(S)-2-methyl-5-(1-methylvinyl)cyclohex-2-en-1-one

Endpoint summary

Description of key information

Skin Irritation:

d-carvone was not irritating to humans after 48 hours exposure.

Eye Irritation:

The ocular irritation potential of d-Carvone was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor.

d-Carvone was estimated to be not irritating to the eyes of New Zealand White rabbits.

Based on the estimated result; d-Carvone can be considered not irritating to the eyes and can be classified under the category “Not Classified” as per CLP regulation.

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:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

data is from peer reviewed journals

Qualifier:

according to guideline

Guideline:

other: as mentioned below

Principles of method if other than guideline:

To assess the dermal irritation potential of d-carvone in humans

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material: d-Carvone- IUPAC name: (5S)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-one- Molecular formula: C10H14O- Molecular Weight: 150.22 g/mole- Smiles Notation: C1[C@H](CC=C(C1=O)C)C(C)=C- Inchl: 1S/C10H14O/c1-7(2)9-5-4-8(3)10(11)6-9/h4,9H,1,5-6H2,2-3H3/t9-/m0/s1- Substance type: Organic- Physical state: Colorless to pale-yellow liquid

Species:

other: humans

Strain:

not specified

Details on test animals or test system and environmental conditions:

No data available

Type of coverage:

occlusive

Preparation of test site:

not specified

Vehicle:

other: petrolatum

Controls:

not specified

Amount / concentration applied:

2% in petrolatum

Duration of treatment / exposure:

48 hours

Observation period:

48 hours

Number of animals:

No data available

Details on study design:

No data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

48 h

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

no signs of irritation observed

Interpretation of results:

other: not irritating

Conclusions:

d-carvone was not irritating to humans after 48 hours exposure.

Executive summary:

A skin irritation study was performed in humans to assess the irritation potential of d-carvone. d-carvone was tested 2% in petrolatum human volunteers in a 48 hours closed patch test. d-carvone was not irritating to humans after 48 hours exposure.

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:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification

Justification for type of information:

data is from OECD QSAR toolbox v3.3 and the QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: Estimated data

Principles of method if other than guideline:

Prediction was done usng OECD QSAR toolbox v3.3

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material: d-Carvone- IUPAC name: (5S)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-one- Molecular formula: C10H14O- Molecular Weight: 150.22 g/mole- Smiles Notation: C1[C@H](CC=C(C1=O)C)C(C)=C- Inchl: 1S/C10H14O/c1-7(2)9-5-4-8(3)10(11)6-9/h4,9H,1,5-6H2,2-3H3/t9-/m0/s1- Substance type: Organic- Physical state: Colorless to pale-yellow liquid

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

no data available

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

3 mg

Duration of treatment / exposure:

single exposure

Observation period (in vivo):

96 hours

Duration of post- treatment incubation (in vitro):

no data available

Number of animals or in vitro replicates:

6

Details on study design:

no data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

other: 96 hours

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

no signs of irritation observed

Estimation method: Takes mode value from the 6 nearest neighbours
Domain  logical expression:Result: In Domain

(((((((("a" or "b" or "c" or "d" )  and ("e" and ( not "f") )  )  and ("g" and ( not "h") )  )  and ("i" and ( not "j") )  )  and "k" )  and ("l" and ( not "m") )  )  and ("n" and ( not "o") )  )  and ("p" and "q" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Michael addition AND Michael addition >> Polarised Alkenes-Michael addition AND Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated ketones by DNA binding by OECD

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Michael Addition AND Michael Addition >> Michael addition on conjugated systems with electron withdrawing group AND Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> alpha,beta-Carbonyl compounds with polarized double bonds  by Protein binding by OASIS v1.3

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Michael addition AND Michael addition >> Polarised Alkenes AND Michael addition >> Polarised Alkenes >> Polarised alkene - ketones by Protein binding by OECD

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Vinyl/Allyl Ketones by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.3

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds OR AN2 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds >> Four- and Five-Membered Lactones OR AN2 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters OR SN1 OR SN1 >> Nucleophilic attack after carbenium ion formation OR SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters OR SN2 >> Alkylation, ring opening SN2 reaction OR SN2 >> Alkylation, ring opening SN2 reaction >> Four- and Five-Membered Lactones OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters by DNA binding by OASIS v.1.3

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Non binder, non cyclic structure by Estrogen Receptor Binding

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Michael Addition AND Michael Addition >> Michael addition on conjugated systems with electron withdrawing group AND Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> alpha,beta-Carbonyl compounds with polarized double bonds  by Protein binding by OASIS v1.3

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct acylation involving a leaving group OR Acylation >> Direct acylation involving a leaving group >> Azlactones and unsaturated lactone derivatives  OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides OR Michael Addition >> Quinoide type compounds OR Michael Addition >> Quinoide type compounds >> Quinone methide(s)/imines; Quinoide oxime structure; Nitroquinones, Naphthoquinone(s)/imines  OR No alert found OR Nucleophilic addition OR Nucleophilic addition >> Addition to carbon-hetero double bonds OR Nucleophilic addition >> Addition to carbon-hetero double bonds >> Ketones OR SN2 OR SN2 >> SN2 Reaction at a sp3 carbon atom OR SN2 >> SN2 Reaction at a sp3 carbon atom >> Activated alkyl esters and thioesters  by Protein binding by OASIS v1.3

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as No superfragment by Superfragments ONLY

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Ketones by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Ethylenglycolethers by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND (!Undefined)Group C Surface Tension > 62 mN/m by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as (!Undefined)Group CN Lipid Solubility < 0.4 g/kg by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "p"

Parametric boundary:The target chemical should have a value of log Kow which is >= 2.04

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of log Kow which is <= 5.8

Interpretation of results:

other: not irritating

Conclusions:

d-Carvone was estimated to be not irritating to the eyes of New Zealand White rabbits.

Executive summary:

The ocular irritation potential of d-Carvone was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor.

d-Carvone was estimated to be not irritating to the eyes of New Zealand White rabbits.

Based on the estimated result; d-Carvone can be considered not irritating to the eyes and can be classified under the category “Not Classified” as per CLP regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin Irritation:

In different studies,d-Carvonehas been investigated for potential for dermal irritation to a greater or lesser extent. The studies are based on in vivo experiments in rabbits along with human data for target chemical and its structurally similar read across substances,Caraway oil [CAS: 8000-42-8] and Dillweed oil [CAS: 8006-75-5]. The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

Various studies for d-Carvone were summarized in Food and Cosmetics Toxicology, Volume 16, Supplement 1, 1978, Pages 673-674; to assess the dermal irritation potential in humans and rabbits.

d-Carvone applied at full strength to intact or abraded rabbit skin underocclusion. Erythema was observed in the treated rabbits which lasted for 24 hours. Hence, d-carvone can be considered to be irritating to skin after 24 hours of exposure. Also, when tested on human subjects at 2% in petrolatum in a 48-hr closed-patch test,d-Carvoneproduced no irritation.

 

Skin irritation effects were also estimated by four different models i.e, Battery, Leadscope, SciQSAR and CASE Ultra used within Danish QSAR database for d-carvone. Based on estimation, no severe skin irritation effects were known when d-carvone was exposed to rabbit skin. Hence, d-carvone can be considered not irritating to skin.

In a prediction done by SSS (2017) using the OECD QSAR toolbox v3.3 with log kow as the primary descriptor, the dermal irritation potential was estimated for d-carvone. d-carvone was estimated to be not irritating to the skin of New Zealand White rabbits.

The experimental and estimated data are in agreement with each other, which substantiate the claim that d-carvone is indeed not irritating to skin.

These results are supported by the experimental study summarized in Food and Cosmetics Toxicology, Volume 11, Issue 6, December 1973, Page 1051;for the structurally similar read across substance,Caraway oil [CAS: 8000-42-8]. Caraway oil was tested 4% in petrolatum on 25 human volunteers in a 48 hours closed patch test. Caraway oil was not irritating to humans after 48 hours exposure.

The above results are further supported by the experimental study summarized in Food and Cosmetics Toxicology, Volume 14, Supplement, 1976, Pages 747-748; for the structurally similar read across substance, Dillweed oil [CAS: 8006-75-5]. Undiluted dillweed oil was applied under occlusion to the intact and abraded skin of rabbits for 24 hours. The rabbits were observed for signs of irritation. Dillweed oil was not irritating to rabbits after 24 hours exposure.

Based on the available data for the target as well as read across substances and applying the weight of evidence approach,d-carvone was not irritating to skin.Comparing the above annotations with the criteria of CLP regulation, test chemical can be classified under the category “Not Classified”.

Eye Irritation:

In different studies,d-Carvonehas been investigated for potential for ocular irritation to a greater or lesser extent. The studies are based on in vivo experiments in rabbits along with predicted data for target chemical and its optical isomers l-carvone[CAS: 6485-90-1]and 2-Methyl-5-(1-methylethenyl)-2-cyclohexenone (Carvone) [CAS: 99-49-0]. The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

In a prediction done by SSS (2017) using the OECD QSAR toolbox v3.3 with log kow as the primary descriptor, the ocular irritation potential was estimated for d-carvone. d-carvone was estimated to be not irritating to the eyes of New Zealand White rabbits.

This is supported by the experimental study summarized in BIOPESTICIDES REGISTRATION ACTION DOCUMENT - l-Carvone, U.S. Environmental Protection Agency, last updated 2009; for the optical isomer,l-carvone[CAS: 6485-90-1]. 10% l-carvone in Tween 80 was instilled into the eyes of 3 New Zealand white rabbits and observed for signs of irritation till 24 hours. Slight transient conjunctivitis with unaffected corneas was observed which resolved within 24 hours.

 Hence, l-carvone can be considered to be not irritating to eyes after 24 hours of exposure.

These results are further supported by the study summarized in Annex 1 Background document to the Opinion proposing harmonised classification and labelling at Community level of carvone , Committee for Risk Assessment RAC -ECHA ,adopted on 4 June,2013;for the optical isomer, 2-Methyl-5-(1-methylethenyl)-2-cyclohexenone (Carvone) [CAS: 99 -49-0]. The study was performed according to OECD 405 Guidelines.

Undiluted carvone(isomers not specified) was instilled into the eyes of the 6 rabbits and observed for ocular lesions. The ocular reactions were observed and scored at 1 hour, 1, 2, 3 days.

Mild irritation was observed till 24 hours, but no reactions were observed after 48 and 72 hours.

Hence, carvone can be considered to be not irritating to eyes.

Based on the available data for the target as well as read across substances and applying the weight of evidence approach,d-carvone was not irritating to eyes.Comparing the above annotations with the criteria of CLP regulation, test chemical can be classified under the category “Not Classified”.

 

 

Justification for classification or non-classification

Available data for d-Carvone indicates that it is not likely to cause severe irritation or corrosion to skin and eyes.

Hence, d-Carvone can be classified under the category “Not Classified” for skin and eyes as per CLP regulation.