Exo-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl propionate

Endpoint summary

Description of key information

Skin corrosion: The substance is considered not corrosive because it is not irritating for skin and eye.

Skin irritation: One key in vivo study and one supporting with the structural analogue Isobornyl acetate (similar to OECD TG 404): Not irritating

Eye irritation: in vivo study with the structural analogue Cyclaprop (Similar to OECD TG 405): Not irritating

Respiratory irritation: Not a respiratory irritant, because no human data are available and is not indicated based on absence of corrosion skin and eye irritation.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Reference 1

Endpoint:

skin 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: read-across information from an analogue is used

Justification for type of information:

The skin irritation of Isobornyl propionate is based on read-across from Isobornyl acetate. The documentation is presented in the Irritation Endpoint summary. The accompanying files are also attached there.

Reason / purpose for cross-reference:

read-across source

Irritation parameter:

erythema score

Basis:

animal: #1, #2 and #3

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

not fully reversible within: 168 hours

Remarks on result:

other: Result obtained from Key study with read-across substance Isobornyl acetate (CAS 125-12-2)

Irritation parameter:

erythema score

Basis:

animal #4

Time point:

24/48/72 h

Score:

1.7

Max. score:

4

Reversibility:

fully reversible within: 168 hours

Remarks on result:

other: Result obtained from Key study with read-across substance Isobornyl acetate (CAS 125-12-2)

Irritation parameter:

edema score

Basis:

animal: #1 and #2

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

not fully reversible within: 168 hours

Remarks on result:

other: Result obtained from Key study with read-across substance Isobornyl acetate (CAS 125-12-2)

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

not fully reversible within: 168 hours

Remarks on result:

other: Result obtained from Key study with read-across substance Isobornyl acetate (CAS 125-12-2)

Irritation parameter:

edema score

Basis:

animal #4

Time point:

24/48/72 h

Score:

1.3

Max. score:

4

Reversibility:

fully reversible within: 168 hours

Remarks on result:

other: Result obtained from Key study with read-across substance Isobornyl acetate (CAS 125-12-2)

Irritation parameter:

erythema score

Basis:

animal: #1, #2 and #3

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

not fully reversible within: 168 hours

Remarks on result:

other: Result obtained from Supporting study with read-across substance Isobornyl acetate (CAS 125-12-2)

Irritation parameter:

edema score

Basis:

animal: #1 and #3

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

not fully reversible within: 168 hours

Remarks on result:

other: Result obtained from Supporting study with read-across substance Isobornyl acetate (CAS 125-12-2)

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1.7

Max. score:

4

Reversibility:

not fully reversible within: 168 hours

Remarks on result:

other: Result obtained from Supporting study with read-across substance Isobornyl acetate (CAS 125-12-2)

Interpretation of results:

other: Not a skin irritant

Remarks:

according to EU CLP (EC No. 1272/2008 and its amendments)

Reference 2

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Apr 1985

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Justification for type of information:

This information is used for read across to Isobornyl propionate.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

4 chemicals were assessed simultaneously per animal, at distant and well defined sites

Qualifier:

according to guideline

Guideline:

other: methods for determination of toxicity (Annex V of the EEC Directive 79/831)

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: A. Smith, 7 Kydcomb Road, Warlingham, Surry
- Housing: Individual in aluminium cages with grid floors and no bedding material.
- Diet: Commercially available pelleted rabbit diet (product ref. 680, Dalgety-Spillers Limited)
- Water: Mains tap water was available at all times via automatic drinking nozzles in each cage
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 22
- Humidity (%): 42 to 65
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

TEST MATERIAL
0.5 mL

Duration of treatment / exposure:

4 hours

Observation period:

168 hours (7 days)

Number of animals:

4 females

Details on study design:

TEST SITE
- Area of exposure: 2.5 cm square on the clipped dorsal skin
- Type of wrap: The test material was placed evenly over a square (2.5 cm) of surgical lint B.P. The lint square was then placed onto the animal’s skin. The lint patches were held in place by encircling the trunk of the animal with a length of ‘Elastoplast’ elastic adhesive bandage (10 cm wide)

REMOVAL OF TEST SUBSTANCE
- Time after start of exposure: The patch was removed after 4 hours.
- Washing: the treated sites were cleansed by gentle swabbing with cotton wool soaked in warm water.

OBSERVATION TIME POINTS
1, 24, 78 and 168 hours after removal of the test substance

SCORING SYSTEM
- Erythema and Eschar formation: 0 (no erythema); 1 (very slight erythema (barely perceptible); 2 (well-defined erythema); 3 (moderate to severe erythema); 4 (severe erythema (beet redness) to slight eschar formation (injuries in depth)
- Oedema formation: 0 (no oedema); 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 of exposure)
- Other signs of reaction to treatment such as corrosive action or systemic effects were fully described.
- Method of calculation: The numerical values or scores given to the erythema observed in each animal of the treated group at the twenty four, forty eight and seventy two hour examinations were summed. This total was then divided by three, the number of examinations that the figures were taken from, and further divided by the number of animals in the group. The value obtained on assessing oedematous reaction were similarly treated. The average scores obtained may be used in any subsequent classification of the material, a value of two or more for either erythema or oedema resulting in the material being regarded as irritant to the skin.

Irritation parameter:

erythema score

Basis:

animal: #1, #2 and #3

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

not fully reversible within: 168 hours

Irritation parameter:

erythema score

Basis:

animal #4

Time point:

24/48/72 h

Score:

1.7

Max. score:

4

Reversibility:

fully reversible within: 168 hours

Irritation parameter:

edema score

Basis:

animal: #1 and #2

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

not fully reversible within: 168 hours

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

not fully reversible within: 168 hours

Irritation parameter:

edema score

Basis:

animal #4

Time point:

24/48/72 h

Score:

1.3

Max. score:

4

Reversibility:

fully reversible within: 168 hours

Irritant / corrosive response data:

- One hour after dosing: well defined erythema and slight oedema were observed in two animals, well defined erythema and very slight oedema were observed in one animal and very slight erythema and oedema of the treated skin were noted in the remaining animal. The response of this animal slightly increased within 24 hours of dosing when well defined erythema and slight oedema were apparent. This reaction had reversed back to that previously described within 72 hours of dosing.
- 168 hours after dosing: Well defined erythema and very slight oedema of the skin were observed in two rabbits at the 168 hour observation, one other animal of the group exhibiting very slight erythema and oedema.

Other effects:

- Other adverse local effects: At the 168 hour timepoint slight desquamation was observed in animal #1 and #2, desquamation was observed in animal #4. No such signs were apparent in animal #3.

Summary of data

	Erythema				edema
Time	Animal #1	Animal #2	Animal #3	Animal #4	Animal #1	Animal #2	Animal #3	Animal #4	Comments
1 hour	2	2	2	1	2	2	1	1	None
24 hours	2	2	2	2	2	2	1	2	None
48 hours	2	2	2	2	2	2	1	1	None
72 hours	2	2	2	1	2	2	1	1	None
168 hours	2	2	1	0	1	1	1	0	Slight desquamation in animals #1 and 2, desquamation in animal #4
Average/animal (1 and 168 hours not included)	2	2	2	1.7	2	2	1	1.3
Average/overall	1.9				1.6

Interpretation of results:

other: Not a skin irritant

Remarks:

in accordance with EU CLP (EC No. 1272/2008 and its updates)

Conclusions:

Based on the mild irritating properties of the substance observed in the presented study in rabbit, the substance is not classified as irritating to the skin.

Executive summary:

A GLP-compliant skin irritation study was performed similar to OECD TG 404. Four Female New Zealand White rabbits were treated with 0.5 mL unchanged test substance on the clipped dorsal skin (applied on 2.5 cm²surgical lint). The material was applied simultaneously with 3 other substances on distant sites. The material was held in contact with the skin using a semi-occlusive patch assembly for 4 hours after witch the patches were removed and the skin was cleaned with cotton wool soaked in warm water. Examinations for sign of reaction to the treatment were made after 1, 24, 48, 72 and 168 hours. One hour after dosing well defined erythema and slight edema were observed in two animals, well defined erythema and very slight edema were observed in one animal and very slight erythema and edema of the treated skin were noted in the remaining animal. The response of this animal slightly increased within 24 hours of dosing when well defined erythema and slight edema were apparent. This reaction had reversed back to that previously described within 72 hours of dosing. Well defined erythema and very slight edema of the skin were observed in two rabbits at the 168 hour observation, one other animal of the group exhibiting very slight erythema and edema. Desquamation from the skin surface was also observed in three rabbits. The average scores calculated from the numerical values given to the irritation observed at the 24, 48 and 72 hour observations were 1.9 for erythema and 1.6 for edema.

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:

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: read-across information from an analogue is used

Justification for type of information:

The eye irritation is derived from Cyclaprop. The read across rationale is presented in the Irritation Endpoint summary. The accompanying files are also attached there.

Reason / purpose for cross-reference:

read-across source

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

other: Result obtained from read-across substance Cyclaprop (CAS 68912-13-0)

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

other: Result obtained from read-across substance Cyclaprop (CAS 68912-13-0)

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24/48/72 h

Score:

0.2

Max. score:

3

Reversibility:

fully reversible within: 48 hours

Remarks on result:

other: Result obtained from read-across substance Cyclaprop (CAS 68912-13-0)

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

other: Result obtained from read-across substance Cyclaprop (CAS 68912-13-0)

Interpretation of results:

other: Not an eye irritant

Remarks:

according to EU CLP )EC No. 1272/2008 and its updates).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Additional information

For Isobornyl propionate skin and eye irritating properties are derived from close structural analogues Isobornyl Acetate and Cyclaprop, respectively. The summaries of the experimental information is presented first and thereafter the read across rationale.

 

Skin irritation of Isobornyl acetate (Key study)

A GLP-compliant skin irritation study was performed similar to OECD TG 404. Four Female New Zealand White rabbits were treated with 0.5 mL unchanged test substance on the clipped dorsal skin (applied on 2.5 cm2surgical lint). The material was applied simultaneously with 3 other substances on distant sites. The material was held in contact with the skin using a semi-occlusive patch assembly for 4 hours after witch the patches were removed and the skin was cleaned with cotton wool soaked in warm water. Examinations for sign of reaction to the treatment were made after 1, 24, 48, 72 and 168 hours. One hour after dosing well defined erythema and slight edema were observed in two animals, well defined erythema and very slight edema were observed in one animal and very slight erythema and edema of the treated skin were noted in the remaining animal. The response of this animal slightly increased within 24 hours of dosing when well defined erythema and slight edema were apparent. This reaction had reversed back to that previously described within 72 hours of dosing. Well defined erythema and very slight edema of the skin were observed in two rabbits at the 168 hour observation, one other animal of the group exhibiting very slight erythema and edema. Desquamation from the skin surface was also observed in three rabbits. The average scores calculated from the numerical values given to the irritation observed at the 24, 48 and 72 hour observations were 1.9 for erythema and 1.6 for edema. The irritating effects observed are insufficient for classification of the substance.

 

Skin irritation of Isobornyl acetate (Supporting study, not presented in a record)

A GLP-compliant skin irritation study was performed similar to OECD TG 404 (RIFM study, 1984). 3 Female New Zealand White rabbits were treated with 0.5 mL test substance on the clipped dorsal skin (2.5 cm2). The material was held in contact with a semi-occlusive patch assembly for 4 hours after witch the patches were removed and the skin was cleaned cotton wool soaked in warm water. The material was applied simultaneously with 3 other substances on distant sites. Examinations for sign of reaction to the treatment were made after 1, 24, 48, 72 and 168 hours. At 24, 48 and 72 hours the erythema score was 2 in all animals. The effect was not fully reversible after 168 hours. The average edema score over these timepoints was 2 in animal 1 and 3 and 1.7 in animal 2. edema was not fully reversible in 168 hours. In animal 2 and 3 desquamation from skin surface was observed at the 168 hour timepoint. The irritating effects observed are insufficient for classification of the substance. The irritating effects observed are insufficient for classification of the substance.

 

Eye irritation of Cyclaprop

The potential of the test substance to cause eye irritation was determined according to OECD TG 405. Four New Zealand White female rabbits were exposed to 0.1 mL of the undiluted test article in one of the eyes. The other eye served as a control. The eyes were examined and the changes graded according to a numerical scale 1 hour, 24, 48, 72 hours after dosing. The animals showed very slight signs of irritation on the treated eyes. All effects were fully reversible within 72 hours. Based on these results, the test material does not have to be classified as irritating to eyes.

 

Respiratory irritation:

For assessing respiratory irritation human data are needed because no suitable in vitro or in vivo tests are available that can identify respiratory irritation (ECHA guidance R.7.2.1.1, 2017). There are no human data such as indicated in R7a, 7.2.3.2 and 7.2.4.2 of the ECHA guidance (2017) that indicate respiratory reactions of the substance e.g. from consumer experience or occupational exposure. The absence of respiratory irritation is also not indicated based on absence of skin and eye irritation (ECHA guidance).

Skin and eye irritation of Isobornyl propionate using skin irritation information from Isobornyl acetate (CAS# 125-12-2) and Cyclaprop (68912-13-0)

Introduction and hypothesis for the analogue approach

Isobornyl propionate has an exo-1,7,7-Trimethylbicyclo[2.2.1]heptane-2-ol (Isobornyl alcohol) backbone to which a propionic ester group is attached.For this substance insufficient skin and eye irritation information is available. In accordance with Article 13 of REACH, lacking information can be generated by other mean, i.e. applying alternative methods such as QSARs, grouping and read-across. The analogue approach is selected since for the structurally related analogues Isobornyl acetate and Cyclaprop reliable data is available on these endpoints.

Hypothesis: Isobornyl propionate has the same skin irritation properties as Isobornyl acetate and the same eye irritation as Cyclaprop.

Available information: Isobornyl acetate was tested for skin and eye irritation according to OECD TG 404 and 405, respectively, receiving Rel. 2. In the skin study mild or minimal irritating effects are observed which are insufficient for skin or eye classification.

Target chemical and source chemical(s)

Chemical structures of the target chemical and the source chemical(s) are shown in the data matrix, including relevant physico-chemical properties.

Purity / Impurities

Isobornyl propionate is a mono-constituent >=88%, with impurities similar to the parent substance and < 10%.

Analogue approach justification

According to REACH Annex XI 1.5 read-across can be used to replace testing when the similarity can be based on a common backbone and a common functional group. When using read-across the result derived should be applicable for C&L and/or risk assessment and it should be presented with adequate and reliable documentation, which is presented below.

Analogue selection:For Isobornyl propionate the one methyl shorter Isobornyl acetate was selected as an analogue being the closest analogue for which experimental skin and eye irritation information is available for skin irritation. For Isobornyl butyrate no such information was found on the ECHA site or in the RIFM database. For eye irritation Cyclaprop is considered a close analogue for which eye irritation information is available and used to fulfil the endpoint because currently access to the eye irritation report for Isobornyl acetate is ongoing.   

Structural similarities and differences:Isobornyl propionate and Isobornyl acetate have the same backbone and functional ester group. The only difference between the two is the propionate and acetate group, respectively, which will result in a higher molecular weight of the first one.

Isobornyl propionate is also very similar to Cyclaprop: These substances have a very similar hydrocarbon backbone and the same functional group. The double bond in Cyclaprop is not near the ester bond and will not present additional electrophilicity and thus reactivity.

Skin and eye absorption: For Isobornyl –propionate and acetate the molecular weight and other physico-chemical properties i.e. log Kow indicate that some skin and eye tissue absorption can occur and that there is only a minimal difference between the two. Also Cyclaprop has similar molecular weight and log Kow and therefore has similar eye tissue absorption.

Reactivity: Isobornyl-propionate and acetate are similarly reactive because these are almost the same substances with one methyl difference in the alkyl-ester chain, which has a slight impact on the log Kow but very not on the reactivity. Isobornyl propionate and Cyclaprop are similarly reactive because these have the same functional propionic ester group.

Uncertainty of the prediction: There are no uncertainties other than those already addressed above.

Conclusion on hazard and risk assessment

For Isobornyl propionate no skin and eye irritation information is available but for two analogues such information is present, which can be used for read across.

When using read across the result should be applicable for classification and labelling and risk assessment as well as presented with reliable and adequate documentation. This documentation is presented in the current document. For Isobornyl acetate skin irritation is present and for Cyclaprop eye irritation information both resulting in absence of skin and eye irritation. This information can be used for read across to Isobornyl propionate.

Final conclusion on hazard and risk assessment: Isobornyl propionate is not a skin or eye irritant and bases on this it is not corrosive either.

 

Data matrix to support the read across to Isobornyl propionate from Isobornyl acetate and Cyclaprop

Common names	Isobornyl propionate	Isobornyl acetate	Cyclaprop
	Target	Source	Source
Chemical structures
CAS no.	2756-56-1	125-12-2	68912-13-0
EINECS	220-410-5	204-727-6	272-805-7
REACH registration	2018	Registered	Registered
Empirical formula	C13H22O2	C12H20O2	C13H18O2
Molecular weight	210.32	196.29	206.28
Phys-chem properties
Physical state	Liquid	Liquid	Liquid
Log Kow (measured)	5.0 (IFF measured)	4.3 (Simonich, EpiSuite)	4.4 (IFF measured)
Skin irritation	Not irritating (Read across)	Not irritating (OECD TG 404)	Not irritating (OECD TG 404)
Eye irritation	Not irritating Read-across	Not irritating (OECD TG 405, ECHA dissemination site)	Not irritating (OECDTG 405)

 

Justification for classification or non-classification

The substance does not need to be classified for skin, eye and respiratory irritation according to EU CLP (EC No. 1272/2008 and its amendments).