in any animal. The test material is not classified as irritant to the skin.
Executive summary:

Introduction. The purpose of the study was to evaluate the acute dermal irritation and/or corrosive effects on skin following the application of the test article CEPIONATE (High ratio of Methylepi-dihydrojasmonate). The test method was in accordance with European Economic Community Guidelines - Annex to Commission Directive 92/69/EEC of July 31, 1992 adapting to technical progress for the seventeenth time Council Directive 67/548/EEC on the approximation of laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances (B.4) and with Organization for Economic Cooperation and Development Guidelines (section 4, subpart 404, Paris 1981 and subsequent revisions).

 

Methods and Results. 0.5 ml of pure test article was applied to abraded skin of New Zealand White rabbits in occlusive conditions. Firstly one rabbit was used and three treatment sites of the skin were prepared. On the first site the test article was applied for an exposure period of 3 minutes. Since no serious gross skin reactions were noted, the test article was applied for an exposure period of 1 hour on the second site. Since no serious gross reactions were observed after the one-hour exposure period, the test article was applied for an exposure period of 4 hours on the third skin site. The test was completed using two additional animals with a 4 hour exposure period and a 72 hours observation period. None of the treated animals showed clinical signs or behavioural alterations. At the application sites, no signs of dermal irritancy were noted in any animal.

 

Conclusion. The test material is not classified as irritant to the skin according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP) and the Directive 67/548/EC.

This study is considered as acceptable and satisfies the requirement for skin irritation endpoint.

The supporting substance is considered adequate for read-across purpose as data relates to a mixture of cis- and trans-isomers whereas the registered substance is the pure cis-isomer (see Iuclid section 13 for additional justification).

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:
key study
Study period:
From 02 May 2000 to 05 May 2000
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
OECD Guideline Study & Test in accordance with National procedures (OPPTS). The study was fully reliable (Klimisch score = 1), however the reliability score was lowered to 2 which is the maximum score for read-across. The supporting substance is considered adequate for read-across purpose as data relates to a mixture of cis- and trans-isomers whereas the registered substance is the pure cis-isomer (see Iuclid section 13 for additional justification).
Reason / purpose for cross-reference:
reference to same study
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2400 (Acute Eye Irritation)
Deviations:
no
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Davidson's Mill Farm, South Brunswick, NJ - USA
- Age at study initiation: adult
- Weight at study initiation: not mentioned in study report
- Housing: suspended stainless steel caging with mesh floors which conform to the size recommendations in the most recent Guide for the Care and Use of Laboratory Animals DHEW (NlH). Litter paper was placed beneath the cage and was changed at least three times per week.
- Diet (e.g. ad libitum): Free access (Pelleted Purina Rabbit Chow #5326)
- Water (e.g. ad libitum): Free access (Filtered tap water was supplied by automatic water dispensing system)
- Acclimation period: six days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 to 23°C
- Humidity (%): 38 to 43%
- Air changes (per hr): not mentioned in the study report
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 02 May 2000 To: 05 May 2000
Vehicle:
unchanged (no vehicle)
Controls:
other: other eye (left eye)
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL
Duration of treatment / exposure:
72 hours
(0.1 ml of the test substance, as received, was instilled into the conjunctival sac of the right eye of each rabbit by pulling the lower lid away from the eyeball. The upper and lower lids were then gently held together for about one second before releasing, to minimize loss of the test substance. The other eye of each rabbit remained untreated with the test substance and served as a control. The rabbits were then returned to their designated cages. Assessment of ocular damage/irritation was made approximately 1 hour and 24, 48 and 72 hours following treatment).
Observation period (in vivo):
Assessment of ocular damage/irritation was made approximately 1 hour and 24, 48 and 72 hours following treatment. An assessment of the initial pain reaction was made immediately after administration of the test material.
Number of animals or in vitro replicates:
3
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): None
- Time after start of exposure: NA

SCORING SYSTEM: see "Attached background material"

TOOL USED TO ASSESS SCORE: Ocular irritation was evaluated using a high-intensity white light (Mag Lite) in accordance with Draize et al. at 1, 24, 48 and 72 hours post-instillation. The fluorescein dye evaluation procedure was used at 24 hours to verify the absence of corneal damage (see below). Individual scores were recorded for each animal. In addition to observations of the cornea, iris and conjunctivae, any other observed lesions were noted.
Prior to instillation, both eyes of a number of animals were examined using a fluorescein dye procedure. One drop of 2% ophthalmic fluorescein sodium was instilled into both eyes of each rabbit. The eyes were rinsed with physiological saline (0.9% NaCl) approximately 30 seconds after instillation of the fluorescein. Using a Blak-Ray® Lamp (compact 4-watt UV Lamp), the eyes were checked for gross abnormalities according to the "Scale for Scoring Ocular Lesions". Only healthy animals without pre-existing ocular irritation were selected for test.
Irritation parameter:
cornea opacity score
Basis:
animal: #1, #2 and #3
Time point:
other: mean 24, 48 and 72 hours
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
animal: #1, #2 and #3
Time point:
other: mean 24, 48 and 72 hours
Score:
0
Max. score:
2
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
other: mean 24, 48 and 72 hours
Score:
0
Max. score:
3
Irritation parameter:
conjunctivae score
Basis:
animal: #2 and #3
Time point:
other: mean 24, 48 and 72 hours
Score:
0.33
Max. score:
3
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
chemosis score
Basis:
animal: #1, #2 & #3
Time point:
other: mean 24, 48 and 72 hours
Score:
0
Max. score:
4
Irritant / corrosive response data:
See above block of fields "Overall Irritation/corrosion results"
Other effects:
None.
All animals appeared active and healthy. Apart from the eye irritation noted below, there were no other signs of gross toxicity, adverse pharmacologic effects or abnormal behaviour. No corneal opacity or iritis was noted during the study. One hour after test substance instillation, all three treated eyes exhibited conjunctivitis. The incidence and severity of irritation decreased with time. All animals were free of ocular irritation within 48 hours.

Table 7.3.2/1: Irritant/corrosive response data each animals at each observation time up to removal from the test

 

Score at time point / Reversibility

Cornea

Iris

(/2)

Conjunctivae

Opacity

(/4)

Redness

(/3)

Chemosis

(/4)

Discharge

(/3)

1 h

0 / 0 / 0

0 / 0 / 0

1 / 2 / 2

0 / 1 / 1

E

24 h

0 / 0 / 0

0 / 0 / 0

0 / 1 / 1

0 / 0 / 0

0 / 0 / 0

48 h

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

72 h

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

Average 24h, 48h, 72h

0 / 0 / 0

0 / 0 / 0

0.0 / 0.33 / 0.33

0.0 / 0.0 / 0.0

0 / 0 / 0

Reversibility*)

-

-

c.

c.

-

Average time for reversion

-

-

48 h

-

-

*) Reversibility: c. = completely reversible; n.c. = not completely reversible; n. = not reversible

 E = scoring masked by residual test substance

All treated eyes appeared normal at the 72-hour observation.

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The individual score for each individual lesion for each animal within 3 scoring times (24, 48 and 72 hrs) were 0.00/0.33/0.33 for erythema, and 0.00/0.00/0.00 for chemosis, discharge, iris lesions and corneal opacity. Under the test conditions, the test material is not classified as irritating to eyes.
Executive summary:

The study was performed to assess the irritancy potential of the test material to the eye of the New Zealand White rabbit. The method was designed to meet the requirements of the OECD Guideline No. 405 “Acute Eye Irritation/Corrosion” (2002) and of the Health Effects Test Guidelines, OPPTS 870.2400 (1998).

0.1 mL of the test substance, as received, was instilled into the right eye of three healthy rabbits. The left eye remained untreated and served as a control. Ocular irritation was evaluated by the method of Draize. No corneal opacity or iritis was noted during the study. One hour after test substance instillation, all three treated eyes exhibited conjunctivitis. The incidence and severity of irritation decreased with time. All animals were free of ocular irritation within 48 hours.

The individual score for each individual lesion for each animal within 3 scoring times (24, 48 and 72 hrs) were 0.00/0.33/0.33 for erythema, and 0.00/0.00/0.00 for chemosis, discharge, iris lesions and corneal opacity.

Under the test conditions, the test material is not classified as irritating to eyes according to the criteria of the Annex VI of the Regulation (EC) No. 1272/2008 (CLP) and of the Directive 67/548/EEC.

This study is considered as acceptable and satisfies the requirement for eye irritation endpoint.

The supporting substance is considered adequate for read-across purpose as data relates to a mixture of cis- and trans-isomers whereas the registered substance is the pure cis-isomer (see Iuclid section 13 for additional justification).

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

No study was available on the substance itself, therefore a read-across approach was used. The supporting substance is considered adequate for read-across purpose as data relates to a mixture of cis- and trans-isomers whereas the registered substance is the pure cis-isomer (see Iuclid section 13 for additional justification).

Skin irritation:

A key study was identified on the supporting substance (Istituto di Ricerche Biomediche, 1996, rel.2). This skin irritation study was performed according to the E.U method B.4, and in compliance with GLP. At the application sites, no signs of dermal irritancy were noted in any animal at any time points. Under the study conditions, the substance was not a skin irritant.

The registered substance is present at 30% in the mixture, i.e. well above the concentration triggering classification of mixture as skin corrosive or skin irritant as defined in the Annex VI of the Regulation (EC) No. 1272/2008, therefore it can be safely concluded that the pure cis-isomer does not need to be classified as skin irritant.

Eye irritation:

A key study was identified on the supporting substance (Product Safety labs, 2000, rel.2). In this eye irritation study performed according to the OECD guideline No. 405, and in compliance with GLP, undiluted test material was instilled into the right eye of 3 rabbits. The individual scores for each animal within 3 scoring times (24, 48 and 72 hrs) were 0.00/0.33/0.33 for erythema, and 0.00/0.00/0.00 for chemosis, discharge, iris lesions and corneal opacity. Under the test conditions, the substance is not an eye irritant.

The registered substance is present at 10 -12% in the mixture, i.e. at the concentration triggering classification of mixture as skin corrosive or skin irritant as defined in the Annex VI of the Regulation (EC) No. 1272/2008, therefore it can be safely concluded that the pure cis-isomer does not need to be classified as eye irritant.


Justification for selection of skin irritation / corrosion endpoint:
The key study is GLP-compliant and of high quality (Klimisch score = 2). The reliability score was lowered to 2 which is the maximum score for read-across.

Justification for selection of eye irritation endpoint:
The key study is GLP-compliant and of high quality (Klimisch score = 2). The reliability score was lowered to 2 which is the maximum score for read-across.

Justification for classification or non-classification

Harmonized classification:

The substance has no harmonized classification according to the Regulation (EC) No. 1272/2008 including ATP4.

Self-classification:

Based on the available data no additional self-classification is proposed regarding both skin and eye irritation according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP) and of the Directive 67/548/EC.

No data was available regarding respiratory irritation.

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