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Eye irritation

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Administrative data

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented study report. Test procedure according to national standards
Cross-reference
Reason / purpose:
reference to same study
Reference
Endpoint:
eye irritation: in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented study report. Test procedure according to national standards
Justification for type of information:
ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source substances and target substance have similar physical-chemical properties and (eco)toxicological properties because they are either stereoisomers of the target substance, are hydrolysed to the same substance or their chemical structure differs only by an additional double bond. This prediction is supported by data on the substances themselves.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The target substance, L-Citronellol, is a mono-constituent substance (EC No. 231-415-7, CAS no. 7540-51-4 consisting of a C8 carbon backbone, methyl substituents at C3 and C7, one double bond and a hydroxyl group. The substance is optically active, comprising a single, pure enantiomeric laevo form.

The source substance, DL-Citronellol, is a mono-constituent substance (EC No. 203-375-0, CAS no. 106-22-9, consisting of a C8 carbon backbone, methyl substituents at C3 and C7, one double bond and a hydroxyl group. The substance is an equimolar mixture of two optical isomers (enantiomers).

The source substance, citronellyl acetate, is a mono-constituent substance (EC No. 205-775-0, CAS no. 150-84-5) consisting of a C8 carbon backbone, methyl substituents at C3 and C7, one double bond and an acetate group.

The source substance, geraniol and it’s isomer, consist of a C8 carbon backbone, methyl substituents at C3 and C7, two double bonds and a hydroxyl group. The only difference between the isomers is the position of the first double bond.

The source substance, geraniol and nerol, is a multi-constituent substance of E/Z isomers (EC No. 906-125-5). The constituents consist of a C8 carbon backbone, methyl substituents at C3 and C7, two double bonds and a hydroxyl group.

The source substance, geraniol, is a mono-constituent substance (EC No. 203-377-1, CAS no. 106-24-1), consisting of a C8 carbon backbone, methyl substituents at C3 and C7, two double bonds and a hydroxyl group. Geraniol is a pure form of the E-isomer.

The source substance, nerol, is a mono-constituent substance (EC No. 203-378-7, CAS no. 106-25-2), consisting of a C8 carbon backbone, methyl substituents at C3 and C7, two double bonds and a hydroxyl group. Nerol is a pure form of the Z-isomer.
The source and target substances are both of high purity with a low concentration of impurities.

3. ANALOGUE APPROACH JUSTIFICATION
The read across hypothesis is based on structural similarity where the source substances only differ in the enantiomeric ratio or an additional double bond. Another source substance is expected to be hydrolysed to the same structure as the target substance.
In a non-chiral environment the target and source chemical DL-Citronellol will have identical properties, but in the chiral environment of living organisms the enantiomers may possess different carcinogenicity and teratogenicity (in a chiral environment, stereoisomers might experience selective absorption, protein binding, transport, enzyme interactions and metabolism, receptor interactions, and DNA binding). All endpoints read-across from DL-Citronellol are considered to be acceptable for this substance assuming that 50% of the target compound is available in the test material.
The source substance citronellyl acetate is read-across from as part of a weight of evidence approach in the repeated dose toxicity endpoint. As this substance is hydrolysed to Citronellol within 2 hours, this read-across endpoint is acceptable in the weight of evidence approach used.
The source substances geraniol, nerol and the reaction mass of geraniol/nerol differ from the target substance only by an additional double bond at C2. These structures are considered to represent a worst case scenario due to the additional potential reactive feature of the second double bond. The genotoxicity, repeated dose and reproductive toxicity endpoints read-across from these substances are therefore acceptable as a worst case assumption.

4. DATA MATRIX
Please refer to the data matrix included in the read-across justification document attached in Section 13.2.
Reason / purpose:
read-across source
Related information:
Composition 1
Reference:
Composition 0
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Qualifier:
according to
Guideline:
other: FEDERAL REGISTER 38, NO. 187, PARA. 1500.42, 5. 27029; 27.09.73
Principles of method if other than guideline:
Method: Draize Test
GLP compliance:
not specified
Test material information:
Composition 1
Species:
rabbit
Strain:
Vienna White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Sex: female
- Weight at study initiation: mean 2.57 kg (2.33 - 3.15 kg)
- Diet: SSNIFF sold by Intermast
Vehicle:
unchanged (no vehicle)
Controls:
other: left eye untreated, serves as control
Amount / concentration applied:
0.1 ml
Duration of treatment / exposure:
application into the conjunctival sac of the lower right eyelid
Observation period (in vivo):
8 days
Number of animals or in vitro replicates:
6
Details on study design:
SCORING SYSTEM:

turgor/swelling of conjunctiva or opacity of cornea:
0 = nonexistant
1 = slight
2 = distinct
3 = intense
4 = severe

affected area of cornea:
1 = 0 < A < 1/4
2 = 1/4 <= A < 1/2
3 = 1/2 <= A < 3/4
4 = 3/4 <= A

redness of conjunctiva:
0 = regular
1 = slightly increased
2 = distinct
3 = intense

secretion:
0 = regular
1 = slightly increased
2 = distinctly increased
3 = highly increased

iris:
1 = ciliary injection
2 = iritia
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
24/48/72 h
Score:
30.5
Max. score:
39
Reversibility:
not fully reversible within: 8 days
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0.28
Max. score:
2
Reversibility:
fully reversible within: 8 days
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
1.72
Max. score:
3
Reversibility:
not fully reversible within: 8 days
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
1.44
Max. score:
4
Reversibility:
fully reversible within: 8 days
Other effects:
- scars in all animals
- suppuration in one animal
- pupil contraction in one animal

Results:

 cornea      iris conjunctiva     calculated irritation scores    
time animal opacity area redness turgor/swelling secretion other cornea iris conjunctiva total mean
24 h 1 1 4 0 2 2 2 scar 20 0 12 32 33,67
2 1 4 0 2 2 2 scar 20 0 12 32
3 1 4 1 2 2 2 scar 20 5 12 37
4 1 4 0 2 2 2 scar 20 0 12 32
5 1 4 1 2 2 2 scar 20 5 12 37
6 1 4 0 2 2 2 scar 20 0 12 32
48 h 1 1 4 0 1 1 1 scar 20 0 6 26 29,00
2 1 4 0 2 2 2 scar 20 0 12 32
3 1 4 1 2 2 3 scar/suppuration 20 5 14 39
4 1 4 0 2 1 1 scar 20 0 8 28
5 1 3 0 1 1 1 scar 15 0 6 21
6 1 4 0 2 1 1 scar/pupil contraction 20 0 8 28
72 h 1 1 4 0 1 1 1 scar 20 0 6 26 28,83
2 1 4 1 2 1 2 scar 20 5 10 35
3 1 4 1 2 2 3 scar/suppuration 20 5 14 39
4 1 4 0 1 0 1 scar 20 0 4 24
5 1 3 0 1 1 1 scar 15 0 6 21
6 1 4 0 2 1 1 scar/pupil contraction 20 0 8 28
8 d 1 0 0 0 0 0 0 scar 0 0 0 0 5,17
2 1 1 0 2 0 1 scar 5 0 6 11
3 0 0 0 1 0 1 scar 0 0 4 4
4 1 1 0 1 0 0 scar 5 0 2 7
5 1 1 0 1 0 0 scar 5 0 2 7
6 0 0 0 1 0 0 scar 0 0 2 2
Mean 24-72 h 1 1.0 4.0 0.0 1.3 1.3 1.3 20.0 0.0 8.0 28.0
2 1.0 4.0 0.3 2.0 1.7 2.0 20.0 1.7 11.3 33.0
3 1.0 4.0 1.0 2.0 2.0 2.7 20.0 5.0 13.3 38.3
4 1.0 4.0 0.0 1.7 1.0 1.3 20.0 0.0 8.0 28.0
5 1.0 3.3 0.3 1.3 1.3 1.3 16.7 1.7 8.0 26.3
6 1.0 4.0 0.0 2.0 1.3 1.3 20.0 0.0 9.3 29.3
Mean 24-72 h 1 3.89 0.28 1.72 1.44 1.67 19.4 1.4 9.7 30.5

24h after application of 0,1 ml of test substance:
slight opacity of complete cornea and in 2/6 cases ciliary injections; 
all animals: distinct redness and turgor/swelling of conjunctiva, increased secretion  of tears and scarred retractions at the eyelid

72h: 
redness and turgor of conjunctiva and secretion in regression

8d: 
3/6 animals show very light opacity of small areas of cornea, 
5/6  show slight redness of conjunctiva, 
2/6 show slightly increased secretion of tears, 
1/6 shows temporary suppuration, 
1/6 shows temporary  contraction of the pupil; 
all animals: irreversible scarred alterations of the eyelid

primary irritation score: 31 -> moderately irritating

Interpretation of results:
Category 2A (irritating to eyes) based on GHS criteria
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
 The test material induced mean corneal opacity scores (24/48/72 hr) of 1 in 6/6 rabbits. Therefore, according the CLP criteria, the substance is classified as Eye irritation, Category 2.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1979
Report Date:
1979

Materials and methods

Test guidelineopen allclose all
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Qualifier:
according to
Guideline:
other: FEDERAL REGISTER 38, NO. 187, PARA. 1500.42, 5. 27029; 27.09.73
Principles of method if other than guideline:
Method: Draize Test
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Citronellol
- Substance No.: 78/741

Test animals / tissue source

Species:
rabbit
Strain:
Vienna White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Sex: female
- Weight at study initiation: mean 2.57 kg (2.33 - 3.15 kg)
- Diet: SSNIFF sold by Intermast

Test system

Vehicle:
unchanged (no vehicle)
Controls:
other: left eye untreated, serves as control
Amount / concentration applied:
0.1 ml
Duration of treatment / exposure:
application into the conjunctival sac of the lower right eyelid
Observation period (in vivo):
8 days
Number of animals or in vitro replicates:
6
Details on study design:
SCORING SYSTEM:

turgor/swelling of conjunctiva or opacity of cornea:
0 = nonexistant
1 = slight
2 = distinct
3 = intense
4 = severe

affected area of cornea:
1 = 0 < A < 1/4
2 = 1/4 <= A < 1/2
3 = 1/2 <= A < 3/4
4 = 3/4 <= A

redness of conjunctiva:
0 = regular
1 = slightly increased
2 = distinct
3 = intense

secretion:
0 = regular
1 = slightly increased
2 = distinctly increased
3 = highly increased

iris:
1 = ciliary injection
2 = iritia

Results and discussion

In vivo

Resultsopen allclose all
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
24/48/72 h
Score:
30.5
Max. score:
39
Reversibility:
not fully reversible within: 8 days
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0.28
Max. score:
2
Reversibility:
fully reversible within: 8 days
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
1.72
Max. score:
3
Reversibility:
not fully reversible within: 8 days
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
1.44
Max. score:
4
Reversibility:
fully reversible within: 8 days
Other effects:
- scars in all animals
- suppuration in one animal
- pupil contraction in one animal

Any other information on results incl. tables

Results:

 cornea      iris conjunctiva     calculated irritation scores    
time animal opacity area redness turgor/swelling secretion other cornea iris conjunctiva total mean
24 h 1 1 4 0 2 2 2 scar 20 0 12 32 33,67
2 1 4 0 2 2 2 scar 20 0 12 32
3 1 4 1 2 2 2 scar 20 5 12 37
4 1 4 0 2 2 2 scar 20 0 12 32
5 1 4 1 2 2 2 scar 20 5 12 37
6 1 4 0 2 2 2 scar 20 0 12 32
48 h 1 1 4 0 1 1 1 scar 20 0 6 26 29,00
2 1 4 0 2 2 2 scar 20 0 12 32
3 1 4 1 2 2 3 scar/suppuration 20 5 14 39
4 1 4 0 2 1 1 scar 20 0 8 28
5 1 3 0 1 1 1 scar 15 0 6 21
6 1 4 0 2 1 1 scar/pupil contraction 20 0 8 28
72 h 1 1 4 0 1 1 1 scar 20 0 6 26 28,83
2 1 4 1 2 1 2 scar 20 5 10 35
3 1 4 1 2 2 3 scar/suppuration 20 5 14 39
4 1 4 0 1 0 1 scar 20 0 4 24
5 1 3 0 1 1 1 scar 15 0 6 21
6 1 4 0 2 1 1 scar/pupil contraction 20 0 8 28
8 d 1 0 0 0 0 0 0 scar 0 0 0 0 5,17
2 1 1 0 2 0 1 scar 5 0 6 11
3 0 0 0 1 0 1 scar 0 0 4 4
4 1 1 0 1 0 0 scar 5 0 2 7
5 1 1 0 1 0 0 scar 5 0 2 7
6 0 0 0 1 0 0 scar 0 0 2 2
Mean 24-72 h 1 1.0 4.0 0.0 1.3 1.3 1.3 20.0 0.0 8.0 28.0
2 1.0 4.0 0.3 2.0 1.7 2.0 20.0 1.7 11.3 33.0
3 1.0 4.0 1.0 2.0 2.0 2.7 20.0 5.0 13.3 38.3
4 1.0 4.0 0.0 1.7 1.0 1.3 20.0 0.0 8.0 28.0
5 1.0 3.3 0.3 1.3 1.3 1.3 16.7 1.7 8.0 26.3
6 1.0 4.0 0.0 2.0 1.3 1.3 20.0 0.0 9.3 29.3
Mean 24-72 h 1 3.89 0.28 1.72 1.44 1.67 19.4 1.4 9.7 30.5

24h after application of 0,1 ml of test substance:
slight opacity of complete cornea and in 2/6 cases ciliary injections; 
all animals: distinct redness and turgor/swelling of conjunctiva, increased secretion  of tears and scarred retractions at the eyelid

72h: 
redness and turgor of conjunctiva and secretion in regression

8d: 
3/6 animals show very light opacity of small areas of cornea, 
5/6  show slight redness of conjunctiva, 
2/6 show slightly increased secretion of tears, 
1/6 shows temporary suppuration, 
1/6 shows temporary  contraction of the pupil; 
all animals: irreversible scarred alterations of the eyelid

primary irritation score: 31 -> moderately irritating

Applicant's summary and conclusion

Interpretation of results:
Category 2A (irritating to eyes) based on GHS criteria
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
 The test material induced mean corneal opacity scores (24/48/72 hr) of 1 in 6/6 rabbits. Therefore, according the CLP criteria, the substance is classified as Eye irritation, Category 2.