Registration Dossier

Administrative data

Description of key information

These endpoints were fulfilled using read across from 3,7-dimethyloct-6-enenitrile (EC 257-288-8 / CAS 51566-62-2), for which the following results were obtained.

Skin irritation/corrosion:

Acute dermal irritation/corrosion was assessed using test guideline equivalent or similar to OECD 404. The test item is not irritant to skin.

Eye irritation:

Eye irritation was assessed according to test guideline OECD 405. The test item is not classified for eye irritation.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Referenceopen allclose all

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: Non-GLP, comparable to current guideline, fully adequate for assessment.
Reason / purpose:
reference to same study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
, occlusive testing
GLP compliance:
no
Species:
rabbit
Strain:
Vienna White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Gaukler, D-6050 Offenbach/Main, FRG.
- Weight at study initiation: males: 2.99 and 3.47 kg, female: 3.05 kg.
- Housing: Individually in stainless steel cages with wire mesh walk floor (floor area: 40 cm x 51 cm). No bedding in the cages; sawdust in the waste trays.
- Diet: Ovator Solikanin 4 mm; Muskator-Werke, D-4000 Düsseldorf 1, FRG (about 130 g per animal daily).
- Water: About 250 mL tap water per animal daily.
- Acclimation period: About 8 days before the beginning of the study in the skin laboratory; same housing conditions as during the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24.
- Humidity (%): 30 - 70.
- Photoperiod (hrs dark / hrs light): 12 h/12 h (6.00a.m. - 18.00p.m./18 p.m. - 8a.m.).
Type of coverage:
occlusive
Preparation of test site:
other: clipped
Vehicle:
unchanged (no vehicle)
Controls:
other: untreated skin sites of the same animal
Amount / concentration applied:
0.5 mL of the undiluted test liquid
Duration of treatment / exposure:
4 hours
Observation period:
8 days
Number of animals:
3
Details on study design:
TEST SITE
- Clipping of fur at least 15 hours before the beginning of the study.
- Application area: 2.5 cm x 2.5 cm.
- Application site: Upper third of the region of the back or flank.

REMOVAL OF TEST SUBSTANCE
- Removal of the test substance: At the end of the exposure period with Lutrol and Lutrol/water (1 : 1).

OTHER
- Additional examinations: After sacrifice the animals are examined by gross pathology. If there are clinical signs of necroses, these are confirmed by
gross- pathological examination after incision of the skin. (If there are differences between the clinical and pathological assessments, only the latter is included in the final report.)
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.67
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
edema score
Basis:
animal: 1,2 and 3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Irritant / corrosive response data:
- After 72 hours one animal showed scaling in the abdominal and lateral position and dyspnea. This animal was death as a result of dysentery (no substance-related finding) 7 days after the study began.
- The two remaining animals showed scaling at day 8.

Score per animal

Readings

Animal

Erythema

Edema

4 hours

1

1

0

 

2

1

0

 

3

1

0

24 hours

1

1

0

 

2

1

0

 

3

1

0

48 hours

1

0

0

 

2

0

0

 

3

0

0

72 hours

1

0

0

 

2

1

0

 

3

0

0

8 days

1

*

*

 

2

0

0

 

3

0

0

* animal died after 7days

Interpretation of results:
GHS criteria not met
Conclusions:
The test item is not irritant to skin.
Endpoint:
skin irritation: in vitro / ex vivo
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
an in vitro skin irritation study does not need to be conducted because adequate data from an in vivo skin irritation study are available
Endpoint:
skin irritation: in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1982
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non-GLP, comparable to current guideline, fully adequate for assessment.
Justification for type of information:
ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The structures of the target and source substances are identical and differ only with respect to the ratio of enantiomers where the target substance is a single pure L-isomer and the source substance is an equimolar mixture of L and D isomers.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The target substance, L-Citronellyl nitrile, is a mono-constituent substance (EC No. 695-909-8, CAS no. 35931-93-2).
The source substance, DL-Citronellyl nitrile, is a mono-constituent substance (EC No. 257-288-8, CAS no. 51566-62-2).
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 only difference between target and source molecules is the enantiomeric ratio. In a non-chiral environment the target and source chemicals 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). Therefore, as a precaution for the developmental toxicity endpoint it is suggested that the NOAEL 250 mg/kg bw/day for L-Citronellyl nitrile is used instead of 500 mg/kg bw/day, as it is not known which form is more potent in vivo. All other endpoints are considered to be acceptable for this substance assuming that 50% of the target compound is available in the test material.

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
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
, occlusive testing
GLP compliance:
no
Species:
rabbit
Strain:
Vienna White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Gaukler, D-6050 Offenbach/Main, FRG.
- Weight at study initiation: males: 2.99 and 3.47 kg, female: 3.05 kg.
- Housing: Individually in stainless steel cages with wire mesh walk floor (floor area: 40 cm x 51 cm). No bedding in the cages; sawdust in the waste trays.
- Diet: Ovator Solikanin 4 mm; Muskator-Werke, D-4000 Düsseldorf 1, FRG (about 130 g per animal daily).
- Water: About 250 mL tap water per animal daily.
- Acclimation period: About 8 days before the beginning of the study in the skin laboratory; same housing conditions as during the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24.
- Humidity (%): 30 - 70.
- Photoperiod (hrs dark / hrs light): 12 h/12 h (6.00a.m. - 18.00p.m./18 p.m. - 8a.m.).
Type of coverage:
occlusive
Preparation of test site:
other: clipped
Vehicle:
unchanged (no vehicle)
Controls:
other: untreated skin sites of the same animal
Amount / concentration applied:
0.5 mL of the undiluted test liquid
Duration of treatment / exposure:
4 hours
Observation period:
8 days
Number of animals:
3
Details on study design:
TEST SITE
- Clipping of fur at least 15 hours before the beginning of the study.
- Application area: 2.5 cm x 2.5 cm.
- Application site: Upper third of the region of the back or flank.

REMOVAL OF TEST SUBSTANCE
- Removal of the test substance: At the end of the exposure period with Lutrol and Lutrol/water (1 : 1).

OTHER
- Additional examinations: After sacrifice the animals are examined by gross pathology. If there are clinical signs of necroses, these are confirmed by
gross- pathological examination after incision of the skin. (If there are differences between the clinical and pathological assessments, only the latter is included in the final report.)
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.67
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
edema score
Basis:
animal: 1,2 and 3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Irritant / corrosive response data:
- After 72 hours one animal showed scaling in the abdominal and lateral position and dyspnea. This animal was death as a result of dysentery (no substance-related finding) 7 days after the study began.
- The two remaining animals showed scaling at day 8.

Score per animal

Readings

Animal

Erythema

Edema

4 hours

1

1

0

 

2

1

0

 

3

1

0

24 hours

1

1

0

 

2

1

0

 

3

1

0

48 hours

1

0

0

 

2

0

0

 

3

0

0

72 hours

1

0

0

 

2

1

0

 

3

0

0

8 days

1

*

*

 

2

0

0

 

3

0

0

* animal died after 7days

Interpretation of results:
GHS criteria not met
Conclusions:
The test item is not irritant to skin.
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
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
an in vitro eye irritation study does not need to be conducted because adequate data from an in vivo eye irritation study are available
Endpoint:
eye irritation: in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1982
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non-GLP compliant guideline study, fully adequate for assessment.
Justification for type of information:
ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The structures of the target and source substances are identical and differ only with respect to the ratio of enantiomers where the target substance is a single pure L-isomer and the source substance is an equimolar mixture of L and D isomers.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The target substance, L-Citronellyl nitrile, is a mono-constituent substance (EC No. 695-909-8, CAS no. 35931-93-2).
The source substance, DL-Citronellyl nitrile, is a mono-constituent substance (EC No. 257-288-8, CAS no. 51566-62-2).
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 only difference between target and source molecules is the enantiomeric ratio. In a non-chiral environment the target and source chemicals 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). Therefore, as a precaution for the developmental toxicity endpoint it is suggested that the NOAEL 250 mg/kg bw/day for L-Citronellyl nitrile is used instead of 500 mg/kg bw/day, as it is not known which form is more potent in vivo. All other endpoints are considered to be acceptable for this substance assuming that 50% of the target compound is available in the test material.

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
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
, limited observation time
GLP compliance:
no
Species:
rabbit
Strain:
Vienna White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Gaukler, D-6050 Offenbach/Main, FRG.
- Weight at study initiation: males: 2.85 and 2.98 kg, female: 3.27 kg.
- Housing: Individually in stainless steel cages with wire mesh walk floor (floor area: 40 cm x 51 cm). No bedding in the cages; sawdust in the waste trays.
- Diet: Ovator Solikanin 4 mm; Muskator-Werke, D-4000 Düsseldorf 1, FRG (about 130 g per animal daily).
- Water: About 250 mL tap water per animal daily.
- Acclimation period: About 8 days before the beginning of the study in the skin laboratory; same housing conditions as during the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24.
- Humidity (%): 30 - 70.
- Photoperiod (hrs dark / hrs light): 12 h/12 h (6.00a.m. - 18.00p.m./18 p.m. - 8a.m.).
Vehicle:
unchanged (no vehicle)
Controls:
other: Negative control: Untreated eye.
Amount / concentration applied:
Undiluted
Amount applied: 0.1 mL
Duration of treatment / exposure:
8 days
Observation period (in vivo):
8 days
Number of animals or in vitro replicates:
3
Details on study design:
Application site: Conjunctival sac of the right eyelid.
No wash out of substance.
Irritation parameter:
cornea opacity score
Basis:
animal: 1-3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Irritation parameter:
iris score
Basis:
animal: 1-3
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
other: not applicable
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
3
Reversibility:
not fully reversible within: 8 days
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1
Max. score:
3
Reversibility:
not fully reversible within: 8 days
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1
Max. score:
3
Reversibility:
not fully reversible within: 8 days
Irritation parameter:
chemosis score
Basis:
animal: 1-3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable

Individual eye irritation scores:

Readings

Animal

Cornea

Iris

Conjunctiva

 

 

Opacity

Area

 

Redness

Swelling

Discharge

1 hours

1

0

0

0

3

1

2

 

2

0

0

0

3

1

2

 

3

0

0

0

3

1

2

24 hours

1

0

0

0

1

0

0

 

2

0

0

0

1

0

0

 

3

0

0

0

1

0

0

48 hours

1

0

0

0

1

0

0

 

2

0

0

0

1

0

0

 

3

0

0

0

1

0

0

72 hours

1

0

0

0

1

0

0

 

2

0

0

0

1

0

0

 

3

0

0

0

1

0

0

8 days

1

0

0

0

1

0

0

 

2

0

0

0

1

0

0

 

3

0

0

0

1

0

0

Interpretation of results:
GHS criteria not met
Conclusions:
The test item is not classified for eye irritation.
Endpoint:
eye 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: Non-GLP compliant guideline study, fully adequate for assessment.
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
, limited observation time
GLP compliance:
no
Species:
rabbit
Strain:
Vienna White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Gaukler, D-6050 Offenbach/Main, FRG.
- Weight at study initiation: males: 2.85 and 2.98 kg, female: 3.27 kg.
- Housing: Individually in stainless steel cages with wire mesh walk floor (floor area: 40 cm x 51 cm). No bedding in the cages; sawdust in the waste trays.
- Diet: Ovator Solikanin 4 mm; Muskator-Werke, D-4000 Düsseldorf 1, FRG (about 130 g per animal daily).
- Water: About 250 mL tap water per animal daily.
- Acclimation period: About 8 days before the beginning of the study in the skin laboratory; same housing conditions as during the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24.
- Humidity (%): 30 - 70.
- Photoperiod (hrs dark / hrs light): 12 h/12 h (6.00a.m. - 18.00p.m./18 p.m. - 8a.m.).
Vehicle:
unchanged (no vehicle)
Controls:
other: Negative control: Untreated eye.
Amount / concentration applied:
Undiluted
Amount applied: 0.1 mL
Duration of treatment / exposure:
8 days
Observation period (in vivo):
8 days
Number of animals or in vitro replicates:
3
Details on study design:
Application site: Conjunctival sac of the right eyelid.
No wash out of substance.
Irritation parameter:
cornea opacity score
Basis:
animal: 1-3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Irritation parameter:
iris score
Basis:
animal: 1-3
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
other: not applicable
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
3
Reversibility:
not fully reversible within: 8 days
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1
Max. score:
3
Reversibility:
not fully reversible within: 8 days
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1
Max. score:
3
Reversibility:
not fully reversible within: 8 days
Irritation parameter:
chemosis score
Basis:
animal: 1-3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable

Individual eye irritation scores:

Readings

Animal

Cornea

Iris

Conjunctiva

 

 

Opacity

Area

 

Redness

Swelling

Discharge

1 hours

1

0

0

0

3

1

2

 

2

0

0

0

3

1

2

 

3

0

0

0

3

1

2

24 hours

1

0

0

0

1

0

0

 

2

0

0

0

1

0

0

 

3

0

0

0

1

0

0

48 hours

1

0

0

0

1

0

0

 

2

0

0

0

1

0

0

 

3

0

0

0

1

0

0

72 hours

1

0

0

0

1

0

0

 

2

0

0

0

1

0

0

 

3

0

0

0

1

0

0

8 days

1

0

0

0

1

0

0

 

2

0

0

0

1

0

0

 

3

0

0

0

1

0

0

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

Additional information

Justification for classification or non-classification

Skin corrosion / irritation

Skin corrosion is defined as the production of irreversible damage to the skin following application of the test substance. Skin irritation is the production of reversible damage to the skin following application of the test substance. 

During in vivo testing, substances are classified as corrosive to the skin if they produce destruction of skin tissue, namely, visible necrosis through the epidermis and into the dermis, in at least 1 tested animal after exposure up to a 4 hour duration. The test substance was assessed for skin corrosion potential and no signs of corrosion were observed up to 8 days after exposure. Therefore the substance is not classified as corrosive to the skin.

 

During in vivo testing, substances are classified as irritating to the skin if a mean value of ≥ 2,3 - ≤ 4,0 for erythema/eschar or for oedema in at least 2 of 3 tested animals from gradings at 24, 48 and 72 hours after patch removal or, if reactions are delayed, from grades on 3 consecutive days after the onset of skin reactions; or if inflammation persists to the end of the observation period; or if there is pronounced variability of response among animals, with very definite positive effects in a single animal. The test substance was assessed for skin irritation potential and no signs or irritation that would lead to classification were observed. Therefore, the substance is not classified as a skin irritant

 

Eye irritation

Serious eye damage is defined as the production of tissue damage in the eye, or serious physical decay or vision following application of the test substance to the anterior surface of the eye which is not fully reversible. Eye irritation means the production of changes in the eye following application of the test substance which is fully reversible. 

Eye irritation was assessed using an in-vivo test method.

During in vivo testing, substances are classified as having irreversible effects in the eye if at least in one animal effects on the cornea, iris or conjunctiva that are not expected to reverse or have not fully reversed within the observation period; or at least in 2 of 3 tested animals, a positive response of corneal opacity ≥ 3 and/or iritis > 1,5 calculated as the mean scores following grading at 24, 48 and 72 hours. A substance is classified as having reversible effects on the eye if when applied to the eye of an animal, a substance produces: at least in 2 of 3 tested animals, a positive response of: corneal opacity ≥ 1 and/or iritis ≥ 1, and/or conjunctival redness ≥ 2 and/or conjunctival oedema (chemosis) ≥ 2 calculated as the mean scores following grading at 24, 48 and 72 hours.

 

The test material did not meet any of the above criteria. Therefore, the substance is not classified for eye irritation.